Journal articles on the topic 'Myeloproliferative neoplasms, prognosis, outcome, myelofibrosis'
To see the other types of publications on this topic, follow the link: Myeloproliferative neoplasms, prognosis, outcome, myelofibrosis.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Myeloproliferative neoplasms, prognosis, outcome, myelofibrosis.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Nangalia, Jyoti, and Anthony R. Green. "Myeloproliferative neoplasms: from origins to outcomes." Hematology 2017, no. 1 (December 8, 2017): 470–79. http://dx.doi.org/10.1182/asheducation-2017.1.470.
Full textAbstract:
Abstract Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
2
Nangalia, Jyoti, and Anthony R. Green. "Myeloproliferative neoplasms: from origins to outcomes." Blood 130, no. 23 (December 7, 2017): 2475–83. http://dx.doi.org/10.1182/blood-2017-06-782037.
Full textAbstract:
Abstract Substantial progress has been made in our understanding of the pathogenetic basis of myeloproliferative neoplasms. The discovery of mutations in JAK2 over a decade ago heralded a new age for patient care as a consequence of improved diagnosis and the development of therapeutic JAK inhibitors. The more recent identification of mutations in calreticulin brought with it a sense of completeness, with most patients with myeloproliferative neoplasm now having a biological basis for their excessive myeloproliferation. We are also beginning to understand the processes that lead to acquisition of somatic mutations and the factors that influence subsequent clonal expansion and emergence of disease. Extended genomic profiling has established a multitude of additional acquired mutations, particularly prevalent in myelofibrosis, where their presence carries prognostic implications. A major goal is to integrate genetic, clinical, and laboratory features to identify patients who share disease biology and clinical outcome, such that therapies, both existing and novel, can be better targeted.
3
Jacquelin, Sebastien, Frederike Kramer, Ann Mullally, and Steven W. Lane. "Murine Models of Myelofibrosis." Cancers 12, no. 9 (August 23, 2020): 2381. http://dx.doi.org/10.3390/cancers12092381.
Full textAbstract:
Myelofibrosis (MF) is subtype of myeloproliferative neoplasm (MPN) characterized by a relatively poor prognosis in patients. Understanding the factors that drive MF pathogenesis is crucial to identifying novel therapeutic approaches with the potential to improve patient care. Driver mutations in three main genes (janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL)) are recurrently mutated in MPN and are sufficient to engender MPN using animal models. Interestingly, animal studies have shown that the underlying molecular mutation and the acquisition of additional genetic lesions is associated with MF outcome and transition from early stage MPN such as essential thrombocythemia (ET) and polycythemia vera (PV) to secondary MF. In this issue, we review murine models that have contributed to a better characterization of MF pathobiology and identification of new therapeutic opportunities in MPN.
4
How, Joan, and Gabriela S. Hobbs. "A Practical Guide for Using Myelofibrosis Prognostic Models in the Clinic." Journal of the National Comprehensive Cancer Network 18, no. 9 (September 2020): 1271–78. http://dx.doi.org/10.6004/jnccn.2020.7557.
Full textAbstract:
Primary myelofibrosis (PMF) has the least favorable prognosis of the Philadelphia chromosome–negative myeloproliferative neoplasms, which also include essential thrombocythemia (ET) and polycythemia vera (PV). However, clinical presentations and outcomes of PMF vary widely, with median overall survival ranging from years to decades. Given the heterogeneity of PMF, there has been considerable effort to develop discriminatory prognostic models to help with management decisions, particularly for the consideration of hematopoietic stem cell transplantation in patients at higher risk. Although earlier models incorporated only clinical features in risk stratification, contemporary models increasingly use molecular and cytogenetic features, leading to more comprehensive prognostication. This article reviews the most widely adopted prognostic models used for PMF, including the International Prognostic Scoring System (IPSS), dynamic IPSS (DIPSS)/DIPSS+, mutation-enhanced IPSS for transplant-age patients (MIPSS70)/MIPSS70+/MIPSS70+ version 2.0, genetically inspired prognostic scoring system, and Myelofibrosis Secondary to PV and ET-Prognostic Model in patients with post-ET/PV myelofibrosis. We also discuss newly emerging prognostic models and provide a practical approach to risk stratification in patients with PMF and post-ET/PV myelofibrosis.
5
Vargas-Viveros, Pablo, Rafael Hurtado Monroy, and Myrna Candelaria-Hernandez. "Significant Improvement In Quality Of Life (QoL) In Patients With Chronic Myeloproliferative Neoplasms and Myelofibrosis Treated With JAK-1 and JAK-2 Inhibitor Ruxolitinib. A Single Institution Experience In Mexico." Blood 122, no. 21 (November 15, 2013): 5252. http://dx.doi.org/10.1182/blood.v122.21.5252.5252.
Full textAbstract:
Abstract Introduction Myeloproliferative Neoplasms can shorten the life of patients and affect severely their quality of life as a result of constitutional symptoms mediated by cytokines and from massive splenomegaly characteristic of these diseases. The objective measurement of symptoms in Myelofibrosis is essential for the presence of general constitutional symptoms as fatigue and is considered adverse prognostic value for survival. The systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with JAK-2 inhibitors. Material and Methods To assess the impact on quality of life in patients with Myeloproliferative Neoplasms treated with the inhibitor Ruxolitinib, there was applied the questionnaire Myelofibrosis Symptom Assessment Form (Mesa et al. Leukemia Research. 2009: 33; 1199-1203) to 16 patients included in the Compassionate Use of Ruxolitinib Program: 8 men and 8 women were included with a median age of 63 years; 4 patients with primary Myelofibrosis, 3 with Myelofibrosis post Polycitemia vera and 9 with Myelofibrosis post essential Thrombocythemia. The median patient follow-up was 9 months. The patients started with a dose of 20 mg Ruxolitinib orally every 12 hours. Results The questionnaire was administered to all patients at each visit and the results of the ratings of the patients were presented as median of each answer at baseline, 3, 6 and 12 months of follow-up (table 1). By comparing the differences of each parameter measured between the start and at 3, 6 and 12 months were statistically significant for all variables (P <0.001, CI: 95%). The most significant changes were observed when comparing data at baseline and follow-up to the maximum time, however were obvious from the first quarter of observation on fatigue and symptoms dependent splenomegaly in most general symptoms, which actually disappeared completely after 3 months of treatment and not relapsed during the track and in the perception of the quality of life of patients. The variables with lower proportional change recorded were general activity, mood, walking tolerance and everyday work. Discussion and conclusions The treatment of Myeloproliferative Neoplasms with Ruxolitinib represents a major advance in the management of malignant Myeloproliferative and achieved excellent improvement in overall constitutional symptom control, splenomegaly and the general perception of the quality of life of these patients. The objective measurement of symptoms of Myelofibrosis is essential, since the presence of general constitutional symptoms as fatigue is considered adverse prognostic value for survival and systematic measurement of symptoms in Myelofibrosis is essential for assessing the outcome of treatment with inhibitors JAK-2. Disclosures: No relevant conflicts of interest to declare.
6
Wolfe, Heather R., Mitchell E. Horwitz, and Lindsay A. M. Rein. "The Use of Allogeneic Hematopoietic Stem Cell Transplantation in Primary Myelofibrosis." Journal of Personalized Medicine 12, no. 4 (April 2, 2022): 571. http://dx.doi.org/10.3390/jpm12040571.
Full textAbstract:
Primary myelofibrosis (PMF) is a BCR-ABL1 negative myeloproliferative neoplasm characterized by clonal proliferation of myeloid cells. This leads to reactive bone marrow fibrosis, ultimately resulting in progressive marrow failure, hepatosplenomegaly, and extramedullary hematopoiesis. PMF is considered the most aggressive of the BCR-ABL1 negative myeloproliferative neoplasms with the least favorable prognosis. Constitutional symptoms are common, which can impact an individual’s quality of life and leukemic transformation remains an important cause of death in PMF patients. The development of the Janus kinase 2 (JAK2) inhibitors have provided a good option for management of PMF-related symptoms. Unfortunately, these agents have not been shown to improve overall survival or significantly alter the course of disease. Allogenic hematopoietic stem cell transplantation (allo-HSCT) remains the only curative treatment option in PMF. However, allo-HSCT is associated with significant treatment-related morbidity and mortality and has historically been reserved for younger, high-risk patients. This review examines patient, disease, and transplant-specific factors which may impact transplant-related outcomes in PMF. Through the vast improvements in donor selection, conditioning regimens, and post-transplant care, allo-HSCT may provide a safe and effective curative option for a broader range of PMF patients in the future.
7
Kim, Tong-Yoon, Daehun Kwag, Jong-Hyuk Lee, Joonyeop Lee, Gi-June Min, Sung-Soo Park, Silvia Park, et al. "Clinical Features, Gene Alterations, and Outcomes in Prefibrotic and Overt Primary and Secondary Myelofibrotic Patients." Cancers 14, no. 18 (September 16, 2022): 4485. http://dx.doi.org/10.3390/cancers14184485.
Full textAbstract:
The Philadelphia-negative myeloproliferative neoplasms (MPNs) are divided in three major groups: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). The 2016 WHO classification incorporates also prefibrotic PMF (pre-PMF) and overt PMF. This study aimed to discriminate the clinical features, genetic alterations, and outcomes in patients with prefibrotic, overt PMF, and secondary MF (SMF). This study included 229 patients with diagnosed myelofibrosis (MF). Among 229 patients, 67 (29%), 122 (53%), and 40 (18%) were confirmed as SMF, overt PMF, and pre-PMF, respectively. The JAK2 V617F mutation was differentially distributed in SMF and PMF, contradictory to CALR and MPL mutations. Regarding nondriver mutations, the occurrence of ASXL1 mutations differed between PMF and SMF or pre-PMF. The three-year overall survival was 91.5%, 85.3%, and 94.8% in SMF, overt PMF, and pre-PMF groups. Various scoring systems could discriminate the overall survival in PMF but not in SMF and pre-PMF. Still, clinical features including anemia and thrombocytopenia were poor prognostic factors throughout the myelofibrosis, whereas mutations contributed differently. Molecular grouping by wild-type SF3B1 and SRSF2/RUNX1/U2AF1/ASXL1/TP53 mutations showed inferior progression-free survival (PFS) in PMF, SMF, and pre-PMF. We determined the clinical and genetic features related to poor prognosis in myelofibrosis.
8
Zhao, Lin-Pierre, Marine Cazaux, Nabih Maslah, Rafael Daltro De Oliveira, Emmanuelle Verger, Juliette Soret-Dulphy, Clemence Marcault, et al. "Myeloproliferative Neoplasms (MPN) Clonal Evolution Landscape and Its Impact on Patients' Prognosis." Blood 138, Supplement 1 (November 5, 2021): 317. http://dx.doi.org/10.1182/blood-2021-149473.
Full textAbstract:
Abstract Introduction: Although myeloproliferative neoplasms (MPN) are driven by three mutually exclusive driver mutations (JAK2, CALR and MPL), targeted deep sequencing studies identified multiple additional somatic mutations potentially impacting MPN evolution. Presence of a high molecular risk (HMR: ASXL1, EZH2, SRSF2 and IDH1/2) or a TP53 mutations has been associated with adverse prognosis. However, to date, the effect of clonal evolution (CEv) on MPN patients' outcome has not been evaluated, as most of the studies assessed mutational-based prognosis stratification from single baseline molecular genotyping. The objective of our study was to describe the clinical and molecular characteristics of patients with CEv in a large cohort of MPN patients and analyze its impact on patients' outcome. Methods: A total of 1538 consecutive patients were diagnosed with MPN according to WHO criteria and followed in our hospital between January 2011 and January 2021. From this large retrospective cohort, we included in this study 446 patients who had at least 2 molecular analyses during the chronic phase of MPN, performed at diagnosis and/or during follow-up using next generation sequencing (NGS), targeting a panel of 36 genes involved in myeloid malignancies. Significant variants were retained with a sensitivity of 1%. CEv was defined as the acquisition of a new additional non-driver mutation between baseline and subsequent NGS evaluation. Statistical analyses were performed using the STATA software (STATA 17.0 for Mac Corporation, College Station, TX). Results: The median age at MPN diagnosis in our whole cohort was 51 years [IQR 41 - 60]. Our cohort included 167 (37%), 205 (46%) and 64 (14%) patients with polycythemia vera, essential thrombocythemia and primary myelofibrosis (MF) respectively. With a median interval of 1.6 years [IQR 1.0 - 2.8] between the first and the second NGS analysis in the whole cohort, CEv occurred in 128 patients (29%). Patients with CEv were significantly older compared to patients without CEv (n=318) (p=0.03). MPN diagnosis, the type of driver mutation and complete blood counts at MPN diagnosis did not differ between the 2 groups. Eighty-one (63%) and 198 (62%) patients with or without CEv respectively had at least one additional non-driver mutation at baseline NGS (p=0.59), while the rate of HMR (n=25 (20%) versus n=79 (25%)) or TP53 (n=7 (5%) versus n=20 (6%)) mutations at baseline NGS did not differ between the 2 groups. Thirty six out of 128 (28%) of patients with CEv had more than 1 acquired mutation. Most recurrently acquired mutations involved the epigenetic regulators TET2 and DNMT3A that were mutated in respectively 33% and 25% of patients with CEv (Figure 1A). Moreover, 38% of CEv patients acquired HMR (ASXL1 (14%), EZH2 (6%), SRSF2 (3%), IDH1/2 (2%)) or TP53 (13%) mutations. After a median follow up of 10.8 years [IQR 6.6 - 17.2] in the whole cohort representing a total of 5635 patient years, 32 (7%) patients died, and 11 (2.5%) and 11 (2.5%) patients with at least 2 NGS performed during MPN chronic phase transformed respectively into secondary MF or myelodysplastic syndrome / acute myeloid leukemia (MDS/AML). Interestingly, CEv (HR 11.27, 95%CI [5.09; 24.96], p<0.001) (Figure 1B), age at MPN diagnosis (HR 1.11, 95%CI [1.07; 1.15], p<0.001) and the presence of HMR mutations at baseline NGS (HR 4.48, 95%CI [2.05; 9.77], p <0.001) independently adversely impacted OS in a COX regression multivariate analysis. CEv also independently adversely impacted MDS/AML free survival (HR 13.15, 95%CI [3.88; 44.47], p<0.001) and secondary MF free survival (HR 21.13, 95%CI [6.18; 72.20], p<0.001) in a COX regression multivariate analysis. Conclusion: Our study on a large retrospective clinically and biologically annotated real-life cohort of MPN patients with long-term follow up shows that CEv independently adversely impacts OS, MDS/AML and secondary MF free survivals. CEv occurred in a clinically relevant proportion of MPN patients (28%) and was associated with patients' age. Acquired mutations mainly involved epigenetic regulators, HMR and TP53 genes. These results suggest that serial molecular monitoring using NGS could be routinely implemented in MPN patients follow up, to assess more accurately disease evolution and potentially update therapeutic management. Figure 1 Figure 1. Disclosures Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ABBVIE: Consultancy; ASTELLAS: Consultancy. Kiladjian: Novartis: Membership on an entity's Board of Directors or advisory committees; Taiho Oncology, Inc.: Research Funding; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Other: Personal fees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees. Benajiba: Gilead: Research Funding; Pfizer: Research Funding.
9
Leiva, Orly, Siyang Ren, Donna S. Neuberg, Ankeet Bhatt, Andrew Jenkins, Rachel P. Rosovsky, Rebecca Karp Leaf, Katayoon Goodarzi, and Gabriela Hobbs. "Pulmonary Hypertension Is Associated with Poor Outcomes in Patients with Myeloproliferative Neoplasms and Cardiovascular Disease." Blood 138, Supplement 1 (November 5, 2021): 3653. http://dx.doi.org/10.1182/blood-2021-149799.
Full textAbstract:
Abstract Background: Myeloproliferative neoplasms (MPNs) are a group of disorders of clonal hematopoiesis and include essential thrombocythemia (ET), polycythemia vera (PV) and primary myelofibrosis (PMF). Cardiovascular disease, including atrial fibrillation (AF), heart failure (HF), pulmonary hypertension (PH), and atherosclerotic heart disease, is an underappreciated cause of morbidity and mortality in MPNs. Additionally, MPNs harbor mutations commonly seen in clonal hematopoiesis of indeterminate potential (CHIP) which has been shown to be associated with increased cardiovascular risk. PH has been associated with MPN and MPN-associated PH is classified as group 5 PH according to the World Health Organization. Although studies have shown PH to occur in between 3.8% to 58% of patients with PMF and has been associated with decreased overall survival in PV, its impact on cardiovascular prognosis, including cardiovascular death (CV death), in patients with MPN has been understudied. Our study aims to investigate the prognostic implication of PH in a high risk MPN population, those with cardiovascular disease. Methods: Our study is a single center retrospective cohort study. Using an institutional database, we identified 197 patients with MPN (ET, PV or PMF) who had cardiovascular disease (AF, hospitalization for HF or acute coronary syndrome after MPN diagnosis) and had undergone right heart catheterization (RHC) or transthoracic echocardiography (TTE). PH was defined as either a mean pulmonary artery pressure ≥ 20 mmHg on RHC or estimated right ventricular systolic pressure (RVSP) ≥ 50 mmHg on TTE. Our primary outcome was CV death (death due to pulmonary embolism, myocardial infarction, stroke, arrhythmia, sudden death or HF). Other outcomes of interest included all-cause mortality, HF hospitalization, VTE and arterial thrombosis. Continuous variables were compared using Student's t-test, categorical variables and outcomes were compared with the Fisher exact test. We used a Fine-Gray model to determine the effect of PH on CV death using other causes of death as competing events. To investigate the effect of PH on our outcomes we also used a multivariable logistic regression model using age, sex, MPN type, MPN treatment, arterial and venous thrombosis prior to and after MPN diagnosis, diabetes, prior HF diagnosis, HF hospitalization after MPN diagnosis, AF, hyperlipidemia, leukemic or secondary myelofibrosis transformation, and diabetes as co-variables. Results: There were 92 patients with PH and 105 patients without PH. Median age at MPN diagnosis was higher in PH vs non-PH patients (73 vs 71, p = 0.038). The median time to diagnosis of PH from MPN diagnosis was 69 months (IQR 43, 113). Patients with PH had higher rates of prior HF (54% vs 32%, p = 0.001) and hypertension (83% vs 64%, p = 0.004), but lower rates of AF (64% vs 79%, p = 0.026) compared with patients without PH. MPN types and driver mutations were not statistically significant between PH and non-PH groups. More patients with PH had leukemic or secondary myelofibrosis transformation compared with patients without PH (23% vs 11%, p = 0.037). Patients with PH had higher rates of CV death (35% vs 9%, p < 0.0001), all-cause death (58% vs 37%, p = 0.004), HF hospitalization (73% vs 36%, p < 0.0001) and VTE (25% vs 12%, p = 0.027) but not arterial thrombosis (39% vs 41%, p = 0.88). Cumulative incidence of CV death was higher in PH compared with non-PH patients (Figure 1A, Fine-Gray HR 5.53, 95% CI 2.58-11.85). After multivariable regression, PH was associated with higher odds of CV death (Figure 1B, aOR 6.1, 95% CI 2.2-19.0), VTE (aOR 3.3, 95% CI 2.0-25.5), HF hospitalization (aOR 3.9, 95% CI 1.6-10.2) but not all-cause death (aOR 1.5, 95% CI 0.7-3.2) or arterial thrombosis (aOR 0.9, 95% CI 0.4-1.9), Figure 1B. Conclusions: In patients with MPN and cardiovascular diseases, PH is associated with worse outcomes including CV death, VTE, HF hospitalization and leukemic/secondary myelofibrosis transformation compared with patients without PH. More investigation is needed but our results suggests early screening for PH may be beneficial in this patient population. Figure 1 Figure 1. Disclosures Neuberg: Madrigal Pharmaceuticals: Other: Stock ownership; Pharmacyclics: Research Funding. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hobbs: Bayer: Research Funding; Incyte Corporation: Research Funding; Merck: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; AbbVie.: Consultancy.
10
Vannucchi, Alessandro Maria, and Paola Guglielmelli. "Molecular prognostication in Ph-negative MPNs in 2022." Hematology 2022, no. 1 (December 9, 2022): 225–34. http://dx.doi.org/10.1182/hematology.2022000339.
Full textAbstract:
Abstract The application of genomic techniques, including cytogenetics and DNA sequencing, to decipher the molecular landscape of patients with myeloproliferative neoplasms (MPNs) has radically modified diagnostic approach and management through improved risk stratification. Three driver mutated genes (JAK2, MPL, CALR) are variably harbored by >80% of patients and associated with clinical characteristics, as well as major disease-related complications and different survival outcomes. Therefore, JAK2 V617F mutation is included in the revised International Prognosis Score of Thrombosis for Essential Thrombocythemia score for prediction of thrombosis in patients with essential thrombocythemia and prefibrotic primary myelofibrosis, while a CALR type 1 mutated genotype constitutes a favorable variable for survival in patients with myelofibrosis (MF). Novel, integrated clinical and cytogenetic/mutation scores (Mutation-Enhanced International Prognostic Score System for Transplantation-Age Patients with Primary Myelofibrosis [MIPSS70/v2], genetically inspired prognostic scoring system [GIPSS], Myelofibrosis Secondary to PV and ET- Prognostic Model [MYSEC-PM]) have been devised that guide selection of stem cell transplantation candidates with MF or help predict the risk associated with the transplant procedure (Myelofibrosis Transplant Scoring System), with greater performance compared with conventional scores based on hematologic and clinical variables only. On the other hand, several clinical needs remain unmet despite the great amount of molecular information available nowadays. These include the prediction of evolution to acute leukemia in a clinically actionable time frame, the identification of patients most likely to derive durable benefits from target agents, in primis JAK inhibitors, and, conversely, the significance of molecular responses that develop in patients receiving interferon or some novel agents. Here, we discuss briefly the significance and the role of genomic analysis for prognostication in patients with MPNs from a clinician's point of view, with the intent to provide how-to-use hints.
11
Lee, Jong-Mi, Howon Lee, Ki-Seong Eom, Sung-Eun Lee, Myungshin Kim, and Yonggoo Kim. "Impact of Integrated Genetic Information on Diagnosis and Prognostication for Myeloproliferative Neoplasms in the Next-Generation Sequencing Era." Journal of Clinical Medicine 10, no. 5 (March 3, 2021): 1033. http://dx.doi.org/10.3390/jcm10051033.
Full textAbstract:
Since next-generation sequencing has been widely used in clinical laboratories, the diagnosis and risk stratification of hematologic malignancies are greatly dependent on genetic aberrations. In this study, we analyzed the genomic landscapes of 200 patients with myeloproliferative neoplasms (MPNs) and evaluated the impact of the genomic landscape on diagnosis and risk stratification. Mutations in JAK2, CALR and MPL were detected in 76.4% of MPNs. The proportion of patients with clonal genetic markers increased up to 86.4% when all detectable genetic aberrations were included. Significant co-occurring genetic aberrations potentially associated with phenotype and/or disease progression, including those in JAK2/SF3B1 and TP53/del(13q), del(5q), −7/del(7q) and complex karyotypes, were detected. We also identified genetic aberrations associated with patient outcomes: TP53 and −7/del(7q) were associated with an inferior chance of survival, RUNX1, TP53 and IDH1/2 were associated with leukemic transformation and SF3B1, IDH1/2, ASXL1 and del(20q) were associated with fibrotic progression. We compared risk stratification systems and found that mutation-enhanced prognostic scoring systems could identify lower risk polycythemia vera, essential thrombocythemia and higher risk primary myelofibrosis. Furthermore, the new risk stratification systems showed a better predictive capacity for patient outcome. These results collectively indicate that integrated genetic information can enhance diagnosis and prognostication in patients with myeloproliferative neoplasms.
12
Bang, Soo-Mee, Jong-Seok Lee, Jeong Yeal Ahn, Jae Hoon Lee, Myung Soo Hyun, Bong Seog Kim, Moo Rim Park, et al. "Vascular events in Korean patients with myeloproliferative neoplasms and their relationship to JAK2 mutation." Thrombosis and Haemostasis 101, no. 03 (2009): 547–51. http://dx.doi.org/10.1160/th08-06-0396.
Full textAbstract:
SummaryEvaluation of the Janus kinase 2 (JAK2) V617F mutation has been widely used for the diagnosis of myeloproliferative neoplasms (MPN). However, its prognostic relevance to clinical outcome is not completely understood. We investigated the association of JAK2 V617F with vascular events in Korean patients with myeloproliferative neoplasms (MPN). We studied 283 patients from 15 centers, who were diagnosed with MPN. The JAK2 V617F status was evaluated by allele-specific polymerase chain reaction (PCR) and sequencing. The patients’ diagnoses were essential thrombocythemia (ET n=146), polycythemia vera (PV n=120), primary myelofibrosis (n=12), and unclassifiable MPN (MPNu n=5). JAK2 V617F was detected in 89 (61%) patients with ET, 103 (86%) with PV, four (33%) with myelofibrosis, and four (80%) with MPNu. A higher number of leukocytes, haemoglobin levels and BM cellularity as well as an older age, lower platelet counts, and diagnosis of PV were significantly correlated with JAK2 V617F. Eighty-three and 43 episodes of thrombosis and bleeding occurred in 100 patients each before and after the diagnosis. Vascular events more frequently occurred in 37% of patients with JAK2 V617F than in 29% of those without the mutation (p=0.045). Among 175 patients whose samples were available for sequencing, 28 patients with homozygous JAK2 V617F had vascular events more frequently (57%) than those who were heterozygotes (39%) or had the wild type (27%) (p=0.03). The multivariate analysis showed that a JAK2 homozygous mutation, hypercholesterolemia and older age were independent risk factors for a vascular event. The results of this study showed that Korean patients with MPN had a similar JAK2 mutation rate and frequency of vascular events when compared to Western patients. The presence of V617F was significantly related to vascular events. Therefore, initial evaluation for the JAK2 mutation and careful monitoring for vascular events should be performed in MPN patients.
13
Debureaux, Pierre-Edouard, Bruno Cassinat, Juliette Soret-Dulphy, Emmanuelle Verger, Nabih Maslah, Pierre-Emmanuel Rautou, Aurelie Plessier, Dominique Valla, Stephane Giraudier, and Jean-Jacques Kiladjian. "Significant Impact of the Molecular Profile on the Prognosis of Patients with Myeloproliferative Neoplasms and Splanchnic Vein Thromboses." Blood 134, Supplement_1 (November 13, 2019): 836. http://dx.doi.org/10.1182/blood-2019-123775.
Full textAbstract:
Introduction: Myeloproliferative neoplasms (MPN) are the most frequent underlying causes of splanchnic vein thromboses (SVT), including Budd-Chiari syndrome (BCS), portal, splenic and mesenteric vein thromboses. This subgroup of MPN patients with SVT (MPN/SVT) has been shown to have distinct clinical and molecular features like younger age and lower JAK2V617Fmutant allele burden (the most predominant driver mutation in MPN/SVT patients) and are often considered as early stages of MPN. However, there is no study that has investigated the contribution of NGS data to the risk stratification of these MPN/SVT patients. Main objective of this study was to evaluate the impact of the presence of additional mutations to the driver mutation in the long term outcome of MPN patients with SVT. Patients and methods: Over the past 10 years, a total of 286 patients with SVT have been referred to our center for diagnostic assessment of an underlying MPN. Among them, a diagnosis of MPN (WHO criteria) was finally made in 197. Full molecular analyses by NGS was available in 61 of these MPN/SVT patients. The molecular profiling of patients was performed using a Capture-based custom NGS panel provided by Sophia Genetics. This panel comprised the coding sequences of 36 genes involved in MPN. Bioinformatics analysis was performed by Sophia Genetics, with a detection limit of variants set at 1%. We compared (i) MPN/SVT patients to our local cohort of 1371 MPN patients without SVT with full NGS data available; (ii) MPN/SVT patients with and without additional mutation to the driver mutation. Results: Median follow-up of MPN/SVT patients was 11 years, 62% were females, 33% had BCS and 67% portal vein thrombosis (Table 1). All patients received anticoagulants and 58 (95%) a cytoreductive therapy after the diagnosis of MPN. The type of MPN was polycythemia vera in 69%, essential thrombocythemia in 25% and myelofibrosis in 6%. The driver mutation was JAK2V617F in 57 (93%), and CALR mutation in 4 patients, respectively, and no patient had MPL mutation. By NGS, an additional mutation was identified in 27 (44%) patients, while 34 patients had only the driver mutation. The most frequent additional mutations were in TET2 (23%), ASXL1 (8%), DNMT3A (7%), IDH1/2 (5%), and LNK (5%) genes. EZH2, SRSF2 and TP53 mutations were found in only 1 patient, respectively. When compared to NGS data from 1371 MPN patients, there was no significant difference in the frequency of each additional mutation, except a slightly lower incidence of ASXL1 mutations in MPN/SVT patients (8% vs 23% in MPN patients, p=0.07). Of note, MPN/SVT patients were younger at MPN diagnosis than the control MPN cohort (44 vs 61 years, p< 10-5). Clinical characteristics were not significantly different between MPN/SVT patients with and without additional mutations (Table 1), including age at SVT or at MPN diagnosis, type of MPN or type of SVT, use of cytoreductive therapy, and median follow-up (11 years in both groups). In contrast, MPN/SVT patients with additional mutations had a significantly higher median JAK2V617F mutant allele burden than those with only JAK2 mutation (34% vs 11%, p=0.003, Figure 1); and higher risk of hematological transformation to myelofibrosis or acute leukemia or death (30% vs 6%, p=0.017). Only few patients experienced recurrence of thrombosis during follow up, with no difference according to the mutational profile (3 (11%) and 6 (17%) in patients with and without additional mutations, respectively). Conclusion: This is to our knowledge the first study assessing the impact of molecular abnormalities in the long term outcome of MPN/SVT patients showing a possible prognostic role for NGS data in these patients. Our results suggest that MPN/SVT patients with only JAK2V617F mutation and a low mutant allele burden (below 50%) are at low risk of adverse hematological outcome. In contrast, NGS may identify a group of patients with additional mutations at very high long term risk of unfavorable hematological evolution (30% transformation or death after 11 years of median follow-up, that is unexpected in such a young MPN population). In this group, a disease modifying therapy like interferon or other targeted therapies should be proposed when possible to reduce this risk of transformation. Disclosures Kiladjian: Novartis: Honoraria, Research Funding; Celgene: Consultancy; AOP Orphan: Honoraria, Research Funding.
14
Ciboddo, Michele, and Ann Mullally. "JAK2 (and other genes) be nimble with MPN diagnosis, prognosis, and therapy." Hematology 2018, no. 1 (November 30, 2018): 110–17. http://dx.doi.org/10.1182/asheducation-2018.1.110.
Full textAbstract:
Abstract Now that the spectrum of somatic mutations that initiate, propagate, and drive the progression of myeloproliferative neoplasms (MPNs) has largely been defined, recent efforts have focused on integrating this information into clinical decision making. In this regard, the greatest progress has been made in myelofibrosis, in which high-molecular-risk mutations have been identified and incorporated into prognostic models to help guide treatment decisions. In this chapter, we focus on advances in 4 main areas: (1) What are the MPN phenotypic driver mutations? (2) What constitutes high molecular risk in MPN (focusing on ASXL1)? (3) How do we risk-stratify patients with MPN? And (4) What is the significance of molecular genetics for MPN treatment? Although substantial progress has been made, we still have an incomplete understanding of the molecular basis for phenotypic diversity in MPN, and few rationally designed therapeutic approaches to target high-risk mutations are available. Ongoing research efforts in these areas are critical to understanding the biological consequences of genetic heterogeneity in MPN and to improving outcomes for patients.
15
Genovese, Elena, Margherita Mirabile, Sebastiano Rontauroli, Stefano Sartini, Sebastian Fantini, Lara Tavernari, Monica Maccaferri, et al. "The Response to Oxidative Damage Correlates with Driver Mutations and Clinical Outcome in Patients with Myelofibrosis." Antioxidants 11, no. 1 (January 5, 2022): 113. http://dx.doi.org/10.3390/antiox11010113.
Full textAbstract:
Myelofibrosis (MF) is the Philadelphia-negative myeloproliferative neoplasm characterized by the worst prognosis and no response to conventional therapy. Driver mutations in JAK2 and CALR impact on JAK-STAT pathway activation but also on the production of reactive oxygen species (ROS). ROS play a pivotal role in inflammation-induced oxidative damage to cellular components including DNA, therefore leading to greater genomic instability and promoting cell transformation. In order to unveil the role of driver mutations in oxidative stress, we assessed ROS levels in CD34+ hematopoietic stem/progenitor cells of MF patients. Our results demonstrated that ROS production in CD34+ cells from CALR-mutated MF patients is far greater compared with patients harboring JAK2 mutation, and this leads to increased oxidative DNA damage. Moreover, CALR-mutant cells show less superoxide dismutase (SOD) antioxidant activity than JAK2-mutated ones. Here, we show that high plasma levels of total antioxidant capacity (TAC) correlate with detrimental clinical features, such as high levels of lactate dehydrogenase (LDH) and circulating CD34+ cells. Moreover, in JAK2-mutated patients, high plasma level of TAC is also associated with a poor overall survival (OS), and multivariate analysis demonstrated that high TAC classification is an independent prognostic factor allowing the identification of patients with inferior OS in both DIPSS lowest and highest categories. Altogether, our data suggest that a different capability to respond to oxidative stress can be one of the mechanisms underlying disease progression of myelofibrosis.
16
Zhang, Lan, Xingnong Ye, Shengjie Wang, Keyi Jin, Shuna Luo, Xiaofei Xu, and Jian Huang. "Next-Generation Sequencing Mutational Landscape and Clinical Features of Chinese Adults with Myeloproliferative Neoplasms." Blood 138, Supplement 1 (November 5, 2021): 4641. http://dx.doi.org/10.1182/blood-2021-145837.
Full textAbstract:
Abstract Myeloproliferative neoplasms (MPNs) include three classical subtypes: polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Since prefibrotic primary myelofibrosis (pre-PMF) was recognized as a separate entity in the 2016 revised classification of MPN, it has been a subject of debate among experts due to its indefinite diagnosis. However, pre-PMF usually has a distinct outcome compared with either ET or overt PMF. We conducted a retrospective study of MPN patients from October 2014 to June 2020 in the Fourth Affiliated Hospital of Zhejiang University. Patients who were diagnosed with ET, pre-PMF or overt-MF according to the 2016 WHO Classification were included. We reviewed the clinical parameters, haematologic information, and genetic mutations of patients using next-generation sequencing (NGS). Mutation screening was performed in 44 patients by next-generation sequencing techniques, 84 genes and 258 mutations were detected. JAK2 was the most frequently mutated gene (25/44, 56.82%), followed by TET2 (14/44, 31.82%), KMT2C (13/44, 29.55%), and ASXL1 (10/44, 23.73%) in MPN (Figure 1-A). The VAFs of all studied genes with mutation frequencies >10% are shown in Figure 1-B. Of the 20 patients with ET, 9 (45%) were positive for the JAK2 mutation, 5 (25%) carried FAT1, 5 (25%) carried KMT2C, and 4 (20%) carried CALR. Of the 5 patients with pre-PMF, 4 (80%) carried JAK2, 3 (60%) carried EP300, and 2 (40%) carried TET2. Of the 19 patients with overt PMF, 12 (63%) carried JAK2, 10 (53%) carried TET2, 7 (37%) carried ASXL1, and 6 (32%) carried KMT2C, as reported in Figure 2. The median follow-up was 36 months for ET, 42 months for pre-PMF, and 53 months for overt PMF. Overall survival between pre-PMF, overt PMF, and ET was significantly different (P<0.001), as shown in Figure 3. During the follow-up time, only one death of ET was registered, so we analysed the impact of clinical parameters and mutational status at diagnosis on outcome in PMF, including pre-PMF and overt PMF. We performed Kaplan-Meier curves to examine the relationships between the clinical parameters and patient survival. We found that male sex (P=0.0107), MPN10 symptoms (P=0.0354), anaemia (haemoglobin<120g/L, P=0.0239), and thrombocytopenia (platelet count <100 ×10 9/L, P=0.0002) were significantly related to inferior OS (Figure 4). Pre-PMF patients exhibited higher leukocyte counts, higher LDH values, a higher frequency of splenomegaly, and a higher incidence of hypertension than ET patients. On the other hand, pre-PMF patients had higher platelet counts and haemoglobin levels than overt PMF patients. Molecular analysis revealed that the frequency of EP300 mutations was significantly increased in pre-PMF patients compared with ET and overt PMF patients. In terms of outcome, male sex, along with symptoms including MPN10, anaemia, thrombocytopenia, and KMT2A and CUX1 mutations, indicated a poor prognosis for PMF patients. In conclusion, we identified differences in the clinical, haematologic, and molecular presentations of ET, pre-PMF, and overt PMF patients, indicating that comprehensive evaluation of not only BM features but also clinical, haematologic, and molecular profiles is needed for accurate diagnosis and treatment of these three disease entities. The molecular analysis revealed that pre-PMF might be relevant to EP300 mutation, demonstrating the value of molecular examination. The results of this study indicated that comprehensive evaluation of BM features, clinical phenotypes, haematologic parameters, and molecular profiles is needed for the accurate diagnosis and treatment of ET, pre-PMF, and overt PMF patients. Acknowledgment:The research was supported by the Public Technology Application Research Program of Zhejiang, China (LGF21H080003), the Key Project of Jinhua Science and Technology Plan, China (2020XG-29 and 2020-3-011), the Academician Workstation of the Fourth Affiliated Hospital of the Zhejiang University School of Medicine (2019-2024), the Key Medical Discipline of Yiwu, China (Hematology, 2018-2020) and the Key Medical Discipline of Jinhua, China (Hematology, 2019-2021). Correspondence to: Dr Jian Huang, Department of Hematology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. N1 Shangcheng Road. Yiwu, Zhejiang, Peoples R China. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
17
Jolin, Judith, Michael Harnois, Luigina Mollica, Pierre Laneuville, Robert Delage, Harold J. Olney, Shireen Sirhan, Lambert Busque, and Natasha Szuber. "Very Elderly Patients with Myeloproliferative Neoplasms: Phenotypic Distinctions and Prognostic Determinants of Complications and Mortality." Blood 138, Supplement 1 (November 5, 2021): 2572. http://dx.doi.org/10.1182/blood-2021-145131.
Full textAbstract:
Abstract Background and methods: Increasing life expectancy has had the impact of increasing the proportion of patients with myeloproliferative neoplasms (MPN) aged ≥75 years (very elderly patients; VEP). However, few studies have evaluated the phenotype and prognostic factors specific to this population. This is a retrospective multicenter chart review (11 Quebec centers) of VEP with polycythemia vera (PV), essential thrombocytosis (ET), and myelofibrosis (MF) diagnosed between 1978 and 2019, enrolled in the CML-MPN Quebec Research Group registry. All diagnoses were made according to World Health Organization 2016 criteria (Blood. 2016;127:2391), with exemption of bone marrow biopsies in select patients. Standard statistical methods were used for all analyses. Results: Of the 753 patients studied in the registry, 114 patients (15%) were ≥75 years old (VEP) (Table 1). These subjects had a median age of 79 years (range 75-95) with incidence of PV, ET and MF of 38%, 51% and 11% respectively. Compared to patients <75 years old, VEP were less likely to be male (35% vs 45%, p = 0.05), had more frequent and higher levels of leukocytosis (11.4 vs 9.7 x 10 9 / L, p <0.0001), were more frequently "triple negative" and less commonly CALR-mutated (p = 0.0005), and presented significantly higher allelic burdens (45% vs 36%, p = 0.03). VEP also had more cardiovascular comorbidities (p <0.0001) and were more often classified as "high risk" (86% vs. 43%, <0.0001). A history of arterial thrombosis prior to/at diagnosis was more common in VEP vs younger patients (14% vs 7.2%, p = 0.02), as was a global history of arterial and/or venous thrombosis at any time during the follow up (25% vs 18%, p = 0.05). Sites of venous events were specifically skewed towards lower extremity deep vein thrombosis in VEP (75%) vs variously distributed in younger patients (p = 0.05). Bleeding rates were similar among the two groups (16% VEP and 17% non-VEP, p = 0.7) while fewer fibrotic (3% vs 8%, p = 0.03) and leukemic transformations (0 vs 2%, p = 0.04) were recorded in VEP. Significantly fewer bone marrow biopsies were performed in VEP (41% versus 54%, p = 0.01). This cohort was, however, more likely to receive cytoreductive therapy (76% vs 67%, p = 0.05), predominantly hydroxyurea (70% vs 59%, p = 0.02). Multivariate analysis revealed the presence of splenomegaly (HR 4.5; 1.2-17.1, p = 0.03) and smoking status (active/former vs never smokers) (HR 5.2; 1.1-24.9, p = 0.03) as predictors of shortened overall survival for the VEP population (Table 2). It also disclosed higher leukocyte count (p = 0.005) and the presence of diabetes mellitus (p = 0.05) as significant risk factors for shortened hemorrhage-free survival. Platelet count (p = 0.03) and smoking status (p = 0.02) were found to be significant determinants of thrombosis-free survival in univariate analysis but did not maintain their significance in multivariate testing. Kaplan-Meier survival data examining age-stratified outcomes in VEP vs younger patients revealed significantly shorter overall survival in VEP (14.2 years vs not reached, p < 0.0001) (Figure 1). The VEP cohort also displayed significantly reduced arterial thrombosis-free survival (incidence of 6.1% vs 3.9%, p = 0.01). There was no significant difference in event data for venous thrombosis-free (4% in both, p = 0.2) and myelofibrosis-free (2.6% versus 7.8%, p = 0.6) survival. Conclusion: This data addressing VEP with MPN exposes, for the first time: i) a characteristic phenotype (predominantly female, higher leukocyte counts, higher allele burden), ii) distinct adverse outcome patterns, particularly with regard to arterial thrombosis, and iii) unique and independent prognostic factors for survival, suggesting that VEP with MPN constitute a biologically, phenotypically, and prognostically distinct population. Figure 1 Figure 1. Disclosures Busque: Novartis: Consultancy. Szuber: Novartis: Honoraria.
18
Mesa, Ruben A., Susan Schwager, Jocelin Huang, Animesh D. Pardanani, Kebede Hussein, John Camoriano, and Ayalew Tefferi. "Weight Loss, Splenomegaly, and Hypocholesterolemia in Myeloproliferative Neoplasms: Patterns and Relevance from the Pre JAK2 Inhibitor Era." Blood 114, no. 22 (November 20, 2009): 3918. http://dx.doi.org/10.1182/blood.v114.22.3918.3918.
Full textAbstract:
Abstract Abstract 3918 Poster Board III-854 BACK GROUND We have previously demonstrated that the myeloproliferative neoplasms (MPNs) of primary myelofibrosis (PMF), polycythemia vera (PV), and essential thrombocythemia (ET) can lead to weight loss, splenomegaly and constitutional symptoms (Cancer 2007;109:68–76). Additionally we have demonstrated that hypocholesterolemia in MPN patients is associated with decreased survival (Blood 2007;110:a2548). Given that current JAK2 inhibitor trials are demonstrating the ability to reverse MPN associated splenomegaly (Haematologica 2009;94(Suppl 2)439 a1088) and cachexia (Blood 2008;112(11):a1760) we sought to determine the baseline natural history for these variables in patients treated prior to the JAK2 inhibitor era. METHODS We analyzed the Mayo MPN database for patients (not treated with JAK2 inhibitors) with information on disease prognosis, presentation, therapies, height and weight at diagnosis, and outcomes. Additionally, when available, we analyzed additional weights during the clinical course, the body mass index (BMI- (weight/(height*height)), spleen size, and peripheral blood studies including lipids. Results: Patients 783 patients with MPNs (followed for a median of 51 months (range 1-871 months); 60% having expired) were identified for the analysis (PV=158, ET=255, PMF=370) with 541 (69%) having a weight at the time of diagnosis, the remainder had a weight obtained a median of 7.8 months after diagnosis. Additionally, 508 patients (65%) had a weight value available from 1–3 additional time points during the course of their disease. Corresponding measurements of splenomegaly, or absence thereof, were noted in 766 cases (98%). Lipid panels (obtained within 18 months of diagnosis) were available in 264 patients. Results by MPN disease type are listed in the Table. Impact on prognosis Univariate analysis of variables discussed which negatively impacted survival included the subtype of MPN (not surprisingly worse for PMF p<0.001), weight loss of greater than 10% during the course of follow-up (P<0.001), or development of splenomegaly of >10 cm below the left costal margin (p=0.004) whereas hypocholesterolemia was significant only for the subset of PMF patients (P=0.03). The IWG-MRT International Prognostic Score (IPSS - Cervantes et. al. Blood 2009) was the only variable prognostically relevant in multivariate analysis (P<0.001). Conclusions Progressive splenomegaly, weight loss, and hypocholesterolemia are common across all MPNs but are most prognostically detrimental in PMF. Ongoing and future trials of JAK2 inhibitors will answer whether reversal of these latter hypercatabolic and proliferative manifestations of disease will improve outcomes for MPN patients. Disclosures: No relevant conflicts of interest to declare.
19
Saraf, Santosh, Ardaman Shergill, Pritesh R. Patel, John G. Quigley, David Peace, Victor R. Gordeuk, and Damiano Rondelli. "Role of Ethnicity in Clinical Outcomes of Patients with Ph-Negative Myeloproliferative Neoplasms." Blood 120, no. 21 (November 16, 2012): 2076. http://dx.doi.org/10.1182/blood.v120.21.2076.2076.
Full textAbstract:
Abstract Abstract 2076 Myeloproliferative neoplasms (MPN) have similar incidence rates across different ethnicities in the United States. However, reported clinical studies rarely address the outcome in patients with different ethnicities. In this study, we retrospectively analyzed 127 patients with a diagnosis of MPN followed at the University of Illinois Hospital between January 2005 and July 2011. Of these patients, 69 were Caucasian and 58 Non-Caucasian (mostly African-American and Hispanic). The median age was 50 years (range: 20–85) in non-Caucasians and 51 years (range: 22–89) in Caucasians. Among 127 patients, 53 had polycythemia vera (PV), 52 essential thrombocythemia (ET), and 22 primary myelofibrosis (PMF). In each disease group, the following parameters were compared at diagnosis between Caucasian and non-Caucasian patients: age/gender, JAK2 V617F mutation status, cytogenetic abnormalities, family history of MPNs, constitutional symptoms, white blood cell (WBC) and platelet count, hemoglobin level, and spleen size. In addition, the two groups were compared for thrombotic or hemorrhagic events, cardiovascular complications, progression of disease, secondary cancer and overall survival. Among 53 PV patients, Caucasians (n=33) had higher WBC counts (11.7 vs. 8.1 ×103 cells/μL, p=0.03) and a greater spleen size (14 vs. 10 cm longitudinal diameter, p=0.03) at diagnosis compared to non-Caucasians (n=20). However, more frequent hemorrhagic (38.9% vs. 6.1%, p=0.003) and cardiovascular (27.8% vs. 3%, p=0.009) complications were seen in the non-Caucasian cohort of patients compared to the Caucasian cohort. Use of hydroxyurea (55% vs. 57%), aspirin (88% vs. 76%), anagrelide (10% vs. 24%), interferon (18% vs. 5%) and anticoagulation (21% vs. 20%) were not significantly different between Caucasians and non-Caucasians. In the ET patients (non-Caucasian: n=27; Caucasian: n=25), there were no significant differences in presenting characteristics, type of therapies, or clinical outcomes between the two groups. The 22 patients with PMF were classified according to the international prognostic scoring system (IPSS) at diagnosis. In 11 non-Caucasian and 11 Caucasian patients, differences of patients at low risk (18% vs. 9%), intermediate-1 (55% vs. 27%), intermediate-2 (27% vs. 55%), or high risk (9% vs. 0%) were not statistically significant. In a multivariate logistic regression analysis, we demonstrated that prior history of thrombosis and older age are independent prognostic factors for subsequent thrombotic or hemorrhagic events (p=0.03 and p=0.003, respectively). Neither WBC at diagnosis nor ethnicity were independent prognostic indicators in this series of patients. With a median follow-up of eight years (range 1–23 years), median overall survival was not reached for PV, ET, or PMF and no significant differences were detected in Caucasian or non-Caucasian groups. Our observations suggest that when given equal access to care, similar clinical outcomes are achieved in Caucasian and non-Caucasian patients with MPNs. Disclosures: No relevant conflicts of interest to declare.
20
Panagiota, Victoria, Michael Heuser, Michelle Maria Araujo Cruz, Anita Badbaran, Rabia Shahswar, Ioanna N. Triviai, Boris Fehse, et al. "Prognostic Impact of Splicing Factor Mutations in Patients with Myelofibrosis Undergoing Allogeneic Hematopoietic Stem Cell Transplantation." Blood 124, no. 21 (December 6, 2014): 3171. http://dx.doi.org/10.1182/blood.v124.21.3171.3171.
Full textAbstract:
Abstract Background: Recurrent somatic mutations in splicing machinery components, including SRSF2, SF3B1 and U2AF1 have been recently identified and frequently found in a large spectrum of myeloid malignancies. The highest reported frequencies were 85% for myelodysplastic syndromes associated with ring sideroblasts (MDS-RS), 44% for MDS without RS and 55% for chronic myelomonocytic leukemia (CMML), 26% in therapy-related MDS or acute myeloid leukemia, 7% in primary acute myeloid leukemia (AML), and 9% in myeloproliferative neoplasms (MPNs). In primary myelofibrosis (PMF), SRSF2 mutations are associated with advanced age, higher DIPSS scores and poor prognosis. On the other hand, SF3B1 and U2AF1 mutations had no prognostic relevance for either overall or leukemia-free survival. Aim: The aim of this study was to investigate the clinical characteristics and prognosis of splicing factor mutations in SRSF2, SF3B1 and U2AF1 in patients with primary myelofibrosis or post ET/PV myelofibrosis that underwent allogeneic stem cell transplantation (alloHSCT). Methods: 158 patients with WHO defined primary myelofibrosis (n=112, 71%) or post-ET/post-PV myelofibrosis (n=46, 29%) underwent allogeneic hematopoietic stem cell transplantation. Bone marrow or peripheral blood samples were obtained before transplantation. U2AF1, SRSF2, and SF3B1 were amplified by PCR and were sequenced and confirmed with Sanger sequencing besides JAK2, CALR and MPL. Results: Mutations in SRSF2, SF3B1 and U2AF1were detected in 12 (8%), 6 (4%) and 9 (6%) patients, respectively. In total, 27 patients (18%) carried at least one of the three main spliceosome pathway mutations. Baseline characteristics were similarly distributed between SRSF2, SF3B1 and U2AF1 mutated and wildtype patients, respectively (primary vs secondary myelofibrosis, donor match, cytogenetic characteristics), except for higher median age of U2AF1 mutated compared to wildtype patients (67 vs. 58 years, P=0.023). We observed no associations between the presence of SRSF2/SF3B1/U2AF1 mutations and the presence of JAK2, CALR and MPL mutation status, respectively. The majority of patients (n=110, 70%) were transplanted with a matched donor (33 from related and 77 from unrelated donors). 48 patients (30%) received a mismatched unrelated allograft. Univariate analysis disclosed no differences in cumulative incidence of relapse (CIR) between mutated and wildtype patients (CIR: SRSF2, P=0.78; SF3B1, P=0.19; U2AF1, P=0.51; all three splicing genes, P=0.83), although none of the six SF3B1 mutated patients relapsed after alloHSCT. Non-relapse mortality (NRM) was not significantly different between mutated and wildtype patients (NRM: SRSF2, P=0.58; SF3B1, P=0.6; U2AF1, P=0.11; all three splicing genes, P=0.77). Furthermore, patients with mutations in one or any of the three main spliceosome genes had a similar 2-year overall survival after allogeneic HSCT as wildtype patients (2y-OS mutant vs wildtype: SRSF2, 75% vs 68%, P=0.8; SF3B1, 83% vs 69%, P=0.4; U2AF1, 38% vs 70%, P=0.13; all three splicing genes, 68% vs 70%, P=0.78). Conclusions: In our study we show that (i) splicing gene mutations are recurrent molecular aberrations in myelofibrosis patients, (ii) are not associated with an adverse prognostic outcome in patients with myelofibrosis undergoing allogeneic transplantation, and (iii) the potential negative prognostic effect of SRSF2 mutations can be overcome by alloHSCT. Splicing gene mutations do not constitute a risk factor for alloHSCT in patients with myelofibrosis. Disclosures No relevant conflicts of interest to declare.
21
Reilly, Christopher R., Daria V. Babushok, Ranjeeta Bahirwani, Jeffery Mondschein, and Elizabeth O. Hexner. "Clinical Characteristics and Outcomes of Transjugular Intrahepatic Portosystemic Shunt Procedure for Portal Hypertension Secondary to Myeloproliferative Neoplasms." Blood 126, no. 23 (December 3, 2015): 1612. http://dx.doi.org/10.1182/blood.v126.23.1612.1612.
Full textAbstract:
Abstract Portal hypertension is a common complication of myeloproliferative neoplasms (MPN) and portends a poor prognosis. Arising in 7-18% of MPN patients, portal hypertension develops through several distinct mechanisms, including abdominal vein thrombosis, extramedullary hematopoiesis (EMH), and nodular regenerative hyperplasia (NRH). Similar to cirrhotic patients, MPN-associated portal hypertension presents with refractory ascites, gastrointestinal bleeding, hepatic encephalopathy, and susceptibility to infections. Transjugular intrahepatic portosystemic shunt (TIPS) procedure has been used empirically to treat refractory ascites and variceal bleeding in MPN-related portal hypertension; however, there is limited data in regards to TIPS effectiveness in MPN-associated portal hypertension. To assess the safety and efficacy of TIPS for treatment of portal hypertension in MPN, we performed a retrospective analysis of outcomes of TIPS procedure in patients with MPN in our institution. Using the University of Pennsylvania electronic medical record database, we identified nine patients with MPN who underwent TIPS procedure for treatment of refractory portal hypertension between 2005 and 2015. Patients with portal hypertension from causes other than MPN were excluded from the study. Clinical characteristics and long-term outcomes were analyzed. The mean age at time of TIPS was 47 years (range 30-67 years). Seven of nine patients were female (78%) and all seven carried a diagnosis of polycythemia vera (PV) or post-PV myelofibrosis (PV-MF); both male patients had a diagnosis of primary myelofibrosis (PMF) (Table 1). All nine patients were positive for JAK2V617F mutation, and one patient had a concurrent diagnosis of Philadelphia-chromosome positive CML. The most common etiology of portal hypertension was Budd-Chiari Syndrome (BCS) in six patients (67%), followed by NRH in five patients (56%), and EMH in two patients (22%); one patient had several distinct causes of MPN-related portal hypertension. Indications for TIPS included refractory ascites in five patients (63%), ascites and esophageal varices in three patients (33%), and ascites and hydrothorax in one patient. All patients demonstrated immediate normalization of portal pressures following TIPS without any reported periprocedural complications (Table 2). Additionally, all patients received indefinite anticoagulation (low molecular weight heparin, 3 patients; vitamin K antagonist, 2 patients; fondaparinux, 2 patients). TIPS intervention had 1-year patency rate of 89%. However, one third of patients required subsequent shunt revision at a median interval of 22.3 months (range 10-34 months) due to stent stenosis or thrombosis despite anticoagulation; one patient had radiographic evidence of TIPS dysfunction without clinical symptoms. Of note, all three patients who developed TIPS stenosis/thrombosis had BCS and NRH. The majority of patients (89%) experienced complete resolution of ascites, while the remaining patient had partial improvement in ascites but no longer required routine paracentesis. Grade 1 and 2 hepatic encephalopathy was the most common complication post-TIPS (67%), occurring in half of the patients with BCS and in all three patients with portal hypertension due to EMH. One patient had variceal bleeding in the setting of TIPS thrombosis. All patients were alive 2 years post-TIPS (excluding one patient with recent TIPS; range 2-5 years). Our study represents the first systematic analysis of outcomes of TIPS procedure for management of portal hypertension in MPN using data from a single-institution over a ten-year period. Our results suggest that TIPS procedure can be performed safely in this high-risk population, and can effectively mitigate the clinical consequences of portal hypertension in patients with MPN. However, the prevalence of TIPS complications, particularly of TIPS stenosis/thrombosis and hepatic encephalopathy, remains significant and must be balanced against the desired clinical benefits. Future studies with a larger number of patients are needed to delineate prognostic factors that identify MPN patients most likely to benefit from TIPS. Disclosures No relevant conflicts of interest to declare.
22
Ionova, Tatyana, Tatyana Nikitina, Elza Lomaia, Alexandr Myasnikov, Tatyana Pospelova, Andrey Evseev, Taras Gritsenko, et al. "Patient-Reported Outcomes in Myelofibrosis Patients Help to Identify Patients' Needs." Blood 126, no. 23 (December 3, 2015): 5198. http://dx.doi.org/10.1182/blood.v126.23.5198.5198.
Full textAbstract:
Abstract Myelofibrosis (MF) is the most symptomatic of the myeloproliferative neoplasms and is associated with the greatest symptom burden and poorest prognosis. Patient-reported outcomes is an effective way to identify patients' needs and risks/benefits of MF treatment. We aimed to study quality of life (QoL) and symptom burden in MF patients in a real-world setting. 44 MF patients - 27 primary MF, 8 post-essential thrombocytopenia, 9 post-polycythemia vera - were enrolled in the multicenter real-world QoL study. Mean age - 60.8±13.3; male/female - 14/30. All the patients received the best available treatment (BAT, n=28) or novel treatment modality ruxolitinib (n=16) for at least 6 months (range 6-160 mths). A high proportion of patients (80%) had intermediate to high prognostic risk scores according to International Prognostic Scoring System. All the patients completed the QoL questionnaire SF-36, symptom assessment questionnaire CSP-MF and Patient Global Impression of Change (PGIC) tool. Integral QoL Index (IQoLI) in MF patients was calculated on the basis of SF-36 and QoL impairment grade was assessed in comparing with QoL population norms (PN). Comparison t-test for independent samples or Mann-Whitney test was applied. The heterogeneity of MF patients population in terms of QoL impairment was shown: 55% of patients had mild QoL impairment (IQoLI≤25% from PN), 7% - moderate (IQoLI≤25-50% from PN), 38% - severe or critical QoL impairment (IQoLI≤50% from PN). Patients receiving BAT exhibited more pronounced QoL impairment as compared to patients receiving ruxolitinib (p<0.05); they had worse physical functioning, general health, vitality, social functioning, and mental health (p<0.05). All the patients experienced multiple symptoms; the most severe symptoms were fatigue, inactivity and pain in bones/muscles. The symptoms were more expressed in patients on BAT as compared to patients on ruxolitinib (p<0.005). Patient's impression of health changes was better in patients treated with ruxolitinib: the mean PGIC score was higher in patients on BAT on ruxolitinib - 4.4 vs 2.3 (p=0.001). Quality of life and perceived change in health condition are better and symptom severity is less in MF patients on ruxolitinib therapy than those on BAT. Results of this real-world study demonstrate benefits of ruxolitinib therapy from patient perspective. Patient-reported outcomes are of help to better identify the needs of MF patients. Disclosures No relevant conflicts of interest to declare.
23
Barbui, Tiziano, Arianna Masciulli, Marco Scarano, Gianni Tognoni, Sara Sisti, Alessandra Di Lelio, Alessandro M. Vannucchi, et al. "Towards a Better Understanding of Epidemiology, Survival and Treatment in Myeloproliferative Neoplasms: Results of the European Leukemianet Registry (ERNEST study)." Blood 124, no. 21 (December 6, 2014): 1849. http://dx.doi.org/10.1182/blood.v124.21.1849.1849.
Full textAbstract:
Abstract Background The promising development of perspectives in innovative therapeutic interventions in myelofibrosis (MF) makes the establishment of large collaborative networks ready to assure reliable comparability of cases and increasingly relevant data. This will provide assurance regarding efficiency and consistency in the development of clinical and epidemiological knowledge. We report here the results of the pilot phase of ERNEST, whose acronym defines its purpose: European Registry for Myeloproliferative Neoplasms: towards a better understanding of Epidemiology, Survival and Treatment. This project promoted by the European LeukemiaNet (ELN) collaboration is coordinated by the Fondazione Mario Negri Sud (Italy) and supported by an unrestricted educational grant by Novartis. Patients and Methods In order to test the feasibility of a prospective epidemiological outcome-oriented registry across centers, expected to vary in the characteristics of their populations and care practices, a retrospective analysis was implemented based on a strictly pre-defined protocol. Patients with Primary Myelofibrosis (PMF), Post- Essential Thrombocythemia Myelofibrosis (PET-MF) and Post- Polycythemia Vera Myelofibrosis (PPV-MF) which were diagnosed in the participant centers between January 2001 and December 2012, with available follow-up information, were eligible for inclusion. Chi-square test and Mann-Whitney test were used to compare data at presentation by diagnosis for categorical and continuous variables respectively. Standard time-to-event methods were used for data analysis, including log-rank test, Kaplan-Meier survival graphs, and Cox proportional hazards models to calculate hazard ratios along with 95% confidence intervals (CI). Multivariable analysis was performed adjusting for unbalanced and relevant prognostic covariates. Results From February 2013 to May 2014, we received data of 1209 evaluable patients from 13 centers in 5 European countries (Italy, Germany, Spain, United Kingdom, Sweden): 61% were PMF, 20% PET-MF and 19% PPV-MF (median age: 66 years). 23%, 37% and 40% of diagnosis were performed between 2001-2004, 2005-2008 and 2009-2012 respectively. Variability was found for the presence of constitutional symptoms (from 43% in PET-MF to 49% in PPV-MF); an excess of splenomegaly emerged in PPV-MF cohort (84% vs 74% and 75% in PMF and PET-MF respectively). Mean value + SD of Hb, WBC and PLT were: 13.9 + 16.5 g/dl, 17.4 + 30.8 109/l, 372 + 316 109/l respectively with higher levels of Hb and WBC in PPV-MF patients than PET-MF and PMF (p<0.001). No variability was seen for presence of peripheral blasts and cytogenetic abnormalities. During follow-up (median duration: 2 years) 405 patients (33.5%) died without any differences among diagnosis subtypes. Leukemic transformation was experienced by 8% of the whole cohort (9% in PMF, 7% in PET-MF and 8%in PPV-MF). A multivariable’s Cox analysis was performed on the whole cohort including sex, diagnosis and International Prognostic Scoring System (IPSS) as covariates of interest. Besides male sex [Hazard Ratio (HR) 1.49 (95% CI (1.21-1.83), p<0.001] the prognostic significance of IPSS was confirmed with an HR 2.19 [(95% CI (1.64-2.92), p<0.001] for IPSS 2, and HR 4.20 [(95% CI (3.20-5.53), p<0.001] for IPSS >3, as compared with the reference category of patients with IPSS 0-1. As shown in Figure 1, an exploratory analysis documented different patterns of predictivity when the analysis was stratified according to the diagnosis subtypes. The determinants of the prognostic value of IPSS in PPV-MF vs PET-MF (and PMF, data not shown) would certainly deserve fully adjusted analysis in prospective well defined cohorts of patients. Conclusions The intensive quality control needed to assure the reliability, representativeness and the comparability of the data across international centers with expertise in this field confirms both the interest, but also the challenge of a cooperative epidemiological effort capable of representing a knowledge producing shared resource in the area of MF and other rare disease. Based also on the methodological and operational challenge resulting from this pilot study, a prospective study has been activated starting on September 2013. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
24
Kuykendall, Andrew, Chetasi Talati, Najla H. Al Ali, Eric Padron, David Sallman, Jeffrey E. Lancet, Kendra L. Sweet, Alan F. List, Kenneth S. Zuckerman, and Rami S. Komrokji. "Characterization of Cytogenetic Abnormalities in Myelofibrosis and Relationship to Clinical Outcome." Blood 128, no. 22 (December 2, 2016): 1937. http://dx.doi.org/10.1182/blood.v128.22.1937.1937.
Full textAbstract:
Abstract Introduction: Cytogenetic abnormalities occur frequently in patients with myelofibrosis (MF) and carry significant prognostic value. A variety of cytogenetic abnormalities have been reported with variable incidence. While the prognostic significance of more common cytogenetic abnormalities is well documented, the prognostic significance of less common abnormalities are difficult to discern due to limiting cohort size. Further, the specific phenotype associated with various cytogenetic abnormalities is less clear. We reviewed our institutional experience in an effort to describe the spectrum of chromosomal abnormalities, assess their correlation with clinical features, and validate their prognostic impact in a cohort of MF patients. Methods: This was a single institution, retrospective study of all patients with a diagnosis of MF who were seen at our center between 2/2001 - 6/2016.We reviewed cases of myelofibrosis in the Moffitt Cancer Center database. Definitions of primary myelofibrosis (PMF), post-essential thrombocythemia myelofibrosis (post-ET MF) and post-polycythemia vera myelofibrosis (post-PV MF) were according to World Health Organization 2016 criteria and the International Working Group for Myeloproliferative Neoplasms, Research and Treatment, respectively. Cytogenetic analysis was documented with preference to date of diagnosis. Overall survival was measured from time of cytogenetic analysis. Results: We identified 312 eligible. Cytogenetic data were available in 278 of 312 (89%) patients. The cohort was 59% male with a median age of 70 years at time of first presentation. PMF comprised 76% of cases with post-PV MF and post-ET MF accounting for 9% and 15% of cases respectively. Cytogenetic analysis was performed within 3 months of diagnosis in 63% and over a year after diagnosis in 24% of patients. Cytogenetic spectrum and frequency is shown in Figure 1. Normal diploid karyotype was present in 55%. The most common cytogenetic abnormality was a deletion of the long arm of chromosome 20 (del 20q), occurring in 39 (14%) cases. Del 20q occurred as an isolated abnormality in 26/39 cases. When occurring in conjunction with other structural abnormalities, it was most often associated with trisomy 9 (6/39). A deletion of the long arm of chromosome 13 (del 13q) was the second most common chromosomal aberration, occurring in 26 (9%) of cases and usually presenting as the sole abnormality (15/26). An extra copy of chromosome 8 (trisomy 8) occurred in 21 (8%) cases and often occurred in conjunction with other cytogenetic abnormalities (11/21). Less common cytogenetic abnormalities included trisomy 9, deletion 7q and deletion 5q, occurring in less than 4% of cases. Monosomal and complex karyotypes accounted for 10% and 8.3% of cytogenetics, respectively. We then assessed relationships between cytogenetic abnormalities and clinical and pathologic features. Del20q was associated with a lower IPSS score (r = -0.18, p = 0.0006). Deletion 13q was associated with older age at presentation (r = 0.14, p = 0.007). Prevalence of trisomy 8 was highest in post-polycythemia vera myelofibrosis (r = 0.14, p = 0.03) and associated with increased peripheral blast percentage (r = 0.16, p < 0.0001). Deletion 5q was associated with decreased hemoglobin (r = -0.13, p = 0.04), transfusion dependence (r = 0.20, p = 0.0009) and conversion to blast phase (r = 0.23, p = 0.0001). Patients with del 20q, del 13q, and trisomy 9 had median overall survival (OS) comparable to patients with a normal karyotype (45 vs 54 months, respectively, p = 0.69). Patients with unfavorable cytogenetic profiles (del 5q, trisomy 8, and chromosome 17 abnormalities) had significantly worse OS when compared to patients with normal diploid karyotype (20 vs 54 months, p = 0.0002) (figure 2). In multivariate regression analysis, controlling for DIPSS, deletion 5q (HR: 0.34 [0.15-0.78]; p = 0.01) and trisomy 8 (HR: 0.35 [0.17-0.73]; p = 0.005) were significantly associated with inferior overall survival. Conclusions: Cytogenetic abnormalities in myelofibrosis provide significant prognostic discrimination in patients with myelofibrosis. Our findings validate the prognostic value of cytogenetics and raise possible heretofore unrecognized clinical associations. Disclosures Lancet: Novartis: Consultancy; Biopath Holdings: Consultancy; Karyopharm: Consultancy; Boehringer-Ingelheim: Consultancy; Quantum First: Consultancy; ERYtech: Consultancy; Pfizer: Research Funding; Celgene: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Kalo Bios: Consultancy; Baxalta: Consultancy; Amgen: Consultancy. Sweet:Incyte Corporation: Research Funding; Pfizer: Speakers Bureau; Karyopharm: Honoraria, Research Funding; Ariad: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Komrokji:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Speakers Bureau.
25
Al-Khabori, Murtadha, Shoaib Al-Zadjali, Iman Al Noumani, Khalil Al Farsi, Salam Al-Kindi, Mohamed Al Huneini, Naglaa Fawaz, et al. "Overall Survival in Patients with JAK2 and ASXL1 Positive Myeloproliferative Neoplasms." Blood 134, Supplement_1 (November 13, 2019): 5383. http://dx.doi.org/10.1182/blood-2019-128309.
Full textAbstract:
Objectives: Mutations in additional sex combs-like transcriptional regulator 1 (ASXL1) have been previously described in myeloid neoplasms (21% in non-Myeloproliferative [MPN; Tefferi A, Leukemia, 2010) and have been associated with a more aggressive disease [Rocquain J et al, BMC Cacer, 2010]. They can also be found in patients with JAK2 positive MPN [Abdel-Wahab O et al, Cancer Research, 2010). Disruption of ASXL1 gene leads to MPN phenotype in zebrafish model (Gjini E, Dis Model Mech, 2019). The co-expression and the prognostic significance of ASXL1 in patients with JAK2 positive MPN are not yet fully defined. We therefore planned to define the prognostic impact of ASXL1 mutations on the Overall Survival (OS) of patients with JAK2 positive MPN. Methods: We included patients with JAK2 V617F positive MPN diagnosed according to the World Health Organization 2016 criteria and treated at the three largest hematology centers in Oman. The entire coding region of ASXL1 gene was sequenced using Next Generation Sequencing (NGS; Ion PGM Sequencer; Thermo Fisher Scientific®). The library was constructed and the templates were prepared using the PGM tool and the variants were annotated using the ClinVar database and the prediction from the Scale-Invariant Feature Transform (SIFT) and or Polymorphism Phenotyping (Polyphen) algorithms. The NGS analysis was done on the frozen diagnostic bone marrow samples. The survival probability was estimated using Kaplan-Meier estimator and Cox regression was used to assess the impact of predictors on the OS outcome. An alpha threshold of 0.05 was used. The R program (version 3.1.2) was used for all statistical analyses. Results: A total of 58 patients with JAK2 V617F positive MPN were included. All of these patients were found to have mutated ASXL1 using the NGS (ASXL1 p.Leu815Pro was found in all patients). The median age of this cohort was 62 years (InterQuartile Range [IQR]: 44 - 70) and female to male ratio was 25:33. The median hemoglobin, hematocrit, white blood cell count and platelet count was 14.7 g/dL, 58%, 11.5 x109/L and 518 x109/L respectively. Out of the 58 patients included, 28 had polycythemia vera, 20 had essential thrombocythemia, 8 had myelofibrosis and 2 had MPN-Unclassified. The median time from diagnosis to last follow up or death was 13 months (IQR: 3-39). During this period, 5 patients died. The probability of OS at 3 years was 88%. The median OS was not reached. In the univariable analysis, age was a statistically significant predictor of OS (p = 0.0355) but not gender (p = 0.434) and MPN subtype (p = 0.7). In the multivariable analysis model of the previous three factors, age remained statistically significant (Hazard ratio = 1.13, p = 0.041). Conclusions: ASXL1 is mutated in high proportion of patients with JAK2 positive MPN. Despite the negative impact of ASXL1 in patients with non-MPN myeloid neoplasms, the patients with combined positivity of JAK2 and ASXL1 in this study had a very good OS probability. Age was a predictor of OS in the univariable and multivariable models. We recommend the development and the assessment of ASXL1 inhibitors as therapeutic strategies in patients with MPN. Disclosures Al-Khabori: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNardisk: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Shire (Takeda): Membership on an entity's Board of Directors or advisory committees; SOBI: Honoraria; AstraZeneca: Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees.
26
Irene Piatek, Caroline, Maria E. Vergara-Lluri, Vinod Pullarkat, Imran N. Siddiqi, Casey O'Connell, Donald I. Feinstein, and Russell K. Brynes. "Autoimmune Myelofibrosis (AIMF) – Clinical Features, Course and Outcome." Blood 122, no. 21 (November 15, 2013): 3714. http://dx.doi.org/10.1182/blood.v122.21.3714.3714.
Full textAbstract:
Abstract Background Bone marrow (BM) fibrosis is commonly recognized in the setting of primary myelofibrosis (PMF) and other myeloproliferative neoplasms. However, a variety of non-malignant conditions are associated with myelofibrosis (MF). While PMF is associated with a limited survival, other causes of MF such as AIMF appear to have a favorable clinical course (Pullarkat et al, Am J Hematol 2001;116:211). We conducted a retrospective chart review of patients diagnosed with non-malignant MF to investigate clinical presentations, therapies, and outcomes of AIMF. Methods Patients diagnosed with MF were identified from pathology records at Los Angeles County-USC Medical Center from 1999-2013. Histories were reviewed for the clinical indication for BM biopsy, medical conditions known to be associated with MF, and clinical course. Patients were excluded if they met diagnostic criteria for PMF or other neoplastic hematologic disorders associated with MF. BM specimens were assessed as described by Pullarkat et al: (1) Presence of diffuse reticulin fibrosis (European Consensus Score; Thiele et al, Haematologica, 2005;90:1128).; (2) Lack of clustered or atypical megakaryocytes; (3) Lack of myeloid or erythroid dysplasia, eosinophilia, or basophilia; (4) Lymphocyte infiltration; (5) Lack of osteosclerosis; (6) Absent or mild splenomegaly; and (7) Presence of autoantibodies. Results Thirteen patients with MF were identified (11 F, 2 M; 23-73 y.). The mean follow up was 3.7 years. 12 presented with both anemia and thrombocytopenia, and represented the most common indication for BM biopsy. 1 of 12 also had severe leukopenia. The remaining patient presented with thrombocytosis. Clinical presentation included symptoms of fatigue, fever, lightheadedness, chest pain, and dyspnea. The spleen was enlarged in 1 patient, borderline enlarged in 4, normal in 6, and unknown in 1. 1 patient had a history of splenectomy. All patients had one or more autoantibodies. These included: ANA (8 patients), dsDNA (1), RF (4), CCP (2), DAT (7), lupus anticoagulant (3), anticardiolipin (2), atypical pANCA (1), anti-MPO (1), anti-SMA (3), anti-SSA (2), and anti-SSB (2). Medical co-morbidities included systemic lupus erythematosus (2 patients), rheumatoid arthritis (2), autoimmune hepatitis and primary sclerosing cholangitis (1), dermatomyositis (1), antiphospholipid antibody syndrome (1), and autoimmune hemolytic anemia (AIHA) (7). 3 AIHA patients had Evan’s syndrome. BM cellularity ranged from normocellular to markedly hypercellular. The reticulin stain showed mild to moderate increase in fibrosis (MF1-2/3). Megakaryocytes were increased in 8 patients, normal in 3 patients, and decreased in 2 patients. Megakaryocytes were normal in appearance and distribution. No myeloid or erythroid dysplasia, eosinophilia, or basophilia were noted. All cases demonstrated increased small lymphocyte infiltrates. IgG4 immunostaining was negative in 4 of 4 specimens tested. In 1 patient with Evan’s syndrome, MF was attributed to chronic romiplostim administration. 1 patient with thrombocytosis was treated as JAK2-negative essential thrombocythemia with normalization of his platelet count after interferon therapy. 4 of 11 remaining patients had a resolution in their cytopenias with steroid treatment with or without additional immunosuppressive agents. Resolution of MF was seen on post-steroid therapy BM biopsy in 2 of these patients. 3 had partial response in their cytopenias when treated with similar immunosuppressive regimens. Thrombocytopenia improved in 1 patient after splenectomy done for an unclear indication. 3 patients died due to unrelated sepsis. Conclusion AIMF is an under recognized cause of MF in patients presenting with cytopenias that responds to steroids and has a good clinical outcome in the majority of patients. While the spectrum of clinical presentations is broad, the BM findings are similar between cases and different from those of PMF. The prognostic and therapeutic differences between AIMF and PMF make distinction between these entities imperative for the treating physician. Disclosures: No relevant conflicts of interest to declare.
27
Szuber, Natasha, Terra L. Lasho, Christy Finke, Curtis A. Hanson, Rhett P. Ketterling, Animesh Pardanani, Naseema Gangat, and Ayalew Tefferi. "Determinants of Long-Term Outcome in Type 1/like Calreticulin-Mutated Myelofibrosis." Blood 132, Supplement 1 (November 29, 2018): 1767. http://dx.doi.org/10.1182/blood-2018-99-117458.
Full textAbstract:
Abstract Background: Type 1 calreticulin (CALR) variants comprise ~70% of all CALR mutations in primary myelofibrosis (PMF) and form a distinct phenotypic and prognostic disease subset (Leukemia. 2014;28:1568). Determinants of long-term outcome have not, however, been systematically appraised in this population. The current study documents the natural history, molecular correlates, and independent predictors of overall (OS), leukemia-free (LFS), and thrombosis-free (TFS) survival in CALR type 1/like-mutated myelofibrosis. Methods: Patients were recruited from the Mayo Clinic, Rochester, MN, USA. Diagnoses were consistent with World Health Organization (PMF, fibrotic/leukemic transformations) (Blood. 2016;127:2391) and International Working Group for Myeloproliferative Neoplasms Research and Treatment criteria (post-essential thrombocythemia (ET) MF) (Leukemia. 2008;22:437). Laboratory and clinical data were retrospectively abstracted corresponding to time of referral (PMF) or myelofibrotic transformation (post-ET MF). Conventional prognostic scoring was as previously outlined (Blood. 2010;115:1703; J Clin Oncol. 2018;36:1769). Recipients of allogeneic stem cell transplant were censored at the time of transplant. Standard statistical methods were used for all analyses using the JMP® Pro 13.0.0 software package (SAS Institute, Cary, NC, USA). Results: A total of 162 consecutive patients with CALR type 1/like-mutated myelofibrosis were identified: 139 (86%) with PMF and 23 (14%) with post-ET MF with median age 55 years (range 23-85), 62% male. The PMF and post-ET MF cohorts displayed similar phenotypic features with the exception of higher platelet counts (median 443 vs 340 x 109/l; P=0.02) in post-ET MF (Table 1). The most frequent co-existing mutations were ASXL1 (n=47; 37%) and SRSF2 (n=4; 3%), with ASXL1 seen more frequently in PMF (39% vs 11% post-ET MF; P=0.07). Over a median follow-up of 6 years (range 0-25 years), a total of 20 (12%) leukemic transformations and 66 (41%) deaths were recorded, with no significant differences between the PMF and post-ET MF cohorts (P=0.16 and 0.11, respectively). Kaplan-Meier survival estimates revealed comparably favorable median OS in both CALR type 1/like-mutated variants: not yet reached and 13 years in post-ET MF vs PMF, respectively (P=0.7) (Figure 1A). Multivariable analysis disclosed moderate to severe sex-adjusted anemia (P<0.001), ≥2% circulating blasts (P<0.001), very high risk (VHR) karyotype (P<0.001), age >70 years (P=0.006), and constitutional symptoms (P=0.008) to be independent predictors of inferior OS in CALR type 1/like-mutated PMF (Table 2). LFS was significantly shortened in the presence of IDH1 mutations (P=0.01) and platelets <100 x 109/l (P=0.02) while IDH2 mutations (P=0.02), leukocytosis ≥11 x 109/l (P=0.03) and history of arterial thrombosis (P=0.04) were independent predictors of shortened TFS. Importantly, myelofibrosis variant (primary vs post-ET) did not influence survival (P=0.7) or complication rates (P=0.8 for LFS, P=0.09 for TFS) (Table 2). The karyotype- and mutation-enhanced international prognostic scoring system (MIPSS70+ version 2.0), was effective in risk stratifying type 1/like CALR-mutated PMF (P-values 0.01 to <0.0001), with the exception of low vs intermediate (P=0.22) and intermediate vs high risk (P=0.49) (Figure 1C). The detrimental influences of unfavorable/VHR karyotype and ASXL1 mutations were confirmed (Figure 2A-B) while borderline adverse and prognostically neutral effects were seen on OS for U2AF1 (n=116; P=0.05) and SRSF2 (n=120; P=0.98) respectively (Figure 2C-D). Conclusions: The current study documents analogous disease patterns in primary and post-ET CALR type 1/like-mutated MF and provides information on determinants of long-term survival. Disclosures No relevant conflicts of interest to declare.
28
Zhao, Lin-Pierre, Rafael Daltro De Oliveira, Clemence Marcault, Juliette Soret, Nicolas Gauthier, Emmanuelle Verger, Nabih Maslah, et al. "SF3B1 mutations in the Driver Clone Increase the Risk of Evolution to Myelofibrosis in Patients with Myeloproliferative Neoplasms (MPN)." Blood 136, Supplement 1 (November 5, 2020): 1. http://dx.doi.org/10.1182/blood-2020-141296.
Full textAbstract:
Introduction: Next generation sequencing (NGS) studies identified additional somatic mutations impacting disease evolution and prognosis in MPN. SF3B1, a component of the U2 small nuclear ribonucleoprotein splicing complex, is frequently mutated in myelodysplastic syndromes where it has been proposed to define a new entity (Malcovati et. al. Blood 2020). In MPN, SF3B1 is mutated in approximately 10% of patients with primary myelofibrosis (PMF) and 3-5% with polycytemia vera or essential thrombocytemia (ET). Recent reports suggested that spliceosome mutations may adversely affect myelofibrosis free survival (MFS) in ET (Tefferi et. al. Br J Haematol. 2020). The main objective of this study was to evaluate the impact of the concomitant presence of driver (JAK2, MPLor CALR) and SF3B1 clonal or sub-clonal mutations on MPN phenotype and evolution in a large single center cohort of MPN patients. Methods: A total of 1243 consecutive patients were diagnosed with MPN according to WHO criteria between January 2011 and May 2020 in our center, of whom 707 had molecular analysis by NGS targeting a panel of 36 myeloid genes performed at diagnosis and/or during follow-up. Significant variants were retained with a sensitivity of 0.5%. Patients were grouped according to variant allele frequencies (VAF) determined by NGS as "driver" SF3B1mutated patients when driver and SF3B1 mutations VAF were similar (double mutated clone), and as "non-driver" SF3B1 mutants when SF3B1VAF was lower than that of the driver mutation, suggestive of a sub-clone. 4 patients with SF3B1 mutations but no driver mutation were excluded. We then compared the characteristics and outcomes of 3 groups of patients according to their SF3B1 mutational status: wild type (WT), driver and non-driver SF3B1 mutations. Results: A total of 39/703 (5.6%) patients had SF3B1 mutations, of whom 11/39 (28.2%) and 28/39 (71.8%) harbored driver and non-driver SF3B1mutations, respectively. Driver SF3B1 mutations were associated with PMF (OR 6.1, 95%CI [1.1; 33.6], p= 0.039) and MPN unclassified (OR 15.6,95%CI [1.1; 116.5], p= 0.007) subtypes, presence of immature myeloid cells ≥ 2% (OR 9.3, CI [2.6; 32.8], p= 0.001) and peripheral blasts ≥ 1% (OR 5.0,95%CI [1.0; 24.7], p= 0.047) at diagnosis (Figure A). Other variables were not significantly different between patients with driver, non-driver and WT SF3B1, including age, driver mutation type, MPN-related symptoms, cytogenetics and high molecular risk mutations (ASXL1, EZH2, SRSF2, IDH1/2or U2AF1). There was no significant difference in the response to therapy: complete hematological response was seen in 5/11 (45.5%), 10/28 (35.7%) and 327/664 (49.3%) of patients with driver, non-driver and WT SF3B1 respectively. After a median follow-up of 103.7 months IQR [47.2; 175.6], evolution to myelofibrosis occurred in 5/7 (71.4%), 6/20 (30.0%) and 99/564 (17.6%) of patients with driver, non-driver and WT SF3B1 respectively. Interestingly, driver SF3B1 but not non-driver SF3B1 mutational status adversely impacted MFS (OR 7.56,95%CI[2.95; 19.38], p<0.001)(Figure B). Other variables independently associated with adverse MFS in multivariate COX regression analysis included age at MPN diagnosis (OR 1.02, 95%CI[1.00; 1.04], p=0.003), JAK2V617F allele burden (OR 1.03, 95%CI[1.02; 1.04], p<0.001), MPL (OR 13.94, 95%CI[4.90; 39.70], p<0.001) and CALR (OR 7.06, 95%CI[3.69; 13.51], p<0.001) mutations. SF3B1 mutational status had no impact on overall survival, transformation to MDS/AML or thrombotic/hemorrhagic events free survival. Conclusion: This study in a large cohort of MPN patients highlights for the first time to our knowledge the adverse impact on MFS of SF3B1 and MPN-driver co-mutated clones. In contrast, presence of an SF3B1 mutation at sub-clonal level didn't increase the risk of MF development. In line with our findings, a recent study reported an association between rapid progression to myelofibrosis and SF3B1 mutations in patients with age-related clonal hematopoiesis (Bartels et al. Leukemia 2020). Further studies are warranted to confirm our results on independent cohorts and to investigate the mechanisms of bone marrow fibrosis development in patients with SF3B1 and MPN-drivermutations. Disclosures Rea: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Kiladjian:BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; AOP Orphan: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Benajiba:Gilead Foundation: Research Funding.
29
Karantanos, Theodoros, Shruti Chaturvedi, Jerry L. Spivak, Linda Resar, Evan M. Braunstein, Styliani Karanika, Donna Marie Williams, Ophelia Rogers, and Alison R. Moliterno. "Independent Association of Male Sex with Presentation and Clinical Outcomes in Myeloproliferative Neoplasms." Blood 132, Supplement 1 (November 29, 2018): 1768. http://dx.doi.org/10.1182/blood-2018-99-112683.
Full textAbstract:
Abstract INTRODUCTION: The chronic MPN, essential thrombocytosis (ET), polycythemia vera (PV) and primary myelofibrosis (PMF), share mutations of JAK2, MPL and CALR, but vary widely with regard to sex distribution, age at diagnosis, disease evolution and outcomes. Given that age at diagnosis influences presenting phenotype, disease progression and clinical outcome, the impact of sex remains undefined. The aim of our study was to evaluate the impact of sex in presenting phenotype, disease progression, complications and mortality in a well-defined, prospective observational cohort. PATIENTS AND METHODS: 630 individuals with ET, PV or PMF were enrolled in our observational cohort between 2005-2015. Median disease duration at the time of evaluation was 7.23 years, whereas 152 were enrolled within one year of diagnosis. All individuals were genotyped for neutrophil JAK V617F variant allele frequency (VAF), and JAK2 V617F-negative individuals were studied for other JAK2 mutations, CALR or MPL mutations. Multivariable logistic regression was used to evaluate associations of sex, age and molecular characteristics with presenting phenotype; multivariable cox regression was used to evaluate associations of sex, age, presenting phenotype, and molecular characteristics with mortality, and survival curves were generated using the Kaplan Meier method. RESULTS: The cohort comprised 630 individuals (246 males and 384 females) with 6819 patient-years of follow up. Over a median follow up of 9 (Q25-75% 6, 15) years, 185 individuals died. Males had a higher mean age of presentation (52.9 versus 48.8 years, P=0.002). Compared with females, males were more likely to present with PMF than PV or ET (P <0.001), and this sex difference remained statistically significant across JAK2 V617F positive and negative groups, and across age groups (≤40 years, >40 and ≤60 years, and >60 years) (Figure 1A). In a multivariable logistic regression model, male sex was significantly associated with PMF as presenting phenotype (P<0.001) after adjusting for age at diagnosis (P=0.4), neutrophil and peripheral blood CD34+ JAK2 V617F VAF (P=0.729 and P=0.064 respectively). Females had a higher rate of venous thromboembolism (15.7% vs. 6.9%, P<0.001) while males had higher rates of progression to acute myeloid leukemia (6.5% vs. 2.9%, P=0.028) and overall mortality (38.2% vs. 23.7% P<0.001). In a multivariable cox regression model, male sex was significantly associated with increased mortality (HR 1.63 [95% CI 1.20-2.22], P=0.002) after adjusting for age at diagnosis (HR 1.10 [95% CI 1.08-1.12), P<0.001), presenting phenotype (PV, HR 1.66 [95% CI 1.13-2.45], P=0.010; PMF 3.70 [95% CI 2.46-5.57), P <0.001), genotype (JAK2V617F+ reference category, CALR HR 0.83 [955 CI 0.49-1.40], P=0.064; MPL HR 0.74 [95% CI 0.23-2.35], P =0.493; triple negative HR 2.72 [95% CI 1.30-5.69], P=0.008), and hydroxyurea therapy (HR 1.00 [95% CI 0.73-1.36], P=0.992). The association of male sex with higher mortality was also seen in subgroup analyses of the JAK2 V617F-positive and JAK2 V617F-negative groups separately (Figure 1B). CONCLUSIONS: Males with MPN have inferior survival compared to females with MPN, even when adjusted for age at presentation, presenting phenotype, and molecular characteristics. Further, males present more frequently with PMF while females present more frequently with ET. These striking sex-based differences in MPN presentation and outcomes demonstrate that male sex is associated with more aggressive disease biology independent of other factors, and further study to dissect the molecular mechanisms are warranted. Moreover, sex stratification should be considered in MPN prognostic risk algorithms and when designing and interpreting results from clinical trials. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
30
Moliterno, Alison R., and Hannah Kaizer. "Applied genomics in MPN presentation." Hematology 2020, no. 1 (December 4, 2020): 434–39. http://dx.doi.org/10.1182/hematology.2020000128.
Full textAbstract:
Abstract Polycythemia vera, essential thrombocytosis (ET), and primary myelofibrosis (PMF) are grouped together as myeloproliferative neoplasms (MPNs) because of shared clinical, pathologic, and molecular features. The 2005 discovery of the driver mutation JAK2V617F, found in more than 70% of individuals with MPNs and 98% of those with PV, has transformed the diagnosis and management of MPNs. Although PV is the most common phenotype associated with JAK2V617F, roughly 60% of individuals with ET or PMF also have the mutation, and JAK2V617F is now recognized as a common lesion in clonal hematopoiesis (CH). JAK2V617F+ CH and MPN are indolent disorders that evolve over time, with transitions to different disease phases, transformation to bone marrow failure or leukemia, and high thrombosis rates. Genomic assessment has taken center stage as an important tool to define disease phenotype, disease burden, prognosis, and even thrombosis risk of MPNs. Genomics has also unveiled the causes and factors that modify the risk of acquiring and expanding CH and MPNs and points to new pathways for targeted therapies to treat and ultimately prevent them. Genomic assessment of patients with MPNs, like other cancers, enables the clinician to capitalize on large population data sets to inform the individual patient of risk, identify treatment, and improve outcomes.
31
Auteri, Giuseppe, Vito Sansone, Daniela Bartoletti, Christian Di Pietro, Emanuele Sutto, Camilla Mazzoni, Nicola Vianelli, Michele Cavo, Fabio Piscaglia, and Francesca Palandri. "Spleen and Liver Fibrosis Is Associated to Treatment Response and Prognosis in Philadelphia-Negative Chronic Myeloproliferative Neoplasms." Blood 138, Supplement 1 (November 5, 2021): 3626. http://dx.doi.org/10.1182/blood-2021-152866.
Full textAbstract:
Abstract Introduction: Spleen and liver stiffness, investigated by transient elastography (TE), have been associated with marrow fibrosis in patients (pts) with Ph-negative myeloproliferative neoplasms (MPNs) (Iurlo et al, Br J Haematol. 2015; Webb et al, Ultrasound Q. 2015). Morover, spleen stiffness was found to be greater in Myelofibrosis (MF) and Polycythemia Vera (PV) compared to Essential Thrombocythemia (ET) (Benedetti et al, J Clin Med. 2020). Tissue stiffness can be assessed by ultrasound shear wave elastography (SWE), the two most common techniques being point SWE (pSWE) and bidimensional SWE (2D.SWE). Aims: The aims of this study are: 1) to identify TE differences between MPN pts and healthy volunteers (HV); 2) to evaluate specific TE features in pts with MF, PV and ET; 3) to assess whether spleen/liver stiffness may identify clinical-laboratory features associated with prognosis in MPNs Methods: In this monocentric study, MPN pts and HV received elastometric evaluation of spleen and liver stiffness by pSWE and 2D.SWE with an Esaote MyLab™9 ultrasound system. Spleen area, portal (PVD) and splenic vein diameter (SVD) were measured. Results: A total of 220 pts were included in this study: 142 (64.5%) MPN and 78 (35.5%) HV. MPN pts were affected by MF (63, 44.4%: 39 primary MF), PV (33, 23.2%) or ET (46, 32.4%). Compared to HV, MPN pts had greater median spleen maximal cross sectional area (79 vs 38 cm2, p<0.001), greater spleen stiffness (pSWE 31.3 vs 23.7 kPa, p<0.001; 2D.SWE 25.2 vs 18.7 kPa, p<0.001), and greater liver stiffness (pSWE 6.0 vs 4.9 kPa, p<0.001; 2D.SWE 5.4 vs 4.7 kPa, p<0.001). Additionally, PVD and SVD were significantly larger in MPNs than in HV (PVD 10.9 vs 9.2 mm, p<0.001; SVD 8 vs 6.3 mm, p<0.001). Comparing each MPN to HV, only MF retained all the significant differences; conversely, liver stiffness and PVD were comparable between ET/PV and HV. Clinical and laboratory features of MPN pts are shown in Tab 1. Compared to PV and ET pts, MF pts had higher spleen (p<0.001) and liver stiffness (p<0.001), larger PVD (p<0.001) and SVD (p<0.001). Conversely, ET and PV displayed comparable TE values. Notably, higher median spleen area (p<0.001), larger SVD (p=0.03) and PVD (p=0.02), higher liver (pSWE/2D.SWE, p<0.001/p=0.002) and spleen stiffness (pSWE/2D.SWE, p=0.01/p=0.001) were associated with increased marrow fibrosis grade. Grade 0-1 marrow fibrosis was present in 15 MF, 17 PV and 34 ET pts. Considering only these 66 MPN pts, spleen (40.8 vs 31.3/25.6 in PV/ET, p=0.006) and liver (6.5 vs 5.6/4.7 in PV/ET, p=0.01) stiffness was significantly higher in MF pts. Notably, increased spleen fibrosis was significantly associated with thrombotic history (32.2 vs 24.3 kPa in pts without previous thrombosis, p=0.02). Also, MPN pts with splanchnic vein thrombosis had higher spleen (pSWE: p<0.001; 2D.SWE: p<0.001) and liver stiffness (pSWE: p <0.001), and increased PVD (p=0.02) and spleen area (p=0003). In MF pts, TE data did not correlate with DIPSS risk category. However, a higher spleen stiffness (pSWE/2D.SWE, p=0.09/ p=0.03), liver stiffness (pSWE/2D.SWE, p=0.001/p=0.01), PVD (p=0.002), and SVD (p=0.01) were associated with larger spleen length by palpation. Also, a reduced SVD was associated with the presence of ≥1 high molecular risk mutation (HMR) (p=0.04). As expected, MF pts treated with JAK-inhibitors showed larger spleen area (143.8 vs 83.7 cm 2, p=0.01) and higher spleen stiffness (34.3 vs 24 kPa, p=0.01) compared to pts under cytoreductive therapy. However, pts in spleen response at the time of TE had lower median SVD/PVD (p=0.05/p=0.07) and reduced spleen stiffness (sSWE/2D.SWE: 31.5/25.9 vs 39.0/32.8 in non-responders, p=0.01/p=0.04) In ET/PV, TE data were comparable in pts with/without a complete hematological response. However, IFN was associated with enlarged spleen area and stiffness compared to cytoreduction. Conclusions: TE evaluation effectively distinguishes MF pts from HV and ET/PV, while ET/PV show relevant similarities to each other and to HV. TE data were significantly associated with prognostically relevant features including marrow fibrosis and history of thrombosis in all MPNs, and presence of large splenomegaly and HMR in MF. Finally, TE data were significantly associated with spleen response in MF. Overall, spleen/liver stiffness may help in correct MPN diagnosis, and may provide clinical guidance, being associated with known prognostic factors and treatment outcome. Figure 1 Figure 1. Disclosures Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau. Piscaglia: ESAOTE: Research Funding. Palandri: CTI: Consultancy; AOP: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees.
32
Hobbs, Gabriela, Jennifer Lombardi Story, Maura A. Blaney, Philip C. Amrein, Amir Tahmasb Fathi, and Andrew Mark Brunner. "Response to induction or hypomethylating agent therapy among patients with myeloproliferative neoplasms progressing to accelerated or leukemic phase." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): e18561-e18561. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e18561.
Full textAbstract:
e18561 Background: Post-myeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) and accelerated phase disease (AP) are associated with poor outcomes; the optimal management of these patients at transformation is uncertain in the era of widely available molecular testing. Methods: We performed a retrospective analysis of adult patients with MPN that had transformed into AML (greater than 20% blasts) or AP (10-19% blasts and dysplastic features) from 2006-2016. Patients were 18 or older at AML/AP diagnosis. Outcomes were described by Kaplan and Meier and the Log rank test. Results: We identified 30 patients, with transformed MPN into AML (n = 23) or AP (n = 7), including one patient in AP at presentation. Most were male (73%). Disease evolved from polycythemia vera (n = 6), essential thrombocythemia (n = 11), primary myelofibrosis (n = 9) and other MPN diagnoses (MPN/MDS overlap, n = 3; MPN NOS, n = 1). The median age at MPN diagnosis was 67.5 yrs, and at transformation 72 yrs. The median time from MPN diagnosis to transformation was 5.6 yrs (range 0.3-36.0). 12 patients had JAK2 V617F testing both at MPN diagnosis and AML diagnosis; 6 had JAK2 mutations at both time points and 2 lost JAK2 at transformation. At AML/AP transformation, 11 patients had NGS mutation testing; the most common somatic mutations were NRAS (5/11), RUNX1 (2/11), and SRSF2 (2/11). 20 patients received treatment outside of supportive care. Of these, 8 achieved a CR or CRi (40%; 7/10 with induction and 1/8 with HMA). The only HMA response was on a trial of HMA+SGN33a. The median survival from AML/AP transformation was 5.8 mo. Of treated patients, median survival was 7.4 mo; 37% of treated patients were alive at 1 yr. Nine patients (31%; 7 with AML and 2 with AP) underwent allogeneic transplantation; 2 relapsed during follow-up. 74% of patients treated with allo-HCT were alive at 1 yr after AML/AP transformation. Conclusions: AML or accelerated phase disease arising out of MPN carries a dismal prognosis. HMA monotherapy had little efficacy in this group (0/7 achieved remission). Allogeneic transplantation offered the best chance of survival at one year, but fewer than a third of patients were able to proceed to transplant.
33
Palandri, Francesca, Nicola Polverelli, Roberto Latagliata, Alessia Tieghi, Emanuela Ottaviani, Monica Crugnola, Margherita Perricone, et al. "Mutations and Long-Term Outcome of 217 Young Patients with Essential Thrombocythemia or Early Primary Myelofibrosis." Blood 124, no. 21 (December 6, 2014): 3190. http://dx.doi.org/10.1182/blood.v124.21.3190.3190.
Full textAbstract:
Abstract Introduction Young adults with Essential Thrombocythemia (ET) or early Primary Myelofibrosis (early-PMF) are a category of patients projected to a prolonged survival but also to an extended utilization of medical resources. Mutations, including those in the calreticulin (CALR) gene, have been reported to affect main clinical features and outcome in large cohorts of patients with Ph-negative MPNs. However, no data are available on mutational status and long-term outcome in young MPN patients. Methods A clinic-pathologic database of ET patients followed in 5 Italian Hematology Centers was created. A total of 217 WHO-diagnosed ET or early-PMF patients ≤ 40 years at diagnosis was retrieved from the general database of 2635 patients. All bone marrow biopsies were reviewed at local institution. Baseline clinical/molecular characteristics and outcome measures (thrombosis, hemorrhages, secondary MF and AL, second neoplasia, death, overall and event-free survival) were evaluated. JAK2V617F allele-burden was assessed in granulocyte DNA by using ipsogen JAK2 MutaQuant Kit (qPCR). CALR mutations were identified by next generation sequencing (NGS) approach on GS Junior (Roche-454 platform); MPL mutations were evaluated by using ipsogen MPLW515L/K MutaScreen Kit. Results Overall, 197 WHO-defined ET and 20 early-PMF (age range: 16-40, median 34) were included in the study. Mutational frequencies were 61% for JAK2, 25% for CALR, 1% for MPL and 13% for triple negative. Baseline clinical characteristics and use of antiplatelet/cytoreductive therapies were comparable in ET and early-PMF, although frequency of triple negative was higher in the early-PMF cohort. Compared to the JAK2 positive population, both CALR and triple-negative patients showed higher platelet count and lower hemoglobin and hematocrit levels (Table 1). Median follow-up was 10.2 years (range: 0.5-37.5). During follow-up, 19 (9,6%) ET and 3 (15%) early-PMF patients experienced a total of 31 thrombotic (arterial: 38%) and 12 hemorrhagic events, with an incidence rate of 0.91% and 0.39% patients/yr, respectively. The cumulative incidence of thrombosis was 0,14% and 0,24% at 15 and at 20 years, respectively. Overall, 10 patients (4,6%) and 1 (0,4%) patients evolved to MF and AL, respectively; 10 developed a second neoplasia. The cumulative incidence of disease progression into MF/AL was 0,03% and 0,13% at 15 and at 20 years, respectively. At last contact, 6 (2,7%) patients had died, at a median age of 61 years (20-71), for an overall survival of 98% at 15 years. Causes of death were related to the myeloproliferative neoplasm (disease evolution or thrombotic complications) in all patients but one. Event-free survival was similar in the ET/early-PMF cohorts considering both every event separately and all together. In univariate analysis, male sex (p=0.003), previous thrombosis (p=0.001), splenomegaly (p=0.037), JAK2V617F (p=0.019) were associated with increased thrombotic risk; in multivariate Cox analysis, only previous thrombosis and male sex remained significant (p=0.012). Baseline splenomegaly was the only predictive factor for subsequent hemorrhages (p=0.017). Abnormal karyotype was associated with secondary MF (p=0.013) and also with second neoplasia (p<0.001). Together with JAK2V617F positivity and leukocytosis >11x109/L, abnormal karyotype was also associated with worse survival in univariate analysis. However, in multivariate analysis only JAK2V617F mutation remained as negative predictor of survival (p=0.019). Also, multivariable analysis confirmed JAK2 mutation and splenomegaly as independent risk factors for cumulative events. Conclusions With the limitations due to the low number of early-PMF, the outcome of young adults with early-PMF and true ET seemed to be comparable. The correlation of abnormal karyotype with MF transformation and second neoplasia suggests the need for an accurate cytogenetic analysis at diagnosis. Mutational status did influence disease phenotype, in terms of baseline characteristics and prognosis. Indeed, JAK2 mutational status confirmed a negative prognostic role for thrombosis and survival, while event-free survival was significantly better in triple-negative patients. Notably, causes of death were mostly related to the hematological malignancy, pointing out the substantial impact that this generally indolent disease may acquire in young adults. Disclosures Latagliata: Novartis: Consultancy; Bristol Myers-Squibb: Consultancy; Celgene: Consultancy; Shire: Consultancy. Cavo:Janssen: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; BMS: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Honoraria.
34
Morsia, Erika, Naseema Gangat, James M. Foran, Jeanne M. Palmer, Michelle A. Elliott, and Ayalew Tefferi. "Efficacy of Venetoclax Plus Hypomethylating Agent in Blast Phase Myeloproliferative Neoplasm." Blood 136, Supplement 1 (November 5, 2020): 21. http://dx.doi.org/10.1182/blood-2020-134701.
Full textAbstract:
Introduction: Myeloproliferative neoplasms (MPN), including primary myelofibrosis (PMF), essential thrombocythemia (ET) and polycythemia vera (PV), have a propensity to evolve into blast phase myeloproliferative neoplasm (BP-MPN) with a 20-year incidence rate of 9.3 %, 3.9% and 2.6%, respectively. (Szuber et al., 2019)Treatment options for BP-MPN are limited and the prognosis of these patients is dismal with a median survival of only 3.6 months and 5-year survival rate of <5%.(Tefferi et al., 2018) Considering the recent reported data on the efficacy of venetoclax when combined with hypomethylating agents (HMA) in acute myeloid leukemia (AML) in both relapsed/refractory and newly diagnosed unfit patients, we have extended such combination therapy for patients with BP-MPN. Methods: We retrospectively analyzed 14 consecutive BP-MPN patients who received venetoclax plus HMA therapy between August 2018 and June 2020. We collected data regarding clinical characteristics of chronic phase MPN and BP-MPN, cytogenetic and leukemia mutation profile, efficacy and outcome. Oral venetoclax was administered in combination with azacitidine 75 mg/m2 days 1-7 (5 patients) or decitabine 20 mg/m2 days 1-5 (9 patients). Venetoclax dose was adjusted based on drug interactions particularly with azole antifungal prophylaxis. Diagnostic, risk and response assignments were according to the 2017 European LeukemiaNet (ELN) criteria.(Döhner et al., 2017) Minimal residual disease (MRD) assessment by flow cytometry, karyotype or next-generation sequencing (NGS) was performed in a subset of patients. Results: Patient characteristics at time of leukemic transformation, treatment details, response rates and overall outcome are shown in Table 1. Median age of patients was 67 years (range 48-81) with poor-risk cytogenetics in 69% of patients. JAK2 was mutated in 10 patients (71%) and CALR in 2 (14%); other mutations included TP53 in 5 patients (36%), TET2 in 4 (29%), KRAS in 3 (21%), IDH1/2 in 3 (21%), ASXL1 in 2 (14%) and U2AF1 in 2 (14%). Eight patients (57%) received venetoclax and HMA combination therapy upfront for their BP-MPN, 2 patients (14%) had failed HMA therapy previously and one patient had prior allogeneic hematopoietic stem cell transplant (AHSCT). Two patients (14%) presented with myeloid sarcoma; one of these two patients documented partial resolution of the extramedullary tumor by imaging studies, after treatment with venetoclax plus HMA. Among the remaining 12 patients, overall response rate (ORR) was 42% (n=5) and included complete remission (CR) in 3 patients (25%) and partial remission (PR) in another 2 (17%). The best response to therapy was seen after a median of 1 month (range, 1-2). Among 3 CR responders, 2 (66.6%) had minimal residual disease negative by NGS and not evidence of preceding MPN, then they successfully transitioned to AHSCT, while the third CR patient at the time of best response showed persistence of the TP53 mutation. Additionally, one PR patient subsequently relapsed and received salvage chemotherapy followed by AHSCT. (Table 2) Although data is limited by the small cohort and short follow up when the outcome of patients treated with venetoclax in combination with HMA were compared to Mayo Clinic's historical control of patients with BP-MPN treated with HMA alone (n=26) or intensive chemotherapy (n=69), there was higher CR rate in patients treated with venetoclax and HMA (25%) compared to those receiving HMA alone (4%; p=0.048) but not to those receiving intensive chemotherapy (35%; p<0.0001). Moreover, the intensive chemotherapy cohort showed 24% of CR with incomplete hematologic recovery (CRi) not seen in patients receiving HMA alone or HMA with venetoclax (Figure1). Conclusions: The relatively high rate of complete response observed in our patients with BP-MPN were similar to those reported in a pivotal study of elderly unfit AML patients treated upfront with venetoclax + HMA with overall response rates of 68%.(DiNardo et al., 2019) Furthermore, responders included patients with adverse molecular risk factors who usually respond poorly to conventional chemotherapy (i.e. TP53 mutated patients). Our observations provide preliminary evidence for the potential efficacy of venetoclax and HMA combination therapy in BP-MPN with the goal of achieving CR/CRi followed by consolidative AHSCT wherever possible to provide durable remission and meaningful survival benefit. Disclosures Foran: Agios: Honoraria, Research Funding; Trillium: Research Funding; Takeda: Research Funding; Kura Oncology: Research Funding; Aptose: Research Funding; Aprea: Research Funding; Actinium: Research Funding; Boehringer Ingelheim: Research Funding; Abbvie: Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Revolution Medicine: Consultancy; Xencor: Research Funding; H3Biosciences: Research Funding.
35
Vinogradova, O. Yu, M. M. Pankrashkina, D. I. Shikhbabaeva, M. V. Chernikov, A. L. Neverova, V. L. Ivanova, E. A. Nikitin, E. V. Usikova, and V. V. Ptushkin. "Possibilities of targeted therapy for myelofibrosis: Moscow experience." Oncohematology 17, no. 4 (November 6, 2022): 94–105. http://dx.doi.org/10.17650/1818-8346-2022-17-4-94-105.
Full textAbstract:
Background. For many years the primary aim of treatment strategy for ph-negative myeloproliferative neoplasms has been to restrain disease progression, with lasting relief and management of symptoms to improve patients’ quality of life. Generally, this did not lead to a significant increase in life expectancy with primary myelofibrosis and didn’t decrease the risk of fibrosis in patients with polycythemia vera and essential thrombocythemia. To date a new class of targeted drugs has been developed, it is JAK2 inhibitors with pathogenetic effects. The results of clinical trials showed the high efficacy of the first registered drug of this its kind – ruxolitinib – that includes a faster reduction in the symptoms of tumor intoxication and in symptoms associated with the development of splenomegaly and increase in the overall survival rates. It is known that the data obtained during clinical trials of medicines may differ from the results obtained in routine clinical practice. In actual practice drugs are used in a much wider heterogeneous population of patients, less limited first of all by age and comorbid characteristics. It is possible to analyze cohorts of patients including a larger number of clinical cases with a longer follow-up period. In this regard of great interest is the actual clinical experience of long-term use of ruxolitinib in patients whose set is limited only by clinical contraindications for prescribing the drug.Aim. To present our own actual experience of targeted therapy of myelofibrosis and compare the results obtained with the data of clinical trials.Materials and methods. Our analysis includes data from 141 patients (67 (47.5 %) men and 74 (52.5 %) women) in a chronic phase myelofibrosis. All patients received ruxolitinib. Of these, 109 (69 %) patients had primary myelofibrosis, 26 (16 %) – postpolycythemia myelofibrosis, 6 (4 %) – postessential thrombocythemia myelofibrosis. The median age at the start of therapy was 62 (18–84) years. The median disease duration before ruxolitinib was prescribed – 79 (1–401) months. According to the dIpSS (dynamic International prognostic Scoring System) criteria, 13 % of patients were assigned to the low risk group, 38 % – to the intermediate-1, 36 % – to the intermediate-2, 13 % – to the high risk group. Most patients (52 %) had grade 3 bone marrow fibrosis.Results. The median duration of treatment was 18 (range from 1 to 115) months. Symptoms of intoxication were relieved 74 (81 %) of 91 patients, the spleen size decreased in 81 % of patients (the spleen size returned to normal in 25 % of patients). The increase in the median hemoglobin level was 15 %. The proportion of patients requiring blood transfusion decreased by 4 times (from 39 to 9 %). Mean platelet levels normalized in most patients with baseline high and low platelet levels. A complete clinical and hematological response was achieved in 16 % (n = 23) of cases, a partial response – in 26 % (n = 37) of cases, clinical improvement – in 21 % (n = 30), disease stabilization – in 33 % (n = 46) of cases. No response was received in 1 (1 %) patient and in 3 (3 %) cases there was progression of the disease. At the time of analysis, 81 (57 %) of 141 patients were continuing the ruxolitinib treatment. The fatal outcome in 33 (22 %) patients was associated with concomitant diseases, among which 20 (14 %) died from proven COvId-19 infection. Overall survival: 1-year 81 %, 2-year 73 %, 5-year 50 %. Overall survival excluding deaths due to COvId-19: 1-year 92 %, 2-year 85 %, 5-year 70 %. Massive splenomegaly and a high degree of fibrosis were unfavorable predictors of prognosis of overall survival.Conclusion. Target therapy with Janus kinase inhibitor ruxolitinib has demonstrated high efficacy in patients with myelofibrosis in routine clinical practice. The most rapid effect ruxolitinib had on the spleen size and the symptoms of intoxication. Tolerability of ruxolitinib therapy was generally satisfactory. The overall and progression-free survival rates in patients with myelofibrosis, receiving ruxolitinib in the clinical setting was consistent with the results of international multicenter clinical trials.
36
Milosevic, Jelena D., Elisa Rumi, Daniela Pietra, Klaudia Bagienski, Tiina Berg, Emanuela Sant'Antonio, Anna Colombo, Francesco Ripamonti, Mario Cazzola, and Robert Kralovics. "Whole Exome Sequencing Identifies Somatic Mutation Patterns Of Myeloid Cells In Patients With Myeloproliferative Neoplasms Treated With Allogeneic Bone Marrow Transplantation." Blood 122, no. 21 (November 15, 2013): 4101. http://dx.doi.org/10.1182/blood.v122.21.4101.4101.
Full textAbstract:
Abstract Allogeneic bone marrow transplantation (ABMT) is so far the only curative treatment option for patients with myelofibrosis (MF), although it carries risk of treatment related mortality and relapse. The effect of somatic mutations present in the clone causing the disease on the outcome of the ABMT is unknown. The aim of the study was to investigate the genetic basis of clonal evolution of MF patients undergoing ABMT and identify candidate prognostic markers of relapse. We performed high-resolution genetic analysis on DNA samples from five patients with MF who received ABMT. The analysis of acquired chromosomal deletions, gains and losses of heterozygosity was performed using SNP 6.0 microarrays. Somatic mutations in the genomes of the patients were identified using whole exome sequencing (WES) of tumor (granulocytes) and matched control tissue (T-lymphocytes). The 51-bp paired-end next generation sequencing was performed using HiSeq2000 system. The somatic origin of mutations was validated by Sanger sequencing. In the three relapsed cases we analyzed both the samples prior to ABMT and at relapse. For the two non-relapse cases only the baseline sample was analyzed, as the chimerism level at last follow up (3 and 5 years after ABMT) was 100% of the donor. We selected one relapse and one non-relapse case who did not carry mutations in JAK2 or MPL, as well as one relapse and one non-relapse case who had close to 100% JAK2-V617F mutational burden. Patient 1 was a 49 year-old diagnosed with MPL-W515A positive post essential thrombocythemia (ET) MF. Following ABMT the patient achieved complete clinical and molecular remission. Three years later the patient developed myelodysplastic syndrome with re-appearance of the MPL-W515A positive clone and within three months refractory anemia with excess blasts II phenotype. The clonal evolution analysis revealed that the clone causing the relapse was the same one present at the initial post-ET MF diagnosis, which acquired additional somatic mutations and chromosomal aberrations. The initial clone causing post-ET MF carried 12 somatic mutations including MPL, DNMT3A, U2AF1, ASXL1, SIRT2, RAD50 and other genes, while no chromosomal aberrations were detectable. The relapsed clone acquired additional 9 somatic mutations in genes TP53, MYO18B, CDYL and others, as well as deletion (del) 7p, del7q, chromothripsis of chromosomes 11 and 16, and del22q. Patient 2 is a 35 year-old diagnosed with post-ET MF. Mutations in JAK2 or MPL were not detected. Prior to ABMT a small clone with a deletion on chromosome 12q targeting SOCS2 gene among 3 other, could be detected by SNP array. The relapsed sample showed a full clone with 2 deletions targeting 2.5Mb region on chromosome 12 containing the SOCS2 gene, as well as a single gene ARID1B on chromosome 6. ARID1B is a member of SWI/SNF chromatin remodeling complex and a putative tumor suppressor. WES identified only 3 somatic mutations in this patient (MTUS2, SP3 and PCDH12). MTUS2 and SP3 mutations arose in the relapsed clone. Patient 3 is a 57 year-old diagnosed with post polycythemia vera MF. The patient carried JAK2-V617F mutation coupled with a 9p UPD, therefore having a 99.2% mutational burden. Within 4 months after BMT the JAK2-V617F clone was detectable with 32% mutational burden, reaching 98% one month later. Apart from 9p UPD no other chromosomal aberration was detectable before BMT or at relapse. Preliminary WES data revealed 7 somatic mutations at relapse, including APBB1 and DOCK4. Patient 4 was diagnosed with JAK2/MPL negative post-ET MF, while patient 5 had primary MF. In patient 4 we identified 10 somatic mutations and no chromosomal aberrations, while patient 5 carried the 9p UPD and a deletion of 20q, 11 somatic mutations and a germline variant in TET2 gene. It seems that the sheer number of somatic mutations does not predict ABMT outcome. As the validation of WES hits is still ongoing, we expect to see other gene mutations that may serve as positive or negative predictors of the ABMT outcome in patients with MF. They will reflect the genomic adaptation that facilitates the escape from the graft-versus-myelofibrosis effect of the donor cells and allows the clonal dominance leading in some cases to disease progression. Further analysis of possible presence of subclones carrying relapse associated mutations before ABMT will have important implications for estimating success of ABMT in MF patients. Disclosures: No relevant conflicts of interest to declare.
37
Santos, Fabio PS, Bianca Lisboa, Tarcila S. Datoguia, Ricardo Helman, Welbert Oliveira Pereira, Renato D. Puga, Mariana Miyagi, et al. "Incidence and Impact of Activating Mutations of the RAS-RAF-MEK-ERK Pathway in Patients with Philadelphia-Negative (Ph-negative) Myeloproliferative Neoplasms (MPNs) and Myelodysplastic/Myeloproliferative Disorders–Unclassified (MDS/MPD-U)." Blood 124, no. 21 (December 6, 2014): 3172. http://dx.doi.org/10.1182/blood.v124.21.3172.3172.
Full textAbstract:
Abstract Introduction: Mutations that activate the RAS-RAF-MEK-ERK pathway have long been known to occur in patients with solid tumors and hematological malignancies. The most common mutations occur in the Ras family of GTPases (HRAS, NRAS, KRAS) and the Raf family of serine-threonine kinases (ARAF, BRAF, CRAF). In myeloid malignancies, RAS mutations have mainly been described in patients with acute myeloid leukemia, chronic myelomonocytic leukemia (CMML) and myelodysplastic syndrome. There are few studies describing the incidence of mutations of the RAS-RAF-MEK-ERK pathway in patients with MPNs other than CMML. Objective: To describe the incidence, clinical features and prognostic impact of Ras and Raf mutations in patients with Ph-negative MPNs and MPN/MDS-U Methods: Paired DNA (sorted CD66b-granulocytes/skin biopsy) from patients with MPNs or MPN/MDS was subjected to whole exome sequencing on a Illumina HiSeq 2000 platform using Agilent SureSelect kit (see our abstract “Whole Exome Sequencing of Myeloproliferative Neoplasms and Myelodysplastic/Myeloproliferative Disorders”). Tumor coverage was 150x and germline coverage was 60x. Somatic variants calls were generated by combining the output of Somatic Sniper (Washington University), Mutect (Broad Institute) and Pindel (Washington University), followed by in-house filters to reduce false positive calls. Statistical calculations were done in Stata, v11.0. Results: We found clonal activating mutations of the RAS-RAF-MEK-ERK pathway in 8 patients (6.7% of cases). Diagnosis included primary myelofibrosis (PMF; N=5), MDS/MPD-U (N=2) and essential thrombocythemia (ET; N=1). Their clinical features are summarized in Table 1 (three of these patients [UPIs #11, #13, #99] are also described in the abstract “Genomic Profile of Patients with Triple Negative (JAK2, CALR and MPL) Essential Thrombocythemia and Primary Myelofibrosis”). There were 7 NRAS mutations and 1 BRAF mutation. In 5 cases the variant allele fraction (VAF) of reads in the tumor sample indicated that the mutation was present in a subclone at the time of sequencing. We next compared the clinical features of these 8 patients with 79 patients (MF=43, ET=35, MDS/MPD=1) who did not harbor these mutations. Patients with NRAS/BRAF mutations had lower hemoglobin (8.3 vs. 11.8 g/dL, p=0.001), higher white blood cell counts (28.37 vs. 7.7 x109/L, p=0.008) and had higher lactate dehydrogenase (1041 vs. 685 IU/L, p=0.02). They also had worse overall survival compared to unmutated cases (Hazard ratio [HR]=11.57; p=0.001). Most patients with NRAS/BRAF mutations had a high number of concomitant driver mutatons (median 5 vs. 1; p<0.0001). When the number of driver mutations was analyzed together with NRAS/BRAF mutations in a Cox model, NRAS/BRAF mutations were no longer independent predictors of survival (HR=1.48; p=0.61). Conclusions: Activating mutations of the RAS-RAF-MEK-ERK pathway occur in 6-7% of patients with Ph-negative MPNs, and they tend to co-occur with a high number of concomitant driver mutations. In most cases the mutation was present in a subclone, suggesting that they are late occurring. Patients with NRAS/BRAF mutations had a trend for worse outcome, but that was mainly dependent on the total number of driver mutations. The activity of MEK and BRAF inhibitors needs to be explored in patients with Ph-negative MPNs who harbor activating mutations of the RAS-RAF-MEK-ERK pathway. Table 1. Clinical features of patients with NRAS/BRAF mutations UPI Diagnosis Mutation VAF Concomitant driver genes and Chromosomal abnormalities Outcomes 7 MF NRAS p.G12S 47% ASXL1, CALR, STAG2, U2AF1 Died from disease progression 11 MF NRAS p.G12R 5% ASXL1, CBL, CUX1 (double mutant), EZH2 Died from disease progression 13 MF NRAS p.G12D 48% ASXL1, DNMT3A, ETV6 (double mutant) JARID2, U2AF1 Died from disease progression 18 MF NRAS p.G13D 25% JAK2, Del(5q) Underwent allogeneic transplantation; disease relapsed day+80; alive 29 MDS/MPD-U BRAF p.D594G 25% JAK2, Del(5q) Transformed to AML; entered CR with induction chemotherapy; underwent allogeneic transplantation; disease relapsed day+35; alive 99 ET NRAS p.G12D 43% ASXL1, CSF3R, STAG2 Alive 109 MF NRAS p.Q61R 19% CALR, DNMT3A, ZRSR2 Alive 122 MDS/MPD-U NRAS p.G12S 7% ASXL1, EZH2 (double mutant), PTPN11, TET2 (double mutant) Transformed to AML; underwent allogeneic transplantation; died on day+58 Disclosures No relevant conflicts of interest to declare.
38
Leiva, Orly, Umberto Campia, Julia Snyder, Briana Barns, Samantha Rizzo, Candrika Khairani, Hanny Al-Samkari, et al. "Increased Risk of Thrombosis in Patients with Myeloproliferative Neoplasms Compared with the General Population Hospitalized with COVID-19." Blood 138, Supplement 1 (November 5, 2021): 1508. http://dx.doi.org/10.1182/blood-2021-151801.
Full textAbstract:
Abstract Background: Coronavirus disease-2019 (COVID-19) is an inflammatory, multisystem infectious disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-COV-2) and is associated with increased risk of thrombosis, particularly among critically ill patients. The myeloproliferative neoplasms (MPNs) include Philadelphia chromosome-negative (Ph-negative) MPNs polycythemia vera (PV), essential thrombocytosis (ET), and primary myelofibrosis (PMF), and Philadelphia-chromosome positive chronic myeloid leukemia (CML). Patients with MPNs, especially PH-negative, have increased risk of thrombotic complications. Given the increased propensity of thrombosis and prognostic significance of thrombosis in both COVID and MPNs, defining the risk of thrombotic complications in this patient population compared to the general population is important. Methods: Using an institutional database within the Mass General Brigham integrated health network, we retrospectively analyzed 63 consecutive patients with MPN who were ≥ 18 years old and tested positive for SARS-COV-2 infection based on polymerase chain reaction (PCR) testing from March 1, 2020 to January 1, 2021. We compared patients admitted to the hospital in our "MPN cohort" with patients admitted to the hospital from a separate COVID-19 (non-MPN cohort) Mass General Brigham registry of 1114 consecutive patients who tested positive for SARS-COV-2 infection based on PCR testing from March 13, 2020 to April 3, 2020. Care was taken to ensure the cohorts were mutually exclusive. The 90-day primary outcome for MPN cohort was a composite of all-cause death, any thrombosis (composite of arterial and venous thromboembolism [VTE]), International Society on Thrombosis and Haemostasis (ISTH) defined major and clinically relevant non-major bleeding. To identify risk factors for primary outcome in MPN cohort we used a multivariable logistic regression using age, sex, hospital admission status, MPN type, cytoreduction for MPN, hypertension, smoking status, baseline anticoagulation (AC), prior thrombosis (stroke, myocardial infarction or VTE) as co-variables. The 90-day outcomes of interest in our MPN vs non-MPN cohort analysis were any thrombosis, death, ISTH major and clinically relevant non-major bleeding and readmission for any reason. To assess impact of MPN status in hospitalized patients in our MPN vs non-MPN comparison, we used a multivariable logistic regression using age, sex, race, Hispanic ethnicity, ICU admission, treatment with steroids and/or Remdesivir, baseline AC and aspirin use, prior thrombosis (stroke, myocardial infarction or VTE), diabetes, heart failure, admission hematocrit, platelet count and D-dimer as co-variables. Continuous variables were compared using student t-test and categorical variables were compared using Fischer's Exact Test with a p value of < 0.05 considered significant. Results: Of the 63 patients with MPN (23 with PV, 17 ET, 4 PMF, 15 CML, 4 other), 27 (43%) were admitted to the hospital for COVID-19 and 5 (8%) required ICU admission. The mean age of all MPN patients was 66, 84% were White, 8% Black and 10% Hispanic. Primary 90-day outcome occurred in 12 (19%) of MPN patients. In multivariable analysis, only admission to hospital was associated with increased odds of composite (aOR 21.11, 95% CI 2.38 - 546.40), Figure 1A. In patients with (n = 27) and without MPN (n = 399) who were admitted to the hospital, patients with MPN were older (mean age 70 vs 61, p = 0.0076), more likely to be White (89% vs 54%, p = 0.0004) and less likely to be Hispanic (7% vs 29%, p = 0.0158), less likely to be admitted to the ICU (19% vs 43%, p = 0.0138), and more likely to be treated with corticosteroids (30% vs 14%, p = 0.025) or remdesivir (41% vs 13%, p < 0.0001). After multivariable logistic regression, diagnosis of MPN was significantly associated with increased odds of thrombosis (aOR 5.38, 95% CI 1.15-25.38) and readmission (aOR 6.28, 95% CI 1.60-24.88), but not bleeding (aOR 3.51, 95% CI 0.62-18.87) or death (aOR 4.29, 95% CI 0.95-18.99), Figure 1B. Conclusions: Thrombotic complications are common in patients with MPN and COVID-19, particularly if hospitalized for COVID-19. After multivariable analysis, MPN patients admitted for COVID-19 had a significantly increased risk of thrombotic complications compared with non-MPN patients. Figure 1 Figure 1. Disclosures Al-Samkari: Dova/Sobi: Consultancy, Research Funding; Novartis: Consultancy; Argenx: Consultancy; Rigel: Consultancy; Amgen: Research Funding; Agios: Consultancy, Research Funding; Moderna: Consultancy. Rosovsky: Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Inari: Consultancy, Membership on an entity's Board of Directors or advisory committees; Dova: Consultancy, Membership on an entity's Board of Directors or advisory committees. Fathi: Agios/Servier: Consultancy, Other: Clinical Trial Support; BMS: Consultancy, Other: Clinical Trial Support; AbbVie: Consultancy, Other: Clinical Trial Support; Pfizer: Consultancy; Trillium: Consultancy; Kura: Consultancy; Blueprint Medicines Corporation: Consultancy; Genentech: Consultancy; Novartis: Consultancy; Trovagene: Consultancy; Daiichi Sankyo: Consultancy; Novartis: Consultancy; Morphosys: Consultancy; Kite: Consultancy; Foghorn: Consultancy; Takeda: Consultancy; Amgen: Consultancy; Seattle Genetics: Consultancy; NewLink Genetics: Consultancy; Forty Seven: Consultancy; Ipsen: Consultancy. Goldhaber: Bayer: Consultancy, Research Funding; Boehringer-Ingelheim: Consultancy, Research Funding; BMS: Research Funding; Boston Scientific BTG EKOS: Research Funding; Daiichi: Research Funding; Janssen: Research Funding; Pfizer: Consultancy, Research Funding; Agile: Consultancy. Piazza: Portola: Research Funding; Bayer: Research Funding; Amgen: Research Funding; BMS: Research Funding; Janssen: Research Funding; BSC: Research Funding. Hobbs: Celgene/Bristol Myers Squibb: Consultancy; Novartis: Consultancy; Merck: Research Funding; Constellation Pharmaceuticals: Consultancy, Research Funding; Bayer: Research Funding; Incyte Corporation: Research Funding; AbbVie.: Consultancy.
39
Aguirre, Luis E. E., Akriti G. Jain, Somedeb Ball, Najla Al Ali, Sara Marie Tinsley-Vance, David A. Sallman, Kendra Sweet, et al. "Triple-Negative Myelofibrosis: Disease Features, Response to Treatment and Outcomes." Blood 138, Supplement 1 (November 5, 2021): 1494. http://dx.doi.org/10.1182/blood-2021-151978.
Full textAbstract:
Abstract Background Myelofibrosis (MF) is the most aggressive subtype among classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Approximately 90% of patients harbor a mutation affecting JAK2, MPL, or CALR which results in constitutive activation of the JAK/STAT pathway, resulting in proliferative and dysfunctional blood cell production, extramedullary hematopoiesis, and constitutional symptoms. Remaining patients are deemed to be "triple-negative" (TN), a designation associated with a poor prognosis. Methods We identified patients with confirmed MF (inclusive of primary MF and MF occurring after essential thrombocythemia or polycythemia vera) treated at Moffitt Cancer Center between 2003-2021. Patients were deemed to be TN if they had tested negative for mutations involving JAK2, MPL and CALR. TN patients were compared to non-TN patients who exhibited a mutation in at least one of these genes. Patients with incompletely driver mutation testing were excluded. Baseline demographic, clinical and molecular characteristics were assessed. Kaplan-Meier method was used to determine overall survival (OS) and leukemia-free survival (LFS). Results 626 patients with a diagnosis of MF were identified, among which 6% (n=38) were confirmed to harbor TN disease. See Table 1 for baseline characteristics of TN vs non-TN patients. Thrombocytopenia was more common in TN disease (28.9% vs 12.2%, p=0.003), as well as elevated EPO titers at baseline (88.9% vs 56.8%, p=0.007). Elevated LDH titers at baseline were less common with TN disease (78% vs 91%, p=0.009). Baseline Hb (p=.009), and % of marrow myeloblasts (p < .005) were lower in the TN cohort. Clinically, there were no differences regarding transfusion dependence, presence of constitutional symptoms or splenomegaly (Table 1). Regarding prognostic scores, patients with TN MF exhibited higher-risk disease per DIPSS+ (65.8% vs 58.1%, p=.034) and GIPSS (62.5% vs 47.1%, p=.001) compared to their non-TN counterparts. There were no significant differences in IPSS, DIPSS+, MIPSS70 or MIPSS70+ stratifications. The median OS (mOS) for the entire population was 82.5 months (95%CI 69.4-95.5). Patients with TN MF had shorter survival rates with a mOS of 37.4 months (95%CI 19.2-55.5) compared to 85.7 mo (95% CI 74.6-96.85) for non-TN disease (p=.009). The rate of transformation to AML was 10.5% for TN MF, 9.7% for JAK2, 7.3% for MPL and 5.2% for CALR MF (TN vs non-TN MF p=0.7). Median LFS was 65.2 mo for CALR, 34.1 mo for TN, 21.9 for JAK2 and 16.9 mo for MPL mutant MF (p = 0.498 for TN vs non-TN phenotypes). Nominally, TN patients had fewer responses (46.2% vs 63.4%) and shorter duration of response to ruxolitinib (8.0 mo vs 12.5 mo), though this did not meet significance (p = 0.21 and 0.5, respectively). There were no differences in response rate to lenalidomide/thalidomide, HMA, HMA/venetoclax (Table 1) Mutations involving SRSF2, SETBP1, IDH2, CBL, and GNAS were significantly enriched in TN disease (see table 2). U2AF1 mutations were more frequently seen in the non-TN cohort (11.2% vs 0%, p=0.032) (Table 2). Conclusion In our independent database of MF, we confirmed the unfavorable prognosis of TN-MF in terms of shorter OS and LFS. While lacking classic driver mutations, TN-MF frequently harbors mutations impacting splicing, epigenetic modification, and signaling that likely drive this aggressive clinical course, and may account for suboptimal responses to JAK inhibition. Figure 1 Figure 1. Disclosures Tinsley-Vance: Taiho: Consultancy; Jazz: Consultancy, Speakers Bureau; Astellas: Speakers Bureau; Fresenius Kabi: Consultancy; Abbvie: Honoraria; Novartis: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Sallman: Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Intellia: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; Magenta: Consultancy; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Membership on an entity's Board of Directors or advisory committees. Sweet: Gilead: Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lancet: ElevateBio Management: Consultancy; Millenium Pharma/Takeda: Consultancy; Celgene/BMS: Consultancy; Agios: Consultancy; Daiichi Sankyo: Consultancy; AbbVie: Consultancy; BerGenBio: Consultancy; Jazz: Consultancy; Astellas: Consultancy. Padron: Stemline: Honoraria; Taiho: Honoraria; BMS: Research Funding; Blueprint: Honoraria; Incyte: Research Funding; Kura: Research Funding. Kuykendall: Prelude: Research Funding; PharmaEssentia: Honoraria; Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; CTI Biopharma: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; BluePrint Medicines: Honoraria, Speakers Bureau; Abbvie: Honoraria; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Komrokji: AbbVie: Consultancy; Geron: Consultancy; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Acceleron: Consultancy; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
40
Malara, Alessandro, Cristian Gruppi, Margherita Massa, Vittorio Rosti, Giovanni Barosi, and Alessandra Balduini. "Plasma EDA Fibronectin in Primary Myelofibrosis Correlates with Bone Marrow Fibrosis and Predicts Splenomegaly." Blood 134, Supplement_1 (November 13, 2019): 1688. http://dx.doi.org/10.1182/blood-2019-130735.
Full textAbstract:
Introduction: Primary myelofibrosis (PMF) is a Philadelphia chromosome negative myeloproliferative neoplasm with adverse prognosis characterized by bone marrow (BM) fibrosis and extramedullary hematopoiesis. Fibronectin (FN) is an extracellular matrix glycoprotein that plays vital roles during tissue repair and regeneration. It exists in different forms. Plasma FN is synthesized by hepatocytes and secreted into the blood plasma, where circulates at a concentration of 300-600 μg/ml in a soluble, compact form. Differently, cellular FN is synthesized by several cell types, such as fibroblasts, endothelial cells, chondrocytes and myocytes. The alternative splicing of EDA and EDB and more complex splicing of the V domain, during transcription of FN1 gene, allows different isoforms of FN to be expressed in a tissue-dependent and temporally regulated manner. Very low levels (1.3-3 μg/ml) of FN containing EDA and/or EDB are present in plasma. Although its function is not well understood, EDA containing FN (EDA-FN) is known to agonize Toll like receptor 4 (TLR4), resulting in NF-κβ-dependent cytokine release; to induce myofibroblast differentiation during wound healing; and to increase agonist-induced platelet aggregation and thrombus formation in vivo. We previously showed that EDA-FN levels are increased in plasma and BM biopsies of PMF patients. Mechanistically, BM EDA-FN sustains megakaryocyte proliferation through TLR4 binding and confer a pro-inflammatory phenotype to cell niches promoting fibrosis progression in Romiplostim-treated mice. In this work we measured the plasma levels of EDA-FN in 104 well characterized patients with PMF to determine whether elevated levels of EDA-FN predict the occurrence of disease-related events. Methods: Plasma circulating EDA FN was measured with an enzyme linked immunosorbent assay developed at the University of Pavia, by our group. We obtained plasma EDA-FN concentration values and health care data of persons with PMF from the data-base of the Centre for the Study of Myelofibrosis at the IRCCS Policlinico S. Matteo Foundation in Pavia. We sequentially excluded persons treated with disease-modifying drugs at any time before or on the date of base-cohort entry, and those who had been splenectomized or had received a stem cell transplant. We also excluded persons with acute inflammatory diseases, autoimmune diseases, other neoplasms, and severe liver or renal dysfunction. For this study we selected everyone giving written informed consent and the study was approved by the local Ethic Committee. Immunofluorescence was performed on spleen sections from PMF patients who underwent splenectomy either because of anemia or symptomatic splenomegaly, or both; and healthy controls that were splenectomized following traumatic lesion of the spleen. Data were analyzed using STATISTICA software. Results: A homozygous JAK2V617F genotype was the major determinant of elevated plasma EDA-FN. Elevated EDA-FN levels were associated with anemia, increased levels of high-sensitivity C-reactive protein, BM fibrosis and splanchnic vein thrombosis at diagnosis. We interpreted these associations as reflecting the role EDA-FN plays in tissue remodeling, inflammation and vascular injury. Interestingly, EDA-FN levels resulted also associated with spleen size, and elevated levels of EDA-FN at diagnosis predicted large splenomegaly (more than 10 cm from the left costal margin) outcome. The evidence that plasma EDA-FN levels were not associated with the CD34+ hematopoietic stem cells mobilization, drove us to hypothesize that EDA-FN could reflect spleen endothelial cell activation and/or neoangiogenesis. Immunofluorescence analysis of spleen specimens from PMF patients and healthy controls revealed that high levels of EDA-FN were present in pathological spleens in strong association with endothelial neoangiogenesis. Conclusions: Quantification of EDA-FN level in PMF strongly correlates with BM fibrosis and may be the first marker of an altered spleen microvasculature that contributes to splenomegaly. Understanding the role of this FN isoform in PMF would be useful for testing new mechanisms of disease progression and new hypotheses about the treatment of splenomegaly in PMF. Disclosures No relevant conflicts of interest to declare.
41
Gisslinger, Heinz, Juergen Thiele, Bettina Gisslinger, Tiina Berg, Martin Schalling, Ashot S. Harutyunyan, Jelena D. Milosevic, et al. "Calreticulin Mutation Status Predicts Improved Disease Outcome in Prefibrotic Primary Myelofibrosis but Not in WHO-Defined Essential Thrombocythemia." Blood 124, no. 21 (December 6, 2014): 3167. http://dx.doi.org/10.1182/blood.v124.21.3167.3167.
Full textAbstract:
Abstract The genomic landscape of myeloproliferative neoplasms (MPNs) has altered dramatically due to the recent discovery of somatic mutations of calreticulin (CALR). This discovery enables for the first time molecular information, in addition to JAK2V617F, to be used in the majority of MPN patients as an affirmative variable to discriminate MPNs from reactive myeloid proliferations. The clinical course of essential thrombocythemia (ET) or primary myelofibrosis (PMF) in patients carrying the CALR mutation was reported to be more indolent than in JAK2 positive patients and was associated with increased survival. Our aim was to investigate whether the impact of CALR expression on prognosis and clinical outcome is different in prefibrotic/early PMF (prePMF) compared to WHO-ET. In a cohort of 348 adult patients with the clinical diagnosis of either ET or PMF mutational analysis for CALR was available. Eligibility criteria for the study included: availability of mutation analysis for JAK2, MPL and CALR; availability of representative, treatment-naive bone marrow biopsy (BM); availability of a histological and clinical consensus on the diagnosis; complete long-term documentation of clinical data and outcome. Consenting clinico-pathological findings in our cohort were consistent with 115 cases showing WHO-ET and 85 patients with prePMF. In comparison to WHO-ET, prePMF revealed minor/borderline age- and gender-matched anemia, slight increase in serum LDH level and leukocyte count, minor to slight splenomegaly, and an occasional left shift in granulo- and erythropoiesis with occurrence of a few myelo-and/or erythroblasts (table 1). An accurate differentiation between both MPN entities was shown to exert a significant difference in terms of overall and relative survival and hematologic transformation into overt PMF and AL. The present study revealed a different CALR mutation frequency in ET in contrast to most of the investigations published recently. We observed CALR mutations in 18% of WHO-ET; JAK2, MPL and CALR wildtype (wt) was observed in 13% of WHO-ET. The discrepancy in the frequencies of CALR positivity in our ET cohort to most of the recently published studies may be due to our strict adherence to the WHO criteria for diagnosis of ET. Regarding prePMF, we observed CALR mutations in 39% of the patients. 92% of the JAK2 and MPL wt subgroup carried the CALR mutation, with JAK2, MPL and CALR wt being observed in only 3% of prePMF. The most remarkable differences between WHO-ET and prePMF were seen in the comparison of the overall survival (figure 1). While the CALR mutation did not have any beneficial influence on survival in WHO-ET, it was associated with a superior overall survival in prePMF. Such a striking difference was not seen at the time of transformation into overt myelofibrosis, and there was only a slightly shorter time to progression to fibrosis in CALR wt prePMFs. There was a trend showing that CALR mutated prePMF patients have shorter thrombosis-free survival compared to CALR wt prePMF patients. There was no impact of the CALR mutations on thrombosis-free survival in WHO-ET. The present data confirm that WHO-ET and prePMF are biologically different sub-entities of MPNs. In prePMF, almost 100% of patients are now associated with a known disease-causing mutation. Our data support the classical clinical approach in the diagnosis of thrombocytosis, using BM histology to differentiate WHO-ET from prePMF and to estimate the outcome of the disease more accurately. Table 1:Total cohort (N=200)WHO-ET (N=115)prePMF (N=85)PAge at diagnosis, years0,04median58,8556,460,7range19-8819-8427-88Sex0,587male784335female1227250Hb, g/dL<0,001median14,114,313,5range8,1-17,68,8-17,68,1-16,6WBC, x109/l0,054median9,258,999,6range4,01-24,544,92-22,34,01-24,54Platelets, x109/l0,739median770770794range78-2530414-249078-2530Palpable splenomegaly<0,001No.51 (12 unk, 1 splenectomy)16 (7 unk, 1 splenectomy)35 (5 unk)%25,513,941,2Fibrotic transformations<0,001No.24 (10 unk)6 (1 unk)18 (9 unk)%125,221,2Thrombotic events0,439No.39 (1 unk)22 (1 unk)17%19,51920prev thrombosis0,042No.503416%2530,418,8JAK2 V617F pos0,08No.1207545%6065,252,9CALR pos0,001No.542133%2718,338,8MPL pos0,189No.844%43,54,7JAK2/MPL/CALR wt0,0029No.18153%9133,5 Figure 1 Figure 1. Disclosures Thiele: AOP Orphan Pharmaceuticals: Consultancy, Honoraria; Incyte Corporation: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Shire: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria.
42
Senyak, Zhenya, Ruben A. Mesa, Nicolaus Kroeger, Koen Van Besien, Wael Saber, Richard T. Silver, Attilio Orazi, et al. "Results from the Myeloproliferative Neoplasm Patient Care Survey: Patient Care Opportunities and Challenges." Blood 132, Supplement 1 (November 29, 2018): 4289. http://dx.doi.org/10.1182/blood-2018-99-113910.
Full textAbstract:
Abstract Background: The myeloproliferative neoplasms (MPNs), including essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) can be characterized by heterogeneous symptoms, disease features, and prognosis. Timely monitoring of blood counts and if needed, referral for discussion of stem cell transplant (SCT), are critical to optimizing survival and quality of life. In connection with the MPN SCT Transplantation Timing Taskforce's (MS3T's) work in developing the DIPPS-based Stem Cell Spectrum Timing Tool, the survey was deployed to explore factors contributing to delayed entry to SCT. National Comprehensive Cancer Network (NCCN) guidelines for MPNs strongly recommend referral to specialized centers with expertise in the management of MPNs (Mesa et. al. 2017). To date, efforts to assess the timing and quality of MPN patient care from the patient's perspective have been minimal. Methods: Patients were recruited from MPN-related Facebook pages, subscribers of MPNforum Magazine and E-mail support groups including the MPN-NET, MPDchat, and the MPN Research Foundation. Hematologists, MPN patients, and advocates constructed the 11-item survey questions and content. The survey was available for patient response between July 4-11th2018. Patients were queried on MPN type, time of diagnosis, and details regarding knowledge of their MPN disease features and care. Data: Demographics.Overall 2382 MPN patients responded to the online survey. Of these, 901 (38%) patients had ET, 865 (36%) had PV, 561 (24%) had MF, 41 (2%) had MPN-unclassifiable or MPN/MDS overlap and 15 (1%) did not respond. Among MF patients, 56% reported having primary MF, 42% secondary MF, 1% prefibrotic MF, and 1% reported having already undergone SCT (1% did not specify type of MF or transplant). The majority of patients were diagnosed with their MPN by a hematology/oncology (77.8%) or family practice (15 %) physician. MPN Care provider and monitoring: Out of all respondents, 35% reported being cared for by an MPN specialist, 36% were not cared for by an MPN specialist and 27% were unsure if their provider was an MPN specialist. Overall less than half (42%) of patients reported having sought a second opinion from an MPN specialist. The majority (87%) of participants knew their mutational status relating to the highly publicized and widely tested JAK2 V617F mutation (73.8%) and CALR (10.2%). However, a statistically insignificant number of patients had any idea of other driving and secondary mutations including MPL, EZH2, SRSF2, IDH1/2 or ASLX-1. Blood counts were reviewed by a hematologist for the majority of patients (93% responded "yes", 4% responded "sometimes", 3% responded "no"). SCT Referral: Among ET and PV, <1% of patients reported being referred to SCT. For MF, 34% of participants reported having been referred for SCT discussion (30% for primary MF and 28% for secondary MF). Conclusions: MPN patients often report receiving care outside of the care of an MPN specialist. Additionally, despite the poor outcomes and higher likelihood of progression to AML, less than a third of patients with secondary MF report being referred for SCT discussion. Independent validation of patient responses, particularly in regards to MPN specialized care and timing of transplant discussion should be investigated further. However, these patient responses suggest many patients may be receiving less than optimal MPN care. These results demonstrate the importance of community hematology/oncology physician and patient education regarding optimal MPN care. Disclosures Mesa: UT Health San Antonio - Mays Cancer Center: Employment; Celgene: Research Funding; Novartis: Consultancy; Incyte Corporation: Research Funding; Pfizer: Research Funding; CTI Biopharma: Research Funding; Genentech: Research Funding; Promedior: Research Funding; NS Pharma: Research Funding; Gilead: Research Funding. Palmer:Novartis: Research Funding. Harrison:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; CTI BioPharma: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau. Verstovsek:Italfarmaco: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Scherber:Gilead: Honoraria.
43
Takagi, Shinsuke, Takashi Mitsuki, Mitsuhiro Yuasa, Kosei Kageyama, Daisuke Kaji, Yuki Taya, Aya Nishida, et al. "Direct Comparison of Long-Term Outcome of Allogeneic Transplantation for Myelofibrosis in Chronic and Leukemic Stage in a Single Institute." Blood 134, Supplement_1 (November 13, 2019): 5382. http://dx.doi.org/10.1182/blood-2019-129859.
Full textAbstract:
INTRODUCTION: Allogeneic hematopoietic cell transplantation provides an opportunity for a cure of myeloproliferative neoplasms (MPNs). Although several studies showed its efficacy even for leukemic transformation (LT) from MPNs, no direct evidence exists which compared the long-term outcome of patients in chronic phase (CP) and LT in a same cohort. METHODS: We retrospectively studied allogeneic hematopoietic cell transplantation for MPNs between 1999 and 2017 in Toranomon Hospital. LT was defined according to the WHO classification in 2016. Risk stratification was according to the dynamic international prognostic scoring system (DIPSS). The spleen index was defined as the measurement of spleen on CT scan. The day of neutrophil and platelet engraftment was defined as the first 3 consecutive days on which the patient's absolute neutrophil and platelet count was >0.5 x 109/L and >20 x 109/L without platelet transfusion, respectively. The study was approved by the ethics committee of Toranomon Hospital (research number #1796), and conducted in accordance with the Declaration of Helsinki. RESULTS: A total of 36 patients were extracted. At transplantation, the disease status of MPN was CP in 16 patients (44%) and LT in 20 (56%). Median spleen index was significantly lower in LT than CP (104 cm2 vs. 150 cm2, p < 0.01), and more CP patients received splenic irradiation before transplantation (p = 0.04). At the start of conditioning regimen, a half of the patients in LT was not in remission even after chemotherapy. Most patients in CP used bone marrow or peripheral blood stem cells, whereas umbilical cord blood (U-CB) was preferred for patients in LT (p < 0.001). Among these 2 cohorts, the cumulative incidence of neutrophil and platelet engraftment was comparable at day 60 and at 1 year after transplantation, respectively (neutrophil engraftment: 87.5% in CP vs. 80.0% in LT, p = 0.11; platelet engraftment: 68.8% in CP vs. 65.0% in LT, p = 0.70). Overall survival (OS) was significantly superior for patients in CP to ones in LT (p = 0.02) (Figure). OS rate at 5 and 10 years after transplantation for patients in CP and LT were 56.2% (95% confidence interval [CI], 1.0 - 35.4) vs. 11.2% (95% CI, 29.5 - 76.2), and 45.0% (95% CI, 17.8 - 69.1) vs. 0%, respectively. Median survival was 7.5 and 0.9 years for patients in CP and LT, respectively. Median follow up of survivors in CP and LT was 1652 days (range, 980 - 5395) and 906 days (range, 522 - 1014), respectively. At 10 years after transplantation, the cumulative incidence of relapse was significantly higher for patients in LT than ones in CP (6.2% in CP vs. 38.0% in LT, p = 0.04). In LT patients, disease recurrence occurred within 3 years after transplantation and 7 out of 17 patients (41%) died of relapse after transplantation. CONCLUSION: To achieve a long-term relapse-free survival, it is crucial for MPN patients to undergo transplantation in chronic phase, not after the development of LT. Delayed decision to transplant may be critical for patients who are at high risk for LT. Figure Disclosures No relevant conflicts of interest to declare.
44
Alsahlawi, Aysha K., Hassan Alkhateeb, Mrinal M. Patnaik, Kebede Begna, Michelle Elliott, William Hogan, Rhett P. Ketterling, Mark R. Litzow, and Aref Al-Kali. "Monosomal Karyotype Predicts Adverse Prognosis In Patients With Chronic Myelomonocytic Leukemia." Blood 122, no. 21 (November 15, 2013): 1334. http://dx.doi.org/10.1182/blood.v122.21.1334.1334.
Full textAbstract:
Abstract Background Chronic myelomonocytic leukemia (CMML) is a clonal hematologic disorder that was classified by the World Health Organization (WHO) as a myelodysplastic/ myeloproliferative overlap disease. Cytogenetic abnormalities have a significant prognostic role in many hematologic neoplasms, but their prognostic value in CMML has been debatable. Recently, monosomal karyotype (MK) has been reported to be a marker of poor prognosis in patients with myelodysplastic syndromes (MDS) and primary myelofibrosis, but its value in CMML is unknown. Aim To study MK effect on clinical outcome for patients diagnosed with CMML Method A retrospective study of all cases diagnosed with CMML at Mayo Clinic Rochester between 1994 to 2011 was performed. Only pts with complete cytogenetic analysis at presentation to our institution were included. MK was defined as the presence of ≥ 2 autosomal monosomies or one autosomal monosomy with at least one structural abnormality (Breems et al, JCO 2008). CK was defined as the presence of at least 3 chromosomal abnormalities. Appropriate IRB approval was obtained in accordance with Helsinki declaration. Comparison between groups’ medians was done using Wilcoxon test, while survival estimates were calculated using Kaplan-Meier curves using JMP V9. Results A total of 262 pts diagnosed with CMML had available cytogenetic data at diagnosis. Median age was 72 years, 176 (67%) were male. Median hemoglobin 10.5 g/dL, white blood cells (wbc) 12 x109/L, platelet 89 x109/L, peripheral blood (PB) blast 0, and bone marrow (BM) blast 4%. CMML2 was seen in 9% while 47% were proliferative (wbc >13). Leukemic transformation was documented in 34 pts (13%). Median overall survival was 513 days. Cytogenetic (CG) analysis was diploid in 167 pts (64%). Trisomy 8 was the most frequent cytogenetic abnormality at 8% (22), followed by complex karyotype (CK) 5% (14), then -7 at 4% (10) and MK 3% (7, six of which were also CK). Comparing pts with diploid CG to other categories indicates: to abnormal CG pts had lower wbc (0.001), PB blasts (p<0.0001), and BM blasts (p=0.0001); to CK pts had lower PB blasts (p=0.003) and higher platelets (p=0.03); to -7 pts had lower wbc (p=0.005), PB blast (p=0.0004), BM blasts (p=0.03) and higher platelets (p=0.03); to +8 pts had lower PB blast (p=0.02) and BM blasts (p= 0.01); no difference was noted when compared to MK. Median OS was statistically significantly worse in MK+ vs MK- (24 vs 527 days, p= 0.002), but not in other comparisons: -7 vs others (250 vs 527 days, p=0.2), CK+ vs CK- (256 vs 527 days, p=0.05), diploid vs others (570 vs 365 days, p=0.1), +8 vs others (312 vs 527 days, p=0.1). Pts with MK+ only or MK+CK+ did worse than CK+ only or other groups (4, 63, 304, 527 days, respectively, p<0.0001). On a multivariate analysis, MK+ (in addition to platelet, BM blast, hemoglobin, and wbc) did have an impact on OS (p=0.0004), while CK+, -7, +8, diploid CG, age, PB blast did not. Conclusion Cytogenetic abnormalities were not frequent findings in pts diagnosed with CMML (36%), but did affect wbc, PB and BM blasts. The most common cytogenetic abnormality was +8 while MK was present at 3% (less than published data in MDS). Only MK predicted statistically significant shorter mOS between all other cytogenetic categories on both univariate and multivariate analysis. This finding needs to be validated by larger cohorts of pts due to its rare occurrence in CMML. Disclosures: No relevant conflicts of interest to declare.
45
Ai, Jing, Valeria Visconte, Ali Tabarroki, Ahmad Zarzour, Christopher Gerace, Karam Al-Issa, Evan Hsi, et al. "Impact of Non-JAK2 Molecular Mutations and Cryptic SNP Lesions in Myelofibrosis Patients Treated with Ruxolitinib." Blood 124, no. 21 (December 6, 2014): 3194. http://dx.doi.org/10.1182/blood.v124.21.3194.3194.
Full textAbstract:
Abstract The identification of the JAK2V617F mutation in myeloproliferative neoplasms (MPN) paved the way for the pivotal studies that led to the FDA approval of a JAK1/2 inhibitor, ruxolitinib (rux) in patients (pts) with myelofibrosis (MF). Improvement in splenomegaly and debilitating disease-related symptoms were the primary clinical responses observed with rux. Although JAK2 mutational status did not impact response/survival in MF pts, cytogenetics had an impact on prognosis. In a related myeloid neoplasm specifically myelodysplastic syndromes, molecular mutations (TET2/DNMT3A) predict for better therapeutic response to DNA methyltransferase inhibitors. We hypothesized that somatic mutations and single nucleotide polymorphism array (SNP-A) lesions are frequent in MF pts treated with rux and may affect their clinical outcomes. To further investigate the predictive and prognostic impact of SNP-A lesions and somatic mutations in MF pts in the rux era, we studied 54 MF pts who received at least 12 weeks of rux therapy (tx) using a modified dose escalation approach (Tabarroki A et al. 55th ASH; Abstract 1586). Clinical (total symptom score [TSS], spleen size), cytogenetic (metaphase cytogenetics [MC], SNP-A), hematologic and survival data were collected before and 12-weeks post rux tx. Categorical data were analyzed using X2 test. A p-value of <.05 was considered statistically significant. Sanger sequencing for genes relevant to myeloid neoplasm pathophysiology like TET2, CBL, LNK, DNMT3A, TP53, SF3B1, U2AF1, SRSF2, ASXL1, EZH2, JAK2, CALR, and IDH1/2 was performed. The median age of the cohort was 66 yrs (41-89); male/female: 28/26. The median follow-up time after initiation of tx was 17 months. The median overall follow-up of the cohort from the time of diagnosis was 35 months. Using DIPSS-plus, pts were stratified as high (24, 44%), int-2 (22, 41%) and int-1 (8, 15%) risk groups. Baseline median WBC=9.4k/μL, Hgb=10.2g/dL, PLT=212k/μl, TSS=20, and median palpable spleen size=13cm. Post-tx median WBC=9.9k/μL, Hgb=10.1g/dL, PLT=150k/μL, TSS=4, and spleen size=6cm. MC identified cytogenetic abnormalities in 24/54 (44.4%) pts. The most frequent chromosomal defects included del(20), +8, and +9. Serial MC was available for 20 pts and no cytogenetic evolution was identified. SNP-A data were available for 29 pts, of which 28 pts had SNP-A lesions. The most commonly involved chromosomes were 9 (15.1%), 20 (14.1%), and 14 (8.5%). Compared to MC analysis, additional SNP-A lesions were found in 66% of pts. Of note 39% of the pts had normal karyotypes but with pathologic SNP-A lesions; another 27% had pathologic SNP-A lesions besides the abnormal MC. Serial SNP-A analysis was available in 10 pts who while on rux tx did not develop any additional/new SNP-A lesion. There was no difference in spleen response rates or TSS between those who carried SNP-A lesions versus those who did not. Molecular analysis was possible for 34 pts. The most frequent somatic mutations observed involved JAK2 (70.6%), ASXL1 (24%), CALR (24%), SRSF2 (15%), and U2AF1 (9%). Pts with int-2 and high DIPSS plus scores were more likely to carry at least 1 mutation in any gene compared to pts with int-1 scores (int-2 vs int-1, p=.05; high vs int-1, p=.06). After a median follow-up of 35 months from diagnosis, 95% of the pts were still alive. 3 pts died from disease progression: 1 had a sole SRSF2 mutation, 1 had an SRSF2 plus CALR mutation, and 1 had a TET2 plus TP53 mutation. SRSF2 mutant pts had more severe thrombocytopenia pre-rux tx (91 vs. 203k/μL; p=.04). ASXL1 mutant pts had increased spleen sizes pre-rux (21 vs. 15cm, p=.06), but had similar response post-rux (10 vs. 8cm, p=0.6) compared to the wild-type. SRSR2 mutant pts had higher DIPSS-plus score (4.4 vs. 3; p=.05). Our study showed that MF pts treated with a rux modified dose escalation approach resulted in meaningful clinical and splenic responses regardless of molecular mutation status. Frequently found cryptic SNP-A lesions in MF pts may explain their poorer outcomes compared to pts with other MPNs. The fact that pts did not acquire additional/new SNP-A lesions during rux tx may be one of the mechanisms of improved survival in these pts. ASXL1, CALR, SRSF2 and U2AF1 were the most frequent non-JAK molecular mutations in MF pts treated with rux and were more frequent in high risk pts. Further studies are necessary to elucidate the clinical/ biological effects of these mutations in MF pts treated with rux. Disclosures Tiu: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees.
46
Takagi, Shinsuke, Kazuhiro Masuoka, Naoyuki Uchida, Mineo Kurokawa, Hirohisa Nakamae, Mitsuru Tsudo, Koji Iwato, Tatsuo Ichinohe, Yoshiko Atsuta, and Akiyoshi Takami. "Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Acute Myeloid Leukemia Transformed from Ph-Negative Myeloproliferative Neoplasm: A Study from the Adult AML Working Group of the Japan Society for Hematopoietic Cell Transplantation (JSHCT)." Blood 124, no. 21 (December 6, 2014): 2547. http://dx.doi.org/10.1182/blood.v124.21.2547.2547.
Full textAbstract:
Abstract BACKGROUND/METHODS: Long-term survivors with Philadelphia chromosome-negative myeloproliferative neoplasms (Ph-neg MPNs) can eventually develop acute myeloid leukemia (AML, i.e. blast transformation). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) can be the only curative treatment for such patients. To clarify its outcome, we retrospectively studied the cases with AML transformed from Ph-neg MPNs using the national registry data of JSHCT. The cases transplanted after 2000 were collected. RESULTS: Thirty-nine cases were extracted (male, n=21; female, n=18). Median age was 57 years (range, 22-71). Underlying Ph-neg MPNs included essential thrombocythemia (ET, n=21), primary myelofibrosis (PMF, n=11) and polycythemia vera (PV, n=7). FAB classification was M0 (n=4), M1 (n=4), M2 (n=10), M3 (n=0), M4 (n=1), M5 (n=3), M6 (n=0), M7 (n=1) and unknown (n=16). Median value of WBC at diagnosis of AML was 8300/uL (250-338000). Karyotype at diagnosis of AML was normal (n=6), complex (n=12), others (n=17) and unknown (n=4). Thirty-two cases (82%) were not in remission at the time of allo-HSCT (1st relapse, n=7; primary induction failure, n=18; untreated, n=12). Median duration between diagnosis of AML and allo-HSCT was 134 days (range, 24-369). The donors were related bone marrow or related mobilized peripheral blood stem cell (rBM/rPBSC, n=8), unrelated bone marrow (uBM, n=15) and unrelated umbilical cord blood (uCB, n=16). Myeloablative conditioning regimens (MAC) were used in 15 cases, and the remaining 24 cases were conditioned by reduced-intensity regimens (RIC), according to CIBMTR definition (Giralt S, et al, 2009). Cumulative incidence of neutrophil engraftment was 74.4% at day 60 (patients engrafted, n=29; death before day 60, n=6; relapse before day 60, n=4). At 2 years after transplant, overall survival (OS) was 29.2%. The median duration of follow up of survivors was 1989.5 days (range, 285-3270). In univariate analysis, age (>57 vs. <57, p=0.87), underlying MPNs (PMF vs. ET vs. PV, p=0.16), disease status at allo-HSCT (CR vs. non-CR, p=0.09), conditioning regimen (MAC vs. RIC, p=0.95) and donor selection (rBM/PBSC vs. uBM vs. uCB, p=0.10) had no impact on OS. The only variable that influenced on OS was chromosome at diagnosis of AML (normal vs. others vs. complex, p=0.02). The cumulative incidence of relapse and non-relapse mortality at 3 years was 34.4% and 38.1%, respectively. CONCLUSION: Although the prognosis of AML transformed from Ph-neg MPNs is dismal in general, the study suggested a promising result that there were curable patients with allo-HSCT. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.
47
Daver, Naval, and Rita Assi. "An Exciting New Era in the Treatment of Myeloproliferative Neoplasms." Oncology & Hematology Review (US) 12, no. 02 (2016): 71. http://dx.doi.org/10.17925/ohr.2016.12.02.71.
Full textAbstract:
Myeloproliferative neoplasms (MPNs), including primary myelofibrosis and myelofibrosis (MF) evolving from a pre-existing MPN (post polycythemia vera- and post essential thrombocythemia-myelofibrosis) are clonal hematopoietic stem cell disorders with heterogeneous symptoms, mutational profile, transformation risk and prognosis. Given the potentially chronic disease course, the goal of therapy in MF is to alleviate associated signs and symptoms, including reduction in spleen size, weight gain, improved performance status, and control of constitutional symptoms, leading to a prolonged survival and reduced transformation to leukemia.
48
Jeryczynski, Georg, Juergen Thiele, Bettina Gisslinger, Maria Theresa Krauth, Martin Schalling, Ana-Iris Schiefer, Ingrid Simonitsch-Klupp, Leonhard Muellauer, and Heinz Gisslinger. "Clinical Impact of Bone Marrow Morphology for the Diagnosis of Essential Thrombocythemia: Comparison Between the British Standards (BCSH) and the WHO Criteria." Blood 126, no. 23 (December 3, 2015): 2816. http://dx.doi.org/10.1182/blood.v126.23.2816.2816.
Full textAbstract:
Abstract Background Accurate diagnosis of essential thrombocythemia (ET) continues to be a challenging issue for both hematopathologists and clinicians. Diagnosis is usually performed by applying either the 2014 British Committee for Standards in Haematology (BCSH) guidelines or the 2008 World Health Organization (WHO) criteria. While the WHO classification requires bone marrow morphology (BM) as a major criterion, the BCSH guidelines allow diagnosis also based solely on clinical symptoms and is more focused on exclusion of the other subtypes of myeloproliferative neoplasia (MPN). However, prefibrotic/early stages of primary myelofibrosis (prePMF) may also present with thrombocytosis, while failing to meet the diagnostic signs and symptoms characterizing overt PMF. Moreover, a small fraction of polycythemia vera (PV) patients may present with low hemoglobin and hematocrit levels, but a platelet count in keeping with BCSH- and WHO-defined ET, thus mimicking phenotypically ET at onset (masked PV). Clinical outcome in prePMF patients is considerably worse than in ET patients, while treatment strategies are likely to change for prePMF patients with the use of interferon-alpha or JAK1/2-inhibitors. Aims The aim of this study was to investigate the prognostic relevance of BM morphology for ET diagnosis as underscored by the WHO classification versus the first set of the BCSH criteria that do not include BM evaluation. Methods A clinic-pathological database including 450 MPN patients was created by clinicians and hematopathologists from a major Austrian center. Treatment-naive BM biopsies were centrally re-reviewed by three of the authors, who were completely blinded to initial data (except for age and gender). Follow-up data, including clinical course and mutation status, were analyzed after the completion of the histopathology review. For purpose of this study we selected two cohorts of ET patients presenting with a sustained platelet count > 450x10^9/L: (1) 209 ET patients in accordance with the diagnostic requirements of the BCSH (A1-A3) that included no BM biopsy examination. (2) 152 patients in strict agreement with the diagnostic guidelines of the WHO including BM biopsy evaluation as major criterion. Both cohorts were compared and analyzed to regarding their presenting clinico-pathological data, driver mutation status, and follow-up. Diagnosis of post-ET myelofibrosis or progression into overt myelofibrosis with myeloid metaplasia was made according to previously published criteria. Results Following the BCSH criteria, 209 patients were diagnosed as ET. When reclassifying those cases according to the WHO criteria including BM morphology examination, 80 (38.3%) patients were diagnosed as prePMF and 14 (6.7%) as PV and two were diagnosed as PMF (0.9%). Comparison of clinical features of BCSH-ET and WHO-ET revealed significant differences in LDH levels and palpable splenomegaly at diagnosis. Fibrosis-free survival was significantly shorter in BCSH-ETs (Fig. 1A) as was overall survival (Fig. 1B). When reclassifying the BCSH cohort according to WHO criteria, progression-free and overall survival were significantly shorter in WHO-confirmed prePMF (Fig. 1C and 1D). Summary/Conclusion The striking differences in outcome are certainly linked with the entry of many prePMF cases in the BCSH-confirmed cohort. The inclusion of these cases, as well as cases with masked PV demonstrates, that BCSH criteria A1-3 may lead clinicians to refrain from performing BM biopsy in patients with elevated thrombocyte counts, which impairs accurate diagnosis with subsequent inadequate management and inferior prognosis. Our results highlight the central role of BM biopsy to achieve accurate diagnosis and differentiation of ET and prePMF. Disclosures Gisslinger: Geron: Consultancy; AOP ORPHAN: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Consultancy; Novartis: Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen Cilag: Honoraria, Speakers Bureau.
49
Luque Paz, Damien, Aurelie Chauveau, Caroline Buors, Jean-Christophe Ianotto, Francoise Boyer, Laura Samaison, Claude Ferec, Cedric Le Marechal, Paul Gueguen, and Valerie Ugo. "Sequential Analysis By Next Generation Sequencing of 18 Genes in Polycythemia Vera and Essential Thrombocythemia Reveals a Association Between Mutational Status and Clinical Outcome after 3-Year Follow-up." Blood 126, no. 23 (December 3, 2015): 2808. http://dx.doi.org/10.1182/blood.v126.23.2808.2808.
Full textAbstract:
Abstract Introduction Myeloproliferative neoplasms (MPN) are molecularly characterized by driver mutations of JAK2, MPL or CALR. Other somatic mutations may occur in epigenetic modifiers or oncogenes. Some of them have been shown to confer a poor prognosis in primary myelofibrosis, but their impact is less known in Polycythemia Vera (PV) and Essential Thrombocythemia (ET). In this study, we investigated the mutational profile using NGS technology in 50 JAK2 V617F positive cases of MPN (27 PV and 23 ET) collected at the time of diagnosis and after a 3 year follow-up (3y). Patients and Methods All patients were JAK2 V617F positive and already included in the prospective cohort JAKSUIVI. All exons of JAK2, MPL, LNK, CBL, NRAS, NF1, TET2, ASXL1, IDH1 and 2, DNMT3A, SUZ12, EZH2, SF3B1, SRSF2, TP53, IKZF1 and SETBP1 were covered by an AmpliseqTM custom design and sequenced on a PGM instrument (Life Technologies). CALR exon 9 mutations were screened using fragment analysis. Hotspots that mutated recurrently in MPN with no sequencing NGS coverage were screened by Sanger sequencing and HRM. A somatic validation was performed for some mutations using DNA derived from the nails. The increase of a mutation between diagnosis and follow-up has been defined as a relative increase of twenty percent of the allele burden. An aggravation of the disease at 3y was defined by the presence of at least one of the following criteria: leukocytosis >12G/L or immature granulocytes >2% or erythroblasts >1%; anemia or thrombocytopenia not related to treatment toxicity; development or progressive splenomegaly; thrombocytosis on cytoreductive therapy; inadequate control of the patient's condition using the treatment (defined by at least one treatment change for reasons other than an adverse event). Results As expected, the JAK2 V617F mutation was found in all patients with the use of NGS. In addition, we found 27 other mutations in 10 genes out of the 18 genes studied by NGS (mean 0.54 mutations per patient). Overall, 29 of 50 patients had only the JAK2 V617F mutation and no other mutation in any of the genes analysed. No CALR mutation was detected. Nine mutations that were not previously described in myeloid malignancies were found. The genes involved in the epigenetic regulation were those most frequently mutated: TET2, ASXL1, IDH1, IDH2 and DNMT3A. In particular, TET2 mutations were the most frequent and occurred in 20% of cases. There was no difference in the number or in the presence of mutations between PV and ET. At 3y, 4 mutations appeared in 4 patients and 15 out of 50 patients (9 PV and 6 ET) were affected by an allele burden increase of at least one mutation. At 3y, 24/50 patients suffered an aggravation of the disease as defined by the primary outcome criterion (16 PV and 8 ET). The presence of a mutation (JAK2 V617Fomitted) at the time of the diagnosis was significantly associated with the aggravation of the disease (p=0.025). Retaining only mutations with an allele burden greater than 20%, the association with disease aggravation is more significant (p=0.011). Moreover, a mutation of ASXL1, IDH1/2 or SRSF2, which is a poor prognostic factor in primary myelofibrosis, was found in 8 patients, all having presented an aggravation of their disease (p=0.001). Only 4 patients had more than one somatic mutation other than JAK2 V617F and all of them also had an aggravation at 3y (p=0.046). In this cohort, appearance of a mutation at 3y was not associated with the course of the disease. Conversely, the increase of allele burden of at least one mutation was associated with an aggravation (p=0.019). Discussion and conclusion Despite the short follow-up and the limited number of patients, this study suggests that the presence of additional mutations at the time of the diagnosis in PV and TE is correlated to a poorer disease evolution. The increase of mutation allele burden, which reflects clonal evolution, also seems to be associated with the course of the disease. These results argue for a clinical interest in large mutation screening by NGS at the time of the diagnosis and during follow-up in ET and PV. Disclosures Ugo: Novartis: Membership on an entity's Board of Directors or advisory committees, Other: ASH travel.
50
Aguirre, Luis E., Akriti G. Jain, Somedeb Ball, Najla Al Ali, Sara Marie Tinsley-Vance, David A. Sallman, Kendra Sweet, et al. "Clinico-Molecular Features and Treatment Outcomes in Primary Myelofibrosis Phenotypes with Protracted Disease Dynamics." Blood 138, Supplement 1 (November 5, 2021): 2571. http://dx.doi.org/10.1182/blood-2021-152026.
Full textAbstract:
Abstract Background Primary myelofibrosis (PMF) is the most aggressive subtype among classical BCR-ABL1 negative myeloproliferative neoplasms (MPN). Driven by constitutive activation of the JAK/STAT pathway, its prognosis is defined by cardinal clinical, cytogenetic and molecular features. While most patients require therapy for symptomatic splenomegaly, disease-related symptoms, or cytopenias, asymptomatic lower-risk patients may be appropriately monitored with active surveillance. The aim of this study was to explore disease characteristics and outcomes among pts who remained on prolonged active surveillance compared to those who received early treatment. Methods We identified patients with confirmed MF (inclusive of primary MF and MF occurring after essential thrombocythemia or polycythemia vera) treated at Moffitt Cancer Center between 2003-2021. Patients were stratified into two cohorts: those remaining on active surveillance for ≥ 36 months following diagnosis and those who received within 36 months of diagnosis. Results Between August 2000 and March 2021, we identified 626 patients with a diagnosis of MF. Among these, 48 (8%) did not receive treatment for at least 3 years. Table 1 summarizes the baseline characteristics comparing those pts who remained on active surveillance for ≥ 36 months (LTO-MF) to those who received treatment within 36 months of diagnosis (ET-MF). The LTO cohort presented at a younger age (median age 63 vs 68; p = 0.001), but otherwise demographic variables were balanced between the two cohorts. LTO patients were more likely to have primary MF (85.4% vs 60.9%, p=0.003). LTO patients were less likely to have leukocytosis (28.2% vs 49.9%, p=0.01), and constitutional symptoms (29.8% vs 44.6%, p=0.05), while having a higher reticulocyte percentage (81.4% vs 64.1%, p=0.02). LTO patients also had lower platelet counts (mean: 274k vs 359k, p=0.006), lower percentage of circulating blasts (0.4% vs 1.2%, p<0.001), and lower percentage of marrow myeloblasts (1.3% vs 1.9%, p<0.001) at baseline. Cohorts had comparable rates of anemia, thrombocytopenia, transfusion dependence, LDH levels and splenomegaly at baseline. Interestingly, the cohorts were well-balanced in terms of risk score based across all major prognostic scoring systems: IPSS (p=0.356), DIPSS (p=0.764), DIPSS+ (p=0.148), GIPSS (p=0.125), MIPSS70 (p=0.924) and MIPSS70+ (p=0.407). There was no association between GPSS karyotype risk and need to start treatment earlier (p=0.481) (Table 1). LTO patients were less likely to harbor JAK2 mutations (58.3% vs 72.4%, p=0.04). No significant differences were seen regarding CALR (p=0.144), MPL (p= 0.271), or triple-negative disease (p=0.521) (Table 2). The median OS (mOS) for the entire population was 82.5 months (95%CI 69.4-95.5). LTO patients had longer OS (mOS 170.3 mo vs 63.9 mo; (p<0.001). Rates of transformation to blast phase were comparable (6.2% vs 9.7%;p=0.441), but median time to blast phase transformation was longer for LTO MF: 66.3 mo vs 29 mo, p=0.011). Expectedly, time to first treatment longer for LTO patients (62.1 mo vs 0.9 mo; (p<0.001). No differences were noted between cohorts in terms of response to ruxolitinib, duration of response to ruxolitinib or response to lenalidomide/thalidomide (p = 0.91, 0.90, 0.83, respectively) Conclusion In this single-center study of patients seen at a tertiary referral center, the vast majority of MF patient required treatment within 36 months of diagnosis. Those monitored with active surveillance were younger, had less proliferative signs/symptoms, were less likely to have JAK2 mutations, and more favorable outcomes. Figure 1 Figure 1. Disclosures Tinsley-Vance: Fresenius Kabi: Consultancy; Novartis: Consultancy; Incyte: Consultancy, Speakers Bureau; Abbvie: Honoraria; Jazz: Consultancy, Speakers Bureau; Taiho: Consultancy; Celgene/BMS: Consultancy, Speakers Bureau; Astellas: Speakers Bureau. Sallman: Magenta: Consultancy; Takeda: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Aprea: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees; Intellia: Membership on an entity's Board of Directors or advisory committees. Sweet: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees. Lancet: AbbVie: Consultancy; BerGenBio: Consultancy; ElevateBio Management: Consultancy; Celgene/BMS: Consultancy; Daiichi Sankyo: Consultancy; Astellas: Consultancy; Agios: Consultancy; Millenium Pharma/Takeda: Consultancy; Jazz: Consultancy. Padron: Incyte: Research Funding; BMS: Research Funding; Taiho: Honoraria; Kura: Research Funding; Blueprint: Honoraria; Stemline: Honoraria. Kuykendall: Novartis: Honoraria, Speakers Bureau; Incyte: Consultancy; BluePrint Medicines: Honoraria, Speakers Bureau; Protagonist: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Prelude: Research Funding; PharmaEssentia: Honoraria; Abbvie: Honoraria; Celgene/BMS: Honoraria, Speakers Bureau; CTI Biopharma: Honoraria. Komrokji: AbbVie: Consultancy; Geron: Consultancy; Acceleron: Consultancy; BMSCelgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Taiho Oncology: Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees.