Journal articles on the topic 'Predicting molecular response in CML'
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Wolf, Dominik, and Sieghart Sopper. "Molecular response prediction in CML: novel ideas?" Oncotarget 8, no. 46 (September 19, 2017): 80105–6. http://dx.doi.org/10.18632/oncotarget.21049.
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Wolf, Dominik, and Sieghart Sopper. "Correction: Molecular response prediction in CML: novel ideas?" Oncotarget 9, no. 88 (November 9, 2018): 35871. http://dx.doi.org/10.18632/oncotarget.26360.
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Attili, S. V., P. Bapsy, D. Lokanatha, K. Govindababu, J. George, L. A. Jacob, H. K. Dadhich, and G. Anupama. "Are skin reactions a surrogate marker in predicting response to therapy in patients with chronic myeloid leukemia receiving imatinib?" Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 17539. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.17539.
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17539 Background: One of the common toxicities observed with small molecule tyrosine kinase inhibitors are skin rashes, which were proven to predict the response to therapy in cases of lung cancer (Ann. Onc., 2005; 16(5): 780 - 785). However, very few have evaluated the same in patients with chronic myeloid leukemia (CML) on treatment with imatinib. Therefore we thought of doing a prospective study to evaluate skin rashes, and compare it with the clinical, hematological, cytogenetic and molecular remission rates in CML patients on Imatinib therapy. Methods: It is a non randomized, prospective study conducted at a tertiary care cancer center with an approximate attendance of 15,000 new cases. The patients were stratified into those who had skin reactions and do not. CTC version 3.0 was used to assess the skin toxicity. Differences in the proportions were calculated with the help of Medcalc Version 7.5. Results: A total of 314 patients with CML were evaluated who were on regular treatment with Imatinib. Hematological response was assessed monthly, cytogenetic analysis (available in 212 patients) at the end of 3rd month and molecular response (available in 136 patients) at the end of 6th months respectively. The response rates in two groups are as follows. *Percentages calculated for the subset of patients in whom results of either cytogenetic or molecular response are available Conclusion: Our findings suggest that skin reactions are not a good marker to predict either response rates or progression free interval in cases of CML. This is further substantiated by the findings that the percent of skin reactions in west are far less compared to our results, who had a better molecular as well as cytogenetic responses. [Table: see text] No significant financial relationships to disclose.
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Hu, Shiwei, Dan Chen, Xiaofei Xu, Lan Zhang, Shengjie Wang, Keyi Jin, Yan Zheng, Xiaoqiong Zhu, Jie Jin, and Jian Huang. "Targeted Next-Generation Sequencing Identifies Additional Mutations Other than BCR∷ABL in Chronic Myeloid Leukemia Patients: A Chinese Monocentric Retrospective Study." Cancers 14, no. 23 (November 23, 2022): 5752. http://dx.doi.org/10.3390/cancers14235752.
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A proportion of patients with somatic variants show resistance or intolerance to TKI therapy, indicating additional mutations other than BCR∷ABL1 may lead to TKI treatment failure or disease progression. We retrospectively evaluated 151 CML patients receiving TKI therapy and performed next-generation sequencing (NGS) analysis of 22 CML patients at diagnosis to explore the mutation spectrum other than BCR∷ABL1 affecting the achievement of molecular responses. The most frequently mutated gene was ASXL1 (40.9%). NOTCH3 and RELN mutations were only carried by subjects failing to achieve a major molecular response (MMR) at 12 months. The distribution frequency of ASXL1 mutations was higher in the group that did not achieve MR4.0 at 36 months (p = 0.023). The achievement of MR4.5 at 12 months was adversely impacted by the presence of >2 gene mutations (p = 0.024). In the analysis of clinical characteristics, hemoglobin concentration (HB) and MMR were independent factors for deep molecular response (DMR), and initial 2GTKI therapy was better than 1GTKI in the achievement of molecular response. For the scoring system, we found the ELTS score was the best for predicting the efficacy of TKI therapy and the Socal score was the best for predicting mutations other than BCR∷ABL.
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Glauche, Ingmar, Christoph Baldow, Sabine Fröhlich, Philipp Schulze, Amit Roy, Milayna Subar, Xiaoning Wang, and Ingo Roeder. "Model-Based Characterization of the Molecular Response Dynamics of Tyrosine Kinase Inhibitor (TKI)-Treated CML Patients – a Comparison of Imatinib and Dasatinib First-Line Therapy." Blood 124, no. 21 (December 6, 2014): 4562. http://dx.doi.org/10.1182/blood.v124.21.4562.4562.
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Abstract Background: Chronic myeloid leukemia (CML) is characterized by the expression of the BCR-ABL fusion protein in virtually all malignant cells in the vast majority of patients. This molecular specificity forms the basis of a highly efficient, targeted therapy by TKIs. The success of this therapeutic approach is the reason that CML has developed into a showcase example for an efficient, targeted tumor therapy. Methods: As previously shown, the application of a single-cell–based mathematical model, which describes CML as a clonal competition between normal and leukemic hematopoietic stem cells, can consistently describe the median long-term BCR-ABL transcript levels in response to the first-generation TKI imatinib [1]. Furthermore, it has been demonstrated that a similar modeling approach also allows predicting the molecular long-term response to imatinib in individual patients [2]. Specifically, we showed that these predictions, including the determination of an optimal, patient-specific time point for potential treatment cessation, can be derived directly from time course data of the BCR-ABL transcript levels. Here we present novel results on the application of a similar analysis strategy for CML patients, treated with the second-generation TKI dasatinib. Based on unpublished data describing the 4-year molecular response dynamics (ie, BCR-ABL transcript levels) observed in a randomized, controlled clinical trial (DASISION [3]), we directly compare the effects of dasatinib (n=253) and imatinib (n=255). Results: These data show an accelerated and deeper median molecular response in the dasatinib arm (Figure 1). We confirmed this observation by statistical analysis, describing the BCR-ABL response kinetics by a bi-phasic exponential model. Comparing different characteristic parameters of this model, we could demonstrate a significantly steeper initial decline in the dasatinib arm compared to imatinib (P < 0.001, t-test on mean initial decline). Beyond the statistical analysis, we apply the above-mentioned single-cell–based mathematical model. Adapting its parameters to the specific kinetic characteristics observed under the different treatment conditions, model predictions for both the population and individual patients are derived for both treatment scenarios. In our presentation we will compare the model predictions of long-term BCR-ABL kinetics under first line imatinib and dasatinib treatment. The population and patient-specific model predictions will include BCR-ABL levels in the peripheral blood and bone marrow, as well as the estimated risk of molecular relapses after stopping treatment and, related to this, optimal time points for potential treatment cessation. Conclusion: Our analysis suggests that the application of model-prediction tools, previously used for the first-generation TKI imatinib, can be applied to other TKIs. The steeper initial decline in the dasatinib arm may be relevant in estimating relapse risk, which will be determined from long-term outcome of ongoing discontinuation trials. [1] Roeder I et al. (2006) Nat. Med. [2] Horn M et al. (2013) Blood. [3] Cortes JE et al. ASH 2013, Abstract #653. Figure 1: Observed median molecular response dynamics of TKI-treated CML patients. Error bars represent inter-quartile ranges. Figure 1:. Observed median molecular response dynamics of TKI-treated CML patients. Error bars represent inter-quartile ranges. Disclosures Glauche: Bristol-Myers Squibb: Research Funding. Fröhlich:Bristol-Myers Squibb: Employment. Roy:Bristol-Myers Squibb: Employment, Equity Ownership. Subar:Bristol-Myers Squibb: Employment. Wang:Bristol-Myers Squibb: Employment.
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Dybko, Jarosław, Bożena Jaźwiec, Olga Haus, Donata Urbaniak-Kujda, Katarzyna Kapelko-Słowik, Tomasz Wróbel, Tomasz Lonc, et al. "The Hasford Score May Predict Molecular Response in Chronic Myeloid Leukemia Patients: A Single Institution Experience." Disease Markers 2016 (2016): 1–5. http://dx.doi.org/10.1155/2016/7531472.
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The Sokal, Hasford, and EUTOS scores were established in different treatment eras of chronic myeloid leukemia (CML). None of them was reported to predict molecular response. In this single center study we tried to reevaluate the usefulness of three main scores in TKI era. The study group included 88 CML patients in first chronic phase treated initially with standard imatinib dose. All of them achieved major molecular response (MMR) in time points defined by European LeukemiaNet (ELN). 42 patients lost MMR in a median time of 47 months and we found a significant difference in MMR maintenance between intermediate-risk (IR) and low-risk (LR) patients assessed by Hasford score. All 42 patients were switched to second-generation TKI (2G-TKI) treatment. At 18 months of 2G-TKI therapy we have still found a significant difference in BCR-ABL transcript levels and MMR rate between IR and LR groups. We did not find any of the described differences discriminating patients by Sokal or EUTOS score. In this retrospective single center analysis we found Hasford score to be useful in predicting molecular response in first chronic phase of CML patients.
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Banjar, Haneen R., and Enaam Alsobhi. "Consistency Test between Scoring Systems for Predicting Outcomes of Chronic Myeloid Leukemia in a Saudi Population Treated with Imatinib." International Scholarly Research Notices 2017 (February 13, 2017): 1–6. http://dx.doi.org/10.1155/2017/1076493.
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Inconsistency in prognostic scores occurs where two different risk categories are applied to the same chronic myeloid leukemia (CML) patient. This study evaluated common scoring systems for identifying risk groups based on patients’ molecular responses to select the best prognostic score when conflict prognoses are obtained from patient profiles. We analyzed 104 patients diagnosed with CML and treated at King Abdulaziz Medical City, Saudi Arabia, who were monitored for major molecular response (achieving a BCR-ABL1 transcript level equal to or less than 0.1%) by Real-Time Quantitative Polymerase Chain Reaction (RQ-PCR), and their risk profiles were identified using Sokal, Hasford, EUTOS, and ELTS scores based on the patients’ clinical and hematological parameters at diagnosis. Our results found that the Hasford score outperformed other scores in identifying risk categories for conflict groups, with an accuracy of 63%.
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Haznedaroglu, Ibrahim C. "MONITORING THE RESPONSE TO TYROSINE KINASE INHIBITOR (TKI) TREATMENT IN CHRONIC MYELOID LEUKEMIA (CML)." Mediterranean Journal of Hematology and Infectious Diseases 6, no. 1 (December 31, 2013): e2014009. http://dx.doi.org/10.4084/mjhid.2014.009.
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The aim of oral tyrosine kinase inhibitor (TKI) treatment in chronic myeloid leukemia (CML) is to get ideal hematological, cytogenetic, molecular responses at the critical time-points. The depth of the response obtained with TKI and time to achieve this response are important for the prediction of prognosis in the patient with CML. The high efficacy of the TKI treatment of CML has prompted the need for accurate methods to monitor response at levels below the landmark of CCyR. Quantification of BCR-ABL transcripts has proven to be the most sensitive method available and has shown prognostic impact with regard to progression-free survival. European LeukemiaNet (ELN) molecular program harmonized the reporting of results according to the IS (Internatıonal harmonization of Scale) in Europe. The aim of this review is to outline monitoring the response to optimal TKI treatment based on the ELN CML 2013 recommendations from the clinical point of view as a physician. Careful cytogenetic and molecular monitoring could help selecting the most convenient TKI drug and to optimize TKI treatment. Excessive monitoring may have an economical cost but failure to optimize TKI treatment may result in CML disease acceleration and death.
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Sopper, Sieghart, Satu Mustjoki, Deborah White, Timothy Hughes, Peter Valent, Andreas Burchert, Bjørn T. Gjertsen, et al. "Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia." Journal of Clinical Oncology 35, no. 2 (January 10, 2017): 175–84. http://dx.doi.org/10.1200/jco.2016.67.0893.
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Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry–based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α–converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.
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de Lavallade, Hugues, Jane F. Apperley, Jamshid S. Khorashad, Dragana Milojkovic, Alistair G. Reid, Marco Bua, Richard Szydlo, et al. "Imatinib for Newly Diagnosed Patients With Chronic Myeloid Leukemia: Incidence of Sustained Responses in an Intention-to-Treat Analysis." Journal of Clinical Oncology 26, no. 20 (July 10, 2008): 3358–63. http://dx.doi.org/10.1200/jco.2007.15.8154.
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Purpose Imatinib is remarkably effective in treating newly diagnosed patients with chronic myeloid leukemia (CML) in chronic phase (CP). To date, most of the available data come from a single multicenter study in which some of the patients were censored for diverse reasons. Here, we report our experience in treating patients at a single institution in a setting where all events were recorded. Patients and Methods A total of 204 consecutive adult patients with newly diagnosed CML in CP received imatinib from June 2000 until August 2006. Response (hematologic, cytogenetic, and molecular), progression-free survival (PFS) and survival were evaluated. Results At 5 years, cumulative incidences of complete cytogenetic response (CCyR) and major molecular response (MMR) were 82.7% and 50.1%, respectively. Estimated overall survival and PFS were 83.2% and 82.7%, respectively. By 5 years, 25% of patients had discontinued imatinib treatment because of an unsatisfactory response and/or toxicity. The 5-year probability of remaining in major cytogenetic response while still receiving imatinib was 62.7%. Patients achieving a CCyR at 1 year had a better PFS and overall survival than those failing to reach CCyR, but achieving a MMR conferred no further advantage. The identification of a kinase domain mutation was the only factor predicting for loss of CCyR. Conclusion Imatinib is highly effective in most patients with CML-CP; patients who respond are likely to live substantially longer than those treated with earlier therapies. Achieving CCyR correlated with PFS and overall survival, but achieving MMR had no further predictive value. However, approximately one third of patients still need better therapy.
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Cea, Michele, Antonia Cagnetta, Gabriella Cirmena, Anna Garuti, Ilaria Rocco, Claudia Palermo, Ivana Pierri, et al. "Hedgehog Signaling Is Useful as a Novel Molecular Marker for Predicting Relapse and Resistance During Chronic Myeloid Leukemia Treatment." Blood 116, no. 21 (November 19, 2010): 1215. http://dx.doi.org/10.1182/blood.v116.21.1215.1215.
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Abstract Abstract 1215 Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder characterized by the expansion of a Leukemic Stem Cell (LSC) clone carrying a Philadelphia translocation, which outgrows the non-malignant haematopoietic stem cells. The tyrosine kinase inhibitors (TKIs) imatinib, nilotinib and dasatinib, are the gold standard for CML treatment since each one shows an impressive rates of complete cytogenetic and molecular response in chronic phase (CP) CML. However the major problem concerning the final efficacy of TKIs therapy is that the majority of responding CP CML patients have detectable BCR-ABL transcripts which might arise from a population of quiescent CML LSC not effectively targeted by TKIs. Therefore the molecular monitoring not always provide a sufficiently precise evaluation of patients to allow the appropriate choice of clinical interventions. Accordingly, it is necessary to monitor the appearance and increase of LSCs to identify and to treat quickly the fundamental responsible for relapse. Thus, we focused Hedgehog (Hh) signalling which has been proved essential for maintenance of cancer stem cells in myeloid leukaemia. Notably recent studies reported that the expansion of BCR-ABL positive leukemic stem cell is dependent on Hh pathway activation. Here, we analyzed the mRNA levels of Smoothened (SMO), a seven-transmembrane domain receptor protein, and Ptch1, a surface receptor regulator of SMO, in 20 CP-CML patients (8 High, 4 Intermediate and 8 Low Sokal Risk respectively) at diagnosis and during the follow-up. Using RT-PCR, in diagnosis setting, we proved that 60% of patients (bone marrow samples) showed Hh signalling significantly activated compared to CD34+ cells from healthy donors. In detail 75% (6/8) of High Sokal Risk CML patients showed an up-regulation of Smo and a down-regulation of Ptch1 mRNA levels, suggestive of active Hh signalling at diagnosis. Conversely Low and Intermediate Sokal Risk CML patients did not show features of Hh activation. Finally we monitored, during the follow-up, the mRNA levels of Smo and Ptch1 together with BCR-ABL to assess the kind of relationship between these parameters. Interestingly we noticed a direct correlation between the increase of BCR-ABL mRNA levels and signs of Hh activity (Smo mRNA increase level and Ptch1 mRNA decrease level). Characteristically, molecular monitoring highlighted that all patients developing resistance to TKIs treatment, showed a tendency to Hh activation (high and low mRNA levels of Patch1 and Smo respectively) few months before the development of Abl KD mutation (10/10). Typically this last behaviour was more evident in patients developing the gatekeeper mutation T315I. Finally, in accordance with published data, we noted that the pharmacological inhibition of Hh signalling impairs the growth of TKIs resistant human CML cell line BaF/T315I, suggesting a novel treatment option. All our data provide molecular evidence for a role of the stemness pathway to predict quickly both the relapse and the TKIs resistance during CML treatment. Therefore, we propose to use Ptch1 and Smo mRNA levels together with BCR-ABL for the molecular monitoring of CP CML. Disclosures: No relevant conflicts of interest to declare.
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Michimata, Daigo, Kazunori Murai, Yasuro Miyairi, Yoshiaki Okano, Yuuzou Suzuki, Hiroyuki Hamada, Akiyoshi Sato, et al. "The Relationship between Molecular Response of BCR-ABL1 Transcripts within 6 Months and Deep Molecular Response at 18 Months to Dasatinib Treatment for Newly Diagnosed Patients with CML-CP." Blood 134, Supplement_1 (November 13, 2019): 2928. http://dx.doi.org/10.1182/blood-2019-125066.
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BACKGROUND: The overall survival of patients with newly diagnosed chronic myeloid leukemia (CML) has improved significantly since the introduction of tyrosine kinase inhibitors (TKIs), and recently, some patients with CML who achieve stable deep molecular response (DMR) to TKI therapy could safely suspend treatment. In addition to European LeukemiaNet criteria (ELN), the European Society for Medical Oncology (ESMO) proposed that less than 0.01% of BCR-ABL1 transcript (MR4.0) on the International Scale (IS) after 18 months is optimal for patients to achieve treatment-free remission. Branford et al. indicated that major molecular response (MMR; less than or equal to 0.1% of BCR-ABL1 IS ; MR3.0) at three months predicts stable undetectable BCR-ABL1 transcript levels during imatinib treatment. However, second-generation TKIs induce more rapid and deeper responses at early time points compared to imatinib; however, whether early molecular response predicts MR4.0 by 18 months to second-generation TKI therapy, remains unclear. AIMS: We retrospectively analyzed BCR-ABL1 transcript levels in patients with CML in chronic phase (CML-CP) at 3, 6, 12, and 18 months after initiating dasatinib treatment to identify molecular milestones that would predict MR4.0 by 18 months. METHODS: Fifty-nine newly diagnosed patients with CML-CP were included in this study. The median age was 61 years (18-81 years), 72% of whom were males, and patients older than 65 years comprised 31% of the overall enrollment. Eighty-six percent of them had low and intermediate Sokal scores. Patients received 100 mg of dasatinib once daily. Dose interruption or reduction was allowed if drug-related grade 3 non-hematological toxicity or grade 3 or worse hematological toxicity occurred.BCR-ABL1/ ABL ratio IS (BCR-ABL1 IS) was performed at approximately 3-month intervals. To assess the kinetics of response, we calculated halving time (HT) of BCR-ABL1 IS. HT-BCR-ABL1 was calculated as described by Branford et al. We used a receiver-operating characteristic (ROC) curve to identify the cut-offs in transcript levels at three and six months. Mann-Whitney test was used to determine statistical significance. Categorical variables were compared using Fisher's exact test. Factors were subjected to multivariate analysis using Cox regression; differences with p<0.05 were considered statistically significant. RESULTS: The median BCR-ABL1 IS level before therapy was 82.1% (range 13.5-157.9 %). The estimated MMR by 12 months and MR4.0 by 18 months were 86.4% and 50.8%, respectively. We analyzed each into a cohort that achieved MR4.0 by 18 months (MR4.0 cohort) and a cohort that did not achieve MR4.0 (non-MR4.0 cohort). The BCR-ABL1 IS level in each cohort is indicated in the Table. Median HT-BCR-ABL1 IS 0-3 months was 10.8 days (6.5-71.3 days) in MR4.0 cohort, and 13.0 days (8.5- 169.6 days, p<0.05) in non-MR4.0 cohort, whereas that of 3-6 months was 24.4 days (6.5-228.9 days) in MR4.0 cohort and 47.3 days (18.0- 154.9 days, p<0.01) in non-MR4.0 cohort. The shape of BCR-ABL1 IS descent was biphasic in MR4.0 cohort. The cut-off values of BCR-ABL1 IS at 3 months and 6 months for prediction of MR4.0 by 18 months were 0.122% (specificity 0.964, sensitivity 0.586, AUC 0.784) and 0.048% (0.852, 0.833, 0.909), respectively. We determined the optimal threshold for predicting MR4.0 by 18 months using these parameters. Some of them (BCR-ABL1 IS 3 months ≤0.122%,BCR-ABL1 IS 6 months ≤ 0.048%, BCR-ABL1 IS 6 months ≤1%: ELN optimal criteria) were identified as predictive cut-off values for MR4.0 by 18 months in univariate analysis (BCR-ABL1 IS 3 months ≤0.122%; 94.4% vs. 30.7%, p<0.01, BCR-ABL1 IS 6 months ≤ 0.048%; 85.7% VS. 20.7%, p<0.01 and BCR-ABL1 IS 6 months <1.0%; 58.8% vs. 0%, p<0.01). However, BCR-ABL1 IS 3 months ≤ 10% (ELN optimal criteria at three months) was not identified as predictive cut-off value for MR4.0 (54.7% vs. 20%, N.S.). Multivariate analysis indicated that BCR-ABL1 IS 6 months ≤ 0.048% was a significant independent factor for achievement of MR4.0 by 18 months (hazard ratio 0.05, p<0.01). CONCLUSION: Even though dasatinib is highly-priced, dasatinib treatment results in higher rates of molecular responses in newly diagnosed patients with CML-CP. Assessment of molecular reduction within six months has become an important landmark to predict MR4.0 by 18 months during dasatinib treatment for patients with the aim to achieve treatment-free remission. Disclosures Oyake: Astellas: Speakers Bureau; Celgene: Honoraria; Chugai: Honoraria; Kyowa-Hakko Kirin: Honoraria. Ito:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Ono: Honoraria.
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White, Deborah, Verity Saunders, A. Bruce Lyons, Susan Branford, Andrew Grigg, L. Bik To, and Timothy Hughes. "In vitro sensitivity to imatinib-induced inhibition of ABL kinase activity is predictive of molecular response in patients with de novo CML." Blood 106, no. 7 (October 1, 2005): 2520–26. http://dx.doi.org/10.1182/blood-2005-03-1103.
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AbstractMost patients with de novo chronic myeloid leukemia (CML) achieve good responses to imatinib, but the rate and degree of molecular response is variable. We assessed the inhibitory concentration 50% for imatinib (IC50imatinib) in 62 patients with de novo chronic-phase CML as a predictor of molecular response. IC50imatinib was determined in pretherapy blood samples by measuring the in vitro imatinib-induced reduction of the phosphorylated form of the adaptor protein Crkl (CT10 regulator of kinase like). There was marked variability between patients, with IC50imatinib ranging from 0.375 to 1.8 μM (median, 0.6 μM). Patients with low IC50imatinib (IC50 ≤ 0.6 μM; n = 36) had a 36% probability of achieving 2-log reduction in BCR-ABL (breakpoint cluster region-abelson) by 3 months compared with 8% in patients with high IC50imatinib (n = 26) (P = .01). The IC50imatinib was also predictive of molecular response at 12 months, with 47% of patients in the low IC50imatinib group achieving 3-log reduction and 23% in the high IC50imatinib group (P = .03). The predictive power of IC50imatinib was particularly strong in patients with low Sokal scores. These data provide strong evidence that intrinsic sensitivity to imatinib is variable in previously untreated patients with CML, and the actual level of BCR-ABL kinase inhibition achieved is critical to imatinib response. The IC50imatinib potentially provides a new prognostic indicator for molecular response in patients treated with imatinib. (Blood. 2005; 106:2520-2526)
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Lee, Ha Yeon, Su Jin Lee, Boram Ha, Jun Ho Yi, Chul Won Jung, Dae-Young Kim, Je-Hwan Lee, et al. "Multicenter Retrospective Study on the Development of Peripheral Lymphocytosis During Second-Line Dasatinib Therapy for Chronic Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 2275. http://dx.doi.org/10.1182/blood.v116.21.2275.2275.
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Abstract Abstract 2275 Background: Dasatinib is known to induce large granular lymphocyte (LGL) expansion, which correlates with better clinical efficacy. The current retrospective study attempted to investigate the incidence of lymphocytosis following second-line dasatinib therapy in chronic myeloid leukemia (CML) and to analyze the clinical factors predictive of the development of lymphocytosis, as well as association with treatment outcomes. Method: Fifty CML patients who failed imatinib treatment and received dasatinib for 3 months or more, were enrolled from 9 centers in the Republic of Korea. The cumulative incidence of lymphocytosis was assessed, and cytogenetic and molecular response, treatment failure, loss of response, progression to advanced disease, and survival were evaluated and analyzed according to the development of lymphocytosis. Results: After a median of 17 months of dasatinib therapy, complete cytogenetic (CCR) and major molecular response (MMR) was noted in 23 and 16 patients, respectively. Twenty three patients (46%) developed lymphocytosis following dasatinib therapy (median onset 4 months). No clinical predictive factor for the development of lymphocytosis was found. The cytogenetic response was significantly better in the group that developed lymphocytosis (LC+), as compared to the group without lymphocytosis (LC-); the LC+ group showed a higher complete cytogenetic response (CCyR; 78.3% vs. 29.6%, p=0.001) and major molecular response (MMR; 52.2% vs. 14.8%, p=0.005), in comparison to the LC- group. The development of lymphocytosis after dasatinib was identified as a favorable independent marker for predicting a CCyR (p=0.002) or MMR following dasatinib therapy (p=0.003). Conclusion: The present study suggested that 1) lymphocytosis following dasatinib therapy is not rare phenomenon with incidence of 46%; 2) it might be associated with higher response following dasatinib therapy. Further study is necessary to identify which subset of lymphocytes was expanded and to reveal the exact mechanism by which dasatinib induces lymphocyte expansion. Disclosures: No relevant conflicts of interest to declare.
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Engler, Jane R., Amity Frede, Verity Saunders, Andrew Zannettino, Deborah L. White, and Timothy P. Hughes. "The poor response to imatinib observed in CML patients with low OCT-1 activity is not attributable to lower uptake of imatinib into their CD34+ cells." Blood 116, no. 15 (October 14, 2010): 2776–78. http://dx.doi.org/10.1182/blood-2010-01-267013.
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Abstract The functional activity of the organic cation transporter 1 (OCT-1) protein in chronic myeloid leukemia (CML) mononuclear cells (MNCs) is highly predictive of molecular response in imatinib treated patients. Here we investigate whether the MNC OCT-1 activity (OA) provides a surrogate indicator of effective targeting of the more immature CD34+ cells. While confirming our previous findings that high MNC OA is significantly associated with the achievement of major molecular response (MMR; P = .017), the present studies found no relationship between high CD34+ OA and the achievement of MMR. Furthermore, no correlation was found between the MNC OA and the CD34+ OA in matched CML samples. These results suggest that the predictive value of the MNC OA may primarily reflect the effective targeting and subsequent reduction of mature CML cells. Therefore kinase inhibition in these mature cells, and not the CD34+ cells, may be the key determinant of response in CML.
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Saussele, Susanne, Michael Lauseker, Verena Hoffmann, Ulrike Proetel, Benjamin Hanfstein, Gabriela M. Baerlocher, Dominik Heim, et al. "Prediction of Molecular Response of Chronic Phase CML Patients by the EUTOS Score: Results of the Randomized CML-Study IV,." Blood 118, no. 21 (November 18, 2011): 3762. http://dx.doi.org/10.1182/blood.v118.21.3762.3762.
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Abstract Abstract 3762 Introduction: The EUTOS Score was developed and validated as a prognostic tool for the achievement of complete cytogenetic response (CCR) at 18 months for chronic phase (CP) CML patients under imatinib therapy. The score identifies high-risk patients not reaching CCR at 18 months with a positive predictive value of 34% and a specificity of 92% using only two variables, peripheral blood basophils and spleen size at diagnosis (Hasford et al. Blood 2011). We sought to evaluate the clinical impact of the EUTOS score to predict molecular response. Therefore, we analyzed the EUTOS score with patients from the German CML-Study IV, a randomized 5-arm trial (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with interferon alpha vs. imatinib in combination with araC vs. imatinib after interferon failure). Results: From July 2002 to December 2010, 1,502 patients with BCR-ABL positive CML in CP were randomized. 129 patients with imatinib after interferon alpha and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1,337 patients were evaluable for overall and progression-free survival (OS and PFS), 1,252 for molecular responses. 749 of these patients were part of the score development sample. Therefore cytogenetic analyses are not described here. By EURO score, 36% of patients (n=475) were low risk, 51% (n=681) intermediate risk, and 12% (n=167) high risk. The EUTOS score was low risk in 88% (n=1163) and high risk in 12% (n=160). The high-risk patients differed between the two scores: EUTOS high-risk patients were classified according to EURO score in 12% as low (n=19), in 45% as intermediate (n=68) and in 43% as high risk (n=73). Patients with high, intermediate, and low risk EURO score achieved MMR in 22, 16, and 13 months and CMR4 (BCR-ABL <=0.01%) in 59, 41, and 34 months. P-values for low vs. intermediate risk groups were borderline only (0.03 for MMR and 0.04 for CMR4), whereas p-values for high vs. low/intermediate risk groups were for both molecular response levels <0.001. At 12 months the proportion of patients in MMR was 38%, 46%, 54% for high, intermediate, and low risk patients, respectively. Similar results were observed with the Sokal score. Patients with high risk EUTOS score achieved deep molecular responses (MMR and CMR4) significantly later than patients with low risk EUTOS score (MMR: median 21.0 vs. 14.8 months, p<0.001, Fig. 1a; CMR4: median 60.6 vs. 37.2 months, p<0.001, Fig. 1b). The proportions of patients achieving MMR at 12 months were significantly lower in the EUTOS high-risk group than in the EUTOS low-risk group (30.8% vs. 50.6%, p<0.001). OS after 5 years was 85% for high and 91% for low risk patients (p=n.s.), PFS was 85% and 90%, respectively. Conclusions: The EUTOS score clearly separates CML patients also according to MMR and CMR4 (MR4). The new EUTOS score should be used in future trials with tyrosine kinase inhibitors in CML. Disclosures: Neubauer: Novartis: Honoraria, Research Funding; Roche: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.
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Alaiya, Ayodele, Naeem A. Chaudhri, Hafiz Malhan, Tarek Owaidah, Zakia Shinwari, Jonathan Fox, Fahad Alsharif, et al. "Proteomics–Based Approach Predicts Molecular Response and Stratifies Responders to Tyrosine Kinase Inhibitors (TKI) in Chronic Myeloid Leukemia (CML) Patients." Blood 124, no. 21 (December 6, 2014): 4556. http://dx.doi.org/10.1182/blood.v124.21.4556.4556.
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Abstract Purpose: Chronic Myeloid Leukemia (CML) among other hematological malignancies has witnessed development of advanced molecular diagnostics. However, there is an unmet need for efficient objective markers for selection of available therapeutic agents and accurate prediction of patient’s response. Clinical proteomics can potentially be complementary to currently existing proven tools to monitor therapy response towards achieving personalized medicine for CML patients. Experimental Design: Thirty four bone marrow and serum, samples from patients with newly diagnosed chronic–phase CML were subjected to expression proteome analysis using combined gel-based 2-DE and label-free in-solution quantitative liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The study aims to identify disease-specific/disease-associated protein biomarkers demanding less invasive procedures for objective prediction of individual’s best treatment options and prognostic monitoring of CML patients (Overview in figure 1). Results: Quantitative protein fingerprints from 2-DE analysis accurately predicts 13 individuals that achieved Major Molecular Response (MMR) at 6 months from 12 subjects without Major Molecular Response (NoMMR) using unsupervised principal component analysis (Figure 1 left lower panel). Some of the results were independently validated using label free quantitative liquid chromatography tandem mass spectrometry. Sixty three (63) differentially expressed proteins were identified (> 2- ∞- fold change, p < 0.05).The panel of proteins also discriminates accurately patients that stay on TKI after 1year of Imatinib Rx from patients ultimately requiring alternative treatment (Second Generation TKI/others). We have had more than 2 years follow up of these patients and the same dataset of potential protein biomarkers could still accurately separates all four sample groups into their respective molecular response and treatment sub groups (Figure 1 middle lower panel). Some of the identified proteins were implicated in hematological diseases as potential biomarkers using Ingenuity Pathway Analysis (Figure 1 right lower panel). Conclusion: Our results highlight the power of Proteomics as a molecular scanner for objective stratification of CML patients for treatment options. We have identified protein signatures capable of prediction of molecular response and choice of therapy for CML patients at 6 months and beyond. Our expression proteomics strategy is very promising for identification of clinically useful biomarkers. These proteins might be valuable once validated, to complement the currently existing parameters for reliable and objective prediction of disease progression, monitoring treatment response and clinical outcome of CML patients as a model of personalized medicine. Figure 1 Overview of our biomarker discovery proteomics approach. Bone marrow and peripheral blood samples were analyzed by 2-DE and LC/MS/MS. Identified proteins were subjected to multivariate statistical analysis and evaluated for early treatment response and prediction of individualized treatment options. Potential markers would be validated for clinical use. Figure 1. Overview of our biomarker discovery proteomics approach. Bone marrow and peripheral blood samples were analyzed by 2-DE and LC/MS/MS. Identified proteins were subjected to multivariate statistical analysis and evaluated for early treatment response and prediction of individualized treatment options. Potential markers would be validated for clinical use. Disclosures No relevant conflicts of interest to declare.
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Fujioka, Yuki, Hiroyoshi Nishikawa, and Naoto Takahashi. "Kinetics of Regulatory T Cells Predict the Recurrence of CML after Stopping Imatinib in Japanese CML Patiens." Blood 128, no. 22 (December 2, 2016): 4240. http://dx.doi.org/10.1182/blood.v128.22.4240.4240.
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Abstract Introduction: Imatinib have dramatically changed the natural history of chronic myeloid leukemia (CML) leading to significant improvement in clinical outcome and survival rates. Recently, treatment free remission (TFR) is proposed as one of the goals in CML treatment, and some prospective trials suggest that imatinib therapy may be safely stopped in CML patients with deep and sustained molecular responses (Lancet Oncol 2010, Blood 2013, JCO 2014). We have previously show that approximately 70% patients with deep and sustained molecular responses could stop imatinib (ASH 2015). On the other hands, the frequency of regulatory T (Treg) cells in imatinib-treated CML patients with complete molecular response (CMR) exhibited significantly lower compared with that in non-CMR (Haematologica, 2013), indicating the important roles of Tregs in CML treatment. Here, we analyzed T-cell profile in Japanese CML patients to identify biomarkers predicting patients that can successfully stop tyrosine kinase inhibitors (TKI) treatment. Methods: Japanese CML patients treated with imatinib for at least three years and confirmed in deeper molecular response (DMR) for at least two years (>4 log reduction of CML cells by four consecutive PCR tests with imatinib therapy for >24 months) were eligible. Patients who received other TKI or stem cell transplantations were excluded. MR4.5 was tested at the beginning of this study using Ipsogen BCR-ABL1 M-BCR IS-PCR kit in a central laboratory (Sysmex, Kobe, Japan). The patientfs peripheral blood was collected at pre- and 1, 3 months after stopping imatinb. Peripheral blood mononuclear cells (PBMCs) ware subjected to direct staining with T-cell markers and analyzed by flowcytometer. Results: Samples of 68 CML patients (77 patients ware enrolled and nine ware excluded due to consent withdrawal or ineligible) were analyzed. We classified these CML patients into three groups (TFR, Fluctuated and Retreatment groups) by clinical courses after stopping imatinib; TFR group (n=33) maintained MR4.5 without further treatment for 2years, Fluctuated group (n=12) moved below and above MR4.5, Retreatment group (n=23) lost MR4.5 and was re-started TKI retreatment. Frequency of CD4+ T cells and CD8+ T cells in CD3+ T cells ware approximately 60% and 25% in all patients at pre-stopping. FoxP3+ T cells are reportedly classified as three fractions with FoxP3 and CD45RA ; FoxP3loCD45+ naïve Treg (nTreg), FoxP3hiCD45- effector Treg (eTreg) which have highly suppressive function and FoxP3loCD45- effector non-Treg which do not possess suppressive activity (figure 1). Average of the frequency of nTreg, eTreg, and non-Treg fractions in CD4+ T cells were 0.6%, 2.9%, and 3.6% (pre-stopping), 0.7%, 3.5%, and 3.9% (On month after stopping) 0.6%, 2.5%, and 3.4% (3 month after stopping), respectively. The frequency of the each fractions (nTreg, eTreg, non-Treg) and total Foxp3+CD4+ T cells (nTreg+eTreg+non-Treg) elevated 1 month after stopping imatinib, but the frequency of Tregs were suddenly dropped to the basal level at 3 months after stopping imatinib. When the kinetics of T cells were evaluated based on three clinical courses, it is noteworthy that Treg elevation after stopping imatinib was not detected in Retreatment group, indicating that Treg repression by imatinib was not observed in this group (figure 2). Conclusion: Treg population in PBMCs elevated transiently after stopping TKI in CML patients with DMR after long-term TKI therapy. This may due to the release of imatinib suppression to Tregs. However, this transient increase of Tregs was not observed in patients who relapsed after stopping imatinib and received TKI retreatment. Together with our previous reports, it is proposed that activation of anti-CML immune responses by decreasing Tregs by imatinib is an important factor for long duration of anti-CML effect by imatinib. Disclosures Takahashi: Novartis: Honoraria, Research Funding; BMS: Honoraria; Pfizer: Honoraria, Research Funding.
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Cortes, Jorge, Moshe Talpaz, Susan O’Brien, Dan Jones, Raja Luthra, Guillermo Garcia-Manero, Francis Giles, et al. "Clinical Significance of Molecular Monitoring in Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) with Imatinib Therapy." Blood 104, no. 11 (November 16, 2004): 272. http://dx.doi.org/10.1182/blood.v104.11.272.272.
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Abstract Most patients (pts) with CML in chronic phase treated with imatinib achieve a major cytogenetic (CG) remission, and increasing numbers of pts are achieving molecular responses. To determine the clinical significance of molecular responses in these pts, we analyzed the results of quantitative PCR monitoring among 280 pts with CML in CP who achieved a complete CG remission with imatinib therapy (117 after IFN-α failure, 163 previously untreated). Pts have been followed for a median of 31.2 mo (range, 3 to 52 mo). The median BCR-ABL/ABL ratio before the start of therapy was 37.43 (range, 0.004 to 170.53). A major molecular response (i.e., BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%) pts, and transcripts became undetectable (i.e., complete molecular response) in 95 (34%). Median time to major molecular responses was 10 mos (range, 2.8 to 46 mos) and for complete 16.7 mos (range, 3 to 48 mos) but responses have occurred as late as 48 mos with no evidence of a time after which responses do not improve any more. In a multivariate analysis, clinical characteristics associated with an increased probability of achieving a major molecular response were early chronic phase previously untreated (p=.03), no splenomegaly (p=.03), and ≤90% Ph-positive metapahases at the start of therapy (p=0.05). Only 9 of 166 (5%) patients who achieved a major molecular response and have had subsequent cytogenetic analysis have lost their cytogenetic response, compared to 25 of 68 (37%) of those who did not achieve this response (p<0.0001). Only 3 of 82 (4%) with complete molecular response have lost their cytogenetic response. Patients achieving a major molecular response 12 mos after the start of therapy have a significantly better complete cytogenetic remission duration than those not achieving this response at this time point, and similar but not statistically significant trends can be detected with earlier responses (at 3 and 6 mos). Pts with more than a 1-log-reduction in transcript levels after 3 mos of therapy have a 90% probability of achieving a 3-log reduction at 24 mos, compared to 55% for those with ≤1-log decrease (p=0.0002). We then evaluated the significance of an increasing trend in transcript levels. None of the 44 pts with an increase of <0.05 has lost the complete CG remission, compared to 6 of 33 (18%) with an absolute increase of 0.05 to 1, and 5 of 11 (45%) with an increase of >1.0 (p=0.0001). The probability of cytogenetic relapse is particularly high for patients who never achieved a major molecular remission. We conclude that achieving a major molecular response, particularly within the first year of therapy with imatinib, is predictive of a durable cytogenetic remission and should be the goal of therapy with imatinib. Increasing transcript levels after achieving a complete CG response predict for a relapse in patients who did not achieve a major molecular response.
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Baba, Aziz, Marjanu Hikmah Elias, Anthony Zian Au, Najlaa Maddin, Siti Maziras Makhtar, Gan Siew Hua, Azlan Husin, Sarina Sulong, Rosline Hassan, and Ravindran Ankathil. "Integrating Molecular, Epigenetic and Pharmacogenetic Approaches in Managing Imatinib Resistance Among Malaysian Chronic Myeloid Leukemia Patients." Blood 124, no. 21 (December 6, 2014): 3150. http://dx.doi.org/10.1182/blood.v124.21.3150.3150.
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Abstract The BCR-ABL targeted therapy using ImatinibMesylate (IM) is considered the standard care in chronic myeloid leukemia (CML) management. Despite shown to produce superior results, up to 33% of CML patients on IM therapy, develop resistance which can be either BCR-ABLdependent (gene amplification or point mutations of BCR-ABL gene) or BCR-ABL independent. We undertook molecular, epigenetic and pharmacogenetic approaches to elucidate the heterogeneous array of mechanisms of resistance in Malaysian CML patients undergoing IM therapy. Using denaturing High Performance Liquid Chromatography followed by sequencing 122IM resistant CML patients were screened for BCR-ABL mutations. As part of epigenetic approach, 175 CML patients comprising of 83 good response and 92 BCR-ABL non mutated IM resistant CML patients were subjected to Methylation Specific High Resolution Melt Analysis (MS-HRM) to quantitate the promoter methylation level of HOXA4 and HOXA5 genes. For pharmacogenetic study, 215 CML patients consisting of 107 IM good response and 108 IM resistant CML patients were genotyped for polymorphisms in ABCB1 (1236 T>C, 2677 G>T/A, 3435 C>T), ABCG2 (34 G>A, 421 C>A), ABCC1 (2012 G>T, 2168 C>A), ABCC2 (-24 C>T, 1249 G>A, 3972 C>T), SLC22A1 (480 C>G, 1201 G>A, 1222 G>A, 1239 G>A, 1258-1260 ATG del, TGGTAAGT 8+/8- ins/del), PXR (1792 A>G) and CYP3A4 (878 T>C) genes using polymerase chain reaction restriction fragment length polymorphism technique. BCR-ABL mutations were detected in 30/122 patients (24.6%). Seventeen different types of mutations (T315I, G250E, E255K, E255V, M351T, Y253H, V289F, E355G, F359V, L387M, H396R, E355A, D276G, A397P and E281K) including 2 novel mutations (G251E and N368S) were identified in varying frequencies.Detection of mutations during course of IM therapy may aid in risk stratification as well as in determining therapeutic strategies. MS-HRM analysis showed varying hypermethylation levels of HOXA4 and HOXA5 genes in CML patients studied. IM treated CML patients with higher than 62.5% of HOXA4 methylation were found to be associated with a higher risk for developing IM resistance (OR 4.71; 95% CI: 2.46-9.03; p<0.001) when compared to the optimal response group.While in HOXA5, IM treated CML patients with higher than 62.5% of HOXA5 methylation were found to be associated with a higher risk for developing IM resistance (OR 4.26; 95% CI: 2.22-8.17; p<0.001) when compared to the optimal response group.Promoter hypermethylation of HOXA4 and HOXA5 genes could be considered as one of the BCR-ABL independent mechanisms mediating IM resistance and could be a potential epigenetic biomarker in supplement to the BCR-ABL gene mutation in predicting IM treatment response among CML patients. In pharmacogenetic analysis, the homozygous and heterozygous variant genotypes such as ABCB1 1236 CC (OR 3.39;95% CI:1.375-8.362; p=0.007), SLC22A1 480CG (OR 4.96; 95% CI: 2.006-12.471;p<0.001), PXR 1792AG (OR 3.17; 95% CI:1.22-8.28;p=0.018) emerged as genotypes significantly associated with IM resistance whereas ABCB1 2677TT/AA (OR 0.32;95% CI:0.137-0.741; p=0.007), and ABCG2 421AA (OR 0.24;95% CI: 0.086-0.645; p=0.003) genotypes showed significant association with IM good response. Nevertheless, the pharmacogenetic data to be sufficiently conclusive to translate into individual drug dose adjustment, further studies on larger sample size are warranted. The overall results suggested that resistance to IM in CML patients is not due to a single or simple mechanism, but is a multi-factorial phenomenon. Because the inhibition of only one mechanism is not effective enough to overcome clinical resistance, simultaneous suppression of several proteins may be required to increase the efficacy of IM treatment in CML patients. (Acknowledgment: Financial support from Fundamental Research Grant Scheme Grant Number: 203/PPSP/6171104, Universiti Sains Malaysia Research University Grant Numbers: 1001/PPSP/812067, 1001/PPSP/812070, 1001/PPSP/812103, and APEX Delivering Excellence 2012 Grant Number: 1002/PPSP/910340). Disclosures No relevant conflicts of interest to declare.
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Saifullah, Hilbeen Hisham, and Claire Marie Lucas. "Treatment-Free Remission in Chronic Myeloid Leukemia: Can We Identify Prognostic Factors?" Cancers 13, no. 16 (August 19, 2021): 4175. http://dx.doi.org/10.3390/cancers13164175.
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Following the development of tyrosine kinase inhibitors (TKI), the survival of patients with chronic myeloid leukaemia (CML) drastically improved. With the introduction of these agents, CML is now considered a chronic disease for some patients. Taking into consideration the side effects, toxicity, and high cost, discontinuing TKI became a goal for patients with chronic phase CML. Patients who achieved deep molecular response (DMR) and discontinued TKI, remained in treatment-free remission (TFR). Currently, the data from the published literature demonstrate that 40–60% of patients achieve TFR, with relapses occurring within the first six months. In addition, almost all patients who relapsed regained a molecular response upon retreatment, indicating TKI discontinuation is safe. However, there is still a gap in understanding the mechanisms behind TFR, and whether there are prognostic factors that can predict the best candidates who qualify for TKI discontinuation with a view to keeping them in TFR. Furthermore, the information about a second TFR attempt and the role of gradual de-escalation of TKI before complete cessation is limited. This review highlights the factors predicting success or failure of TFR. In addition, it examines the feasibility of a second TFR attempt after the failure of the first one, and the current guidelines concerning TFR in clinical practice.
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Jankovic, Radmila, Ana Krivokuca, Ivana Boljevic, Sinisa Radulovic, and Milena Cavic. "Molecular prediction of chronic myeloid leukemia risk and resistance to imatinib." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e18543-e18543. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e18543.
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e18543 Background: Chronic myeloid leukemia (CML) is characterized by the Bcr-Abl genetic translocation which leads to constitutive tyrosine kinase signaling. Treatment with tyrosine kinase inhibitors as imatinib eliminates CML cells, but resistance often occurs. No specific molecular risk factors or imatinib-resistance predictors have been validated so far, thus the aim of this study was to determine genetic factors that would allow for a better management of this disease. Methods: An age and gender matched case-control study of 57 CML patients and 63 healthy controls was performed. In vitro experiments were performed on K562 cells and an imatinib-resistant K562R cell line. CML patients were treated with imatinib and stratified into responders (complete molecular response after three months, CMR) and non-responders. RNA was isolated from blood leukocytes or cells and used for cDNA synthesis. Gene expression levels were evaluated by real-time PCR and the results analyzed using the delta-delta-Ct method. Differences in expression levels and their prognostic/predictive potentials were evaluated by t-test, linear regression analysis and receiver operating characteristics curve, with statistical significance set at p < 0.05. Results: In CML patients, the Bcl2 and IGF-1R mRNA expression level were higher than in controls (1.03 ± 0.06 vs. 0.92 ± 0.18, p < 0.0001; 1.14 ± 0.15 vs. 1.03 ± 0.15, p = 0.0001, respectively). Prior to treatment, the Bcl2 mRNA levels were lower for the K562 than for the resistant K562R cell line (1.13±0.04 vs. 1.62±0.01, p < 0.0001), and the same was observed for IGF-1R (1.22±0.01 vs. 1.29±0.01, p = 0.001). Patients who achieved a CMR after imatinib treatment had significantly lower pre-treatment levels of Bcl-2 and IGF-1R (0.99 ± 0.05 vs. 1.04 ± 0.06, p = 0.005; 1.12 ± 0.02 vs. 1.15 ± 0.04, p = 0.0123, respectively) compared to patients who did not achieve a CMR, which confirmed the in vitro observed data. Conclusions: High levels of Bcl-2 and IGF-1R mRNA were detected in CML patients, and the analysis of their expression might be used as a low-cost CML screening tool. Successful imatinib treatment was correlated with significantly lower pre-treatment Bcl-2 and IGF-1R levels in vitro and in vivo, which might also be used as a low-cost molecular predictor of a favorable clinical response .
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Stella, Stefania, Valentina Zammit, Silvia Rita Vitale, Maria Stella Pennisi, Michele Massimino, Elena Tirrò, Stefano Forte, et al. "Clinical Implications of Discordant Early Molecular Responses in CML Patients Treated with Imatinib." International Journal of Molecular Sciences 20, no. 9 (May 6, 2019): 2226. http://dx.doi.org/10.3390/ijms20092226.
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A reduction in BCR-ABL1/ABL1IS transcript levels to <10% after 3 months or <1% after 6 months of tyrosine kinase inhibitor therapy are associated with superior clinical outcomes in chronic myeloid leukemia (CML) patients. In this study, we investigated the reliability of multiple BCR-ABL1 thresholds in predicting treatment outcomes for 184 subjects diagnosed with CML and treated with standard-dose imatinib mesylate (IM). With a median follow-up of 61 months, patients with concordant BCR-ABL1/ABL1IS transcripts below the defined thresholds (10% at 3 months and 1% at 6 months) displayed significantly superior rates of event-free survival (86.1% vs. 26.6%) and deep molecular response (≥ MR4; 71.5% vs. 16.1%) compared to individuals with BCR-ABL1/ABL1IS levels above these defined thresholds. We then analyzed the outcomes of subjects displaying discordant molecular transcripts at 3- and 6-month time points. Among these patients, those with BCR-ABL1/ABL1IS values >10% at 3 months but <1% at 6 months fared significantly better than individuals with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (event-free survival 68.2% vs. 32.7%; p < 0.001). Likewise, subjects with BCR-ABL1/ABL1IS at 3 months >10% but <1% at 6 months showed a higher cumulative incidence of MR4 compared to patients with BCR-ABL1/ABL1IS <10% at 3 months but >1% at 6 months (75% vs. 18.2%; p < 0.001). Finally, lower BCR-ABL1/GUSIS transcripts at diagnosis were associated with BCR-ABL1/ABL1IS values <1% at 6 months (p < 0.001). Our data suggest that when assessing early molecular responses to therapy, the 6-month BCR-ABL1/ABL1IS level displays a superior prognostic value compared to the 3-month measurement in patients with discordant oncogenic transcripts at these two pivotal time points.
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Engler, Jane R., Amity Frede, Verity A. Saunders, Andrew Christopher William Zannettino, Deborah L. White, and Timothy P. Hughes. "OCT-1 Activity in CML CD34+ Cells Is Not Predictive of Molecular Response to Imatinib Treatment in CP-CML Patients, Despite the Strong Predictive Value of MNC OCT-1 Activity." Blood 114, no. 22 (November 20, 2009): 2189. http://dx.doi.org/10.1182/blood.v114.22.2189.2189.
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Abstract Abstract 2189 Poster Board II-166 Introduction. The organic cation transporter 1 (OCT-1) is the major active influx transporter for imatinib in PB mononuclear cells (MNC) from CML patients. We have previously demonstrated that the functional activity of the OCT-1 protein (OCT-1 Activity, OA) in MNC from chronic phase (CP) CML patients is highly variable (mean: 7.2 ng/200,000 cells, standard deviation: 6.4). We also demonstrated that the MNC OA is significantly related to a patient's sensitivity to imatinib-induced kinase inhibition, and their subsequent molecular response. In addition, we have recently demonstrated that OA is predictive of event free and transformation free survival to 5 years (White ASH submitted 2009). This is of a greater importance for those patients on lower doses of imatinib (below 600mg). For these patients who have a low MNC OA, 82% failed to achieve a major molecular response (MMR) by 18 months of imatinib treatment, as opposed to 17% for patients with a high MNC OA (p=0.022). Recently, we have shown that the OA in CML CD34+ cells is significantly lower than that found in mature CML cells (mean CD34+: 3.9, CD34-: 11.6 ng/200,000 cells, p<0.001, n=36), however interpatient variation in CD34+ OA still remains (standard deviation: 2.65). Given the importance of low MNC OA as a prognostic indicator of poor molecular response, we sought to ascertain whether a patient's MNC OA was related to the OA in their CD34+ cells, and as such could be used as a surrogate indicator for efficient targeting of the primitive population. To do this, we firstly looked for a correlation between the OA in a patient's MNC and their CD34+ cells. Secondly, we assessed the predictive value of CD34+ OA for MMR in imatinib treated patients. Methods. MNC and CD34+ cells were isolated from imatinib naïve, newly diagnosed CP-CML patients using density gradient centrifugation and magnetic cell sorting, respectively. OA was determined using [14C]-labeled imatinib and the OCT-1 inhibitor prazosin. OA is calculated as the difference between the uptake and retention of imatinib in the absence and presence of prazosin. Statistical analyses were performed using the Mann-Whitney Rank Sum or Student's t-test, correlations were performed using the Spearman-Rank Order. Results. In 34 CML patients no correlation was observed between the OA in their MNC and the OA in their CD34+ cells (R=0.09, p=0.577). Furthermore, when these patients were divided as having high or low OA in their MNC (about a previously described median of 7.2 ng/200,000 cells), no difference was seen between the OA in their corresponding CD34+ cells (Table 1). Finally, in 19 patients where 12 month response data was available, patients were grouped according to the achievement or not of MMR by 12 months. MNC OA was found to be significantly associated with the achievement of MMR (Table 2). This suggests that patients with a high OA in their MNC achieve better molecular responses, which is in agreement with our previous findings. However, assessment of CD34+ OA failed to demonstrate a relationship between OA and the achievement of MMR (Table 2). Therefore, a low OA in patient's CD34+ cells (unlike MNC) does not appear to be associated with poor molecular responses. Conclusion. No relationship was identified between the OA measured in a patient's MNC and that in their CD34+ cells. Furthermore, CD34+ OA is not predictive of a patient's molecular response to imatinib treatment. This is in contrast to MNC OA, which is predictive of event free and transformation free survival to 5 years of imatinib treatment. This data suggests that the predictive value of the MNC OA may primarily reflect the effective targeting and subsequent eradication of mature CML cells. And that kinase inhibition in these mature cells (as opposed to CD34+ progenitor cells) may be the key determinant of MMR achievement in CP-CML. Supported by Novartis Oncology, Clinical Development, TOPS Correlative Studies Network Disclosures: Zannettino: Novartis Pharmaceuticals: Research Funding. White:Novartis Pharmaceuticals: Honoraria, Research Funding. Hughes:Novartis Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau.
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Hazazi, Ali, Mohammed Albayedh, Fawaz Albloui, and Mishal Alsulami. "Overview of Molecular Quantification of the BCR-ABL Oncogene in CML Patients." Biosciences Biotechnology Research Asia 19, no. 3 (September 29, 2022): 693–98. http://dx.doi.org/10.13005/bbra/3021.
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Chronic myeloid leukemia (CML) is considered a common blood cancers and accounts for approximately 15–20% of the total cases of leukemia. Recent studies indicated that above 95% of patients suffering of CML have been found with a distinctive Philadelphia chromosome that originates from a mutual translocation between both arms of chromosomes 9 and 22. During this mutation the translocation of the ABL gene located on chromosome 9 get transferred to the breakpoint cluster region (BCR) of chromosome 22 as an effect of a joined BCR-ABL gene. Furthermore, BCR-ABL oncogene is characteristically found in CML, causing cells to divide uncontrollably and inducing severe consequences among CML patients. In line with this, applying quantification technique of the BCR-ABL gene using molecular approaches is crucial for patient controlling, initiation of the proper treatment, measurement of response to therapy, and prediction of relapse. Of greater significance, molecular assay and monitoring of the BCR-ABL gene in CML using quantitative RT-PCR provides physicians with essential diagnostic and prognostic information.
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Millot, Frédéric, Meinolf Suttorp, Stéphanie Ragot, Guy Leverger, Jean-Hugues Dalle, Birgitta Versluijs, Birgitte Lausen, and Marina Borisevich. "Discontinuation of Imatinib in Children with Chronic Myeloid Leukemia: An International Registry of Childhood Chronic Myeloid Leukemia (I-CML-Ped) Study." Blood 136, Supplement 1 (November 5, 2020): 53–54. http://dx.doi.org/10.1182/blood-2020-135844.
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Background: Imatinib, a tyrosine kinase inhibitor (TKI) is currently proposed as first line therapy in children with chronic myeloid leukemia (CML) in chronic phase (CP). Studies in adults with CML demonstrated that 40 to 50% of patients with prolonged deep molecular response under TKI could discontinue TKI permanently without molecular relapse. However, data regarding TKI discontinuation in children with CML are limited. Methods: Using the ELN criteria we identified in the International Registry of Childhood Chronic Myeloid Leukemia 18 patients less than 18 years of age at diagnosis with CML in CP exhibiting under imatinib treatment sustained deep molecular response >MR4.0 (DMR) for ≥ 2 years and then discontinued the TKI. We retrospectively analyzed outcome of these patients and treatment-free remission rate (TFR) at various time points. Treatment with imatinib was resumed in case of molecular relapse defined as loss of major molecular response (MMR). Results: There were 11 boys and 7 girls. From diagnosis in CP until TKI discontinuation the 18 children showed no progression, resistance, warning or suboptimal response or switch to another TKI before discontinuation. Median age at diagnosis of CML was 11.9 years (range, 2.3 to 15.8 years) and median age at discontinuation of TKI was 16 years (range, 9 to 24 years). Median overall follow-up from diagnosis of CML was 107 months (range, 67-209 months). DMR was achieved after a median time of 12 months (range, 3 - 50 months) on imatinib. Before discontinuation median treatment duration of imatinib was 73.25 months (range, 32 to 109 months) and median duration of MR4.0 was 46.2 months (range, 23.9 to 98.6 months). Seven patients experienced molecular relapse 4.1 months (range, 1.9-6.4 months) after stopping and restarted imatinib. Two patient resumed imatinib 3.6 and 3.4 months after discontinuation because of increased in transcript level (from 0.001% to 0.01 and 0.012, respectively) but without loss of MMR. The median molecular follow up after discontinuation was 116 months (range, 71 to 209 months) for the patients without molecular relapse. The proportion of patients maintaining molecular free remission was 61% (95% CI, 38%-83%), 56% (95% CI, 33%-79%) and 56% (95% CI, 33%-79%) at 6, 12, and 36 months, respectively (Figure 1). Six of the 7 children who experienced molecular relapse after discontinuation again achieved MR4.0 at median of 4.7 months (range, 2.5-18 months) after restart of imatinib; the remaining patient achieved MMR but not DMR and was switched to Dasatinib. No withdrawal syndrome was observed in this cohort of 18 patients. In univariate analysis, age, sex, Sokal and ELTS scores, imatinib treatment duration before discontinuation and duration of DMR until imatinib discontinuation had no influence on treatment free remission. Conclusion: These data indicate that imatinib could be safely discontinued in children younger than 18 years of age at diagnosis of CML with sustained MR4.0 for at least 2 years under imatinib. Larger studies of TKI discontinuation in children with CML are needed in order to identify factors predicting treatment free remission. Disclosures Dalle: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medac: Consultancy, Honoraria; Orchard: Consultancy, Honoraria; Bellicum: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, 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; bluebird bio: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi-Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Honoraria; AbbVie Pharmacyclics: Membership on an entity's Board of Directors or advisory committees.
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Agrawal, Mridul, Philipp Erben, Benjamin Hanfstein, Hannah Daikeler, Juliana Popa, Thomas Schenk, Armin Leitner, Richard C. Woodman, Andreas Hochhaus, and Martin C. Müller. "MDR1 Expression and Pre-Treatment Tumor Load Predict Molecular Response in CML Patients On Nilotinib Therapy After Imatinib Failure." Blood 114, no. 22 (November 20, 2009): 2615. http://dx.doi.org/10.1182/blood.v114.22.2615.2615.
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Abstract Abstract 2615 Poster Board II-591 Introduction: The majority of patients with chronic myeloid leukemia (CML) in chronic phase achieve and maintain complete cytogenetic remission after frontline therapy with imatinib mesylate. In case of resistance or intolerance to imatinib, a switch to second generation tyrosine kinase inhibitors, such as nilotinib or dasatinib, is recommended. Mutations in the BCR-ABL kinase domain and various BCR-ABL independent mechanisms, e.g. clonal evolution and pathways bypassing BCR-ABL are considered as leading causes of resistance. Efficacy of imatinib and nilotinib depends on intracellular drug levels, which are influenced by the activity of the efflux transporter protein multidrug resistance 1 (MDR1, ABCB1 or P-gp). MDR1 involvement in the pathogenesis of resistance to nilotinib was postulated (Mahon et al., Cancer Res 2008). Aim: Hence, we evaluated the predictive impact of MDR1 expression levels as well as pre-treatment BCR-ABL load from imatinib resistant CML patients on molecular responses during second line therapy with nilotinib. Patients and Methods: Imatinib resistant patients in chronic phase CML treated with nilotinib (n=94) were investigated. Baseline BCR-ABL mutations were detected by D-HPLC and direct sequencing. MDR1 and BCR-ABL mRNA expression levels were determined by quantitative reverse transcription PCR (qRT-PCR) using LightCycler™ technology, normalized against beta-glucuronidase (GUS) expression and standardized according to the international scale (IS). Log-rank tests were performed to analyze and compare the time to achieve major (MMR, BCR-ABL IS ≤0.1%) or good molecular response (BCR-ABL IS ≤1%). Results: Within 12 or 24 months of nilotinib therapy, 22% and 27% of patients achieved MMR, and 37% and 41% of patients attained good molecular response, respectively. After 12 or 24 months, patients with MDR1/GUS ratios ≥2.5 (60%) achieved MMR in an estimated rate of 45% and 53%, whereas those with initial MDR1/GUS ratios <2.5 (40%) showed MMR in 14% and 14%, respectively (p=0.034). Good molecular response was attained in 52% vs 49% and 63% vs 66% after 12 and 24 months (ns). Further, BCR-ABL load prior to nilotinib revealed a significant impact on consecutive molecular response. BCR-ABL IS <28% separated best concerning prediction of MMR after 12 and 24 months (53% vs 25% and 53% vs 34%, p=0.002) and good molecular response (62% vs 44% and 85% vs 51%, p=0.004). Combining the two methods implied the definition of a low risk group (20%; pre-treatment BCR-ABL IS <28% and MDR1/GUS ratios ≥2.5) in contrast to a high risk group (27%; pre-treatment BCR-ABL IS ≥28% and MDR1/GUS <2.5) achieving MMR in 67% vs 6% of the patients after 24 months (p=0.0004). No relevant differences were found looking at subgroups of patients bearing BCR-ABL mutations. Conclusions: Pre-treatment expression levels of MDR1 and BCR-ABL tumor load predicts molecular responses of imatinib resistant chronic phase CML patients within the first two years of treatment with nilotinib. Disclosures: Woodman: Novartis Oncology: Employment. Hochhaus:Novartis : Research Funding.
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Boender, Piet, Jeroen Janssen, Linda Smit, Rob Ruijtenbeek, Adrienne van den Berg, Rik de Wijn, and Gert J. Ossenkoppele. "Application of Kinase Activity Profiles to Predict Upcoming TKI Resistance In CML-Patients." Blood 116, no. 21 (November 19, 2010): 3425. http://dx.doi.org/10.1182/blood.v116.21.3425.3425.
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Abstract Abstract 3425 Background: Major breakthroughs in CML research have revolutionized therapy by the introduction of a specific inhibitor of BCR-ABL activity; first Imatinib and now even more potent TKIs like Nilotinib and Dasatinib are available. Imatinib can induce complete hematologic responses in virtually all patients and complete cytogenetic responses in almost 90% of patients and progression free survival in 84% of patients. Patients that reach a more than 1000-fold reduction of the BCR-ABL transcript level (major molecular response) have durable responses with not a single event of progression. Unfortunately, not all patients attain such a favourable response. Primary and secondary resistance develops in around 20% of cases.Predicting the development this resistance would be of great clinical value. Aim: To establish a classifier based on peptide phosphorylation patterns as fingerprints using samples of peripheral blood cells or bone marrow of CML patients undergoing Imatinib treatment in order to enable prediction of emerging resistance against Imatinib. Methods: Stored (“snapfrozen”) mononuclear cell fractions, isolated by Ficoll-Paque centrifugation of bone marrow or peripheral blood of CML patients under continuous Imatinib treatment and in various stages of their disease were lysed in M-PER buffer supplemented with phosphatase and protease inhibitors. Kinase activity profiles of these lysates were generated with standard Tyrosine Kinase PamChip® Arrays that contain 144 peptides as kinase substrates on their porous surface. Peptide phosphorylation was followed through binding of a fluorescently labelled anti-phosphotyrosine antibody during flow-through cycling of the lysates. Activity profiles were generated with PamGene's BioNavigator software. The resulting data were analysed using the R-based package CMA (“Classification for MicroArrays”) that enables the survey and evaluation of most usual classification methods with double cross-validation procedures. Results: A distinct classifier for Imatinib response prediction could be derived for the bone marrow samples, collected at various intervals after diagnosis (18 Imatinib sensitive versus 19 Imatinib resistant patients, of which the samples were collected 3 months to 1.5 year before resistance emergence). Of the twenty-one classification methods that were studied the SupportVectorMachine (SVM) algorithm resulted in the smallest error rate: this was 16% with a standard error of 0.062 and a sensitivity of 84% and specificity of 82% respectively, meaning 3 misclassified sensitive patients and 3 misclassified resistant patients. This classifier has to be validated in a blinded, independent test set. Conclusions: We demonstrated that with this method it is possible to predict Imatinib resistance. Differences in phosphorylation patterns as detected using PamGene's peptide microarray technology with the aid of multivariate statistical analysis suggest the presence of an ongoing process in CML-patients destined in due time to a relapse in spite of continuous Imatinib treatment. We regard these initial class prediction results to be a basis for further development of this kinase activity based test for Imatinib response prediction in CML patients already at the time of diagnosis. Perspectives: Our approach of using kinase activity profiling for the prediction of Imatinib resistance, could equally well be applied to predict response to various other kinase inhibitors. These response predictions could be combined in the same test by adding these inhibitors in vitro and might direct the optimal drug selection at the time point of diagnosis. Disclosures: Boender: PamGene International BV: Employment. Ruijtenbeek:PamGene International BV: Employment. van den Berg:PamGene Inetrnational BV: Employment. de Wijn:PamGene International BV: Employment.
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Verma, Dushyant, Hagop M. Kantarjian, Jenny Shan, Susan O'Brien, Amit Verma, Elias Jabbour, Srdan Verstovsek, Tapan Kadia, Mary Beth Rios, and Jorge Cortes. "Sustained Complete Molecular Response to Imatinib in Chronic Myeloid Leukemia (CML): a Target Worth Aiming and Achieving?." Blood 114, no. 22 (November 20, 2009): 505. http://dx.doi.org/10.1182/blood.v114.22.505.505.
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Abstract Abstract 505 Background: Therapy with imatinib and other tyrosine kinase inhibitors leads to complete cytogenetic response (CCyR) in 80-90% of patients in chronic phase (CP) of CML, but most patients have residual disease documented by real-time quantitative polymerase chain reaction (PCR). Only a minority of patients achieve complete molecular response (CMR), as defined by undetectable levels of BCR-ABL fusion transcripts by PCR with sensitivity of at least 4.5 logs. Achieving CMR may offer the possibility of treatment discontinuation. Aims: To identify patients with sustained CMR (CMR of at least 6 months consecutively on 2 different dates) so as to define i) incidence of sustained CMR, ii) significance in long-term outcome (event-free survival, survival, transformation), and iii) predictive factors for CMR. Methods: We analyzed records of all patients with CML in early chronic phase (ie, within 12 months from diagnosis) treated with imatinib as frontline therapy at MD Anderson Cancer Center from July 2000 to Aug 2009. Major molecular response was defined as a BCR-ABL/ABL ratio of ≤0.05%, and CMR as undetectable transcripts in an assay with a sensitivity of at least 4.5 logs. Molecular responses were considered sustained only if they met the criteria for response in at least 2 consecutive assays separated over a period of at least 6 months. All patients were followed by PCR every 3 months for the first 1-2 years, then every 3-6 months. Rates of molecular response are reported on an intention-to-treat analysis. Results: 281 patients were included: 271 in CP and 10 in CP with clonal evolution at the time of diagnosis. The median age was 48 years (range 15-83), 119 (42%) were females, median CML duration 1 month (mo) (range 0-12). Seventy-three (26%) patients received an initial imatinib dose of 400 mg and 208 (74%) with 800 mg. The median follow-up is 65 mo (range 2-107) with 249 (89%) treated for over 12 mo, 225 (80%) for over 24 mo, 211 (75%) for over 36 mo, 154 (55%) for over 60 months, and 29 (10%) treated for over 96 mo. 55 (20%) have discontinued therapy (34 -12%-, because of resistance, and 21 -7%- because of intolerance). Overall, 248 (88%) achieved a CCyR, 80 (28%) a MMR without CMR, and 123 (44%) a CMR in at least one measurement. MMR was sustained in 95 (34%) and CMR in 84 (30%). The median time to CCyR was 3 mo (range 2-30), to sustained MMR 18 mo (range 6-78), and to sustained CMR 30 mo (range 6-84). The median event free survival was not reached for patients in CCyR with CMR/MMR without CMR/no MMR. Among patients who did achieve a CCyR, those that had a sustained CMR by 24 mo of therapy had an EFS of 100% at 5 yrs, compared to 96% for those with MMR but no CMR, and 86% for those with CCyR but no MMR (p=0.02). The rate of survival free from transformation to accelerated or blast phase at 5 yrs was 100% for those with CMR at 24 mo, compared to 96% for those with MMR but no CMR, and 91% for those with CCyR but no MMR (p=0.1). On univariate analysis, factors predicting sustained CMR were platelet count >450×109/L (p=0.001), CCyR at 3 mo (p=0.0005) and at 6 mo (p<0.0001). Conclusion: These results suggest that achieving a CMR is an important endpoint for patients with CML treated with imatinib as initial therapy. Treatment strategies that may increase the rate of sustained CMR should be investigated. Disclosures: Kantarjian: Novartis: Research Funding. Rios:Novartis: Consulting and speakers' bureau-honoraria . Cortes:Novartis: Research Funding.
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Masuko, Masayoshi, Tatsuo Furukawa, Tadashi Koike, Kazue Takai, Koichi Nagai, Kenji Kishi, Yoshinobu Seki, et al. "Early Responses At 3 Months and 12 Months After Starting Imatinib As Predictive Factors For The Achievement Of Deep MR In Japanese CML Patients." Blood 122, no. 21 (November 15, 2013): 2744. http://dx.doi.org/10.1182/blood.v122.21.2744.2744.
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Abstract Background and Purpose Imatinib therapy shows excellent efficacy for chronic myeloid leukemia (CML) patients. The five-year overall survival of chronic-phase CML patients treated with imatinib can be expected to reach over 90%. Now, the goal of therapy has become the achievement of therapy-free remission (TFR) for most patients. However, predictive markers for achieving deep molecular response (MR) or TFR are yet to be elucidated. The recently published European LeukemiaNet recommendations 2013, which are mostly based on Caucasian studies, show the importance of an early response at 3 months or 12 months after starting imatinib treatment to assess optimal response. Using the registry of our study group, we assessed whether early cytogenetic or molecular responses at 3 months and 12 months after starting imatinib are associated with the achievement of deep MR or long-term outcome in Japanese CML patients. Patients and Method We reviewed 135 CML patients in the registry of our study group. Imatinib was started between December 2001 and June 2008. We retrospectively analyzed 92 CML patients (35 patients with prior therapy before imatinib) who could be assessed for partial cytogenetic response (PCyR: Ph<35% or bcr/abl transcript <10%) at 3 months after starting imatinib treatment, and 81 patients (25 patients with prior therapy before imatinib) who could be assessed for major molecular response (MMR: bcr/abl transcript <10% or 300 copies/μg) at 12 months in our multicenter observation study group. The clinical data was reviewed in August 2010. We excluded patients who had been switched from imatinib to a second tyrosine kinase inhibitor (TKI) before August 2010. We compared overall survival and the cumulative achievement of deep MR (negative bcr/abl transcript by PCR or the TMA-HPA method) between patients with and without PCyR at 3 months, also between patients with and without MMR at 12 months. The probability of overall survival and the cumulative incidence of deep MR were calculated by the Kaplan-Meier method and compared by the log-rank statistic. Results Seventy-six out of 92 patients (82.6%) achieved PCyR at 3 months. Forty out of 81 patients (49.3%) achieved MMR at 12 months. The patients with PCyR at 3 months showed significantly better overall survival (p=0.004) and higher cumulative achievement of deep MR (p=0.009) than the patients without PCyR. Overall survival between the patients with and without MMR at 12 months did not show a significant difference (p=0.06). However, the patients with MMR at 12 months showed significantly higher cumulative achievement of deep MR (p<0.001) than the patients without MMR. Conclusion Early cytogenetic and molecular responses at 3 months and 12 months after starting imatinib are also predictive factors for good prognosis and the achievement of deep MR in a registry of Japanese patients. Our data confirm the criteria of optimal response in European LeukemiaNet recommendations 2013 was appropriated for Japanese CML patients in practical setting. Disclosures: No relevant conflicts of interest to declare.
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Glauche, Ingmar, Hendrik Liebscher, Christoph Baldow, Matthias Kuhn, Philipp Schulze, Tom Haehnel, Astghik Voskanyan, et al. "A New Computational Method to Predict Long-Term Minimal Residual Disease and Molecular Relapse after TKI-Cessation in CML." Blood 128, no. 22 (December 2, 2016): 3099. http://dx.doi.org/10.1182/blood.v128.22.3099.3099.
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Abstract Predicting minimal residual disease (MRD) levels in tyrosine kinase inhibitor (TKI)-treated chronic myeloid leukemia (CML) patients is of major clinical relevance. The reason is that residual leukemic (stem) cells are the source for both, potential relapses of the leukemicclone but also for its clonal evolution and, therefore, for the occurrence of resistance. The state-of-the art method for monitoring MRD in TKI-treated CML is the quantification of BCR-ABL levels in the peripheral blood (PB) by PCR. However, the question is whether BCR-ABL levels in the PB can be used as a reliable estimate for residual leukemic cells at the level of hematopoietic stem cells in the bone marrow (BM). Moreover, once the BCR-ABL levels have been reduced to undetectable levels, information on treatment kinetics is censored by the PCR detection limit. Clearly, BCR-ABL negativity in the PB suggests very low levels of residual disease also in the BM, but whether the MRD level remains at a constant level or decreases further cannot be read from the BCR-ABL negativity itself. Thus, also the prediction of a suitable time point for treatment cessation based on residual disease levels cannot be obtained from PCR monitoring in the PB and currently remains a heuristic decision. To overcome the current lack of a suitable biomarker for residual disease levels in the BM, we propose the application of a computational approach to quantitatively describe and predict long-term BCR-ABL levels. The underlying mathematical model has previously been validated by the comparison to more than 500 long-term BCR-ABL kinetics in the PB from different clinical trials under continuous TKI-treatment [1,2,3]. Here, we present results that show how this computational approach can be used to estimate MRD levels in the BM based on the measurements in the PB. Our results demonstrate that the mathematical model can quantitatively reproduce the cumulative incidence of the loss of deep and major molecular response in a population of patients, as published by Mahon et al. [4] and Rousselot et al. [5]. Furthermore, to demonstrate how the model can be used to predict the BCR-ABL levels and to estimate the molecular relapse probability of individual patients, we compare simulation results with more than 70 individual BCR-ABL-kinetics. For this analysis we use patient data from different clinical studies (e.g. EURO-SKI: NCT01596114, STIM(s): NCT00478985, NCT01343173) where TKI-treatment had been stopped after prolonged deep molecular response periods. Specifically, we propose to combine statistical (non-linear regression) and mechanistic (agent-based) modelling techniques, which allows us to quantify the reliability of model predictions by confidence regions based on the quality (i.e. number and variance) of the clinical measurements and on the particular kinetic response characteristics of individual patients. The proposed approach has the potential to support clinical decision making because it provides quantitative, patient-specific predictions of the treatment response together with a confidence measure, which allows to judge the amount of information that is provided by the theoretical prediction. References [1] Roeder et al. (2006) Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications, Nat Med 12(10):1181-4 [2] Horn et al. (2013) Model-based decision rules reduce the risk of molecular relapse after cessation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia, Blood 121(2):378-84. [3] Glauche et al. (2014) Model-Based Characterization of the Molecular Response Dynamics of Tyrosine Kinase Inhibitor (TKI)-Treated CML Patients a Comparison of Imatinib and Dasatinib First-Line Therapy, Blood 124:4562 [4] Mahon et al. (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11(11):1029-35 [5] Rousselot et al. (2014) Loss of major molecular response as a trigger for restarting TKI therapy in patients with CP- CML who have stopped Imatinib after durable undetectable disease, JCO 32(5):424-431 Disclosures Glauche: Bristol Meyer Squib: Research Funding. von Bubnoff:Amgen: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Saussele:ARIAD: Honoraria; Novartis: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria, Other: Travel grants; BMS: Honoraria, Other: Travel grants, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding. Guilhot:CELEGENE: Consultancy. Mahon:NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; PFIZER: Honoraria; ARIAD: Honoraria. Roeder:Bristol-Myers Squibb: Honoraria, Research Funding.
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Alaiya, Ayodele, Naeem Chaudhri, Tarek Owaidah, Jonathan Fox, Zakia Shinwari, Eman Barhoush, Fahad Alsharif, et al. "Expression Proteomics As Surrogate Biomarkers For Early Treatment Response In Chronic Myeloid Leukemia (CML) Patients." Blood 122, no. 21 (November 15, 2013): 4016. http://dx.doi.org/10.1182/blood.v122.21.4016.4016.
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Abstract Purpose Despite advancements in diagnosis and treatment modalities for hematological malignancies, presently, there are no reliable blood tests for disease prognosis or prediction of patient’s response to particular treatments. Identification of such biomarkers for diagnostic or therapeutic response in clinical monitoring of hematologic diseases such as Chronic Myeloid Leukemia (CML) would be very useful. Experimental Design The ability to identify biomarkers in body fluids (i.e., plasma or serum) will not only involve minimally invasive procedures, but also more importantly, the potential for monitoring disease progression and effective response to therapy in relatively early stages. In this study, global proteome analysis of serum, plasma, and bone marrow samples from 28 patients with newly diagnosed chronic–phase CML were analyzed by using expression proteomics technology (label free quantitative liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS). The goal was to evaluate for early treatment response and discovery disease–specific /disease-associated proteins for prognostic monitoring and patient’s response to therapy at protein level. Results We identified a panel of 15 differentially expressed proteins (> 2- °- fold change, p< 0.001) to accurately discriminate between CML patients that achieved Major Molecular Response (MMR) vs. No-Major Molecular Response (NoMMR) at 6 months (Figure 1 & Table 1). Six (6) of the 15 identified proteins were filtered and mapped as potential biomarkers using Ingenuity Pathway Analysis. Among the identified proteins implicated in hematological diseases include Group-specific component (vitamin D binding protein), haptoglobin and vitronectin. Others were inter-alpha-trypsin inhibitor heavy chain 1, leucine-rich alpha-2-glycoprotein 1 and metallophosphoesterase 1. We also observed most of these proteins to be located in extracellular space, acts as transporters and have been implicated as markers of hematological disease and inflammatory response. Our data indicates that multivariate analysis of quantitative proteome data can potentially be useful as a means of unsupervised artificial intelligence algorithm for classification and stratification of clinical CML patients. Conclusion Our results highlight the power of proteomics in the discovery of biomarkers for more accurate prediction of prognosis and monitoring treatment response in CML patients. These proteins might be valuable, once validated, to complement the currently existing parameters for reliable and objective prediction of disease progression, monitoring treatment response and clinical outcome of CML patients. Disclosures: No relevant conflicts of interest to declare.
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Ma, Jialu, Nathan Pettit, John Talburt, Shanzhi Wang, Sherman M. Weissman, and Mary Qu Yang. "Integrating Single-Cell Transcriptome and Network Analysis to Characterize the Therapeutic Response of Chronic Myeloid Leukemia." International Journal of Molecular Sciences 23, no. 22 (November 18, 2022): 14335. http://dx.doi.org/10.3390/ijms232214335.
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Chronic myeloid leukemia (CML) is a myeloproliferative disease characterized by a unique BCR-ABL fusion gene. Tyrosine kinase inhibitors (TKIs) were developed to target the BCR-ABL oncoprotein, inhibiting its abnormal kinase activity. TKI treatments have significantly improved CML patient outcomes. However, the patients can develop drug resistance and relapse after therapy discontinues largely due to intratumor heterogeneity. It is critical to understand the differences in therapeutic responses among subpopulations of cells. Single-cell RNA sequencing measures the transcriptome of individual cells, allowing us to differentiate and analyze individual cell populations. Here, we integrated a single-cell RNA sequencing profile of CML stem cells and network analysis to decipher the mechanisms of distinct TKI responses. Compared to normal hematopoietic stem cells, a set of genes that were concordantly differentially expressed in various types of stem cells of CML patients was revealed. Further transcription regulatory network analysis found that most of these genes were directly controlled by one or more transcript factors and the genes have more regulators in the cells of the patients who responded to the treatment. The molecular markers including a known drug-resistance gene and novel gene signatures for treatment response were also identified. Moreover, we combined protein–protein interaction network construction with a cancer drug database and uncovered the drugs that target the marker genes directly or indirectly via the protein interactions. The gene signatures and their interacted proteins identified by this work can be used for treatment response prediction and lead to new strategies for drug resistance monitoring and prevention. Our single-cell-based findings offered novel insights into the mechanisms underlying the therapeutic response of CML.
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Dybko, Jaroslaw, Olga Haus, Bozena Jazwiec, Tomasz Lonc, Mateusz Sawicki, and Kazimierz Kuliczkowski. "Hasford Score Is Correlated with 18 Month Molecular Response for Chronic Myeloid Leukemia Patients Treated with Second Generation Tyrosine Kinase Inhibitors and It May be Useful to Differentiate Low and Intermediate Risk Patients: A Single Institution Experience." Blood 126, no. 23 (December 3, 2015): 5163. http://dx.doi.org/10.1182/blood.v126.23.5163.5163.
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Abstract BACKGROUND: Chronic myeloid leukemia (CML) has been a model disease for a variety of studies concerning scoring systems, graft versus leukemia effect or tyrosine kinase inhibitors (TKI) treatment for many years. Scoring systems playing an important role in modern medicine to establish risk-adjusted optimal therapy [1] have been always essential for CML changing treatment modalities [1-3]. The three principal risk scores : Sokal [2], Hasford [1] and European Treatment and Outcome Study (EUTOS) [3] were established in different eras of CML therapy with implications for prognosis and disease outcome [4]. Hasford metric was designed based on data of patients treated with interpheron alpha [1] and it failed to differentiate patients who achieved low and intermediate risk scores according to CCyR, MMR, and 5 years EFS [5]. However in our previous study we found Hasford score to be correlated with the long-term molecular response in patients treated with imatinib [6]. This study presents the analysis of patients treated with second generation tyrosine kinase inhibitors (2G-TKI) due to their loss of MMR on imatinib. Hasford score still distinguish patients with low and intermediate risk and correlates with 18 month molecular response. PATIENTS AND RESULTS: The original group of 88 CML patients (F/M:42/46, median age 51 (21-83), 57 low risk and 31 intermediate risk assessed by Hasford risk score) in first chronic phase without any additional chromosomal abnormalities receiving standard dose imatinib was described in our previous study [6]. Of these, 42 patients lost MMR in a median time of 47 months. Within this group we identified 20 low risk (LR) and 22 intermediate risk (IR) patients. All 42 patients were switched to 2G-TKI. The observation after 3 months of 2G-TKI treatment was also previously described. After 18 months of 2G-TKI treatment median bcr-abl transcript levels in the LR group were 0.002 (0.000-0.02) but in the IR group bcr-abl levels were 0.03 (0.000-21.1) (p=0.03, Figure 1). All 20 low risk patients achieved major molecular response (MMR). In the intermediate risk group the response rate (MMR) was approximately 73% (16/22) and there is a significant difference in a probability of achieving MMR in both groups (Fig.2, p=0.0002). CONCLUSIONS: We are aware of Hasford score limited usefulness in predicting MMR in large studies. However in our study it is still a tool to distinguish low and intermediate risk patients by their molecular response on 2G-TKI after imatinib failure. We find our results relevant to the discussion on optimizing scoring systems and first line treatment of CML patients. REFERENCES: 1. Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group. Journal of the National Cancer Institute. 1998;90:850-8. 2. Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in "good-risk" chronic granulocytic leukemia. Blood. 1984;63:789-99. 3. Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011;118:686-92. 4. Hu B, Savani BN. Impact of risk score calculations in choosing front-line tyrosine kinase inhibitors for patients with newly diagnosed chronic myeloid leukemia in the chronic phase. European journal of haematology. 2014;93:179-86. 5. Yahng SA, Jang EJ, Choi SY, Oh YJ, Bang JH, Park JE, Jeon HL, Lee SE, Kim SH, Byun JY, Kim DW. Comparison of Sokal, Hasford and EUTOS Scores in Terms of Long-Term Treatment Outcome According to the Risks in Each Prognostic Model: A Single Center Data Analyzed in 255 Early Chronic Phase Chronic Myeloid Leukemia Patients Treated with Frontline Imatinib Mesylate. Blood 2012;120:Abstract 2794 6. Dybko J, Medras E, Haus O, Jazwiec B, Wrobel T, Kuliczkowski K. The Hasford Score Correlates with the Long-Term Molecular Response to Imatinib Treatment for Chronic Myeloid Leukemia Patients and May be Useful for Differentiating Low and Intermediate Risk Patients: A Single Institution Experience. Blood 2014;124:Abstract 3152 Figure 1. Figure 1. Figure 2. Figure 2. Disclosures No relevant conflicts of interest to declare.
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Bocchia, Monica, Anna Sicuranza, Paola Pacelli, Patrizia Pregno, Mario Annunziata, Federica Sorà, Elisabetta Abruzzese, et al. "Prospective Monitoring of Peripheral Blood CD26+ Leukemia Stem Cells in Chronic Myeloid Leukemia Patients from Time of TKI Discontinuation." Blood 134, Supplement_1 (November 13, 2019): 2919. http://dx.doi.org/10.1182/blood-2019-122814.
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Background and rationale In chronic myeloid leukemia (CML) about half of patients (pts) achieving a deep and stable molecular response (MR) with tyrosine kinase inhibitors (TKIs) may discontinue TKI treatment without disease recurrence. As such, treatment free remission (TFR) has become an ambitious goal of treatment. Given the evidence that deepness and duration of molecular response are necessary but not sufficient requisites for a successful TFR, additional biological criteria to possibly identify more and better CML patients suitable for an efficacious discontinuation are today focus of research in CML. Leukemia stem cells (LSCs) are supposed to be the reservoir of disease. We first showed in a cross-sectional study including 112 pts in TFR for a median of 31 months (mos) that residual circulating CD34+/CD38-/CD26+ CML-specific LSCs were still detectable in the majority of CML pts despite stable and deep molecular response. This evidence suggested that the level of BCR-ABL transcript only may not reflect the actual residual CML LSCs burden and that there could be a "threshold" of LSCs predicting a successful TFR. Aims To further study the behavior of residual LSCs during TKI discontinuation we designed a prospective multicentered study (AIRC IG 20133 study) in which we monitored circulating CD26+ LSCs in CML pts from the time of TKI discontinuation until molecular relapse. Methods CML pts meeting the current molecular criteria for TKI withdrawal entered this multicenter study. At TKI stop (baseline) and at +1, +2, +3, +6, + 12 mos after discontinuation and at any time if molecular relapse, CML pts were evaluated for peripheral blood number of CD34+/CD38-/CD26+ LSCs by centralized flow-cytometry analysis and for BCR-ABL transcript level by standard (IS) quantitative RT-PCR assay. Results 49 consecutive CML pts were enrolled in the study so far. Pts characteristics at diagnosis, type of TKI, disease response and treatment duration before discontinuation are shown in Tab. 1. After a median time of 7 mos since TKI stop (range 1-24), 13/49 (26.5%) pts lost their molecular response and restarted TKI treatment. Median time to relapse after discontinuation was 4 mos (range 2-7). 36/49 (73.4%) pts are still in TFR after a median time of 7.5 mos (range 1-24). If considering a cut-off of 6 mos from discontinuation as the period with higher risk of relapse, 14/36 pts actually in TFR have discontinued treatment for ≤ 6 mos (range 1-6) while 22/36 pts are in TFR for a median of 10 mos (range 7-24). Regarding residual CML LSCs evaluation, at baseline 23/49 (46%) pts had still measurable circulating CD26+LSCs with a median number of 0.0204µ/L (range 0.0077-0.1197), while 26/49 (54%) had no detectable CD26+ LCSs. Considering the small number of molecular relapses no statistical difference in number of residual CD26+ LSCs at time of discontinuation was shown between pts losing vs maintaining TFR (13 pts median CD26+ LSC 0.0237/µ/L, range 0-0.1197 and 36 pts median CD26+ LSCs 0.0204/µ/L, range 0-0.1039, respectively). However, the number of pts with undetectable CD26+ LSCs at baseline was 6/13 (45%) and 20/36 (55%) in the two subgroups, respectively. Considering subsequent time points, the 13 relapsed pts showed a small yet progressive increase of residual CD26+ LSCs number until molecular relapse, while the 36 pts in TFR showed a fluctuation of CD26+ cells number. However, Kendall rank correlation coefficient, Mood test and bi-linear relation model of the whole cohort showed no correlation between BCR-ABL/ABLIS ratio and number of residual CD26+ LSCs either at baseline or at each time points after discontinuation, thus confirming our previous observations. Conclusions Yet very preliminary our results showed that CD26+ LSCs are detectable at time of TKI discontinuation and during TFR. Moreover, at least for the observation median time of the study (7.5 mos) the persistence of "fluctuating" values of residual CD26+ LSCs do not hamper the possibility to maintain a stable TFR. Due to the short follow up and the small number of molecular relapsed pts we could not find a threshold of CD26+ LSCs predictive of TFR loss. Our data may suggest other factors then LSCs "burden" to play an active role in controlling disease recurrence. Additional studies evaluating CD26+ LSCs ability to modulate the immune system through a variable expression of immune response inhibitory molecules and through their interactions with effectors cells are ongoing. Table Disclosures Bocchia: Novartis: Honoraria; Incyte: Honoraria; BMS: Honoraria. Pregno:Bristol Myers Squibb: Honoraria; Incyte: Consultancy, Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Abruzzese:Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy; BMS: Consultancy. Crugnola:Novartis: Honoraria; Incyte: Honoraria. Iurlo:Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria; Novartis: Honoraria. Galimberti:Roche: Speakers Bureau; Celgene: Speakers Bureau; Novartis: Speakers Bureau. Liberati:Bristol & Mayer: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria.
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Couto Mascarenhas, Cintia Do, Maria Helena Almeida, Eliana C. M. Miranda, Bruna Virgilio, Marcia Torresan Delamain, Gislaine O. Duarte, Vagner O. Duarte, Carmino A. De Souza, and Katia B. Pagnano. "Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line." Blood 122, no. 21 (November 15, 2013): 4041. http://dx.doi.org/10.1182/blood.v122.21.4041.4041.
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Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.
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Takahashi, Naoto, Taiichi Kyo, Yasuhiro Maeda, Takashi Sugihara, Kensuke Usuki, Tatsuya Kawaguchi, Noriko Usui, et al. "Discontinuation of Imatinib in Japanese Patients with Chronic Myeloid Leukemia,." Blood 118, no. 21 (November 18, 2011): 3759. http://dx.doi.org/10.1182/blood.v118.21.3759.3759.
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Abstract Abstract 3759 Imatinib treatment dramatically improves survival in chronic myeloid leukemia (CML) patients, but whether its effects of imatinib can be considered a cure remains controversial. This is because primitive, quiescent, Philadelphia-positive stem cells from patients with CML are insensitive to imatinib in vitro. Nonetheless, it was recently recognized that some patients with a complete molecular response (CMR) could sustain that response after discontinuation of imatinib. In a non-randomized prospective study, Mahon et al. reported that among patients with CMR lasting at least 2 years, CMR was sustained in 41% after discontinuation of imatinib. To characterize the clinical outcomes and profiles of chronic phase CML patients who discontinued imatinib, we conducted a nationwide survey in Japan. Among 3,242 imatinib-treated CML patients, 50 (1.5%) were identified who discontinued imatinib therapy for at least 6 months; of those, 43 were analyzed further. Molecular recurrence was detected in 19 patients, and the complete molecular response (CMR) rate was estimated to be 47% following imatinib discontinuation. Notably, the durations of imatinib therapy and CMR before cessation of therapy were significantly longer, and imatinib dose intensity and the frequency of prior IFN-a administration were significantly higher, in patients sustaining CMR for 12 months after cessation than in those with molecular recurrence. No significant correlations were detected between molecular recurrence and age, sex, Sokal risk, imatinib daily dose, combination with IFN-a, or time to achieve CMR. Moreover, we found a significant difference in estimated CMR rate following discontinuation between patients who had sustained CMR for greater than 24 months prior to imatinib discontinuation and those with less than 24 months (78% vs. 15%, p =0.0002 by Log-rank test, Figure). Based on multivariate regression analysis, only imatinib dose intensity and prior IFN-a administration were independently predictive of molecular recurrence within 12 months (p =0.0035, p =0.0060). The identified prediction formula was: Y= −0.0061 x dose intensity of imatinib(g)-3.17171 x prior IFN-a(Yes=1/No=0) +4.0124. If 1/(1+exp(-1 × Y)) > 0.5, molecular recurrence was predicted; the total accuracy rate of the formula was 82.5%. Although the depth of the molecular response should be a factor influencing long-term sustained CMR after discontinuation of imatinib, other factors, for example an immunological mechanism modified by IFN-a, might control quiescent CML stem cells. To increase the “cure” rate among CML patients, it will be necessary to establish a treatment strategy on the basis of large prospective study of imatinib discontinuation. This should entail the use of a highly sensitive and strict method for monitoring minimal residual disease over the course of a long follow-up period. Disclosures: No relevant conflicts of interest to declare.
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Kronenwett, Ralf, Elena Diaz-Blanco, Thorsten Graef, Ulrich Steidl, Slawomir Kliszewski, Ingmar Bruns, Frank Neumann, et al. "Molecular Phenotype of Malignant CD34+ Hematopoietic Stem and Progenitor Cells in Chronic Myelogenous Leukemia." Blood 106, no. 11 (November 16, 2005): 2863. http://dx.doi.org/10.1182/blood.v106.11.2863.2863.
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Abstract In this study, we examined gene expression profiles of immunomagnetically enriched CD34+ cells from bone marrow (BM) of 9 patients with untreated CML in chronic phase and from 8 healthy volunteers using Affymetrix GeneChips. Additionally, in 3 patients CD34+ from peripheral blood (PB) were compared with those from BM. Differential expression of 12 candidate genes was corroborated by quantitative real-time RT-PCR. Following hybridization of labelled cRNA to Affymetrix GeneChips covering 8793 genes we used the statistical scripting language “R” for data analysis. For normalization a method of variance stabilization transformations was used. To identify significantly differentially expressed genes we used the Significance Analysis of Microarrays (SAM) algorithm. The intraindividual comparison of CD34+ cells from BM and PB in CML showed no differentially expressed genes which is different to normal CD34+ cells which had distinct gene expression patterns comparing circulating and sedentary CD34+ cells (Steidl et al., Blood, 2002). Comparing malignant BM CD34+ cells from CML with normal BM CD34+ cells 792 genes were significantly differentially expressed (fold change: >1.3; q-value: <0.03). 735 genes had a higher and 57 genes a lower expression in CML. Gene expression patterns reflected BCR-ABL-induced functional alterations such as increased cell-cycle and proteasome activity as well as decreased apoptosis. Downregulation of several genes involved in DNA repair and detoxification in CML might be the basis for DNA instability and progression to blast crisis. An interesting finding was an upregulation of fetal hemoglobin (Hb) components such as Hb gamma A and G in leukemic progenitor cells whereas no difference in adult Hb expression was observed suggesting an induction of fetal Hb synthesis in CML. Looking at genes involved in stem cell maintenance we found an upregulation of GATA2 and a reduced expression of proteins from the Wnt signalling pathway suggesting an increased self-renewal of CML hematopoietic stem cells compared to the normal counterpart. Moreover, several genes playing a role in ubiquitin-dependent protein catabolism and in fatty acid biosynthesis such as fatty acid synthase (FAS) were stronger expressed in CML. The functional role of FAS for leukemic cell growth was assessed in cell culture experiments. Incubation of the leukemic cell line K562 with the FAS inhibitor cerulenin (10 μg/ml) for 3 days resulted in death of 99% of cells suggesting that survival of leukemic cells depends upon endogenous fatty acid synthesis. In an attempt to find a specific gene expression pattern associated with response to imatinib therapy we divided the patients included in this study into two groups: maximal reduction of BCR-ABL transcript level <3-log vs. >3-log (major molecular remission) during therapy. Comparing pretherapeutic gene expression profiles of both groups we could not identify a pattern predictive for major molecular response. In conclusion, malignant CD34+ cells in CML have a specific gene expression pattern which seems not to be predictive for response to imatinib therapy.
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Iacobucci, Ilaria, Nicoletta Testoni, Gianantonio Rosti, Marilina Amabile, Angela Poerio, Simona Soverini, Sabrina Colarossi, et al. "Imatinib Mesylate Determines a High Frequency of Major Molecular Responses in Newly Diagnosed Philadelphia Chromosome-Positive Chronic Phase Chronic Myeloid Leukemia (CML) on Behalf of the GIMEMA Working Party on Chronic Myeloid Leukemia (GIMEMA-CML)." Blood 106, no. 11 (November 16, 2005): 1100. http://dx.doi.org/10.1182/blood.v106.11.1100.1100.
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Abstract Imatinib has became the standard therapy for patients with CML. In order to determine the frequency of molecular response to imatinib and its long-term prognostic implications, we analyzed the results of molecular monitoring in 260 newly diagnosed CML Sokal low-risk patients, enrolled in a prospective clinical trial (protocol CML 023 of the GIMEMA Working Party on CML). Imatinib was given at the dose of 400 mg daily. Bone marrow samples were collected prior to therapy and every 12 months, peripheral blood samples were collected at the same check-points and at 3 months, 6 months and every 6 months thereafter. Relative BCR-ABL expression was measured by real-time quantitative PCR (TaqMan) normalized for ABL and the result was expressed as a ratio of BCR-ABL to ABL multiplied by 100. All experiments were performed in duplicate. The median follow-up time from the time treatment was started is 6 months (range, 1–18). At the time of writing, are valuable for cytogenetic and molecular analysis at 12 months on imatinb 82 patients. At this time, complete cytogenetic remission (CCgR) was achieved in 90% of patients. Median BCR-ABL/ABL ratio before the start of imatinib was 16.1 (range, 112.6–0.004), it was 0.35 (range, 81.57–0.0006) at 3 months, 0.1 (range, 45.84–0.0002) at 6 months and 0.05 (range, 7.57–0.000001) at 12 months. Considering a major molecular response as reaching an absolute value of BCR-ABL/ABL ratio < 0.05%, we observed how after 12 months of treatment imatinib has determined a major molecular response in 52% of patients. If we were to use an absolute value of BCR-ABL/ABL ratio < 0.12 %, that has been demonstrated to be equivalent at a 3-log reduction (as referred by Hochhaus A), instead of an absolute value of 0.05%, a major molecular response would be achieved in about 70% of early chronic phase patients. BCR-ABL transcripts were undetectable at least one occasion (complete molecular response) in 4% of patient with a CCgR. Only 2 patients (2%) had no response to imatinib, in one of these we found the presence of the point mutation Y253H. In conclusion, our results demonstrate that imatinib determines a high frequency of complete cytogenetic remission and major molecular remission in newly diagnosed CML patients. Achieving a major molecular response, particularly within the first year of therapy, could be predictive of a durable cytogenetic remission.
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Garuti, Anna, Adalberto Ibatici, Gabriella Cirmena, Maurizio Miglino, Riccardo Varaldo, Colombo Nicoletta, Roberta Grasso, et al. "The Persistence of p190 BCR-ABL Transcripts Is Associated with Lower Probability of Molecular Response to Imatinib in Early and Late Chronic Phase CML Patients." Blood 106, no. 11 (November 16, 2005): 3282. http://dx.doi.org/10.1182/blood.v106.11.3282.3282.
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Abstract Background. It has been demonstrated that about 70% of patients with CML in chronic phase (CP) at diagnosis co-expressed p210 and p190 BCR/ABL transcripts, although at a much lower level (Blood1996;87:5213–17). In previous studies, the co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was considered as indicative of higher tumor burden. However, the clinical relevance of p190 BCR-ABL mRNA monitoring in CML pts under Imatinib on bone marrow (BM) samples is not known. Materials and Methods. BM samples were obtained from 83 pts with CP-CML treated with Imatinib at a daily oral dose ranging between 300–500mg. These included 192 samples from 43 pts with late CP-CML (post-IFN failure) and 140 samples from 40 pts with early CP-CML who received Imatinib as first line therapy. Median follow-up was 18 (3–58) and 39 (12–58) months for early and late CP-CML, respectively. As part of a diagnostic work-up, BM samples from each patient were assessed for expression of both p210 and p190 BCR/ABL levels by real-time quantitative reverse transcription PCR (QRT-PCR) using a TAQ-Man system (ABI Prism 7700 Perkin Elmer) for BCR-ABL and ABL genes. The median number of BM assessment was 3 (2–6) for early CP-CML and 4 (2–10) for late CP-CML. A major molecular response (MMR) was defined as BCR-ABL/ABL ratios less than 0.05%. A specific nested RT-PCR screening was assessed for detection of p210 (b2a2, b3a2) and p190 (e1a2) BCR-ABL transcripts to confirm the negative data of p210 and p190 in QRT-PCR. Results. A MMR was obtained in 20 pts (50%) and 20 pts (46%) in early and late CP-CML respectively. However, early CP-CML pts showed a significantly greater reduction in p210 BCR-ABL levels compared to late CP-CML after 12 months of Imatinib therapy (p=0.006), indicating a different kinetic of molecular response. Co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was 73% for early CP-CML, whereas it was not available for late CP-CML. To test whether the persistence of p190 BCR-ABL transcript was predictive of MMR, we divided CML pts in 2 groups, those with 0 or 1 p190 BCR-ABL positive samples (group 1) and those with 2 or more positive samples (group 2) during the follow-up. We found that CP-CML pts of the group 2 showed a significant lower probability to obtain MMR molecular response compared to pts of group 1 both for late and early CML patients respectively [17/24 (71%) vs 5/19 (26%) with p=0.0039)], [15/21 (71%) vs 6/18 (33%) with p=0.017)]. This correlation holds also for complete cytogenetic response (data not shown). Conclusions. In this study, approximately 50% of pts reached a MMR; half of them had undetectable values of p210 BCR-ABL transcripts. However, in a proportion of pts with complete cytogenetic response and low level of p210 BCR-ABL transcript, the expression of p190 is still detectable. The persistence of p190 signal despite the 2–3log fall in p210 BCR-ABL levels, may be of prognostic significance and may disclose unfolded concepts of biological relevance.
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Marin, David, Amr R. Ibrahim, Claire Lucas, Gareth Gerrard, Lihui Wang, Richard M. Szydlo, Richard E. Clark, et al. "Assessment ofBCR-ABL1Transcript Levels at 3 Months Is the Only Requirement for Predicting Outcome for Patients With Chronic Myeloid Leukemia Treated With Tyrosine Kinase Inhibitors." Journal of Clinical Oncology 30, no. 3 (January 20, 2012): 232–38. http://dx.doi.org/10.1200/jco.2011.38.6565.
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PurposeWe studied BCR-ABL1 transcript levels in patients with chronic myeloid leukemia in chronic phase (CML-CP) at 3, 6, and 12 months after starting imatinib to identify molecular milestones that would predict for overall survival (OS) and other outcomes more reliably than serial marrow cytogenetics.Patients and MethodsWe analyzed 282 patients with CML-CP who received imatinib 400 mg/d as first-line therapy followed by dasatinib or nilotinib if treatment with imatinib failed. We used a receiver operating characteristic curve to identify the cutoffs in transcript levels at 3, 6, and 12 months that would best predict patient outcome. We validated our findings in an independent cohort of 95 patients treated elsewhere.ResultsPatients with transcript levels of more than 9.84% (n = 68) at 3 months had significantly lower 8-year probabilities of OS (56.9% v 93.3%; P < .001), progression-free survival, cumulative incidence of complete cytogenetic response, and complete molecular response than those with higher transcript levels. Similarly, transcript levels of more than 1.67% (n = 87) at 6 months and more than 0.53% (n = 93) at 12 months identified high-risk patients. However, transcript levels at 3 months were the most strongly predictive for the various outcomes. When we compared OS for the groups defined molecularly at 6 and 12 months with the usual cytogenetic milestones, categorization by transcript numbers was the only independent predictor for OS (relative risk, 0.207; P < .001 and relative risk, 0.158; P < .001, respectively).ConclusionA single measurement of BCR-ABL1 transcripts performed at 3 months is the best way to identify patients destined to fare poorly, thereby allowing early clinical intervention.
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Marin, David, Corinne Hedgley, Richard E. Clark, Jane F. Apperley, Letizia Foroni, Dragana Milojkovic, Christopher Pocock, John M. Goldman, and Stephen O'Brien. "The Predictive Value of Early Molecular Response in Chronic Phase CML Patients Treated with Dasatinib First Line Therapy." Blood 118, no. 21 (November 18, 2011): 785. http://dx.doi.org/10.1182/blood.v118.21.785.785.
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Abstract Abstract 785 We assessed the correlation between molecular response at 3 and 6 months of dasatinib 100mg daily treatment and subsequent cytogenetic and molecular responses in 150 newly-diagnosed chronic phase CML patients treated with front line dasatinib in the UK SPIRIT 2 study (imatinib vs dasatinib). The median age was 54 years (range 18.4–82.1); 90 patients were male. The Sokal risk distribution was: 39 low, 65 intermediate and 46 high. At diagnosis 26 patients had splenomegaly >10cm below the costal margin; median WBC and platelet count were 65.7 (2.2-428) and 404 (101-2,433). The median hemoglobin level was 11.0 g/dl (4.17-15.8). The median percentage of blasts and basophils in peripheral blood was 0.4% (0-13.5) and 3.6% (0-19.2) respectively. The dose of dasatinib was adjusted according to tolerance. BCR-ABL1 transcripts in the peripheral blood were analyzed at 12 week intervals using RQ-PCR. Results were expressed as percentage ratios relative to an ABL1 internal control and expressed on the international scale. Complete molecular response (CMR) was defined as two consecutive samples with no detectable transcripts (RQ-PCR negative) and ABL1 control >40,000 (the median ABL1 control in the CMR samples was 96,000). In addition, we also explored a less stringent definition of CMR, namely CMR4.5 which was recently defined by the EUTOS group as BCR-ABL1 ratio of 0.0032 on the international scale, consistent with a 4.5 log reduction in the transcript level, without necessarily being RQ-PCR negative. With a median follow up of 15 months (range 6–29) the 2 year cumulative incidences (CI) of CCyR, MMR, CMR4.5 and CMR were 84.5, 72.1, 24.1 and 5.6% respectively. The median BCR-ABL/ABL ratios at 3, 6, 12 and 24 months were 0.830%, 0.093%, 0.040% and 0.034% respectively. We investigated the predictive value of the BCR-ABL1 transcript levels at 3 (>10% vs ≤10% and >1% vs ≤1%) and 6 months (>1% vs ≤1%) of dasatinib therapy on the 2 years CI of cytogenetic and molecular responses. The 135 patients who at 3 months had a BCR-ABL1/ABL1 ratio ≤10% and the 81 patients who had a ratio ≤1% had a significantly better 2 year CI of CCyR (89.1% vs 50.2%, p=0.02 and 100% vs 84.7%, p=0.01), MMR (83.7% vs 14.2%, p=0.004 and 85.2% vs 54.3 p<0.001), CMR4.5 (25.0% vs 0%, p<0.18 and 37.6 v 3.3% p=0.001) but not CMR (6.7 vs 0%, p=0.51 and 7.1 vs 0% p=0.46). Similarly, the 109 patients who at 6 months had a transcript ratio ≤1% had a better 2 year CI of MMR (86.3 vs 13.9%, p<0.001), CMR4.5 (31.2 vs 0%, p=0.03) and CMR (14.3 vs 0%, p=0.04) than the remaining patients. We used a receiver operating characteristic (ROC) curve to identify the optimal cut-off in the transcript level at 3 and 6 months that would predict the probability of each outcome with maximal sensitivity and specificity. Table 1 shows the results of applying the optimal cutoffs for each outcome in the 3-month analysis. Then we investigated whether the various outcomes could be better predicted using the cut-offs defined at 3 or at 6 months (including both the 1 and 10% cut-offs and the newly identified cut-offs) by using a multivariate model. For each outcome the cut-off defined at 3 months shown in Table 1 was superior. No pre-therapy patient characteristics were an independent predictor for cytogenetic or molecular response.Table 1.CI of the various responses according to cut-offs identified in the ROC analysis.3 month BCR-ABL1/ABL1 ratio (%)n2 year CI (%)pCCyR10493.3p<0.001≤2.724675.9>2.72MMR7987.6p<0.001≤0.967152.7≥0.96CMR4.55649.7p<0.001≤0.378947.1>0.387CMR4220.1p=0.01≤0.241080>0.24 The key finding from this analysis is that patients who achieve a transcript level ≤10% after 3 months of dasatinib (135 of 150) have an 89.1% probability of eventually achieving CCyR, compared to 50.2% for patients with higher transcript levels (p=0.02). This preliminary observation may allow the identification of around 10% of dasatinib-treated patients for whom other forms of treatment might be considered although our conclusions require verification in further studies. The predictive power of RQ-PCR assessment can be greatly improved by identifying the optimal cut-offs for the specific outcomes, which is particularly important when predicting for the achievement of CMR. It remains uncertain whether these differences in response will translate into differences in survival and the SPIRIT 2 study continues to address this question. Disclosures: No relevant conflicts of interest to declare.
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Alaiya, Ayodele, Mahmoud Aljurf, Zakia Shinwari, Fahad Z. Alsharif, Hazza A. Alzahrani, Syed Osman Ahmed, Tarek Owaidah, et al. "Proteomics Analysis Reveals Protein Panels That Are Associated with Prediction to Tyrosine Kinase Inhibitors Response, Bone Marrow Transplant, Survival and Disease Outcome of Chronic Myeloid Leukemia Patients." Blood 132, Supplement 1 (November 29, 2018): 5434. http://dx.doi.org/10.1182/blood-2018-99-118754.
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Abstract Clinical and molecular diagnosis of most hematological malignancies including Chronic Myeloid Leukemia (CML) can be accurately made. However, prediction of treatment response and estimation of disease survival period eludes the currently available tools for patient care. Quantitative expression proteomics can potentially be developed as effective tool to monitor therapy response towards achieving personalized medicine for CML patients. We have over 10 years follow up period for some of the CML patients, and the majorities of them are alive and doing well on Imatinib. On the other hand, a small fraction of the patients were switched to alternative Tyrosine Kinase Inhibitors (TKI) and some underwent bone marrow transplants (BMT). Our follow up results stratified all 37 analyzed newly diagnosed CP-CML patients into 5 distinct cohorts including 52% on Imatinib, 12% on Nilotinib, 9% on Dasatinib, and 15% BMT, while 12% of the patients had disease-related mortality. Kaplan-Meier survival curve showed no significant difference between all patients on TKI and BMT that were alive under a follow up period of 4-11 years compared. On the other hand 3 of 4 patients had disease related deaths less than 2 years of diagnosis. Only one patient survived for almost 10 years (Figure 1). Besides survival analysis, peripheral blood samples obtained from the patients at time of diagnosis were subjected to expression proteome analysis using label-free quantitative liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). A subset of significantly differentially expressed proteins was able to distinctively discriminate samples into their respective treatment response and disease outcome groups based on unique protein expression signatures (P<0.05 and > 2- ∞- fold change, (Figure 2). Some of the identified proteins were implicated in hematological diseases including CML as potential biomarkers using Ingenuity Pathway Analysis. These protein signatures once validated in larger sample cohorts might be capable of prediction of molecular response, choice of therapy and disease outcome for CML patients. Therefore; allowing for identification of would be high risk patients that might potentially benefit from aggressive treatment at point of diagnosis pre initiation of conventional therapy. Altogether our findings indicate that analysis of panel of protein markers have the potential of clinical utility for prediction of response to therapy, disease survival and objective prognostication of disease outcome, thus bringing personalized medicine closer to CML patients. Disclosures No relevant conflicts of interest to declare.
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Picou, Frederic, Jean-Claude Chomel, Marie Christine Bene, Marc G. Berger, Thierry Fest, Valerie Ugo, Eric Lippert, et al. "Prediction of One-Year Molecular Response to Imatinib at Diagnosis of Chronic Myeloid Leukemia By Scoring Gene Expression Levels of Antioxidant Enzymes." Blood 132, Supplement 1 (November 29, 2018): 3024. http://dx.doi.org/10.1182/blood-2018-99-118297.
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Abstract Introduction Frontline treatment of patients in chronic phase of chronic myeloid leukemia(CP-CML) is classically based on tyrosine kinase inhibitors (TKI). Imatinib was introduced in 1998, then second- and third-generation TKIs have been developed. This therapeutic arsenal suggest a possible personalized treatment. The choice of TKI could be guided on the one hand by the potential adverse effects depending on the co-morbidities and on the other hand, the efficiency of treatment since an optimal response during the first year is a therapeutic goal (Baccarani M et al. A review of the European LeukemiaNet recommendations for the management of CML. Ann Hematol 2015, 94 Suppl 2:S141-7). Treatment inefficacy may be related to the persistence of quiescent leukemic cells, characterized by a decreased metabolic activity and redox metabolism inducing a low proliferation rate athough the BCR-ABL mutation is present. The level of reactive oxygen species (ROS) being regulated by antioxidant enzymes, we hypothesized that scoring gene expression levels of major antioxidant enzymes could be of clinical interest when considering the response to imatinib. By combining the gene expression profiles of CP-CML patients at the time of diagnosis and their molecular response (BCR-ABL1/ABL1 ratio) at one-year, we determined a theranostic Imatinib-Response Score (IRS) potentially useful to optimize therapeutic decisions (patent # WO2016083742). Methods The expression of antioxidant genes was quantified from blood samples collected from 122 CP-CML patients at diagnosis and 102 healthy volunteers (HealthOx protocol, ClinicalTrials.gov # NCT02789839). Sokal-scores were calculated and all patients were treated with imatinib for at least one year. Quantification of the BCR-ABL1/ABL1 ratio allowed to determine of the one-year response according to the ELN definition (optimal: BCR-ABL1/ABL1 ≤ 0.1%, warning: BCR-ABL1/ABL1 0.1-1%, failure: BCR-ABL1/ABL1 > 1%). RNA extraction was performed after red blood cell lysis and RNA quality was checked with a 2100 Bioanalyzer (Agilent). The expression of antioxidant genes (SOD1, SOD2, SOD3, CAT, TXN, TXN2, GLRX, GLRX2, GLRX3, GLRX5, GPX1, GPX2, GPX3, GPX4, GPX7, GSR, PRDX1, PRDX2, PRDX3, PRDX4, PRDX5, PRDX6) and 3 housekeeping genes (ACTB, B2M, RPL13A) was quantified by RT-qPCR (LightCycler® 480 and UPL technology, Roche). All targets were concomitantly analyzed in triplicates and average values from patients and aged-matched healthy controls were used to determine Relative Quantification (RQ) values by the 2-ΔΔCt method. Mutations in the ABL kinase domain were studied by direct sequencing. IRS were determined by logarithmic logistic regression performed thanks to the glm() function of the stats package (R v3.2.2 software). The generalized linear model was obtained by logistic regression with weighted RQ and was validated by split-sample strategy (10,000 repeats). Samples were divided into two groups ("learning" and "test" groups) randomly mixing optimal responses and failures. Results and conclusion None of the patients had a mutation in the BCR-ABL kinase domain. The expression levels of numerous antioxidant genes were different when considering optimal response and failure to imatinib treatment. A multifactorial strategy by linear combination of normalized RQ values was used to calculate IRS, which allowed for an efficient discrimination between optimal response(IRS = -3.42±1.44) and failure (IRS = 1.76±0.64) (p-value = 1.4 10-9). The probability of one-year response to imatinib was assessed by empirical cumulative distribution function. This function allowed the prediction of optimal response and failure. As expected, the IRS values of patients with a warning response, not used to build the mathematical model (external validation), were located between those of optimal response and failure. Interestingly, the IRS was not correlated with Sokal-score of CP-CML patients (R2= 0.0333), reinforcing its potential usefulness for clinical management. Altogether, this retrospective multicentric study allowed the determination of a molecular score to predict imatinib response. This simple biological strategy using diagnosis blood sample of CP-CML patients will benefit from prospective studies to adapt therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.
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Martynkevich, Irina, Vasily Shuvaev, Ekaterina Petrova, Lyubov Polushkina, Lyudmila Martynenko, Marina Ivanova, Natalya Cybakova, et al. "Early Molecular Response in Chronic Myeloid Leukemia Patients Predicts Future Response Status." Blood 124, no. 21 (December 6, 2014): 5529. http://dx.doi.org/10.1182/blood.v124.21.5529.5529.
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Abstract Objectives and background: The level of early MR is important for the optimization of therapy and making a decision to a switch to 2nd line therapy in patients (pts) who have not achieved an optimal response (OR). According to the recent recommendations at definition of OR on CML therapy, pts must have the level of BCR-ABL transcript gene at 10% or less and Ph-positive cells 35% or less at 3 months. But, in half of all cases of pts with BCR-ABL >10% at 3 months progression events happen between 3 and 6 months. The goal of our research was to investigate the prognostic impact of a large BCR-ABL transcript amount at 3 months on the subsequent response and the long-term outcome of CML pts treated frontline with IM. Methods: We have examined 185 pts, who have got IM from January 2010 up to the present. Molecular monitoring has been done regularly in all patients according to ELN recommendations. Median age was 49 years. All pts were in CP. BCR-ABL transcript levels were assessed by real-time quantitative PCR. Results: In our study 54% (100/185 cases) of pts achieved the optimal response with BCR-ABL transcript levels ≤10% at 3 months, 50,3% (93/185 cases) did it - with BCR-ABL transcript levels ≤1% at 6 months, and only 18% achieved the optimal response at 12 months. The comparative analysis has shown statistical differences in all characteristics in 2 groups of pts, who either achieved or not the optimal response at 3 months. Pts with BCR-ABL transcript levels ≤10% more often achieved CCgR at 6 months (g=0,0000), CCgR during all period (g=0,0004), MMR at 12 months (g=0,0000), MMR during all period (g=0,0012) and MR4 during all period (g=0,0000), pts had londer event-free (g=0,0432) and overall (g=0,0279) 4-year survival. Figure 1 Figure 1. In our center we have switched 6 patients to the 2nd TKI - those who didn't achieve the optimal response at 3 months. The switching showed the positive influence on loss level expression of BCR-ABL gene in 5 out of 6 patients. After that all patients achieved the optimal response in the future. For example, we had one patient with failure of IM at 3 months. We switched him the therapy to NI in 5 months after the diagnosis. As a result the patient achieved CCgR at 1,5 months, and the deep molecular response 4,5 log at 3 months. Conclusions: Early and deep responses to TKIs are predictive of long-term response and favorable survival outcomes. 3-month reduction in BCR-ABL transcript levels to >10% is a factor of bad effectiveness of TKI therapy and requires switching to the 2nd TKI. Timely switching to the 2nd TKIs allows us to achieve an optimal response in CML patients with level BCR-ABL >10% at 3 months. References: Timothy P. Hughes, Giuseppe Saglio, Hagop M. Kantarjian et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood, 27 February 2014 x Volume 123, Number 9. Disclosures No relevant conflicts of interest to declare.
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de Lavallade, Hugues, Jamshid S. Khorashad, Marco Bua, Dragana Milojkovic, Eduardo Olavarria, Alistair Reid, Jaspal S. Kaeda, John M. Goldman, Jane F. Apperley, and David Marin. "Long Term Durability of Major Molecular Responses for Patients Treated with Imatinib after Failure of Interferon-Alfa Is Equivalent to That of Patients Achieving Major Molecular Responses to Imatinib as Primary Therapy." Blood 110, no. 11 (November 16, 2007): 1037. http://dx.doi.org/10.1182/blood.v110.11.1037.1037.
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Abstract Imatinib is remarkably effective in treating patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) but somewhat less effective in treating patients who have previously received interferon-alfa (IFN), most of whom can be classified as being in ‘late CP’. For such patients who have failed IFN, a proportion achieve complete cytogenetic responses (CCyR) and subsequently major molecular responses (MMolR) on imatinib, but the durability of these responses is not yet established. We analyzed long-term outcomes for 216 consecutive CML-CP patients who started on imatinib after failing IFN at our institution. Their Sokal risk score was ‘low’ in 58 (27%) patients, ‘intermediate’ in 75 (35%) and ‘high’ in 83 (38%). At the time of starting imatinib 73 (34%) patients were IFN intolerant, 40 (18%) were hematologically resistant to IFN and 103 (48%) were cytogenetically resistant; of this last group 58 (27%) had primary resistance and 45 (21%) secondary resistance. The median interval between diagnosis and start of imatinib was 38 months (range 6 to 217). Ninety-two patients (42.6%; 95CI, 36.0–49.5%) achieved CCyR during follow-up; the estimated cumulative incidence of CCyR at 5 years was 46.8% (95CI 40.0–53.7%). Forty-five patients (20.8%; 95CI, 15.6–26.9%) achieved a MMolR; the estimated cumulative incidence of MMolR at 5 years was 23.7% (95CI 16.6–32.8%). The independent factors predicting achievement of MMolR were prior response to interferon and favorable Sokal category: the relative risks (RR) for achievement of a MMolR response were 3.34 for patients with secondary cytogenetic resistance to IFN (p< 0.0001) and 0.5 and 0.2 for the Sokal intermediate and high risk groups respectively (p=0.012). For the 45 patients who achieved a MMolR the median follow-up was 68 months (range, 32–85 months); 24 (53%) patients achieved a 4-log reduction in the BCR-ABL transcript level, and in 10 (22%) cases the transcripts became undetectable. By intention-to-treat analysis the estimated progression-free survival (PFS, defined as loss of complete hematologic response or progression to advanced phase) for this group at 72 months was 100%. At latest follow-up 7 patients (16%) had lost their MMolR but only 2 (4%) of these had lost their CCyR. When comparing those 45 patients with 76 CML-CP patients who received front-line imatinib and achieved a MMolR (out of 207 patients at our institution), we found no differences in terms of cumulative loss of CCyR (p=0.60) or of MMolR (p= 0.94), suggesting a comparable durability of the responses in these two patient groups. In conclusion, although patients who receive imatinib in late CP generally fare worse than patients starting imatinib soon after diagnosis, patients in the two groups who achieve a MMolR have equivalent outcomes.
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Ezeanosike, Obumneme B., and Onyenmechi J. Afonne. "Prognostic significance of micro RNA 150 marker in BCR-ABL positive chronic myeloid leukaemia patients on imatinib mesylate." International Journal of Contemporary Pediatrics 4, no. 5 (August 23, 2017): 1557. http://dx.doi.org/10.18203/2349-3291.ijcp20173763.
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Background: Micro-RNAs control gene expression by destabilizing targeted transcripts and inhibiting their translation. In chronic myeloid leukaemia (CML), abnormal expressions of miRNAs have been described. The current treatment for newly diagnosed cases of CML is imatinib mesylate which produces rapid haematological responses. It is currently impossible to predict whether a patient will develop resistance to imatinib mesylate. This makes identification of predictors of resistance to imatinib an important goal in management of patients with CML. MicroRNA expression patterns can be used to predict outcome which can be remission or relapse. This study therefore, was set to assess the possible use of microRNA 150 for prognostication.Methods: Fifty peripheral blood samples previously collected from CML patients who were being treated with imatinib mesylate and stored in the refrigerator at +4°C were analyzed for the expression of microRNAs 150. Total RNA was extracted from guanidium isothiocynate (GITC) lysate of the blood samples using RNeasy mini spin column. The total RNA was converted to complimentary DNA by random hexamer priming using Murine Moloney Leukaemia Virus Reverse Transcriptase. Real time Multiplex PCR was used for detecting Breakpoint Cluster Region-Abelson Murine Leukaemia (BCR-ABL) transcript type.Results: The patients’ samples showed an expression of miRNA-150. Correlation of BCR-ABL ratio with miRNA-150 was done and the Spearman correlation coefficient (Rho) between BCR-ABL1 and miRNA-150 was 0.442 (p = 0.001; CI = 0.18-0.65) showing that there was a positive correlation between BCR-ABL1 and miRNA-150. The coefficient of determination was 20% (CI = 3-42%), which implies that about 20% of BCR-ABL1 ratio could be accounted for by the miRNA-150 values.Conclusions: Therefore, once patients who are on imatinib achieve molecular remission of the CML, the miRNA-150 can be useful in predicting outcome which could be relapse or complete molecular remission but is weak at diagnosis in predicting such outcome.
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Vigneri, Paolo, Fabio Stagno, Stefania Stella, Alessandra Cupri, Michele Massimino, Agostino Antolino, Vincenzo Abbadessa, et al. "BCR-ABLIS Expression at Diagnosis and After 3 or 6 Months of Treatment Predicts CML Response to IMATINIB Therapy." Blood 116, no. 21 (November 19, 2010): 3426. http://dx.doi.org/10.1182/blood.v116.21.3426.3426.
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Abstract Abstract 3426 Imatinib mesylate (IM) has shown remarkable efficacy for the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. However, while most individuals achieve an optimal response to conventional IM therapy, approximately 30% either fail IM or develop intolerance to the drug. Thus, there is a growing need for biological parameters predictive of IM response (at diagnosis or during the first months of therapy) in order to recognize pts with a more aggressive disease that should receive alternative treatments. We examined the outcomes of the first 193 CML pts accrued to the observational SCREEN (Sicily and Calabria CML REgional ENterprise) multicenter non-sponsored study, and analyzed the responses of this unselected population. Pts characteristics were as shown in Table 1. All subjects received IM 400 mg daily. Median follow-up was 26 months (range 3–60). Complete hematological (CHR), cytogenetic (CCyR) and major molecular responses (MMR) were rated according to the European Leukemia Net 2006 guidelines. Peripheral blood samples were used for BCR-ABL determination by quantitative real-time polymerase chain reaction according to the International standardized Scale (IS). To identify parameters predictive of IM response, pts were stratified according to clinical and molecular responses or BCR-ABL transcript levels at diagnosis and analyzed for their outcome on an intention to treat basis. At 12 months, cumulative incidences of CHRs, CCyRs and MMRs were 100%, 82% and 43%, respectively. At 24 months, incidences of CCyR and MMR increased to 87% and 67%. According to the ELN criteria, 121 pts (62%) achieved an optimal response; 36 pts (19%) had a suboptimal response; 32 pts (17%) failed IM because of either primary (20 pts) or secondary (12 pts) resistance. Only 4 pts (2%) were intolerant to IM. Kaplan-Meyer estimates for overall, progression-free, event-free and failure-free survival at 60 months were 99%, 96% 80% and 72%. When we clustered all subjects in optimal responders (ORs) and suboptimal/resistant (S/R) pts and correlated response to therapy with various molecular characteristics we found that the amount of BCR-ABLIS transcripts at diagnosis predicted response to IM. Indeed, the median amount of BCR-ABLIS at diagnosis displayed by patients that failed IM or achieved a suboptimal response was significantly higher (104.154IS) than that of patients obtaining an optimal response (53.478IS; p=0.000611). As WBC counts were not significantly different between ORs and S/R pts (p=0.2065), increased amounts of BCR-ABLIS transcripts were probably representative of the aggressiveness of the leukemic clone. We also observed that pts displaying >10% BCR-ABLIS after 3 or 6 months of IM had a significantly lower chance of achieving a CCyR compared to pts with BCR-ABLIS levels lower than 10% (p<0.001). IM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR, CCyR and MMR. However, 35–40% of newly diagnosed CML pts will either fail IM or obtain a suboptimal response. High levels of BCR-ABLIS transcripts at diagnosis may allow the rapid identification of CML pts that are likely to fail IM or to achieve a suboptimal response. Furthermore, failing to achieve BCR-ABLIS transcript levels <10% after 3 or 6 months of IM treatment significantly reduces the probability of subsequently obtaining a CCyR. Table 1. Characterisitics of CML pts included in the SREEN study Age (median yrs) 54 (range 24–90) Sex (M/F) 108/85 WBC × 109/L (median) 64.8 (range 3.4–718.0) Hb (g/dL) 12.1 (range 7.5–17.0) PLT × 109/L (median) 330.0 (range 67.0–1690.0) Organomegaly % 58 Sokal risk stratification % 49 Low/36 Intermediate/15 High Ph+ % (diagnosis) 96 ACA % (diagnosis) 7 BCR-ABL transcript variants % 38 e13a2/53 e14a2/9 other BCR-ABLIS % (median at diagnosis) 58.641 Disclosures: No relevant conflicts of interest to declare.
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Esposito, Nicola, Fabrizio Quarantelli, Luigia Luciano, Barbara Izzo, Anna Lucia Peluso, Marco Picardi, Susan Branford, et al. "The Expression of shp-1 and SHP-2: A Novel Powerful Predictor of Major Molecular Response (MMR) Achievement in Chronic Myeloid Leukemia Gleevec-Treated Patients Enrolled into the TOPS Clinical Trial." Blood 112, no. 11 (November 16, 2008): 1106. http://dx.doi.org/10.1182/blood.v112.11.1106.1106.
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Abstract Imatinib (Ima) has dramatically improved the outcome of patients affected by chronic myeloid leukemia (CML) and became the standard care for patients with newly diagnosed CML in chronic phase (CP). In spite of treatment progresses and novel biological findings, Sokal index is still a dominant prognostic determinant of newly diagnosed CML patients also in the era of targeted therapies. In this study we investigated the predictive role of the levels of expression of two SHP-constitutive non receptor protein tyrosine phosphatase, the SHP-1 and SHP-2, in leukemia cells obtained from 48 newly diagnosed CML patients enrolled into the TOPS (Tyrosine kinase inhibitor Optimization and Selectivity) trial. TOPS is a prospective, open-label, randomized (2:1) Phase III trial that compared Ima 800mg/d to 400mg/d in CP-CML. The findings end point of the trial is the rate of major molecular response (MMR) indicated by several reports as a parameter that predict a benefit for progression free survival (PFS). Results indicate that the mRNA levels of both SHP1 and SHP2 assayed by QPCR in peripheral blood of newly diagnosed the patients and expressed as ratio to ABL, are significantly different between those patients who do and do not achieved MMR by 12 months (7.4 ± 3.8 vs 6.0 ± 3.2, p = 0.017 for SHP1/Abl % and 0.19 ± 0.15 vs 0.10 ± 0.12, p = 0.017 for SHP2/ABL%). There is not statistical evidence that patients who achieved MMR earlier than 12 months i.e. at 6 and 9 months, have different baseline levels of SHP1 or SHP2, however the data are suggestive of a difference which might become statistically significant with a larger sample size. Complete cytogenetic response, CCyR, was a secondary end point of the TOPS study, overall, 65% have achieved CCyR by 6 months, and 85% by 12 months, and although not statistically different, results indicate that both SHP1 and SHP2 levels tended to be higher in patients who obtained CCyR, and the our further study with a larger sample size will show if the differences might become significant. .SHP1/ABL % and SHP2/ABL % are weakly correlated each other in the patients, therefore each independently acts as predictor of MMR at 12 months and logistic regression indicated that the combination increases their prognostic value for predicting MMR in the first 12 months and using logistic regression, Sokal score does not add any discriminating power to either of those markers (either alone or in combination). In conclusion, our results indicate, that the levels of expression of SHP1 and SHP2 are useful predictors of MMR in newly diagnosed CP-CML patients. These data confirm our prior findings from “in vitro” studies, which investigated the role of SHP1 and SHP2 phosphatases in mechanisms which regulate Imatinib sensitivity.
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Branford, Susan. "Molecular monitoring in chronic myeloid leukemia—how low can you go?" Hematology 2016, no. 1 (December 2, 2016): 156–63. http://dx.doi.org/10.1182/asheducation-2016.1.156.
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Abstract Molecular monitoring of BCR-ABL1 transcripts for patients with chronic myeloid leukemia (CML) is now used to assess response to tyrosine kinase inhibitors (TKIs), including treatment failure that mandates a change of therapy. Therefore, many centers have adopted the molecular technique for measuring BCR-ABL1 and rely on conversion of values to the international reporting scale for appropriate clinical interpretation. However, the technique has a degree of inherent variability despite standardized procedures, which means care should be taken by the clinician when assessing response based on BCR-ABL1 cutoff limits. The last few years have witnessed the emergence of a new molecular response target, which is the achievement and maintenance of a deep molecular response. The ability to achieve treatment-free remission for some patients has shifted the relevant boundary for molecular response. However, the definitive safe BCR-ABL1 transcript level and length of the maintenance phase after which treatment cessation can be attempted has not yet been determined. For patients with TKI resistance, BCR-ABL1 kinase domain mutation analysis remains an essential assessment to guide therapy. Furthermore, low-level mutation detection is clinically relevant for response prediction to subsequent TKI therapy for some patients. Multiple low-level mutations may be a biomarker of a clonally diverse disease with the propensity for resistance evolution. Overall, molecular monitoring, including low-level monitoring is a fundamental component of management for patients with CML.