Artykuły w czasopismach: „Relapse”

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Wudhikarn, Kitsada, Pinyo Rattanaumpawan i Margarida M. Silverman. "Characterization of Extramedullary Relapse After Allogeneic Stem Cell Transplant in Acute Myeloblastic Leukemia: Distinct Entity and Outcome". Blood 120, nr 21 (16.11.2012): 1972. http://dx.doi.org/10.1182/blood.v120.21.1972.1972.

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Abstract Abstract 1972 Introduction: Relapse after allogeneic stem cell transplant (SCT) is a major cause of morbidity and mortality of acute myeloblastic leukemia (AML) patients. Most relapses primarily involve bone marrow whereas extramedullary (EM) relapses are relatively uncommon. Data on natural history, optimal management and treatment outcome in EM relapse following allogeneic SCT are limited. Method: We retrospectively reviewed 130 AML patients who underwent allogeneic SCT at the University of Iowa Hospitals and Clinics between January 2003 and December 2010. Pre-transplant baseline characteristics and post-transplant variables were abstracted. Patterns of relapse after allotransplant, management and outcome were reported. Result: Among 130 AML patients who underwent allogeneic SCT, we identified 61 (47%) relapsed AML after allotransplant. Of 61 relapsed cases, there were 7 (12%) isolated EM, 44 (72%) isolated bone marrow (BM) and 10 (16%) concurrent BM + EM relapses. Among 17 EM relapsed cases, there was a higher prevalence of acute monocytic leukemia subtype (41.5% VS 2.3%, odd ratio [OR] = 4.1, p=0.03), moderate to severe chronic graft versus host disease (GVHD) (35.3% VS 4.6%, OR=2.3, p=0.01) compared to non-EM relapsed patients. Median time to relapse in EM cases was significantly longer than non-EM group (428 days, 95% confidence interval [CI] 203–652 VS 162 days, 95%CI 100–231, p=0.003). EM relapse sites included 1 pulmonary (6%), 3 (18%) genitourinary, 7 (41%) skin/soft tissue, 2 (12%) gastrointestinal and 4 (23%) multisystem involvement. Of 17 EM relapsed cases, 12 (71%) had immunosuppression withdrawn, 13 (76%) received systemic chemotherapy with/without donor lymphocytic infusion and 7 (41%) had radiation therapy to EM relapse sites. The 6-month survival after relapse of EM patients was significantly higher than non-EM group (29.4%, 95%CI 10.7–51.2 VS 6.8%, 95%CI 1.8–16.7, p=0.014). Further subgroup analysis showed that isolated EM relapsed group had significantly higher 6-month survival after relapse than systemic relapse group (isolated BM or concurrent EM + BM) (42.9%, 95%CI 9.8–73.4 VS 9.3%, 95%CI 3.4–18.7, p=0.008). Table 1 compares the management and outcome between isolated EM relapse and concurrent BM + EM relapse. At the time of analysis, three (18%) of 17 EM relapsed cases (all of which were isolated EM patients) achieved disease controlled/remission and remained alive at 10, 13 and 19 months following relapse respectively. Cox proportional hazards analysis identified low hematopoietic cell transplant comorbidity index (HR 0.86, 95%CI 0.74–0.99, p=0.038), relapse after 180 days (HR 0.05, 95%CI 0.01–0.16, p<0.001) and presence of chronic GVHD (HR 3.57, 95%CI 1.02–12.45, p=0.04) to be associated with favorable survival after relapse. Conclusion: EM relapse of AML after alloSCT presents later than bone marrow relapse and occurs despite the presence of GVHD, especially chronic GVHD. As transplant survival has improved, increasing EM relapses have been observed. Although appropriate management is unknown, prognosis of EM relapse is better than systemic relapse and durable remission can be achieved. Disclosures: No relevant conflicts of interest to declare.

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Wang, Yucai, Umar Farooq, Brian K. Link, Melissa C. Larson, Rebecca L. King, Matthew J. Maurer, Cristine Allmer i in. "Late Relapses in Patients With Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy". Journal of Clinical Oncology 37, nr 21 (20.07.2019): 1819–27. http://dx.doi.org/10.1200/jco.19.00014.

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PURPOSE In patients with diffuse large B-cell lymphoma (DLBCL), most relapses occur within the first 2 years of diagnosis. We sought to define the rate and outcome of late relapses that occurred after achieving event-free survival at 24 months (EFS24). METHODS We prospectively followed 1,324 patients with newly diagnosed DLBCL from 2002 to 2015 and treated with immunochemotherapy. Cumulative incidences of late DLBCL and indolent lymphoma relapses were analyzed as competing events. Postrelapse survival was defined as time from first relapse to death from any cause. RESULTS In 847 patients who achieved EFS24, the cumulative incidence of late relapse was 6.9% at 3 years, 9.3% at 5 years, and 10.3% at 8 years after EFS24. The incidence of DLBCL relapse was similar in patients with DLBCL alone at diagnosis (6.3% at 5 years), compared with patients with concurrent indolent lymphoma at diagnosis (5.2%; P = .46). However, the rate of indolent lymphoma relapse was higher in patients with concurrent indolent lymphoma (7.4% v 2.1% at 5 years; P < .01). In patients with DLBCL alone, the rate of DLBCL relapse was similar in the germinal center B-cell–like (GCB) (4.1% at 5 years) and non-GCB (4.0%; P = .71) subtypes, whereas the rate of indolent lymphoma relapse was higher in patients with the GCB subtype (3.9% v 0.0% at 5 years; P = .02). Postrelapse survival was inferior for patients who relapsed with DLBCL than for those who relapsed with indolent lymphoma (median 29.9 months v unreached; P < .01). CONCLUSION Patients with DLBCL with a concurrent indolent lymphoma and those with the GCB subtype had a higher rate of late relapse, owing to increased relapses with indolent lymphoma. Patients who relapsed with DLBCL had a worse prognosis than those who relapsed with indolent lymphoma.

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Ganzel, Chezi, Wang Xin Victoria, Adele K. Fielding, Jacob M. Rowe, Susan M. Richards, Georgina Buck, Rajesh Chopra i in. "in Philadelphia-Chromosome-Negative Acute Lymphoblastic Leukemia, Late Relapses Are Not Uncommon, Occur Mostly in Patients at Standard Risk and Have a Relatively Favorable Outcome. Results of the International ALL Trial: MRC Ukallxii/ECOG E2993". Blood 126, nr 23 (3.12.2015): 795. http://dx.doi.org/10.1182/blood.v126.23.795.795.

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Abstract This study was coordinated by the ECOG-ACRIN Cancer Research Group (Robert L. Comis, MD and Mitchell D. Schnall, MD, PhD, Group Co-Chairs) and the Medical Research Counsel, United Kingdom, and supported in part by Public Health Service Grants CA180820, CA180794, CA180790, CA189859, CA180853, CA180791, and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Its content is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute. Background: Late relapse in acute leukemia is considered a relatively rare event. Patients with acute myeloid leukemia (AML) are often considered cured of the disease at 3 years, but information regarding adult acute lymphoblastic leukemia (ALL) patients is scarce. Data are presented from one of the largest prospective adult ALL studies, the MRC UKALLXII/ECOG E2993, to evaluate the rate and characteristics of late relapse in ALL. For this purpose, late relapse was defined, arbitrarily, as relapse 3 years post achievement of complete remission (CR) and very late relapse was defined as relapse > 5 years from CR. Methods: The UKALLXII/ECOG E2993 was an international ALL trial conducted jointly by the MRC in the United Kingdom and ECOG in the United States. All patients received identical induction therapy, followed by central nervous system prophylaxis. Patients with a sibling donor (or a matched unrelated donor in Philadelophia-chromosome-positive ALL) were assigned to receive an allogeneic hematopoietic stem cell transplant (HSCT); all others were randomized to undergo an autologous transplant or protracted standard consolidation/ maintenance therapy. The study accrued 2109 patients from 1993 to 2008. Following relapse, patients were followed for survival. For this report only patients registered before the tyrosine kinase inhibitors era are included in the analysis. Results: 1518 study patients were eligible for this analysis, 1208 (79.6%) Philadelphia-chromosome negative (Ph-neg) and 267 (17.5%) Philadelphia-chromosome positive (Ph-pos). 1381 (91%) of the patients achieved CR; 93% of the Ph-neg and 82% of the Ph-pos. 572 patients (37.7%) underwent allogeneic HSCT. The median duration of follow-up of patients who achieved CR was 10 years. Among the 1381 patients who achieved CR, 626 (45.3%) had a documented relapse; 566 (90.4%) relapsed within 3 years of CR and 60 (9.6%) relapsed beyond 3 years ('late relapse') (Figure 1). Among these 60 patients, 18(2.9%) relapsed after 5 years ('very late relapse'). Table. Patients n CR All relapses Relapses< 3 years Relapses≥ 3 years Relapses≥ 5 years All patients 1518 1381 (91%) 626 (45.3%) 566 (90.4%) 60 (9.6%) 18 (2.9%) Ph-neg 1208 (79.6%) 1123 (93%) 485 (40.1%) 429 (88.5%) 56 (11.5%) 17 (3.5%) Ph-pos 268 (17.5%) 219 (82%) 124 (56.6%) 122 (98.4%) 2 (1.6%) 1 (0.8%) Relapse beyond 3 years occurred in 4.3% of all who achieved CR, in 5% of Ph-neg and 0.01% of Ph-pos patients. Among the 60 late relapses, the median time to relapse was 46 months. 61.7% of the late-relapse patients were males, median age was 32 years, 88.3% were B-lineage ALL and the median white cell count at diagnosis was 6000/ul. 56.7% were in cytogenetic standard risk, 8.3% at high risk and the data of 35% are unknown. The median survival for the late relapse patients was longer than for those who relapsed within 3 years. The overall survival (OS) of the 56 Ph-neg patients who relapsed beyond 3 years is shown in Fig 2. Table.Relapse > 3 yearsRelapse > 3 yearsMedian survival from relapse (months)5.411.23-year OS from relapse6.5%29%5-year OS from relapse5.6%19% Conclusions: Late relapses in adults with Ph-neg ALL are not uncommon. About 10% of relapses occur beyond 3 years and 4.3% of all ALL patients who achieved a CR can expect to have a late relapse. These data are in contrast to AML where only 1% of patients relapse beyond 3 years (Watts JM et al, 2014). Most of the late relapse patients were at standard risk and appeared to have a relatively favorable outcome post relapse. Patients with ALL, particularly those who are Ph-neg, cannot be considered as cured at 3 years and need to be closely followed. Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 1. Time to relapse of Ph-pos and Ph-neg ALL Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Figure 2. Survival from relapse for Ph-neg patients who relapsed after 3 years from CR. Disclosures Rowe: Amgen: Consultancy; BioSight Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; BioLineRx Ltd.: Consultancy. Douer:Gilead: Consultancy.

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Stolpa, Weronika, Magdalena Zapała, Bartosz Zwiernik i Agnieszka Mizia-Malarz. "Relapses Children’s Acute Lymphoblastic Leukemia, Single Center Experience". Children 9, nr 12 (30.11.2022): 1874. http://dx.doi.org/10.3390/children9121874.

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The prognosis in children and adolescents with relapsed ALL, despite intensive therapy, including hematopoietic stem cell transplantation, is still challenging. This study aims to analyze the incidence of relapsed ALL and survival rates in correlation to the risk factors. Materials and methods: 125 pediatric patients with ALL diagnosed in our department between 2000-2018; age 1–18 years old (median 6.4); female 53.6 % vs. male 46.4 %. Results: 19 pts (15.2%) were diagnosed with a relapse. Three pts (15.8%) had been diagnosed with very early relapses (2/3 T-ALL), 12 pts (63.1%) as an early relapse, and 4 pts (21.1%) as a late relapse. Bone marrow was the most frequent relapses localization. The five-year survival has been achieved by six patients (31.6%). A significant difference was found in regard to the five-year overall survival and relapse type (p < 0.05). The group with very early relapses (3/3; 100%) has not reached the five-year survival. Conclusions: 1. The main prognostic factor in children’s ALL relapses is still the time of the onset of the relapse. 2. The T lineage acute lymphoblastic leukemia is a worse prognostic factor. 3. The analysis of the above relapse risk factors alongside cytogenethic markers and flow cytometry or polymerase chain reaction minimal residual disease is very important for first-line chemotherapy improvement and a more personalized choice of therapy for ALL patients.

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Platte, Victoria, Anika Bergmann, Barbara Hildebrandt, Dagmar Wieczorek, Esther Schuler, Ulrich Germing, Jennifer Kaivers i in. "Clinical and Cytogenetic Characterization of Early and Late Relapses in Patients Allografted for Myeloid Neoplasms with a Myelodysplastic Component". Cancers 14, nr 24 (18.12.2022): 6244. http://dx.doi.org/10.3390/cancers14246244.

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An improved understanding of relapse kinetics is required to optimize detection and treatment strategies for the post-transplant relapse of myeloid neoplasms. Therefore, we retrospectively analyzed data from 91 patients allografted for MDS (n = 54), AML-MRC (n = 29) and chronic myelomonocytic leukemia (CMML, n = 8), who relapsed after transplant. Patients with early (<12 months, n = 56) and late relapse (>12 months, n = 35) were compared regarding patient-, disease- and transplant-related factors, including karyotype analyses at diagnosis and relapse. After a median follow-up of 17.4 months after relapse, late relapses showed improved outcomes compared with early relapses (2-yr OS 67% vs. 32%, p = 0.0048). Comparing frequency of distinct patient-, disease- and transplant-related factors among early and late relapses, complex karyotype (p = 0.0004) and unfavorable disease risk at diagnosis (p = 0.0008) as well as clonal evolution at relapse (p = 0.03) were more common in early than in late relapses. Furthermore, patients receiving transplant without prior cytoreduction or in complete remission were more frequently present in the group of late relapses. These data suggest that cytogenetics rather than disease burden at diagnosis and transplant-related factors determine the timepoint of post-transplant relapse and that upfront transplantation may be favored in order to delay relapse.

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Nagane, Motoo, Nobuyoshi Sasaki, Yuki Yamagaishi, Kuniaki Saito, Keiichi Kobayashi i Hirofumi Nakatomi. "CTNI-81. REAL-WORLD TREATMENT RESULTS OF RELAPSED PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA TREATED BY MEDICAL THERAPIES". Neuro-Oncology 25, Supplement_5 (1.11.2023): v96—v97. http://dx.doi.org/10.1093/neuonc/noad179.0363.

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Abstract Recurrence of primary central nervous system lymphoma (PCNSL) is a condition which often leads to morbidity and mortality. Consensus regarding the optimal treatment regimen for relapsed PCNSL has not been achieved due to the rarity of the disease. In this study, we conducted a retrospective, single-institution study to investigate real world treatment results of relapsed PCNSL treated by several medical therapeutic regimens. Relapsed PCNSL patients treated at the authors’ institution were identified, and progression-free survival (PFS), overall survival (OS) were analyzed among patients treated by medical therapies. Patients treated by radiotherapy, treated for intraocular or systemic relapses, or best supportive care, were excluded from the survival analysis. 83 patients with first, 44 with second, 25 with third relapse were identified. Upon each relapse, number of patients who received medical therapies for CNS lesions, radiotherapy, treatment for intraocular or systemic relapse, and best supportive care were 48 (57.8%), 5(6%), 4(4.8%), 26(31.3%) (first relapse), 31(70.5%), 3(6.8%), 1(2.3%), 9(20.5%) (second relapse), 13(52.0%), 0, 1(4%), 11(44.0%) (third relapse), respectively. A total of 101 CNS relapses were treated by medical therapies, and PFS (months), OS (months) of the four groups of treatments (rituximab, methotrexate, procarbazine and vincristine [R-MPV], methotrexate [MTX], tirabrutinib, and others) were as follows. PFS: 13.0, 4.5, 2.7, 3.0, and OS: 70.0, 26.4, 51.2, 9.7 (all relapse). PFS: 12.7, 7.0, 3.0, 3.2, and OS: 58.9, 33.1, not reached(n/r), 16.1 (first relapse). PFS: 34.3, 3.9, 25.3, 1.5, and OS: n/r, 28.1, 25.5, 7.5 (second relapse). PFS: 10.1, 3.9, 2.4, 2.9, and OS: 14.9, 22.3, n/r, 8.1 (third relapse). In relapsed PCNSL, favorable PFS was observed in patients treated by R-MPV. Favorable OS was also observed in tirabrutinib, which might suggest that tirabrutinib failure were effectively salvaged by R-MPV. R-MPV might confer better prognosis in relapsed PCNSL.

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Barz, Malwine J., Jana Hof, Stefanie Groeneveld-Krentz, Jui Wan Loh, Annabell Szymansky, Kathy Astrahantseff, Arend von Stackelberg i in. "Subclonal NT5C2 mutations are associated with poor outcomes after relapse of pediatric acute lymphoblastic leukemia". Blood 135, nr 12 (19.03.2020): 921–33. http://dx.doi.org/10.1182/blood.2019002499.

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Abstract Activating mutations in cytosolic 5′-nucleotidase II (NT5C2) are considered to drive relapse formation in acute lymphoblastic leukemia (ALL) by conferring purine analog resistance. To examine the clinical effects of NT5C2 mutations in relapsed ALL, we analyzed NT5C2 in 455 relapsed B-cell precursor ALL patients treated within the ALL-REZ BFM 2002 relapse trial using sequencing and sensitive allele-specific real-time polymerase chain reaction. We detected 110 NT5C2 mutations in 75 (16.5%) of 455 B-cell precursor ALL relapses. Two-thirds of relapses harbored subclonal mutations and only one-third harbored clonal mutations. Event-free survival after relapse was inferior in patients with relapses with clonal and subclonal NT5C2 mutations compared with those without (19% and 25% vs 53%, P < .001). However, subclonal, but not clonal, NT5C2 mutations were associated with reduced event-free survival in multivariable analysis (hazard ratio, 1.89; 95% confidence interval, 1.28-2.69; P = .001) and with an increased rate of nonresponse to relapse treatment (subclonal 32%, clonal 12%, wild type 9%, P < .001). Nevertheless, 27 (82%) of 33 subclonal NT5C2 mutations became undetectable at the time of nonresponse or second relapse, and in 10 (71%) of 14 patients subclonal NT5C2 mutations were undetectable already after relapse induction treatment. These results show that subclonal NT5C2 mutations define relapses associated with high risk of treatment failure in patients and at the same time emphasize that their role in outcome is complex and goes beyond mutant NT5C2 acting as a targetable driver during relapse progression. Sensitive, prospective identification of NT5C2 mutations is warranted to improve the understanding and treatment of this aggressive ALL relapse subtype.

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Maxwell, Rebecca, Beate Häberle, Roland Kappler, Dietrich von Schweinitz, Mark Rassner, Julia von Frowein i Irene Schmid. "Hepatoblastoma Relapse—Findings from the German HB99 Trial and the German Liver Tumor Registry". Cancers 16, nr 4 (6.02.2024): 696. http://dx.doi.org/10.3390/cancers16040696.

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Survival rates for HB patients have improved; however, outcomes for patients who relapse remain poor. A retrospective review of information gathered for the HB99 study and the German Liver Tumor Registry identified 25 relapse patients (6.9%, 25/362). The median time from initial diagnosis to first relapse was 13 months (range: 5–66 months). Two patients relapsed >36 months after initial diagnosis. A total of 68% (17/25) of relapses were metastatic, 24% local, and 8% combined. 67% of local relapses were alive at the last follow-up, in contrast to 53% of metastatic and 0% of combined relapses. At the last follow-up, 73% (8/11) of patients with lung relapses were still alive (0/4 with peritoneal, 1/2 with CNS involvement). A total of 20% of the patients had AFP-negative relapses, 64% of the relapse patients achieved a second complete remission, 69% were still in complete second remission at the last follow-up (median FU of 66 months), and 83% (5/6) of irinotecan-naïve patients who received relapse treatment including irinotecan were in second complete remission at the last follow-up. The 3-year overall survival/event-free survival from relapse was 63%/48% respectively. There is a good chance that HB patients will achieve a second remission despite a first relapse. However, patients who suffer further relapses tend to have a poorer prognosis.

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Hill, Rebecca, Stacey Richardson, Edward Schwalbe, Debbie Hicks, Janet Lindsey, Stephen Crosier, Gholamreza Rafiee i in. "MBRS-44. TIME, PATTERN AND OUTCOME OF MEDULLOBLASTOMA RELAPSE ARE ASSOCIATED WITH TUMOUR BIOLOGY AT DIAGNOSIS AND UPFRONT THERAPY: A COHORT STUDY". Neuro-Oncology 22, Supplement_3 (1.12.2020): iii405—iii406. http://dx.doi.org/10.1093/neuonc/noaa222.553.

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Abstract Disease relapse occurs in ~30% of children with medulloblastoma, and is fatal in the majority. We sought to establish whether clinico-molecular characteristics at diagnosis are associated with the nature of relapse, subsequent disease-course, and whether these associations could inform clinical management. We surveyed the clinical features of medulloblastoma relapse (time-to-relapse, pattern-of-relapse, time-to-death and overall outcome) in 247 centrally-reviewed patients who relapsed following standard-upfront-therapies. We related these to clinico-molecular features at diagnosis, prognostic factors, and first-line/relapse treatment. Patients who received upfront craniospinal irradiation (CSI-treated) displayed prolonged time-to-relapse compared to CSI naïve patients (p<0.001). Similarly, in CSI naïve patients, CSI at relapse, alongside re-resection and desmoplastic/nodular histology, were associated with long-term survival. In CSI-treated patients, the nature of relapse was subgroup-dependent. Local-nodular relapse patterns were enriched in relapsed-MBSHH patients (p<0.001), but a notable proportion (65%) also acquired distant-diffuse disease (p=0.010). MBGroup3 relapsed quickly (median 1.3 years), MBGroup4 slowly (median 2.1 years). Distant-disease was prevalent in MBGroup3 and MBGroup4 relapses (90%) but, in contrast to relapsed-MBSHH, nodular and diffuse patterns of distant-disease were observed. Furthermore, nodular disease was associated with a prolonged time-to-death post-relapse (p=0.006). Investigation of second-generation MBGroup3/4 subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time-to-relapse; subtype II a rapid time-to-death. Subtypes II/III/VIII developed a significantly higher incidence of distant-disease at relapse, whereas subtypes V/VII did not. The nature of medulloblastoma relapse are biology and therapy-dependent, providing immediate translational opportunities for improved disease management through biology-directed surveillance, post-relapse prognostication and risk-stratified selection of second-line treatment.

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Kelaidi, C., L. Ades, S. Chevret, M. A. Sanz, A. Guerci, X. Thomas, S. de Botton i in. "Late Relapses in APL Treated with ATRA and Anthracycline Based Chemotherapy: The European APL Group Experience (APL 91 and APL 93 Trials)." Blood 106, nr 11 (16.11.2005): 890. http://dx.doi.org/10.1182/blood.v106.11.890.890.

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Abstract The routine use of frontline ATRA and anthracycline-based chemotherapy has greatly improved the outcome of APL, particularly by reducing the incidence of relapses, notably early relapses. The incidence and characteristics of late relapses after this combined treatment, however, are not known. Methods: Between 1991 and 1997 (APL 91 and 93 trials) 630 newly diagnosed APL pts received ATRA combined to or followed by DNR-AraC chemotherapy (total of 3 courses), with or without (randomisation) maintenance treatment by continuous 6MP + MTX and/or intermittent ATRA (Blood1993; 82:3241–3249, Blood1999; 94:1192–1200). 582 (92.5%) pts achieved CR. 154 (26.4 %) had a first relapse, after 5 to 120 months. Results: 19 of the first relapses (i.e. 12.3% of the first relapses and 3.2% of pts who achieved CR) occurred more than 4 years after CR achievement (late relapses). Their median age was 45 (range 20–68), and M/F 7/12. Median time to relapse was 72 months (range 50–120). All late relapses involved the bone marrow only. t(15;17) and /or PML-RAR were seen in all cases at relapse. Pts were retreated with ATRA + anthracycline based chemotherapy (CT) (n = 14), ATRA alone (n =2), anthracycline based CT without ATRA (n=1), As2O3 (n =1), ATRA+ As2O3(n =1). 17 of them (89.4%) achieved CR2 and 2 had early death. CR2 pts were allografted (n = 3) autografted (n= 5), received consolidation and maintenance CT +/− ATRA (n = 7), and maintenance ATRA alone (n=2). 14 patients remained in CR2 after 5+ to 78+ months,2 (including 1 of the 2 pts salvaged and maintained with ATRA alone) relapsed after 9 and 22 months and died, and 1 patient developed secondary MDS and died. CR2 was already longer than CR1 in 5 cases. 3 year survival from relapse was 77% (median not reached). By comparison to patients who did not relapse and patients who relapsed < 4 years, patients with late relapse were not different for age and initial platelets. They were more often females and had lower initial WBC counts than patients who relapsed <4 years (M/F=0.54 vs. 2, p=0.01, and mean WBC 7000/mm3 vs. 18000/mm3, p<0.05) but similar to patients who did not relapse (M/F= 0.86 and mean WBC=8100/mm3). Percentages of patients with late relapses having received maintenance treatments (known in APL 93 trial to have reduced the incidence of relapse) were intermediate between those with early relapses and those who did not relapse Conclusion: late relapse was seen in about 3% of APL treated with ATRA and chemotherapy. Initial characteristics of those patients were rather those of “low risk” APL (especially with WBC< 10000/mm3 and female predominance). Their prognosis was overall favourable, in spite of the fact that they generally occurred before As2O3 was available. Combined maintenance with low dose chemotherapy and ATRA during first line treatment may further reduce their incidence, as it does for earlier relapses.

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Li, Benshang, Yongjin Li, Shuhong Shen, Yingchi Zhang, Samuel Brady, Xiaotu Ma, Yu Liu i in. "Mutational Landscape and Temporal Evolution during Treatment of Relapsed Acute Lymphoblastic Leukemia". Blood 132, Supplement 1 (29.11.2018): 917. http://dx.doi.org/10.1182/blood-2018-99-119144.

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Abstract Introduction Relapsed childhood acute lymphoblastic leukemia (ALL) is a leading cause of cancer-related death in children and has poor prognosis due to acquired drug resistance. However, the clonal evolution leading to drug resistance at ALL relapse is incompletely understood. Methods We performed whole-genome sequencing (WGS) of samples at diagnosis and relapse from 103 Chinese patients, most of whom were enrolled on the Shanghai Children's Medical Center (SCMC) ALL2005 frontline treatment protocol. We also performed ultra-deep sequencing at 5,000-50,000X coverage of 211 serial bone-marrow samples from 17 of these patients (3-23 per case) collected during ALL therapy. Fifteen ALL subtypes were identified based on copy number variation, structural re-arrangement and gene fusion by WGS and RNA-Seq analysis. Cases were selected based on sample availability with no bias on age, gender, cytogenetics, or immunophenotype compared to the characteristics of all relapsed cases at SCMC; however only one CRLF2-rearranged case was observed suggesting that CRLF2-rearrangement could be a rare event in Asian patients. Functional impact of novel mutations was assessed by ectopic expression in ALL cell lines. Results Relapse-specific somatic alterations were significantly enriched in 12 genes (NT5C2, NR3C1/2, PRPS1/2, TP53, CREBBP, MSH2/6, PMS2, WHSC1, and FPGS) predominantly involved in drug metabolism and response pathways. These somatic alterations were present in over 50% (56/103) of relapsed ALLs and were enriched in patients with early relapse (9-36 months from diagnosis) compared to very early (<9 months) or late relapse (>36 months) patients. NR3C1 mutations resulted in loss of glucocorticoid receptor transcriptional activity and severely impaired glucocorticoid response in vitro, while FPGS mutations led to reduced enzymatic activation of methotrexate. Genome-wide analysis identified 9 mutational signatures, including two novel ones exclusive to relapse. Novel signature 1 was characterized by C>G mutations and was present in 15% of the relapsed cases with an enrichment for hyperdiploid ALL, while novel signature 2, present in 14% of the relapsed cases, was characterized by C mutations (C>T in particular) followed by a G. These novel signatures gave rise to relapse-specific drug resistance mutations, including PRPS1, TP53, NT5C2, and KRAS mutations. The majority (59%) of the cases underwent a selective sweep as the relapse clone arose from a subclone detectable at diagnosis; however, very early relapse cases were less likely to experience a clonal sweep and had multiple lineages present at relapse. In patients tracked serially through multiple relapses, the clonal composition of drug resistance variants evolved substantially in response to chemotherapy. For example, in one patient, two independent NT5C2-mutant clones appeared at relapse, manifesting convergent evolution (Fig. 1a). One of the NT5C2-mutant clones expanded after subsequent treatment while the other diminished in prevalence. Sequential acquisition of multiple drug resistance mutations was also evident, with one patient sequentially acquiring KRAS, FBXW7, NR3C1 and FPGS mutations over a period of 5 years through multiple relapses (Fig. 1b). Indeed, 17% (18/103) of patients acquired multiple drug resistance mutations at relapse. The median time from detecting resistant clones to relapse was 41 days, suggesting that ultra-deep sequencing offers a means for early detection of genetic lesions that could serve as an indicator of relapse to enable earlier therapeutic intervention. Conclusions Very early relapses likely have different resistance mechanisms than early or late relapses, perhaps due to increased intrinsic resistance or the presence of multiple drug-resistant clones. At least a subset of relapse-specific drug resistance mutations may be acquired de novo, rather than pre-existing, as evidenced by resistance mutations bearing the novel relapse-specific mutational signatures which are likely to be therapy-induced. Relapsed ALL can acquire multiple drug resistance mutations targeting different drug classes. Frequent monitoring of disease, such as via cell-free DNA sequencing, may enable earlier detection of relapse and facilitate timely treatment to avoid selection for drug-resistant clones. Disclosures No relevant conflicts of interest to declare.

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Johnson, Kristina K., Deirdra R. Terrell, Bernhard Lammle, Johanna Kremer Hovinga, James N. George i Sara K. Vesely. "Predicting Risk for Relapse in Patients Who Have Recovered from Thrombotic Thrombocytopenic Purpura (TTP)." Blood 108, nr 11 (16.11.2006): 91. http://dx.doi.org/10.1182/blood.v108.11.91.91.

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Abstract The greatest concern for patients who have recovered from an acute episode of TTP is the risk for relapse. We have analyzed the experience of The Oklahoma TTP-HUS Registry to estimate the risk for relapse and to identify the time to relapse and factors that determine the risk for relapse. The Registry has complete follow-up data on 333 of 335 consecutive patients who had their first episode of clinically diagnosed TTP, 1989–2005. Patients who were discovered to have an alternative diagnosis for their signs of TTP, patients whose TTP followed bone marrow transplantation and patients with drug-induced TTP were not analyzed. Among the 219 remaining patients, 172 achieved a remission (defined as survival >30 days after the last plasma exchange treatment) and were at risk for relapse. Among these 172 patients, 22 (21%) of 107 patients with idiopathic TTP relapsed and 5 (8%) of 65 patients in other clinical categories (pregnancy associated, bloody diarrhea prodrome, autoimmune disease) relapsed (P<0.02). ADAMTS13 has been measured at the time of diagnosis of the first episode in 92% of consecutive patients since November 1995. Among patients who had ADAMTS13 activity <10% at the time of their initial diagnosis, 13 of 30 (43%) relapsed compared to 2 of 81 (2%) patients who had initial ADAMTS13 activity of ≥10% (P<.001). These 30 patients have been followed a median of 63 months (range, 6–124 months). Nine of the 13 patients who have relapsed have had only 1 relapse; the others have had 2–4 relapses. Nine patients had their first relapse within one year of their initial episode; the others had their first relapse within 4 years. Eleven patients followed > 4 years have never relapsed. Time to First Relapse in 30 patients with ADAMTS13 Activity < 10%. Time to First Relapse in 30 patients with ADAMTS13 Activity < 10%. The Table compares the clinical features of the 13 ADAMTS13 deficient patients who relapsed to the 17 patients who did not relapse. Comparison between ADAMTS13 deficient patients who did and did not relapse Clinical features Relapse No Relapse P n=13 n=17 Data are median values from the initial episode. Severe neurologic abnormalities were coma, stroke, seizure, or focal signs. Age (years) 46 39 0.04 Race (% black) 62% 29% 0.08 Sex (% men) 38% 0% 0.01 Severe neurological abnormality (%) 46% 35% 0.55 Hematocrit (%) 21% 21% 0.82 Platelets (/μL) 7,000 10,000 0.68 Creatinine (mg/dL) 1.0 1.0 0.66 LDH (U/L) 1363 1434 0.62 ADAMTS13 inhibitor (% moderate/strong) 38% 53% 0.43 Number of plasma exchanges 22 14 0.23 CONCLUSIONS: Patients with idiopathic TTP have a greater risk for relapse than other patients. Patients who initially have severely deficient ADAMTS13 activity (<10%) have the highest risk for relapse. Most initial relapses occur within the first year following the initial episode; all occurred within 4 years. Most patients have only 1 relapse. Among patients who have ADAMTS13 deficiency (<10%), the only features that predict a greater risk for relapse are older age and male sex.

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Rheingold, Susan R., Lingyun Ji, Xinxin Xu, Meenakshi Devidas, Patrick A. Brown, Lia Gore, Naomi J. Winick i in. "Prognostic factors for survival after relapsed acute lymphoblastic leukemia (ALL): A Children’s Oncology Group (COG) study." Journal of Clinical Oncology 37, nr 15_suppl (20.05.2019): 10008. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.10008.

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10008 Background: Survival of pediatric ALL patients (pts) now approaches 90%, but is historically poor for those who relapse. Methods: In the largest cohort assembled to date we analyzed overall survival (OS) rate post relapse, defined as duration between date of relapse and death, among pts diagnosed from 1996-2014 treated on 10 contemporary COG frontline trials. Comparisons of post-relapse OS were based on logrank tests, with two-sided p values reported. Results: Of 15,874 pts enrolled on frontline trials, 1,967(12%) relapsed. Relapse rates ranged from 35% in infant ALL to 9.7% in pts with NCI standard risk B-ALL. Rates were similar for T and B-ALL, 11% vs. 12%. Relapse patterns differed by phenotype: almost half of non-infant B-ALL relapses occurred late (≥36 mos), and at all time periods bone marrow (BM) relapse predominated. Conversely 65% of T-ALL relapses were early ( < 18 mos) with similar number of isolated CNS (iCNS) and isolated BM (iBM) relapses. Median time to relapse was shorter for infant ALL and T-ALL (both 13.8 mos) compared to B-ALL (34.4 mos). The 5yr OS rates (±SE) after relapse for B, T, and infant ALL were 52±1%, 33±3% and 19±4%, respectively, with greater variability in OS by site in T vs. B-ALL. 5yr OS rates for pts with early BM relapse was similar for both B and T-ALL (28%), but pts with B-ALL who relapsed between 18-36 mos fared better than pts with T-ALL (OS 50±2% vs 34±8%, p = 0.014). The 5yr OS rates for pts with late relapses were 65±2% for B-ALL and 50±12% for T-ALL. In multivariable analysis, time to relapse, site of relapse, age < 1 or > 10 yrs at diagnosis, initial WBC > 100K, and T-cell phenotype were associated with worse outcomes post relapse (all p < 0.01). Sex, CNS status at diagnosis, or prior therapy on POG versus CCG/COG backbone did not influence OS. Compared to pts treated from 1988-2002 (Nguyen et al. Leukemia 2008), 5yr OS rate post relapse has improved over time for B-ALL from 37±2% to 52±1% (p < 0.001) and T-ALL from 23±4% to 33±3% (p < 0.05). 5-yr OS rates improved significantly for pts with iBM from 24±2% to 45±2% (p < 0.001) and marginally for pts with iCNS from 59±3% to 65±3% (p = 0.15). Conclusions: In the modern era there are fewer relapses for B and T-ALL, however sites of recurrence and outcomes differ by phenotype. Infants continue to do poorly. Compared to prior analyses, survival after relapse is significantly improved.

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Hamilton, Robert J., Madhur Nayan, Lynn Anson-Cartwright, Eshetu G. Atenafu, Philippe L. Bedard, Aaron Hansen, Peter Chung i in. "Treatment of Relapse of Clinical Stage I Nonseminomatous Germ Cell Tumors on Surveillance". Journal of Clinical Oncology 37, nr 22 (1.08.2019): 1919–26. http://dx.doi.org/10.1200/jco.18.01250.

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PURPOSE Active surveillance (AS) for testicular nonseminomatous germ cell tumors (NSGCT) is widely used. Although there is no consensus for optimal treatment at relapse on surveillance, globally patients typically receive chemotherapy. We describe treatment of relapses in our non–risk-adapted NSGCT AS cohort and highlight selective use of primary retroperitoneal lymph node dissection (RPLND). METHODS From December 1980 to December 2015, 580 patients with clinical stage I NSGCT were treated with AS, and 162 subsequently relapsed. First-line treatment was based on relapse site and extent. Logistic regression was used to explore factors associated with need for multimodal therapy on AS relapse. RESULTS Median time to relapse was 7.4 months. The majority of relapses were confined to the retroperitoneum (66%). After relapse, first-line treatment was chemotherapy for 95 (58.6%) and RPLND for 62 (38.3%), and five patients (3.1%) underwent other therapy. In 103 (65.6%), only one modality of treatment was required: chemotherapy only in 58 of 95 (61%) and RPLND only in 45 of 62 (73%). Factors associated with multimodal relapse therapy were larger node size (odds ratio, 2.68; P = .045) in patients undergoing chemotherapy and elevated tumor markers (odds ratio, 6.05; P = .008) in patients undergoing RPLND. When RPLND was performed with normal markers, 82% required no further treatment. Second relapse occurred in 30 of 162 patients (18.5%). With median follow-up of 7.6 years, there were five deaths (3.1% of AS relapses, but 0.8% of whole AS cohort) from NSGCT or treatment complications. CONCLUSION The retroperitoneum is the most common site of relapse in clinical stage I NSGCT on AS. Most are cured by single-modality treatment. RPLND should be considered for relapsed patients, especially those with disease limited to the retroperitoneum and normal markers, as an option to avoid chemotherapy.

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Ríos-Garcés, R., J. Hernández-Rodríguez, S. Prieto-González, M. C. Cid i G. Espígol-Frigolé. "AB0763 CHARACTERISTICS OF RELAPSES IN EOSINOPHILIC GRANULOMATOSIS WITH POLYANGIITIS. A SINGLE CENTRE EXPERIENCE". Annals of the Rheumatic Diseases 82, Suppl 1 (30.05.2023): 1588. http://dx.doi.org/10.1136/annrheumdis-2023-eular.2850.

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BackgroundEosinophilic granulomatosis with polyangiitis (EGPA) is a heterogeneous disease with a variable, relapsing course. Real-world data regarding specific characteristics of relapses in this patients are scarce.ObjectivesWe aim to describe and analyse the relapses presented in a single-center cohort of EGPA patients.MethodsMedical charts of EGPA patients regularly controlled at our department were reviewed to describe demographics, clinical characteristics at diagnosis and at relapse, number of relapses, disease activity at relapse, treatment of the relapses, damage accrual, and laboratory results. The definition of relapse was the same used in the MIRRA trial: a) active vasculitis (BVAS >0), b) active asthma or active nasal or paranasal sinus disease leading either to an increase in the dose of prednisone > 4mg/day, initiation of or increase in immunosuppressive therapy, or hospitalization[1].ResultsA total of 59 EGPA patients were followed regularly at our department. All fulfilled either ACR 1990 and/or MIRRA trial inclusion criteria for EGPA. The mean age at diagnosis was 51.6 years, 59.3% were female and 91.5% were Caucasian. Among them, 76.3% were ANCA positive and 23.7% were ANCA negative. The mean time of follow-up was 10.7 ± 8.2 years. During the follow-up, a total of 324 relapses were diagnosed in 47 patients, with 12 patients experiencing no relapse. A relapse-free survival analysis showed that 35% of patients had a relapse in the first year, 51% at 2 years, 59% at 3 years and 64% at 5 years. The main clinical symptoms at relapse were asthma (in 248 flares, 76.5% of them), followed by rhinitis (100, 30.9%), sinusitis (60, 18.5%), skin involvement (19, 5.9%), fever (18, 5.6%), arthralgia (16, 4.9%), lung infiltrates (15, 4.6%), myalgia (12, 3.7%), peripheral nervous system involvement (11, 3.4%), cardiac involvement (6, 1.9%), arthritis (3, 0.9%), weight loss (2, 0.6%), alveolar hemorrhage (2, 0.6%), gastrointestinal involvement (2, 0.6%) and central nervous system involvement (2, 0.6%). No renal involvement was seen at flare. Median BVAS at relapse was 2 (IQR 2-4, range 0-28). When determined, median blood eosinophils at relapse were 500 cells/mm3(IQR 100-1000) and in 73% of the measures eosinophils did not reach 10% of the total leucocyte count. Median CRP was 0.6 mg/dl (IQR 0.2-2.4) and median ESR 14 mm/h (IQR 8-32). ANCA were measured in 37 relapses only, being positive in 14 of them. The median prednisone dose at relapse was 6.25mg/day and the median increase for treating the relapse was 30 mg/day. In 53 relapses, patients were already taking azathioprine. In 47, mepolizumab. In 36, methotrexate. In 11, mofetil mycophenolate. When comparing patients who relapsed vs. those who did not, and those who relapsed less than 1 time every 2 years vs those who relapsed more than 1 time every 2 years, no predictive factor of relapse was seen.ConclusionAfter a mean follow-up of 10.7 years, 324 relapses were diagnosed in 59 patients. First relapse occurred in 35% of patients at 1 year and in 64% at 5 years. The clinical spectrum of relapses was predominantly asthma, followed by ear, nose and throat, being vasculitic manifestations much less frequent. No predictive factors of relapse were identified.References[1]Wechsler ME et al. N Engl J Med. 2017.Figure.AcknowledgementsThis study was supported by Instituto de Salud Carlos III (ISCIII) through the project PI18/00461, part of Plan Estatal de Investigación Científica y Técnica y de Innovación 2013–2016, and co-funded by the European Union. Roberto Ríos-Garcés is a recipient of a Río Hortega grant from Instituto de Salud Carlos III, Spain (CM19/00032).Disclosure of InterestsRoberto Ríos-Garcés: None declared, José Hernández-Rodríguez: None declared, Sergio Prieto-González: None declared, Maria C. Cid Paid instructor for: Vifor and GSK, Consultant of: GSK, Abbvie and Janssen, Grant/research support from: Kiniksa, Georgina Espígol-Frigolé Consultant of: Janssen.

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Rajkumar, Prabu, Girish Kumar Chethrapilly Purushothaman, Manickam Ponnaiah, Devika Shanmugasundaram, Jayasree Padma, Rang Lal Meena, Selvaraj Vadivoo i Sanjay M. Mehendale. "Low risk of relapse and deformity among leprosy patients who completed multi-drug therapy regimen from 2005 to 2010: A cohort study from four districts in South India". PLOS Neglected Tropical Diseases 15, nr 11 (23.11.2021): e0009950. http://dx.doi.org/10.1371/journal.pntd.0009950.

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Introduction Relapse of leprosy among patients released from treatment (RFT) is an indicator of the success of anti-leprosy treatment. Due to inadequate follow-up, relapse in leprosy patients after RFT is not systematically documented in India. Relapsed leprosy patients pose a risk in the transmission of leprosy bacilli. We determined the incidence of relapse and deformity among the patients RFT from the leprosy control programme in four districts in South India. Methods We conducted two follow-up surveys in 2012 and 2014 among the leprosy patients RFT between 2005 and 2010. We assessed them for any symptoms or signs of relapse, persistence and deformity. We collected slit skin samples (SSS) for smear examination. We calculated overall incidence of relapse and deformity per 1000 person-years (PY) with 95% confidence intervals (CI) and cumulative risk of relapse. Results Overall, we identified 69 relapse events, 58 and 11, during the first and second follow-up surveys, respectively. The incidence of relapse was 5.42 per 1000 PY, which declined over the years after RFT. The cumulative risk of relapse was 2.24%. The rate of deformity among the relapsed patients was 30.9%. The overall incidence of deformity was 1.65 per 1000 person years. The duration of M. leprae detection in smears ranged between 2.38 and 7.67 years. Conclusions Low relapse and deformity rates in leprosy RFT patients are indicative of treatment effectiveness. However, a higher proportion of detection of deformity among relapsed cases is a cause for concern. Periodic follow-up of RFT patients for up to 3 years to detect relapses early and ensure appropriate treatment will minimize the development of deformity among relapsed patients.

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Fonseca, Adriana, Cecile Faure-Conter, Matthew Murray, Jason R. Fangusaro, Stewart Goldman, Shivani Bailey, Gabriele Calaminus i in. "The role of tumor markers for relapse detection in central nervous system non-germinomatous germ cell tumors (CNS-NGGCT): A pool analysis of cooperative group clinical trials." Journal of Clinical Oncology 38, nr 15_suppl (20.05.2020): 2503. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.2503.

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2503 Background: CNS-NGGCT are rare tumors that have been successfully treated with multimodal therapies. With a 5-yr EFS and OS of 72-84% and 82-93% respectively, surveillance and relapse detection is essential. Tumor marker (TM) elevation has proven to be a highly sensitive method of relapse detection in extra-cranial-NGGCT. We aim to determine the role of TM for relapse surveillance in children and adolescents with CNS-NGGCTs. Methods: European and North American data from germ cell tumor trials (SIOP GCT96, SFOP-TGM TC 90/92, COG-ACNS0122 and COG-ACNS1123) were pooled for analysis. Additionally, patients treated in the UK, Germany and France under strict protocol-guidelines were included. Details regarding imaging, pathology and TM elevation at diagnosis and relapse were collected. We report the proportion of relapses detectable by TM elevation. Results: Four-hundred and eighty-four patients enrolled in prospective cooperative group CNS-NGGCT trials from 1989 to 2016 were pooled for analysis. One-hundred and thirteen (23%) patients experienced a relapse/progression (SIOP GCT96: n = 57; SFOP TGM TC 90-92 n = 23, COG-ACNS0122 n = 16 & COG-ACNS1123 n = 17) and constitute the population of this report. Median age at diagnosis was 13 (range:1-30) years. The most common primary location was pineal in n = 60 (53%) patients. The site of relapse was available for 100 patients, 48 patients relapsed locally, 36 relapsed with distant disease, combined relapses were seen in 22 patients and 4 patients relapsed with TM elevation alone. TM in serum and/or CSF at diagnosis was available in 93(82%) patients, and in 90(80%) patients at the time of relapse. Eighty-four patients had TM available at both timepoints. At diagnosis 81 (96%) patients had TM elevation and 3 (4%) had negative TM. At relapse, 74(94%) patients with positive TM at diagnosis had TM elevation, while 7(6%) had TM negative. Conversely, 2/3 patients with negative TM at diagnosis, relapsed with elevated TM. Conclusions: Herein, we have assembled the largest prospective cohort to date of relapsed intracranial germ cell tumors. TM are highly sensitive detecting relapse/progression in CNS-NGGCT patients with elevated TM at diagnosis. The routine use of TM for relapse surveillance in patients with CNS-NGGCT can decrease the frequency of cross-sectional imaging, therefore, reducing lengthy hospital visits, sedation procedures and decreasing health-care costs.

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Blum, William, Sam Penza, Sherif Farag, Belinda Avalos, Guido Marcucci, Thomas Lin, John C. Byrd, Patrick Elder i Edward A. Copelan. "Incidence of Extramedullary Relapse of Acute Myeloid Leukemia Following Transplantation with Busulfan-Based Conditioning Regimens." Blood 104, nr 11 (16.11.2004): 5123. http://dx.doi.org/10.1182/blood.v104.11.5123.5123.

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Abstract Rates of extramedullary relapse are reported to be more than twice as high following transplantation with busulfan-based conditioning regimens (Simpson et al, Bone Marrow Transplantation 1998, Lee et al, Bone Marrow Transplantation 2000) compared to total body irradiation (TBI)-based regimens (Mortimer et al, J. Clin Oncol 1989) in acute myeloid leukemia (AML). Up to 50% of relapses following transplantation with busulfan-based therapies are reported to be extramedullary, with more than 25% as isolated extramedullary relapses. We analyzed 228 consecutive AML patients who underwent allogeneic (n=192) or autologous (n=36) transplantation following busulfan-based conditioning regimens between 2/84 and 12/03. One hundred twenty-three patients were in remission at the time of transplantation, 67 had relapsed disease, and 38 had never achieved remission. One hundred twenty-seven patients received BuCy, 77 received BuCyVP16, and 24 (all autologous) received BuVP16. All patients had a lumbar puncture demonstrating no evidence of leukemia, and all received intrathecal methotrexate prophylaxis prior to receiving busulfan. Seventy-nine patients (35%) relapsed (any site) at a median of 6 months (range, 1 to 44 months) after transplantation. Fifteen patients (7%) relapsed at extramedullary sites, including 7 in the CNS. Ten patients (4%) had isolated extramedullary relapses at a median of 13 months (range, 1 to 44 months) after transplantation. Four had isolated CNS relapses, and 4 had isolated cutaneous relapses. Of patients transplanted in remission, only 2 relapsed at extramedullary sites, including one patient with an isolated CNS relapse. This retrospective study includes a substantially larger cohort of patients with longer follow-up than prior studies examining extramedullary relapse in patients with AML following transplantation with busulfan-based conditioning. In contrast to other reports, these results demonstrate that the incidence of extramedullary relapse is comparable to that reported with TBI-based conditioning regimens for patients with AML.

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Florvall, Cecilia, Peder Frederiksen, Jakob Lauritsen, Mikkel Bandak, M. Gry G. Kier, Mette S. Mortensen, Michael Kreiberg i Gedske Daugaard. "Relapse and Mortality Risk of Stage I Testicular Cancer". Journal of Insurance Medicine 47, nr 2 (1.01.2017): 114–24. http://dx.doi.org/10.17849/insm-47-02-114-124.1.

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Objectives. – To assess the medical insurance risk for patients with stage I testicular cancer (TC), by calculating the overall mortality risk with and without relapse, and compare it to men from the Danish population. Background. – Testicular cancer is the most common malignancy in young males. Outcomes of a Danish cohort of 3366 patients with stage I TC (1366 non-seminomas (NSTC) and 2000 Seminomas (STC)), were analyzed. Method. – The data were analyzed by the “illness-death” model. For the analysis of the transitions between diagnosis, relapse and death we adopted a parametric approach, where the relationship between the intensities and the effect of covariates were specified by Poisson regression models for NSTC and STC individually. Results. – In the NSTC group, 422 patients relapsed. Six relapses (1.4%) occurred after 5 years of follow-up. In the STC group, 389 relapsed. The relapse rate after 5 years was 4.1%. The overall mortality analyses showed that the standardized mortality ratio (SMR) for men with NSTC without relapse, was slightly lower than in the matched general population of Danish men (SMR = 0.9). In STC patients without relapse, SMR was 0.80. Relapse raised the overall mortality by a factor 2.0 for NSTC and 1.5 for STC. Conclusions. – The fact that few relapses occur 5 years after diagnosis is an important finding for risk assessment in life insurance. It makes it possible to insure men diagnosed with stage I TC, who have not experienced relapse 5 years after diagnosis, on normal terms.

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Hansen, M., i C. Hahn. "P.004 Autoimmune Encephalitis: Modifiable and Non-Modifiable Predictors of Relapse". Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 48, s3 (listopad 2021): S21. http://dx.doi.org/10.1017/cjn.2021.287.

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Background: Approximately 25% of encephalitis cases in North America are immune mediated. For most forms of autoimmune encephalitis (AIE), risk of relapse is unclear and little evidence exists to guide which patients have the highest risk and whether standard treatments reduce this risk. Our objective was to determine the factors associated with AIE relapse. Methods: We performed a chart review consisting of patients with AIE presenting to the Calgary Neuro-Immunology Clinic and Tom Baker Cancer Centre between 2015 and 2020. Predictors of relapse were determined with use of t-test. Results: Outcome data was assessable in 39/40 patients, 17/39 (44%) patients relapsed. Seropositive patients and those with abnormal CSF were more likely to relapse, although neither reached statistical significance (p=0.12, 0.059). Patients with longer duration of steroid and steroid sparing treatment prior to relapse, and those on steroids at the time of relapse, had milder relapses (p=0.024, 0.026, 0.047). There was no difference in steroid or steroid sparing treatment use at 3, 6, and 12 months between groups. Conclusions: Risk of relapse in AIE is high (44%), with most relapses occurring in the first 3 years. Continuous immunosuppression lessens the severity of relapse, although our study did not confirm it reduced the occurrence of relapse.

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Kumar, Prashanth, Nisha Joseph, Dhwani Almaula, Lawrence H. Boise, Jonathan L. Kaufman, Charise Gleason, Sagar Lonial i Ajay K. Nooka. "Patterns of Relapse Among Myeloma Patients Post-Autologous Stem Cell Transplant". Blood 128, nr 22 (2.12.2016): 4524. http://dx.doi.org/10.1182/blood.v128.22.4524.4524.

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Abstract Introduction: In younger patients that are transplant-eligible, autologous stem cell transplant (ASCT) prolongs overall survival based on several prospective randomized control trials. Nevertheless, ASCT is not a curative approach and majority of the patient's relapse, requiring further salvage therapeutic options. However, in the face of an ongoing paradigm shift in myeloma therapeutics, there is a significant knowledge gap regarding how patients relapse following ASCT. We analyzed the patterns of relapse among myeloma patients after ASCT. Methodology: We have evaluated a total of 975 patients that underwent ASCT during the period January 2008 through June 2014 from our myeloma database. 273 patients had documented evidence of first relapse post-ASCT on the laboratory parameters, radiologic or pathologic findings based on IMWG criteria for relapse. We categorized the relapses as biochemical vs symptomatic, and described their frequencies and characteristics. Median time of follow up from diagnosis is 68 months and from ASCT is 54 months. We used IBM SPSS version 23.0 to generate the survival statistics. Results: Median time from ASCT to relapse is 20 months. A total of 182 (66.7%) patients (105M, 77F) experienced biochemical relapse, while 91 (33.3%) patients (50M, 41F) had symptomatic relapse. More IgA patients (30.8% vs 23.1%, p=0.06) relapsed as symptomatic myeloma. While characterizing relapses, we did not find any differences in symptomatic relapses by the risk group [high risk (31.3%) vs standard risk (31.9%), p=0.193, ISS stage I (29.3%) vs II (32.9%) vs III (32.8%), p=0.807] or by maintenance [yes (30.7%) vs no (38.1%), p=0.211]. Among the patients that had a symptomatic relapse, presence of new bone lesions (52%) and anemia (42%) are the most common forms of relapse seen. Only 4% presented as hypercalcemia and 1% presented as renal failure illustrating the benefits of closer follow up. Overall survival is similar among patients that relapsed as biochemical or symptomatic relapse (log rank, p=0.105). More importantly, impressive median OS of 145 months from the ASCT among this entire cohort (at median follow up 54 months, figure 1). Conclusions: Two-thirds of the patients relapse as a biochemical relapse post-ASCT. The patterns of biochemical vs symptomatic relapses were similar among patients by maintenance, by risk status and also by the ISS stage. The significant improvement in OS among the entire cohort emphasizes the power of the new therapeutic salvage strategies aimed at gaining the survival advantage even among this selected group of patients undergoing early relapses. Disclosures Kaufman: Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Incyte: Consultancy; Pharmacyclics: Consultancy. Lonial:Novartis: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Celgene: Consultancy; Onyx: Consultancy; Onyx: Consultancy; Merck: Consultancy; Janssen: Consultancy; BMS: Consultancy; BMS: Consultancy; Millenium: Consultancy; Celgene: Consultancy. Nooka:Spectrum, Novartis, Onyx pharmaceuticals: Consultancy.

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Muirhead, Rebecca, Lisa Durrant, Katherine Hyde i Maria Hawkins. "Volumetric analysis of anal cancer relapses following radical chemoradiation." Journal of Clinical Oncology 32, nr 3_suppl (20.01.2014): 576. http://dx.doi.org/10.1200/jco.2014.32.3_suppl.576.

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576 Background: Definitive chemoradiotherapy is standard of care in anal squamous cell carcinoma. The ACT II trial set the standard achieving three year overall survival rates of 73%. However patients with locally advanced disease have a ~50% local relapse rate. Studies have failed to demonstrate an improvement in local relapse rate by altering the systemic therapy. Although 2/3 of relapses are local as opposed to regional or distant, there is limited knowledge on the 3D position of these relapses. We aim to retrospectively review the patterns of local failure in three dimensions, relative to the radiotherapy plan. Methods: Between February 2007 and April 2012, 77 patients were treated for squamous cell carcinoma of the anus with radical chemoradiotherapy. Early stage (T0/2) and locally advanced (T3/4) tumours constituted 53% and 44% respectively. 37% of patients had nodal disease. As per ACT II protocol we used a gross tumour volume (GTV) to PTV margin of 3cm and prescribed to a dose of 50.4Gy. In patients with a local recurrence, imaging from the time of recurrence was imported into the radiotherapy planning system. The volume and site of gross recurrence was noted relative to the previous GTV and 95% isodose line. The mean dose delivered to the relapsed area was calculated. Results: Median follow-up was 42 months (range 14 to 78 months). Eight (10%) patients failed to respond. Six (8%) patients developed an isolated local relapse, 2 (3%) distant metastatic disease alone and 1 both local and distant relapse. Of those that relapsed locally, 5 patients were T2N0, one T3N0 and 1 node positive. There were no regional relapses. The entire macroscopic relapse lay within the 95% isodose line of the 50.4Gy in all patients. The median percentage of relapse that lay within GTV was 63% (range 29 to 100%). A GTV to PTV margin of 2cm would have encompassed all macroscopic relapses. The median doses to relapsed area was 52Gy (range 51Gy to 53Gy) with the minimum dose to any relapsed area being 49Gy. Conclusions: The majority of relapses centred on the GTV suggesting the gross tumour was uncontrolled with current doses in these patients. A reduction of GTV to PTV margin may be appropriate, facilitating trials of dose escalation with the aim of improving outcomes.

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Kaspers, Gertjan, Martin Zimmermann, Dirk Reinhardt, Brenda Gibson, Rienk Tamminga, Olga Aleinikova, Hortensia Armendariz i in. "Central Nervous System (CNS) Involvement In Pediatric Relapsed Acute Myeloid Leukemia: Results and Lessons From Study Relapsed AML 2001/01". Blood 116, nr 21 (19.11.2010): 184. http://dx.doi.org/10.1182/blood.v116.21.184.184.

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Abstract Abstract 184 Acute Myeloid Leukemia - Therapy, excluding Transplantation: Pediatric and Adult AML Therapy Introduction: With improving initial antileukemic therapy, CNS disease might become more important in AML. We therefore evaluated the incidence of CNS involvement in a large series of children with first relapsed AML. In addition, clinical and biological features of children with and without CNS involvement at relapse were compared, and finally the prognostic significance of CNS involvement at relapse was studied. Materials and Methods: Patients were selected from those registered in the setting of study Relapsed AML 2001/01 (ISRCTN code 94206677), based on having first relapsed AML and precise information on the location of the relapse, and on the type of CNS involvement. The latter was distinguished in asymptomatic and symptomatic disease. The protocol prescribed intensive intrathecal triple chemotherapy in case of CNS disease: first dose immediately before start of reinduction course 1. Second and subsequent doses every 7 days until 1 week after complete blast clearance of the CSF or disappearance of radiological abnormalities. Then, 2 more doses were given, one immediately before the start of the second reinduction course, and the other at the start of consolidation treatment. Cranial radiotherapy was not generally recommended and was actually used in 18% of patients with CNS relapse. Systemic therapy consisted of FLAG with or without liposomal daunorubicin (1:1 randomisation), followed by FLAG and allogeneic stem cell transplantation. This clinical study also enrolled patients with a combined relapse, or an isolated extramedullary relapse, or a bone marow relapse (isolated or combined) with <20% blasts in the BM, and these patients were also eligible for randomisation. The study was closed for enrollment in April 2009, and median follow-up for patients at risk is well above 3 years. Results: Out of 477 patients, 45 (9.4%) had CNS relapse, which percentage did not differ significantly between individual study groups. The far majority (41/45) of these patients had a combined relapse, only 4 patients had isolated CNS relapse. All 4 isolated relapses concerned early relapse, as compared to 66% of patients with a combined relapse including the CNS and to 48% of patients with first relapsed AML not involving the CNS (p-trend = 0.004). For further analyses, isolated and combined relapses involving the CNS were combined. Patients with CNS relapse were younger at relapse, mean 5.6 (SD 5.2) vs 9.7 (SD 5.3) years, p<0.0001. There was a trend for a higher percentage of males among those with CNS involvement, 71 vs 57%, p=0.07, and a trend for a higher WBC (mean 22.1 vs 13.4 × 109/l, p=0.09). Patients with CNS relapse more often had AML FAB type M5 (48 vs 16%, p<0.001), and more often MLL gene rearrangements (26 vs 11%, p=0.049) than patients with non-CNS relapse. Clinical outcome did not differ significantly between both groups, and patients with relapsed AML and CNS involvement had a 58% CR2 rate (vs 64% for the remaining patients), and a 4-years pOS of 32% (SE 8%) vs 37% (SE 2%) for the remaining patients. The majority of events within patients with relapsed AML and CNS involvement concerned refractory disease (12/45 patients), while early death occurred in 7 patients, death in CR in 3 patients, and 9 patients developed a 2nd relapse (in 3/9 patients again involving the CNS). Relapsed patients with CNS involvement had a higher rate of second complete remission when treated with liposomal daunorubicin, than if treated with FLAG only (82 v 38%, p=0.019), but overall survival was not significantly different between both treatment arms in this subgroup of patients. Conclusion: Isolated CNS relapse is rare in pediatric AML, but CNS involvement is observed in more than 9% of patients with first relapsed AML. CNS involvement is more frequent in younger patients, males and those with a high WBC at relapse. Biologically, patients with CNS involvement at relapse more frequently have acute monoblastic leukemia and MLL gene rearrangement, than patients with non-CNS relapse. Despite CNS disease at relapse, second complete remission was achieved in more than half of patients, and long-term survival was achieved in about one third of patients. Thus, intensive salvage treatment of pediatric patients with relapsed AML and CNS involvement is justified. Prevention of CNS relapse by improved therapy for newly diagnosed AML is warranted, with special attention to several subgroups which seem at higher risk for CNS relapse. Disclosures: Off Label Use: Liposomal daunorubicin in pediatric relapsed AML.

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Tringale, Kathryn, Joachim Yahalom, Michael Scordo, Behroze Vachha, Lauren Schaff, Christian Grommes i Brandon Imber. "NIMG-98. IDENTIFYING PATTERNS OF FAILURE AFTER INITIAL THERAPY IN PRIMARY CNS LYMPHOMA IN A LARGE PATIENT COHORT". Neuro-Oncology 24, Supplement_7 (1.11.2022): vii187—vii188. http://dx.doi.org/10.1093/neuonc/noac209.716.

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Abstract INTRODUCTION Treatment of primary CNS lymphoma (PCNSL) has rapidly evolved, emphasizing improved efficacy while reducing neurotoxicity. PCNSL has historically been considered a multifocal disease and many patients relapse after first-line therapy. We evaluated relapse patterns in a large cohort of contemporarily treated patients. METHODS Consecutive PCNSL patients treated at MSKCC between 1983-2020 were analyzed. T1 post-contrast-enhancing disease on baseline MRI was characterized. Site of initial relapse was characterized as purely local (involving/adjacent to initial site) vs distant intraparenchymal, or other (e.g., both local and distant, systemic, ocular). Progression-free survival (PFS) was evaluated using Kaplan Meier methods. RESULTS Of 645 patients, 564 were eligible for analysis (diffuse large B-cell histology, sufficient data, ≥ 1 MRI response assessment). Median follow-up was 2.7 years (IQR 1.2-5.6). Median age was 63 years (range 19-90). Baseline disease was often supratentorial (420, 74%), multifocal (274, 49%), and bilateral (224, 40%). Fewer had leptomeningeal disease (94/430 CSF+, 22%; 117/559 radiographically positive, 21%). Most received methotrexate (MTX)-based induction (534, 96%), most commonly rituximab, MTX, procarbazine, vincristine (R-MVP; 257, 46%) or MVP (144, 26%). Overall, 286 (51%) patients relapsed with a median PFS of 2.1 years (95% CI 1.8-2.5). Of 275 characterizable relapses, 75 (27%) were exclusively local intraparenchymal, 91 (33%) were distant intraparenchymal, and 109 (40%) were other. Baseline unifocal disease often relapsed unifocally (66/118 baseline unifocal; 56%). Of 126 unifocal relapses, 45 (36%) were local. Of 202 patients with baseline supratentorial disease, 152 (75%) relapsed supratentorially. Unilateral relapses often remain ipsilateral (49% left- and 54% right-hemispheric lesions at baseline and relapse). CONCLUSIONS In a large PCNSL cohort, relapses often maintained baseline characteristics. For a disease historically considered multifocal, a substantial proportion of relapses were local. Future analyses will evaluate predictors of relapse, which can further efforts in informing personalization of treatment in the era of cellular therapies.

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Cohen, Jonathon B., Madhusmita Behera, Carrie A. Thompson i Christopher R. Flowers. "Evaluating surveillance imaging for diffuse large B-cell lymphoma and Hodgkin lymphoma". Blood 129, nr 5 (2.02.2017): 561–64. http://dx.doi.org/10.1182/blood-2016-08-685073.

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Abstract Up to 50% of patients with Hodgkin lymphoma and diffuse large B-cell lymphoma will relapse, requiring additional therapy. Although surveillance imaging is commonly performed in clinical practice, its ability to identify asymptomatic relapses and improve survival for patients is not well defined. We evaluated the surveillance imaging role in relapse detection and reviewed its impact on survival for relapsed patients, and found that current imaging approaches do not detect most relapses prior to clinical signs and symptoms or improve survival.

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Kumar, Rahul, Maximilian Deng, Kyle Smith, Anthony P. Y. Liu, Vasilisa Rudneva, Girish Dhall, Laura Kleese i in. "PATH-54. MULTI-DIMENSIONAL MOLECULAR CHARACTERIZATION OF PATIENT-MATCHED MEDULLOBLASTOMA AT DIAGNOSIS AND RELAPSE". Neuro-Oncology 21, Supplement_6 (listopad 2019): vi155. http://dx.doi.org/10.1093/neuonc/noz175.649.

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Abstract INTRODUCTION Recurrent medulloblastoma (MB) confers an abysmal prognosis with ~10% 5-year overall survival. Optimal treatment paradigms for relapsed disease are largely unknown. Conservation of molecular subgroup at relapse has been described and divergent clonal evolution implicated, yet multi-dimensional molecular characterization of larger cohorts are warranted to substantiate these findings and to disclose potential mechanisms underlying treatment failure and disease recurrence. METHODS A multi-institutional series of 85 patient-matched, primary MBs and their relapses was profiled by DNA methylation array (Illumina 450K/850K). Entity and molecular subgroup classifications were assigned using random forest tumor classifiers (Molecular Neuropathology v.11b4). Genome-wide copy-number aberrations were also inferred from these data while parallel next-generation (whole-exome or targeted panel) sequencing on the majority of the cohort facilitated inference of somatic driver mutations. RESULTS Comprised of WNT (1%), SHH (41%), Group 3 (22%), Group 4 (35%), primary tumors largely retained subgroup affiliation at relapse with the notable exception of 14% of cases. The majority (8/12) of discrepant classifications were determined to be secondary glioblastomas, while three Group 4 primary tumors relapsed as Group 3. Amongst conserved pairs, copy-number analyses suggest somatic clonal divergence between primary MBs and their respective relapses with an average of 0.8 (range 0–5) primary-specific and 2.0 (range 0–11) relapse-specific cytogenetic alterations. Despite high global methylation correlations between primary/relapse pairs (median 0.95), epigenetic evolution at relapse is suggested by the lower degree of conservation amongst promoter-associated probes (median 0.83, p < 2.2e-16). CONCLUSION Secondary malignancy, particularly glioblastoma, may masquerade as relapsed MB, highlighting the utility of molecular characterization for relapsed disease and necessity for vigilant clinical surveillance. By deciphering the evolution of MB from diagnosis to relapse, a fundamental understanding of disease pathogenesis may be garnered, motivating rational and targeted clinical interventions in early therapy and at the time of relapse.

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Oki, Yasuhiro, Dai Chihara, Yoshitoyo Kagami, Shouji Ine, Harumi Kato, Hirofumi Taji, Kazuhito Yamamoto i Yasuo Morishima. "Patterns of Relapse and Value of Follow up Procedures in Patients with Diffuse Large B Cell Lymphoma (DLBCL) Who Achieve a Complete Remission (CR)". Blood 112, nr 11 (16.11.2008): 5306. http://dx.doi.org/10.1182/blood.v112.11.5306.5306.

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Abstract Purpose: Optimal follow up schedule and choice of diagnostic modalities have not been well studied in patients with DLBCL who achieve CR after initial treatment. We analyzed patterns of relapse in patients with DLBCL who were treated with CHOP±R therapy and achieved CR in our institution between 1999 and 2007. We generally follow such patients with physical exam and blood tests including LDH every 3 months and CT scans every 3 to 6 months for the first two years. Follow up schedule varied afterwards. Patients and methods: Thirty-eight patients experienced relapse, in whom we first determined if relapse was detected by symptoms which prompted diagnostic processes such as imaging studies and/or biopsy or by prescheduled follow up blood test or systemic CT scans. Other characteristics of these patients including time from diagnosis to relapse, time from last systemic CT scan that showed no evidence of disease to relapse, and time from relapse to death were analyzed. Results: Twenty-seven patients (71%) presented with symptoms (“symptomatic patients”); 12 with palpable superficial masses, 5 with local pain, 5 with neurological symptoms due to central nervous system (CNS) involvement, 2 with persistent fever, 1 with gastrointestinal bleed, 1 with nasal congestion and 1 with persistent cough. Eleven patients (29%) were asymptomatic when relapse was detected (“asymptomatic patients”). Two showed elevated serum LDH levels which prompted imaging studies leading to the diagnoses. Nine were found to have relapsed diseases by prescheduled systemic CT scans. Among 27 symptomatic patients, 7 (18% of all relapses) had diseases that were not detectable by CT scans (5 isolated CNS relapses, 1 GI relapse, and 1 subcutaneous relapse in upper extremity). Patient characteristics at the time of initial diagnosis were similar in the two groups. Median time from initial diagnosis to relapse in symptomatic and asymptomatic patients were 11.9 months (range 3.8–98.1) and 12.5 months (range 7.2–50.7), respectively (p=0.635). Median time from last systemic CT scan to relapse were 2.9 months (range 0.1–33.0) and 5.2 months (range 1.9–10.8), respectively (p=0.895). Time from relapse to death of any cause were similar in the 2 groups (log-rank p=0.423) but the median time was longer in asymptomatic patients (16.6 months vs 39.8 months). Since late relapses potentially tend to be detected by symptoms due to infrequent CT scans, analyses were next limited only to those who relapsed within 2 years after diagnosis. The results were similar between symptomatic and asymptomatic group. Conclusions: This study showed that more than two thirds of patients were symptomatic at the time of relapse. And up to 18% of relapsed diseases were undetectable by routine CT scans. Half of “symptomatic” patients noticed their symptoms less than three months after last CT scan, suggesting that even every 3 months CT would miss these relapses before patients were symptomatic. Longer median survival (though the overall difference was not significant) in “asymptomatic patient” could be attributed in part to “early detection of relapse and intervention” but in contrast, asymptomatic patients might have had less aggressive diseases allowing prescheduled CT scans to detect the diseases before they are symptomatic. Important question is whether delaying detection of relapse and treatment till patient is symptomatic would be associated with worse clinical outcome. This question is also translated into whether routine CT scan is even necessary, and if so, what is the optimal schedule of imaging studies. Answers to these questions may depend on the estimated risk of relapse based on various prognostic factors. Larger scale studies are needed in this area.

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Hansen, M., i C. Hahn. "P.027 Autoimmune encephalitis: modifiable and non-modifiable predictors of relapse". Canadian Journal of Neurological Sciences / Journal Canadien des Sciences Neurologiques 50, s2 (czerwiec 2023): S65. http://dx.doi.org/10.1017/cjn.2023.131.

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Background: Approximately 25% of encephalitis cases in North America are autoimmune (AIE). For most forms of AIE, it is unclear which patients have the highest relapse risk and whether standard treatments reduce this risk. Our objective was to determine the overall risk of relapse and whether chronic immunosuppressive therapy modifies that risk. Methods: We performed a chart review consisting of all patients with AIE presenting to the Calgary Neuro-Immunology Clinic and Tom Baker Cancer Centre between 2015 and 2020. Predictors of relapse were determined with use of t-test. Results: Outcome data was assessable in 39 patients, 17/39 (44%) patients relapsed, and most relapses (76%) occurred within 3 years. Patients not on any immunosuppression at the time of relapse had a greater increase in CASE score, a proxy for presentation severity, at relapse compared to those on immunosuppression (p=0.0035). Conclusions: The risk of relapse in AIE is high (44%). Immunosuppression at the time of relapse, which may occur up to 3 years after initial presentation, lessens the relapse severity, although it remains unclear if it can reliably prevent relapses. Our data enforces the importance of long-term follow up and that ongoing immunosuppression may be helpful, particularly in the first 3 years after initial presentation.

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Absi, Ahmed, Brian J. Bolwell, Ronald Sobecks, Brad Pohlman, Steve Andresen, Lisa Rybicki i Matt Kalaycio. "High Incidence of Extramedullary Relapses Following Allogeneic Bone Marrow Transplant (Allo-BMT) in Adults with Acute Lymphoblastic Leukemia." Blood 104, nr 11 (16.11.2004): 5117. http://dx.doi.org/10.1182/blood.v104.11.5117.5117.

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Abstract Allo-BMT represents a curative therapy for certain patients with ALL. Unfortunately, leukemia relapse still represents a major problem following allo-BMT. Studying the pattern of relapses following allo-BMT may shed some light into the exact mechanisms of such relapses and suggest better ways to prevent them. Extramedullary relapses have been reported following allo-BMT for ALL. We investigated the pattern of ALL relapses in 57 patients after allo-BMT. All donors were HLA matched serologically at HLA A, B, and DR. All patients were treated with high-dose busulfan (16 mg/kg) combined with cyclophosphamide (120 mg/kg) with or without etoposide (50 mg/kg) and all received GVHD prophylaxis, excluding T-cell depletion. We identified 57 patients with ALL treated with BMT between 1987 and 2001. 45 patients (78.9%) had a matched related donor (MRD) and the rest had matched unrelated donors (MUD). 22 patients (39%) relapsed, 8 patients had an isolated extramedullary (IEM) relapse and 14 patients had bone marrow relapse (BM-R) with or without an isolated extramedullary relapse. The median time to relapse for the IEM relapses was 432 days with a range of 139–1422. This was significantly longer than the median time to relapse with BM (median 192 days and range 40–498) P=0.016. The following table shows the characteristics of both groups: Number Ph + B-cell ALL CR-1 Extensive GVHD BM-R 22 3 (14%) 7 (32%) 5 (23%) 4 (18%) IEM-R 8 3 (37%) 5 (62%) 2 (25%) 2 (25%) IEM relapses occurred in different organs including mastoid sinus, mediastinum, pericardium, nasopharyngeal lymphoid tissue, bone, CNS, and breast. Hematopoietic chimerism was determined utilizing the polymerase chain reaction (PCR) amplification of Short Tandem Repeat (STR) loci on DNA extracted from peripheral blood leukocytes compared with Pre-Transplant STR loci of donors and recipients. At the time of relapse all the patients with IEM relapses had 100% donor chimerism. Treatment plans for those IEM relapses included donor lymphocytes infusion (DLI), local radiation therapy, reinduction chemotherapy, imatinib for Ph+ patients, and one patient had an additional Allo-BMT. Only one patient in the IEM relapse group eventually had a relapse in the bone marrow, only 2 patients (25%) were alive more than 2 years following relapse and 3 patients died due to transplant complications. We concluded from our review that IEM relapse following Allo-BMT for ALL is not an uncommon occurrence. These relapses may have a wide-range of clinical presentations depending on the organ affected which makes the diagnosis of this type of relapse challenging. These relapses have, usually, a late occurrence compared to BM-R, and their pathogenesis is poorly understood. Full donor chimerism does not exclude the possibility of IEM relapse.

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Kalinina, I. I., D. A. Venyov, O. V. Goronkova, D. D. Baydildina, K. A. Voronin, M. A. Maschan i A. A. Maschan. "Treatment results of children and adolescents with relapsed AML who were initially treated according to the AML-MM-2006 protocol". Russian journal of hematology and transfusiology 68, nr 2 (17.07.2023): 152–65. http://dx.doi.org/10.35754/0234-5730-2023-68-2-152-165.

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Introduction. Relapse of acute myeloid leukemia (AML) develops in children who received intensive chemotherapy and achieved the first complete remission (CR1). Only intensive anti-relapse chemotherapy followed by allogeneic hematopoietic cell transplantation (allo-HSCT) may lead to cure.Aim — to present the results of treatment of children with AML who relapsed after completion of treatment or while on therapy according to the AML-MM-2006 protocol.Materials and methods. The study included children with AML who relapsed after completion of treatment of the first-line therapy according to the AML-MM-2006 protocol. During the follow-up period (median — 4.6 years), 68 relapses were registered among 187 patients who reached CR1 (early — 36, late — 26; with a change of phenotype to ALL-6). The cumulative probability of relapse was 40 %. Four (6 %) patients with relapsed AML initially belonged to the group of standard, 33 (54 %) — of intermediate risk of relapse of AML and 25 (40 %) — to the group of high risk. Eleven (18 %) were patients with “CBF-leukemia”, 19 (31 %) — with rearrangements of the 11q23 (KMT2A gene). Fludarabine, high doses of cytarabine and idarubicin in 33 (80 %) or mitoxantrone in 8 (20 %) patients were used to induce the second complete remission (CR2) in 41 patients (66 %).Results. Out of 53 patients who received chemotherapy as a second induction therapy, CR2 was achieved in 30 patients (57 %) (in 9 — with early, in 21 — with late relapse) after chemotherapy courses; 2 patients died within 30 days of the start of CT; 21 patients were refractory to chemotherapy. HSCT after relapse was performed in 51 patients, mainly from a haploidentical donor. Twenty-five patients underwent HSCT in CR2, 26 — in the status of “active disease”. Among patients transplanted into CR2, the probability of relapse was 20 %, and the overall survival rate was 80 %. Among patients transplanted outside of CR2, the probability of achieving CR2 was 77 %, the probability of relapse was 50 % and overall survival (OS) 58 %. The probability of OS in the group as a whole reached 52 %. The most significant prognostic factors of an unfavorable outcome were early relapse, refractory course of relapse, M7 variant of AML, complex karyotype and rearrangements of the ETV6 gene, combined (“bone marrow + CNS damage + non-hematopoietic tissue”) relapse and relapse after HSCT performed in CR1.Conclusion. About 50 % of patients with relapses of AML can be cured with the help of high-dose chemotherapy and allo-HSCT.

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Shimoni, Avichai, Avital Rand, Izhar Hardan, Noga Shem-Tov, Etai Zilbershatz, Ronit Yerushalmi i Arnon Nagler. "Isolated Extra-Medullary Relapse of Acute Leukemia after Allogeneic Stem-Cell Transplantation; Different Kinetics and Better Prognosis Than Systemic Relapse." Blood 112, nr 11 (16.11.2008): 2148. http://dx.doi.org/10.1182/blood.v112.11.2148.2148.

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Abstract Allogeneic stem-cell transplantation (SCT) is a potentially curative treatment for acute leukemia, however relapsing disease is the major cause of treatment failure after SCT. Isolated extramedullary relapse is considered a rare event and its characteristics and prognosis are less defined than in systemic relapse. We analyzed outcomes of 356 consecutive patients (pts) with AML/MDS (n=277) and ALL (n=79) given SCT over an 8-year period in a single institution. This was a relatively high-risk group with only 34% of pts been in CR1. 68% of transplants were myeloablative, 54% of the donors were HLA matched siblings, 39% unrelated and 7% haploidentical and cord blood. With a median follow-up of 30 months (range, 1–103), 158 patients are alive; 75 died of treatment related causes, 149 patients relapsed (123 of them have died). The overall and disease-free survival rates were 37% (95CI, 31–43) and 31% (95CI, 25–36), respectively. The cumulative incidence of relapse was 47% (95CI, 42–54). Seventeen pts had an isolated extramedullary relapse (11.4% of all first relapses after SCT); CNS (n=6), mediastinum (n=2), pleura (n=2), skin (n=2), breast (n=2), bone (n=1), other soft tissue masses (n=2). Isolated extramedullary relapse occurred later after SCT [median 14 months (range, 1–38)] than systemic relapse [median 3 months (range, 1–59), p=0.002]. Pts with an isolated extramedullary relapse were younger than pts with systemic relapse, median age 38 and 46 years, respectively (p=0.02). Isolated extramedullary relapse occurred more commonly in ALL (23% of relapses) than MDS/AML (8%, P=0.02). There was a trend for higher incidence in pts transplanted in remission (16% of relapses) than in pts transplanted in active disease (8%, p=0.09). There was no relation to donor or conditioning type. Interestingly, among 14 pts having isolated extramedullary relapse more than 3 months after SCT, 11 had a history of chronic GVHD (79%), compared with 29 of 70 pts with systemic relapse (41%, p=0.01). Pts with isolated extramedullary relapse were most often treated with systemic chemotherapy (including intrathecal chemotherapy in CNS relapse) followed by radiation therapy when feasible and DLI in the absence of active GVHD. Pts with systemic relapse were treated with chemotherapy and DLI or a second SCT. Among the 17 pts with isolated extramedullary relapse, 12 achieved CR (71%), 5 remained in continuous CR, 7 relapsed again, 2 systemic (both died), 5 extramedullary (2 of them are in long-term remission). Among the 132 pts with systemic relapse, 35 achieved CR (27%), 14 died in remission, 7 remained in continuous CR, 14 relapsed again, 9 systemic (all died), 5 extramedullary (1 of them is in long-term remission). After a second relapse, only pts with an extramedullay relapse survived long-term. The median survival after relapse was 2.5 and 20 months after systemic and isolated extramedullary relapse, respectively, and the 2-year OS rates were 7% and 38%, respectively (p=0.0002). The CNS was the most common site of extramedullary relapse. In all, 9 pts (AML-4, ALL-5) had an isolated relapse, 6 first and 3 second relapse after SCT. Eight pts achieved CR with intrathecal therapy, 7 were given cranio-spinal irradiation and only one recurred in the CNS. Four are in continuous CNS and systemic remission 6,13,43 and 43 months after relapse. In conclusion, isolated extramedullary relapse of acute leukemia after SCT is relatively common, especially in ALL. It occurs later than systemic relapse and more commonly in pts with chronic GVHD, suggestive that GVL is able to prevent systemic recurrence but is less successful in the extramedullay sites. When treated aggressively with a combination of chemotherapy, radiation therapy and immunotherapy prognosis is better with isolated extramedullary relapse and long-term survival is feasible.

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Vose, Julie M., John C. Chan, Philip J. Bierman, Alejandro Arevalo, Fausto Loberiza, Kai Fu, Dennis Weisenburger, Robert G. Bociek, Martin Bast i James O. Armitage. "Relapse from Complete Remission More Than 5 Years after Therapy for Diffuse Large B-Cell Lymphoma (DLBCL): Relapse Histology Most Commonly DLBCL with a Germinal Center B-Cell (GCB) Phenotype." Blood 110, nr 11 (16.11.2007): 3430. http://dx.doi.org/10.1182/blood.v110.11.3430.3430.

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Abstract Although many patients are successfully treated for DLBCL, relapses can occur especially in the higher risk patients. Relapses in successfully treated DLBCL patients most frequently occur within the first 2–3 years. However in a small number of patients, relapses occurring after 5 years do happen and have been frequently reported to be a relapse of follicular lymphoma. We evaluated 805 patients with DLBCL treated with an anthracycline based chemotherapy through the Nebraska Lymphoma Study Group from 1983–1998. The patients were treated prior to the use of rituximab in this patient population. Two hundred and three patients relapsed from a documented complete remission. Of these, 30 (15%) relapsed more than 5 years after treatment (range 5.3 – 14.5 years, median 6.8 years). The median age at relapse was 71 years (range 32 – 85) and 58% were male. Patients with late relapses had relatively good prognostic features at the time of diagnosis. None had a low performance status, 71% were stage I/II, 78% had no systemic symptoms, 78% had a normal LDH, and 67% had an IPI of 0/1. All patients had biopsies to document relapse. Eighty one percent of the relapses were documented DLBCL, 11% had composite lymphoma with DLBCL and follicular grade 3 (FL3) lymphoma, 4% had FL3 alone, and 4% had follicular grade 1 (FL1). Using immunohistochemistry to predict GCB vs. non-GCB origin, 72% of the patients had a GCB phenotype at diagnosis and 90% had a GCB phenotype at relapse. Four patients had no therapy at relapse and 2 patients had radiotherapy. The remaining patients received a variety of combination chemotherapy regimens with or without rituximab and 2 patients underwent autologous stem cell transplantation. Seven patients had durable complete remissions to their second line chemotherapy regimens (4 with chemo + rituximab and 2 autologous stem cell transplantation). Three of these survivors died of unrelated causes and 4 are alive in remission 19–119 months after the salvage therapy or autologous transplantation. Conclusions: Most patients with late relapses of DLBCL initially present with good prognostic characteristics at the time of the origninal diagnosis. Unlike previous studies, the most common type of histology in this study at the time of late relapse was DLBCL and not follicular lymphoma. However, the vast majority of the late relapse DLBCL patients had a GCB phenotype both at diagnosis and at relapse. Patients with late relapses usually do respond to salvage therapy and can have second prolonged remissions with chemotherapy and/or autologous stem cell transplantation.

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KÄLSCH, ANNA-ISABELLE, ELENA CSERNOK, DOMINIK MÜNCH, RAINER BIRCK, BENITO A. YARD, WOLFGANG GROSS, THORSTEN KÄLSCH i WILHELM H. SCHMITT. "Use of Highly Sensitive C-Reactive Protein for Followup of Wegener’s Granulomatosis". Journal of Rheumatology 37, nr 11 (17.08.2010): 2319–25. http://dx.doi.org/10.3899/jrheum.100302.

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Objective.Since Wegener’s granulomatosis (WG) represents a relapsing disease, efforts have been made to reliably predict relapses using blood tests. Followup measures such as conventionally determined C-reactive protein (CRP), antineutrophil cytoplasmic antibody (C-ANCA) titer, and proteinase-3 (PR3) ELISA are applied. We evaluated whether during remission elevated highly sensitive CRP (hsCRP) precedes relapse as a marker of subclinical inflammation and thus might improve clinical assessment.Methods.We investigated 227 sera of 57 patients with WG: 74 sera collected from patients in remission who subsequently relapsed (before relapse), 30 sera collected during relapse, and 123 sera from patients in remission without relapse. We also distinguished between major and minor relapse. hsCRP, conventionally determined CRP (CRP), C-ANCA, PR3-ELISA, and erythrocyte sedimentation rate (ESR) were measured using commercial kits, and levels were correlated to clinical status.Results.Only hsCRP and ANCA titer, but not CRP levels, were higher in sera from patients who subsequently relapsed versus those who did not, indicating patients at risk. Levels of hsCRP, CRP, and ESR were higher in sera collected during relapse than in the sera before relapse. hsCRP, conventional CRP, and ESR were also higher in samples collected during major relapse than before major relapse. Looking at the levels just before relapse compared to previous levels during remission, none of these measures rose directly before the clinical manifestation of the relapse.Conclusion.Our study provides evidence for an additional value of hsCRP in the clinical assessment of patients with WG.

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Lee, A. Y., J. M. Connors, P. Klimo, S. E. O'Reilly i R. D. Gascoyne. "Late relapse in patients with diffuse large-cell lymphoma treated with MACOP-B." Journal of Clinical Oncology 15, nr 5 (maj 1997): 1745–53. http://dx.doi.org/10.1200/jco.1997.15.5.1745.

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PURPOSE To examine the clinical course of patients who experienced a late relapse after initial curative chemotherapy for advanced-stage diffuse large-cell lymphoma. PATIENTS AND METHODS Between April 1981 and June 1986, 127 patients with de novo advanced-stage diffuse large-cell lymphoma were treated with a 12-week chemotherapy program (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin [MACOP-B]). The overall survival rate at 10 years is 52%. One hundred six patients (83%) entered a complete remission (CR) and 43 of them relapsed. With a median follow-up duration of 146 months, 26 patients relapsed early and 17 relapsed late, ie, after a continuous CR (cCR) of greater than 24 months. All late relapses occurred in patients with B-cell lymphoma. RESULTS After 24 months from diagnosis, the rate of late relapse averaged 2.2% per year and reached a projected 22% actuarial risk of late relapse after 10 years. The median time to late relapse was 69 months (range, 38 to 141). Ten patients relapsed with aggressive histologic subtypes and were treated with curative intent using anthracycline-based chemotherapy. Four remain in second CR, one is alive with disease, and five died of disease or while on treatment. The 6-year overall survival rate from the time of relapse (SFR) for these 10 patients is 42%. Six patients relapsed with low-grade follicular lymphoma. These patients received various treatments intended to control, but not necessarily cure disease. One is in second CR, one is alive with disease, and four died of disease or while on treatment. The 6-year overall SFR rate for these six patients is 40%. bcl-2 translocation and Bcl-2 protein expression at diagnosis did not predict for the type of late relapse. One patient did not undergo repeat biopsy at relapse and died 9 months later despite aggressive therapy. CONCLUSION Curative therapy should be attempted in patients who relapse late with aggressive-histology lymphoma and those who relapse with follicular histology may benefit from palliative treatment. The behavior of late-relapse lymphoma is similar to de novo lymphoma, with outcome dictated by the histologic subtype at relapse.

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Romano, Emanuela, Michael Scordo, Stephen W. Dusza, Daniel G. Coit i Paul B. Chapman. "Site and Timing of First Relapse in Stage III Melanoma Patients: Implications for Follow-Up Guidelines". Journal of Clinical Oncology 28, nr 18 (20.06.2010): 3042–47. http://dx.doi.org/10.1200/jco.2009.26.2063.

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Purpose Stage III melanoma is associated with a high risk of relapse and mortality. Nevertheless, follow-up guidelines have largely been empirical rather than evidence-based. Patients and Methods Clinical records of stage III patients with no evidence of disease seen at Memorial Sloan-Kettering Cancer Center (MSKCC) between 1992 and 2004, who ultimately relapsed, were reviewed retrospectively to evaluate date of first relapse, time to first relapse, method of first relapse detection, and survival. We also determined overall 5-year relapse-free survival (RFS) of all stage III patients seen at MSKCC during this period. Results The overall 5-year RFS for stage IIIA, IIIB, and IIIIC patients was 63%, 32%, and 11%, respectively. Among relapsing patients, 340 had adequate follow-up to be evaluable for all parameters. Site of first relapse was local/in-transit (28%), regional nodal (21%), or systemic (51%). First relapses were detected by the patient or family, physician, or by screening radiologic tests in 47%, 21%, and 32% of patients, respectively. Multivariate analysis revealed that better overall survival was associated with younger age and first relapse being local/in-transit or nodal, asymptomatic, or resectable. For each substage, we estimated site-specific risk of first relapse. Conclusion Patients detected almost half of first relapses. Our data suggest that routine physical examinations beyond 3 years for stage IIIA, 2 years for stage IIIB, and 1 year for stage IIIC patients and radiologic imaging beyond 3 years for stages IIIA and IIIB and 2 years for stage IIIC patients would be expected to detect few first systemic relapses.

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Douer, Dan, Lynette Zickl, Charles A. Schiffer, Frederick R. Appelbaum, James H. Feusner, Lois E. Shepherd, Cheryl L. Willman i in. "Late Relapses Following All-Trans Retinoic Acid for Acute Promyelocytic Leukemia Are Uncommon, Respond Well to Salvage Therapy and Occur Independently of Prognostic Factors At Diagnosis: Long-Term Follow-up of North American Intergroup Study I0129". Blood 118, nr 21 (18.11.2011): 83. http://dx.doi.org/10.1182/blood.v118.21.83.83.

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Abstract Abstract 83 The European APL91 and the North American Intergroup study I0129 reported in the 1990s that ATRA combined with chemotherapy markedly improves the outcome of APL. Large randomized and single arm studies from around the world with both short and relatively long-term follow-up, confirm this impact of ATRA, while optimizing their mode of administration. However, the incidence and outcome of late relapses have not been well established. Furthermore, as strategies to minimize or eliminate chemotherapy by combining ATRA and arsenic trioxide are being adopted, the long-term durability of ATRA and chemotherapy regimens is even more relevant. We now report on late relapses among the APL patients enrolled in the North American Intergroup study I0129 conducted between 4/92 -2/95. Methods: 380 patients (excluding 14 who had never received ATRA, and 3 ineligible) from 6 cooperative oncology groups, were randomized to induction with either ATRA or chemotherapy with daunorubicin and ara-C (DA). Patients then received two cycles of anthracycline-containing consolidation chemotherapy and then irrespective of their induction arm, patients were randomized to receive 1 year of maintenance with ATRA or observation (Obs) (Tallman et al NEJM 1997). Late relapse was defined as relapse 3 years or later from CR. Data analysis as of March 25, 2011 with a median follow-up of 11.8 (ranges 0.4–14.5) years. Results: Of 191 pts on DA and 189 pts on ATRA induction arms, 85 vs. 116 (total 201) were last known to be alive, median OS 3.6 years (95% CI: 2.0, 8.7) vs. not yet reached (p=0.0007), respectively. CR was achieved in 272 (72%) pts, and 113 are known to have relapsed. In addition, 70 relapsed pts. had received ATRA at any time, of them 60 pts relapsed early and 10 pts. relapsed late; 43 pts relapsed patients did not receive any ATRA and all relapsed early (P=0.01). Follow up information is known so far on 5 late relapses. Relapse sites: BM -4 Pts, CNS – 1pt. Late relapse salvage: chemotherapy-5 pts., alloBMT-2 pts., Auto BMT -1pt., arsenic trioxide –none. Of the 10 late relapses, 3 died, all from disease progression. Median duration in CR1 prior to late relapse: survivors vs. died 3.9 and 4.1yrs, respectively. Only 35 (34%) of the early relapses are alive. Two second malignancies in the breast were identified, all in no known relapse pts. Conclusions: This is among the largest studies with very long follow-up to report that, in newly diagnosed APL patients receiving consolidation chemotherapy, the significantly higher OS rate after induction with ATRA compared to chemotherapy, is sustained. Most relapses in APL occur early, including in patients who had received ATRA at any time. Late relapses after 3 years: 1) are uncommon (4%) and are very rare after 4 years (1); at that time CR1 patients are most likely cured; 2) survive longer than early relapses, independent of CR1 duration, implicating the effectiveness of salvage therapy; 3) do not differ from early relapses in WBC and age at diagnosis; 4) were slightly more likely to be on ATRA maintenance. As the number of long-term APL survivors increases, future studies should address survivorship, late treatment-related complications, and determine whether some late relapses represent new therapy-related AML. Finally, if the high rate of early death (Park et al Blood, 2011) can be reduced, more patients will benefit from the high cure rate reported by this and other studies. Disclosures: No relevant conflicts of interest to declare.

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Schönau, V., G. Corte, S. Ott, K. Tascilar, F. Hartmann, B. Manger, B. Hellmich i in. "POS0809 CHARACTERIZATION OF RELAPSES IN PATIENTS WITH GIANT CELL ARTERITIS (GCA) PATIENTS- DATA FROM THE REAL-LIFE TREATMENT AND SAFETY (REATS)-GCA COHORT". Annals of the Rheumatic Diseases 81, Suppl 1 (23.05.2022): 694.1–694. http://dx.doi.org/10.1136/annrheumdis-2022-eular.3543.

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BackgroundGiant cell arteritis (GCA) has the tendency to relapse once treatment is tapered or stopped. Such relapses represent a potential threat to GCA patients as they can lead to severe symptoms and organ damage.ObjectivesTo assess the frequency and type of relapses in patients with GCAMethodsThe Real-Life Treatment and Safety (REATS)-GCA cohort has been established by extracting the data on clinical presentation, inflammatory markers, imaging, comorbidities, treatments and serious adverse events of GCA patients from 6 specialized centres in Germany. We undertook descriptive and survival analyses (Kaplan-Meier), and compared baseline characteristics of participants with vs. without relapse. Ethical approval for the cohort was obtained.ResultsWe included 395 patients with a mean age of 71 years, including 264 (66.8 %) females and 129 (32.7%) males. Diagnosis of GCA was supported by temporal artery ultrasound in 37%, 18F-FDG-PET/CT in 29%, temporal artery biopsy in 14% of patients and by MRI or clinically in the remaining patients. 31% of patients presented with an isolated cranial manifestation and 18% with isolated extracranial manifestations. Most common presenting symptoms were headache (57%), fatigue (55%), weight loss (42%) and polymyalgia (38%) (Table 1). The most common comorbidities at the time of study inclusion were arterial hypertension (68%), followed by osteoporosis (26%). Within a median total follow-up duration of 22.2 (11.7-40.6) months, 97 of the 395 patients relapsed including 15 patients who relapsed more than once. The median (IQR) time to first relapse was 12.5 (7.1-21.8) months. Median relapse-free survival was 7.8 years with a relapse risk of 12% (CI, 9 to 15%) at 1 year and 38% (CI, 30 to 45%) at 5 years (Figure 1). Most common symptoms at relapse were headache (35%), polymyalgia (23%), fatigue (19%) and night sweats (12%) (Table 1). Three patients relapsed with sudden loss of vision. Among the 114 relapses observed, 94 (83%) occurred under prednisolone treatment with a median dose of 7.0 mg/day (IQR 4.0-12.5). 26 (23%) occurred under methotrexate and 14 (12%) under tocilizumab treatment. Comparing the baseline characteristics that were documented in this study, we did not find a statistically significant difference in relapsing versus non-relapsing GCA patients.Table 1.Symptom at disease onsetN=395 (%)Symptom at relapseN=97 (%)Headache216 (54.7)Headache35 (30.7)Fatigue208 (52.7)Polymyalgia (PMR)23 (20.2)Weight loss159 (40.3)Fatigue19 (16.7)Polymyalgia (PMR)144 (36.5)Vision impairment13 (11.4)Night sweats140 (35.4)Night sweats12 (10.5)Headache in the temple area125 (31.6)Headache in the temple area12 (10.5)Jaw pain121 (30.6)Jaw pain11 (9.6)Vision impairment118 (29.9)Morning stiffness7 (6.1)Morning stiffness89 (22.5)Weight loss7 (6.1)Fever80 (20.3)Claudication upper limb6 (5.3)Swelling temporal arteries77 (19.5)Arthralgia6 (5.3)Vision loss57 (14.4)Claudication lower limb5 (4.4)Scalp tenderness38 (9.6)Vision loss3 (2.6)Claudication upper limb38 (9.6)Arthritis3 (2.6)Claudication lower limb34 (8.6)Scalp tenderness2 (1.8)Arthralgia28 (7.1)Fever2 (1.8)Arthritis3 (0.8)Swelling temporal arteries2 (1.8)Figure 1.ConclusionAbout one fourth of GCA patients relapsed and the overwhelming majority of relapses occurred before patients were able to stop glucocorticoids. The leading symptoms at relapse are headache and fatigue, while loss of vision is rare (0.76%). Baseline characteristics seem to be poorly informative about the risk of relapse, therefore regular monitoring of GCA patients is necessary.AcknowledgementsThis research was financially supported by Roche Pharma Ag and Chugai Pharma Europe Ltd.Disclosure of InterestsVerena Schönau Speakers bureau: Novartis, Janssen, Grant/research support from: Roche, Chugai, Giulia Corte: None declared, Sebastian Ott: None declared, Koray Tascilar: None declared, Fabian Hartmann: None declared, Bernhard Manger: None declared, Bernhard Hellmich: None declared, Alexander Pfeil: None declared, Peter Oelzner: None declared, Wolfgang A. Schmidt: None declared, Andreas Krause: None declared, Marc Schmalzing: None declared, Matthias Fröhlich: None declared, Michael Gernert: None declared, Nils Venhoff: None declared, Jörg Henes: None declared, Jürgen Rech Speakers bureau: Abbvie, Biogen, BMS, Chugai, GSK, Lilly, MSD; Novartis, Roche, Sanofi, Sobi, UCB,, Consultant of: Biogen, BMS, Chugai, GSK, Lilly, MSD, Novartis, Roche, Sanofi, Sobi, UCB, Grant/research support from: Sobi, Novartis, Georg Schett: None declared

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Szela, Joel, Angy Hanna i Matthew Sims. "2419. Timing of Secondary Prophylaxis Against Clostridium difficile Infection After Antibiotic Exposure". Open Forum Infectious Diseases 6, Supplement_2 (październik 2019): S835. http://dx.doi.org/10.1093/ofid/ofz360.2097.

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Abstract Background Clostridium difficile infection (CDI) is the most common nosocomial infection, and is increasing. The major risk for CDI is antibiotic (abx) use. We have previously shown that secondary prophylaxis with vancomycin decreases CDI relapse in patients with recent CDI given abx to treat another infection. The median time to relapse after use of abx was 3 days. In an effort to further elucidate the best way to employ secondary prophylaxis against CDI, we examined all patients with CDI in our institution in 2016 and timing of relapse as related to another exposure to abx and the success of prophylaxis relative to the timing and the duration of prophylaxis. Methods All patients positive by PCR for C difficile at our institution in 2016 were examined for receipt of abx within 3 months of a positive PCR. The relapse rates for all patients, patients who received abx with or without secondary prophylaxis, and patients who did not receive abx were calculated. Timing of the relapse from the prior CDI and from receipt of abx were determined as was impact of prophylaxis, particularly in patients who relapsed despite prophylaxis. Results 1748 patients were identified, representing 2181 episodes of CDI. The relapse rates and timing based on prior CDI, receipt of additional abx prior to relapse, and use of prophylaxis are shown in Table 1. Prophylaxis decreased the overall relapse rate from 19.2% to 11.6%. Time to relapse in patients who relapsed despite prophylaxis was significantly longer indicating prophylaxis was having an effect. The failure appears dependent on when prophylaxis was started relative to abx and how long prophylaxis was given relative to abx. Conclusion Prophylaxis is effective in preventing relapses in patients given abx after CDI however the timing and duration of prophylaxis significantly impacts the effectiveness. The majority of CDI relapses after abx occur within 3 days and can be prevented by prophylaxis. Relapses that occur after 3 weeks appear unrelated to the use of abx and are not preventable through prophylaxis. Failures of prophylaxis within the first 1 week are likely related to starting prophylaxis too late after abx and failures that occur between 1 and 3 weeks after abx are likely related to ending prophylaxis too early. Disclosures All authors: No reported disclosures.

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Wang, Yucai, Umar Farooq, Brian K. Link, Mehrdad Hefazi, Cristine Allmer, Matthew J. Maurer, Thomas E. Witzig i in. "Relapses after Achieving EFS24 in Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era". Blood 132, Supplement 1 (29.11.2018): 454. http://dx.doi.org/10.1182/blood-2018-99-113213.

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Abstract Introduction: The addition of Rituximab to chemotherapy has significantly improved the outcome of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients treated with immunochemotherapy for DLBCL who achieve EFS24 (event-free for 2 years after diagnosis) have an overall survival equivalent to that of the age- and sex-matched general population. Relapses after achieving EFS24 have been considered to be unusual but have been understudied. We sought to define the rate, clinical characteristics, treatment pattern, and outcomes of such relapses. Methods: 1448 patients with newly diagnosed DLBCL from March 2002 to June 2015 were included. Patients were enrolled in the Molecular Epidemiology Resource (MER) of the University of Iowa/Mayo Clinic Lymphoma SPORE, treated per physician choice (predominantly R-CHOP immunochemotherapy) and followed prospectively. An event was defined as progression or relapse, unplanned re-treatment after initial therapy, or death from any cause. Cumulative incidence of relapse and non-relapse mortality after achieving EFS24 were analyzed as competing events using Gray's test in the EZR software. Post-relapse survival was defined as time from relapse to death from any cause and analyzed using Kaplan-Meier method in SPSS (V22). Results: Among the 1448 patients, 1260 (87%) had DLBCL alone at diagnosis, and 188 (13%) had concurrent indolent lymphoma (follicular lymphoma 115, marginal zone lymphoma 18, chronic lymphocytic leukemia 14, lymphoplasmacytic lymphoma 4, unspecified 37) at diagnosis. After a median follow-up of 83.9 months, 896 patients achieved EFS24. For all 896 patients who achieved EFS24, the cumulative incidence of relapse (CIR) was 5.7%, 9.3% and 13.2%, respectively, at 2, 5 and 10 years after achieving EFS24. Patients with concurrent indolent lymphoma at diagnosis had a higher CIR compared to those with DLBCL alone at diagnosis (10.2 vs 4.8% at 2 years, 15.7 vs 8.0% at 5 years, 28.8 vs 9.7% at 10 years, P<0.001; Figure 1). There were a total of 84 patients who relapsed after achieving EFS24. The median age at initial diagnosis was 66 years (range 35-92), and 48 (57%) were male. At diagnosis, 11 (13%) had ECOG PS >1, 37 (50%) had LDH elevation, 62 (74%) were stage III-IV, 14 (17%) had more than 1 extranodal site, and 26 (31%) were poor risk by R-IPI score. There were 58 patients with DLBCL alone at diagnosis who relapsed after achieving EFS24, and 38 (75%) relapsed with DLBCL, 13 (25%) relapsed with indolent lymphoma (predominantly follicular lymphoma), and pathology was unknown in 7 patients. In contrast, there were 26 patients with concurrent indolent lymphoma at diagnosis who relapsed after achieving EFS24, and 9 (41%) relapsed with DLBCL, 13 (59%) relapsed with indolent lymphoma, and pathology was unknown in 4 patients. In the 47 patients who relapsed with DLBCL after achieving EFS24, 45% received intensive salvage chemotherapy, 19% received regular intensity chemotherapy, 9% received CNS directed chemotherapy, and 36% went on to receive autologous stem cell transplant (ASCT). In the 26 patients who relapsed with indolent lymphoma after achieving EFS24, 27% were initially observed, 54% received regular intensity chemotherapy, 4% received intensive salvage chemotherapy, and 19% received ASCT after subsequent progression. The median post-relapse survival (PRS) for all patients with a relapse after achieving EFS24 was 38.0 months (95% CI 27.5-48.5). The median PRS for patients who relapsed with DLBCL and indolent lymphoma after achieving EFS24 were 29.9 (19.9-39.9) and 89.9 (NR-NR) months, respectively (P=0.002; Figure 2). Conclusions: Relapses after achieving EFS24 in patients with DLBCL were uncommon in the rituximab era. Patient with DLBCL alone at diagnosis can relapse with either DLBCL or indolent lymphoma (3:1 ratio). Patients with concurrent DLBCL and indolent lymphoma at diagnosis had a significantly higher CIR, and relapses with DLBCL and indolent lymphoma were similar (2:3 ratio). Even with high intensity salvage chemotherapy and consolidative ASCT, patients who relapsed with DLBCL had a significantly worse survival compared to those who relapsed with indolent lymphoma. Late relapses with DLBCL remain clinically challenging, with a median survival of 2.5 years after relapse. Figure 1. Figure 1. Disclosures Maurer: Celgene: Research Funding; Nanostring: Research Funding; Morphosys: Research Funding. Witzig:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Ansell:Takeda: Research Funding; Pfizer: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Merck & Co: Research Funding; Bristol-Myers Squibb: Research Funding. Cerhan:Celgene: Research Funding; Jannsen: Other: Scientific Advisory Board; Nanostring: Research Funding.

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Kapke, Jonathan, Narendranath Epperla, Namrata Shah, Kristin Richardson, George Carrum, Parameswaran Hari, Mehdi Hamadani, Sai Ravi Pingali, Reem Karmali i Timothy S. Fenske. "Impact of Routine Surveillance Imaging on Outcomes in Patients with Classical Hodgkin Lymphoma (cHL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)". Blood 126, nr 23 (3.12.2015): 3169. http://dx.doi.org/10.1182/blood.v126.23.3169.3169.

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Abstract Background: It is common for classical Hodgkin lymphoma (cHL) patients following auto-HCT to undergo surveillance imaging to monitor for disease progression or relapse. Although post auto-HCT surveillance imaging is employed at most centers, the literature remains unclear on how this practice affects overall survival. Furthermore, surveillance imaging results in significant amounts of radiation exposure as well as invasive procedures to work up false positive findings. We studied cHL patients who underwent auto-HCT at three transplant centers to define how many surveillance imaging studies were obtained, how often relapses were detected by surveillance imaging versus clinically (based on signs, symptoms or laboratory findings), and whether survival was improved if relapse was detected by surveillance imaging versus clinically. Methods: Classical HL patients who underwent auto-HCT between 2000 and 2013 were identified using clinical databases. Pre-transplant patient and disease characteristics were collected. Progression-free survival (PFS) and overall survival (OS) were determined. Patients were classified as having “radiographic” or “clinical” relapses. PFS and OS were compared for these two groups. Results: A total of 148 patients with cHL who underwent auto-HCT were identified. Patient characteristics are presented in Table 1. Of these 148 patients, 20 relapsed or progressed prior to or at their initial post-transplant disease assessment (day 100 evaluation). The remaining 128 patients were then analyzed to determine which patients had relapse/progression, and how relapses were detected. 31 patients relapsed post day 100 evaluation. The date of relapse for 2 patients was unknown, and these patients were excluded. For the 29 remaining patients, the median time to relapse was 389 days post-transplant. Of these patients, 14 (48%) had relapse detected clinically and 15 (52%) had relapse detected by surveillance imaging. Comparing the radiographic and clinically detected groups, median PFS post auto-HCT was 426 vs 318 days respectively (p= 0.62, log rank test) and median survival post auto-HCT was 1270 vs 931 days respectively (p= 0.71, log rank test, Figure 1). For patients who never relapsed after auto-HCT, a median of 6 surveillance imaging studies were performed (with a median follow up of 5 years post-transplant). Conclusions: In cHL patients post auto-HCT, the majority of relapses were detected by surveillance imaging. However, the survival of patients with relapse detected by surveillance imaging was not superior to those whose relapse was detected clinically. Given this, combined with the radiation exposure and cost associated with surveillance imaging, the practice of surveillance imaging post auto-HCT appears to have limited utility in cHL. Disclosures Hari: Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; BMS: Consultancy. Hamadani:Takeda: Research Funding; Cellerant: Consultancy; MedImmune: Consultancy; Celgene: Consultancy. Fenske:Seattle Genetics: Honoraria; Celgene: Honoraria; Millennium/Takeda: Research Funding; Pharmacyclics: Honoraria.

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Ortega, J. A., M. E. Nesbit, H. N. Sather, L. L. Robison, G. J. D'Angio i G. D. Hammond. "Long-term evaluation of a CNS prophylaxis trial--treatment comparisons and outcome after CNS relapse in childhood ALL: a report from the Childrens Cancer Study Group." Journal of Clinical Oncology 5, nr 10 (październik 1987): 1646–54. http://dx.doi.org/10.1200/jco.1987.5.10.1646.

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The current status of children with acute lymphoblastic leukemia (ALL) who had developed CNS disease while being treated on protocol CCG-101 was investigated. Seven hundred thirty-six eligible patients were entered into the study between June 1972 and July 1974. All children who were greater than 18 months of age were eligible for randomization to a CNS prophylaxis trial for which one regimen gave only a short course of intrathecal methotrexate (IT MTX) as prophylaxis. All other regimens included radiation therapy as prophylaxis. Current follow-up (median, greater than 10 years) shows no significant difference by standard life-table analysis for ultimate survival, although a substantial excess of CNS episodes occurred on the IT MTX regimen. Of the 675 patients who completed induction therapy and achieved remission in the study, 100 (14.8%) developed CNS disease as the first evidence of relapse. Fifty-five of these 100 had no subsequent CNS episodes. Only 17 of these 55 patients are surviving without further relapses since the CNS episode. The median time to isolated CNS relapse was 457 days. Time to the initial CNS relapse was found to be the most important factor for predicting outcome. Thirty-five of the 55 patients with isolated relapse subsequently relapsed in the bone marrow, and of these, 32 have died. Twenty patients of the 100 with CNS disease as the first evidence of relapse developed two episodes of CNS involvement and 17 of these 20 patients subsequently relapsed in the bone marrow; only one patient survived. Twenty-five patients of the 100 have shown a pattern of chronic CNS disease with multiple CNS relapses. The overall disease-free survival for the 100 patients who developed one or more relapse was only 16%. These data demonstrate that the occurrence of a CNS relapse is an indicator of poor subsequent outcome. Comparison of results of groups receiving different CNS prophylaxis required careful consideration of the entire pattern of relapses and mortality.

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Fossard, Gaelle, Emmanuelle Nicolas-Virelizier, Philippe Rey, Francois Ducray, Emmanuel Jouanneau, Pierre Faurie, Amine Belhabri i in. "Utility Of Post Therapy Brain Surveillance Imaging In The Detection Of Primary CNS Lymphoma (PCNSL) Relapse". Blood 122, nr 21 (15.11.2013): 933. http://dx.doi.org/10.1182/blood.v122.21.933.933.

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Abstract Introduction The optimal follow-up strategy for primary CNS lymphoma (PCNSL) patients in remission after first line therapy is not clear. The goal of this study is to determine the utility of planned brain surveillance imaging in the detection of relapse in a large cohort of PCNSL patients. Methods Patients were from consecutive PCNSL cases (N=209) included in Leon Berard Cancer Centre registry (Lyon, France), from 1987 to 2011 (date of diagnosis). Patients were all treated by chemotherapy, 92% of them by high-dose methotrexate containing chemotherapy followed by brain radiotherapy for 107 patients (51%). All patients were followed for relapse, retreatment and death. Patient clinical records were reviewed for details at relapse and relationship to planned follow-up visits and brain surveillance imaging. Results Among the 209 PCNSL patients, 28 (13%) presented toxic death, one patient died from another reason and 41 patients (20%) had a progressive disease during first-line therapy. The remaining 139 patients (66%) entered in post-treatment observation, 128 of them in complete remission (92%) and 11 in partial remission (8%). The median follow up was 36 months for the patients who entered in post-treatment observation. Among these 139 patients, 7 (5%) were lost of follow-up, 62 (45%) patients are still in remission and 70 (50%) relapsed. Among these 70 relapses, 15 (21%) were detected by planned brain surveillance imaging but 53 (76%) patients were symptomatic and presented earlier than a planned follow-up visit; two patients (3%) had no information at time of relapse. If we consider only patients in complete remission who entered in post-treatment observation, 13 (20%) relapses were detected by brain surveillance imaging and 50 (80%) patients presented symptoms between planned visits and imaging. Among the 7/11 patients considered in partial remission after initial treatment who relapsed, two (29%) relapses were detected by brain surveillance imaging and five (71%) by symptoms between planned visits and imaging. Among the 53 symptomatic patients at relapse, 41 (77%) presented a brain tumor relapse, six had an isolated leptomeningeal relapse, one a spinal cord localization and five an extra-cerebral relapse (three abdominal nodes, one soft-tissue mass, one testis). The most common symptoms at relapse were cognitive troubles, motor or sensitive deficits, epilepsy, and alteration of performance status. We did not observe any difference between asymptomatic relapse patterns before and after 2 years with 54% relapses before the two years of follow-up (brain imaging mainly every 4 months) and 46% relapses after 2 years of follow-up (brain imaging mainly every 6 months). Conclusions This study showed that PCNSL relapses frequently occurred outside of planned follow-up visits and were notably detected by symptoms between two brain surveillance imaging. Even during the two first years of follow-up with a closed brain imaging monitoring, planned surveillance imaging seemed not efficient. Disclosures: No relevant conflicts of interest to declare.

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Yamasaki, Kai, Kazuki Tanimura, Yuki Okuhiro, Kota Hira, Chika Nitani, Keiko Okada, Hiroyuki Fujisaki i in. "MBCL-22. EFFICACY OF DOUBLE-CONDITIONING REGIMEN COMPRISING THIOTEPA AND MELPHALAN FOR RELAPSED MEDULLOBLASTOMA – A SINGLE INSTITUTION EXPERIENCE". Neuro-Oncology 22, Supplement_3 (1.12.2020): iii393. http://dx.doi.org/10.1093/neuonc/noaa222.498.

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Abstract BACKGROUND The prognosis of relapsed medulloblastoma was dismal. Recently, we published the promising outcome of metastatic medulloblastomas treated with a double-conditioning regimen comprising high-dose thiotepa and melphalan (HD-TM). Here, we report a single-center study of HD-TM for relapsed medulloblastomas. MATERIALS AND METHODS From April 2006 to January 2019, 17 consecutive medulloblastoma patients with the first relapse were identified, and of which 10 received HD-TM were retrospectively reviewed. RESULTS The median age at first relapse was 11.9 years (range 1.8–31.7). The median follow-up period was 23.5 months after 1st relapse. Four localized relapses at the posterior fossa and 6 metastatic relapses including 3 with multiple sites were observed. Surgical resection and re-irradiation were administered in 5 and 9 patients, respectively. Two-year PFS and OS after relapse were 21±18.1% and 60±21.9%, respectively, and significantly better than in patients who did not receive HD-TM. Among 7 evaluable patients, tumor shrinkage was observed in 6 after HD-TM administration including 3 patients who were resistant to prior chemotherapy. At the present time, 5 patients are alive with no evidence of disease (NED). The last 5 patients received re-irradiation including 12 Gy craniospinal irradiation (CSI), and 4 are alive with NED. In multivariate analysis for all patients, both HD-TM and re-irradiation were associated with improved OS and PFS, but disseminated relapse had no prognostic value (p=0.56). CONCLUSION HD-TM contributes to prolonged survival when combined with re-irradiation. HD-TM might become a curative approach for relapsed medulloblastoma, especially when combined with CSI.

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Weeks, J. C., B. Y. Yeap, G. P. Canellos i M. A. Shipp. "Value of follow-up procedures in patients with large-cell lymphoma who achieve a complete remission." Journal of Clinical Oncology 9, nr 7 (lipiec 1991): 1196–203. http://dx.doi.org/10.1200/jco.1991.9.7.1196.

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Salvage therapy for relapsed large-cell lymphoma (LCL) is more effective in patients with minimal disease, suggesting that early detection of relapse might increase the chance of long-term survival. To determine whether current follow-up procedures are effective in identifying preclinical disease, we analyzed patterns of relapse in 139 LCL patients who achieved a complete remission (CR) with high/moderate-dose methotrexate with leucovorin, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone (M/m-BACOD). The timing and results of all posttreatment follow-up tests were examined in the 36 patients who relapsed from complete remission (CR) and 46 controls who remain in CR. Despite conscientious posttreatment follow-up, only two of the 36 relapses (6%) were detected before the development of symptoms. Sixty-seven percent of patients relapsed in new disease sites (42% in new and old sites, and 25% in new sites only). Consistent with this observation, the tests most sensitive to clinical relapse were those not targeted to specific sites of disease: gallium scan (sensitivity, 90%), physical examination (80%), and lactate dehydrogenase (LDH) (65%). Of screening tests performed, only LDH was successful in detecting preclinical relapse, with a sensitivity of 42% and specificity of 85% for impending symptomatic relapse. These results indicate that conventional screening was ineffective in detecting preclinical relapse in LCL patients. We recommend prospective evaluation of a strategy that (1) screens with a frequency appropriate to a patient's risk of relapse, (2) uses sensitive test(s) not targeted to specific sites, and (3) limits aggressive screening to those high-risk patients eligible for potentially curative salvage therapy.

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Moerdler, Scott, Arlene Naranjo, Sheena Tenney, Rochelle Bagatell, Alice L. Yu i Wendy B. London. "Patterns of relapse after immunotherapy in patients with high-risk neuroblastoma." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 10043. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10043.

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10043 Background: While the addition of anti-GD2 immunotherapy led to improvement in outcomes in patients on the Children’s Oncology Group (COG) ANBL0032 study, relapse remains a concern. Prior studies demonstrated the prognostic importance of time to first relapse, however, the effect of immunotherapy on timing and patterns of relapse in neuroblastoma (NBL) have yet to be evaluated. The purpose of this exploratory analysis was to describe the impact of immunotherapy on patterns of relapse in patients with high-risk NBL, including a descriptive comparison of sites of relapse based on post-consolidation treatment received [dinutuximab with cytokines and isotretinoin (DIN) vs isotretinoin alone (ISO)]. Methods: A retrospective, descriptive analysis of patients on ANBL0032 was performed, including patients randomized to DIN or ISO and those non-randomly assigned to DIN after ISO arm closure. Pt characteristics including age, stage, MYCN amplification status, tumor grade, mitosis-karyorrhexis index (MKI) and ploidy were summarized descriptively and relapse sites were tabulated. For DIN patients who subsequently relapsed, overall survival (OS) was calculated starting from the time of first relapse after enrollment on ANBL0032 (“post-relapse OS”). Kaplan-Meier OS curves were generated based on site of relapse. Results: The analytic cohort included 1,431 (DIN = 1,327; ISO = 104) patients. Among DIN patients, 492 relapsed, many in > 1 site. In the randomized cohort (n = 248), 122 relapsed (DIN = 68/144; ISO = 54/104). The frequencies (DIN; ISO) by site of relapse in the randomized cohort were: bone (53%; 54%), CNS (16%; 11%), lymph node (13%; 17%), abdominal (10%; 17%), paraspinal (6%; 2%), liver (3%; 4%), other soft tissue (22%; 7%). A higher proportion of ISO patients had marrow relapse (29.4% DIN; 48.2% ISO); however, the proportion of DIN patients with lung relapses appeared higher (9% vs 2%). Among all relapsed patients, the proportion with bone relapse did not appear to differ between treatment groups, regardless of MYCN status. Among patients with MYCN amplified disease, the proportion with marrow relapse did not appear to differ based on treatment [21/149 (14.1%) DIN; 3/20 (15.0%) ISO]; however, among patients with MYCN non-amplified disease, the proportion with marrow relapse appeared higher in the ISO group [16/23; 69.6%] vs the DIN group [52/193 (26.9%)]. Conclusions: In this exploratory analysis of patients on COG ANBL0032, the pattern for site of relapse appears to differ between patients treated with DIN vs ISO. While immunotherapy remains the treatment of choice in this population, the findings from this retrospective exploratory analysis warrant further investigation to decrease the risk for post-immunotherapy relapse. Clinical trial information: NCT00026312.

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Moerdler, Scott, Arlene Naranjo, Sheena Tenney, Rochelle Bagatell, Alice L. Yu i Wendy B. London. "Patterns of relapse after immunotherapy in patients with high-risk neuroblastoma." Journal of Clinical Oncology 40, nr 16_suppl (1.06.2022): 10043. http://dx.doi.org/10.1200/jco.2022.40.16_suppl.10043.

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10043 Background: While the addition of anti-GD2 immunotherapy led to improvement in outcomes in patients on the Children’s Oncology Group (COG) ANBL0032 study, relapse remains a concern. Prior studies demonstrated the prognostic importance of time to first relapse, however, the effect of immunotherapy on timing and patterns of relapse in neuroblastoma (NBL) have yet to be evaluated. The purpose of this exploratory analysis was to describe the impact of immunotherapy on patterns of relapse in patients with high-risk NBL, including a descriptive comparison of sites of relapse based on post-consolidation treatment received [dinutuximab with cytokines and isotretinoin (DIN) vs isotretinoin alone (ISO)]. Methods: A retrospective, descriptive analysis of patients on ANBL0032 was performed, including patients randomized to DIN or ISO and those non-randomly assigned to DIN after ISO arm closure. Pt characteristics including age, stage, MYCN amplification status, tumor grade, mitosis-karyorrhexis index (MKI) and ploidy were summarized descriptively and relapse sites were tabulated. For DIN patients who subsequently relapsed, overall survival (OS) was calculated starting from the time of first relapse after enrollment on ANBL0032 (“post-relapse OS”). Kaplan-Meier OS curves were generated based on site of relapse. Results: The analytic cohort included 1,431 (DIN = 1,327; ISO = 104) patients. Among DIN patients, 492 relapsed, many in > 1 site. In the randomized cohort (n = 248), 122 relapsed (DIN = 68/144; ISO = 54/104). The frequencies (DIN; ISO) by site of relapse in the randomized cohort were: bone (53%; 54%), CNS (16%; 11%), lymph node (13%; 17%), abdominal (10%; 17%), paraspinal (6%; 2%), liver (3%; 4%), other soft tissue (22%; 7%). A higher proportion of ISO patients had marrow relapse (29.4% DIN; 48.2% ISO); however, the proportion of DIN patients with lung relapses appeared higher (9% vs 2%). Among all relapsed patients, the proportion with bone relapse did not appear to differ between treatment groups, regardless of MYCN status. Among patients with MYCN amplified disease, the proportion with marrow relapse did not appear to differ based on treatment [21/149 (14.1%) DIN; 3/20 (15.0%) ISO]; however, among patients with MYCN non-amplified disease, the proportion with marrow relapse appeared higher in the ISO group [16/23; 69.6%] vs the DIN group [52/193 (26.9%)]. Conclusions: In this exploratory analysis of patients on COG ANBL0032, the pattern for site of relapse appears to differ between patients treated with DIN vs ISO. While immunotherapy remains the treatment of choice in this population, the findings from this retrospective exploratory analysis warrant further investigation to decrease the risk for post-immunotherapy relapse. Clinical trial information: NCT00026312.

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Herrity, Elizabeth Kathryn, Tommy Alfaro, Mariana Pinto Pereira, Igor Novitzky-Basso, Wilson Lam, Ivan Pasic, Fotios Michelis i in. "Clinical, Cytogenetic and Immunophenotypic Spectra of Post-Transplant Relapse Following Allogeneic Hematopoietic Stem Cell Transplantation for Myelodysplastic Syndrome". Blood 142, Supplement 1 (28.11.2023): 2206. http://dx.doi.org/10.1182/blood-2023-187145.

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Introduction Allogeneic hematopoietic stem cell transplantation (HCT) is a curative therapy used to treat myelodysplastic syndrome (MDS). Relapse post-HCT confers poor outcomes and subsequent therapy is not standardized. Like acute myeloid leukemia (AML), several mechanisms are known to be involved in post-HCT relapse including clonal evolution in favor of chemotherapy-resistant clones and tumor immune escape. Systemic reviews are scarce in the MDS post-HCT relapse population. Accordingly, the present study aimed to investigate clinical, cytogenetic, and immunophenotypic (IP) spectra for MDS post-HCT relapse patients (pts), along with subsequent therapies, and clinical outcomes following post-HCT relapse. Patients and methods A retrospective study was conducted and found that 231 MDS pts received HCT between April 2010 and September 2022 at the Princess Margaret Cancer Centre (PMCC). The primary endpoint was overall survival (OS) following post-HCT relapse. Secondary endpoints explored time to relapse (TTR), relapse presentation (i.e., MDS or AML), clonal evolution (i.e., changes in cytogenetics or IP profiles), and therapeutic strategies delivered after relapse. Results Of the 231 MDS pts treated with HCT, 52 (23%) relapsed in a median of 4.5 months (range 0.9-59.8 months). Twenty-five (48%) pts relapsed with MDS (i.e., blast <20%), while 27 (52%) relapsed with AML (i.e., blast ≥20%) in the marrow. Fifteen (65%) pts showed cytogenetic changes at the time of post-HCT relapse. Eleven (48%) of which presented with more aggressive findings (i.e., additional structural abnormalities and monosomal karyotype). Ten of 17 (59%) pts presented with changes in their IP profile at post-HCT relapse, 7 (70%) of which relapsed with AML. Combined these findings give evidence of clonal evolution in favor of more aggressive malignant clones that are often responsible for post-HCT relapse. Treatment with hypomethylating agents (HMA) alone or in combination after post-HCT relapse increased OS to 5.6 months in comparison to those not receiving HMA of whom OS was 1.4 months (p=0.0003). Stratified by disease presentation cytogenetic clonal evolution was seen in 6/12 (50%) of the post-HCT MDS relapses, and 9/11 (82%) of the post-HCT AML relapses. Cytogenetic abnormalities at diagnosis and post-HCT relapse, respectively included in descending order: structural abnormalities (n=14/23, 61%; n=20/23, 87%), complex karyotype (n=12/23, 52%; 17/23, 74%), -5/del(5q) (n=11/23, 48%; n=10/23, 43%), -7/del(7q) (n=8/23, 35%; n=11/23, 48%), monosomy karyotype (n=8/23, 35%; n=11/23, 48%), -17 (n=3/23, 13%; n=5/23, 22%), der(5)/t(5;17) (n=2/23, 9%; n=5/23, 22%), -20 (n=2/23, 9%; n=3/23, 13%), and inv(3) (n=1/23, 4%, n=2/23, 9%). Seventeen pts had paired IP profiles available both prior to HCT and at post-HCT relapse, of which 10 (59%) had profile changes of at least 1 antigen. Seven of 10 (70%) pts that relapsed with AML post-HCT had IP expression changes, compared to 3/7 (42.9%) pts that relapsed with MDS post-HCT. Summarized IP findings include reduced expression of CD7 (n=2/6, 33%), altered expression of CD34 (n=3/15, 20%), altered expression of CD117 (n=3/14, 21%), and reduced expression of HLA DR (n=4/15, 27%). The presence of IP expression changes at post-HCT relapse suggests evidence of clonal evolution or immune escape as the mechanism behind the relapsed disease. Overall survival duration was 3.97 months; the 12-month OS rate was 20.0% (10.0-32.5%). Post-HCT relapse treatments included hypomethylating agents (HMA; n=13/46, 28%), HMA with donor lymphocyte infusion (DLI; n= 7/46, 15%), HMA with Venetoclax (VEN; n=7/46, 15%), chemotherapy (n=9/46, 19%), best supportive care (8/46, 17%) and second HCT (n=2/46, 4%). Patients that received HMA with or without DLI or VEN had a longer survival duration of 5.6 months (95% CI [3.4-13.2 months]) compared to those not receiving HMA 1.4 months (95% CI [0.6-0.39 months, p=0.0003]). The 12-month survival rate was also significantly in favor of pts that received HMA following post-HCT relapse (35.3% [95% CI 17.2-54.0%] vs 4.3% [95% CI 0.3-18.0%]). Conclusion Patients with MDS undergoing HCT may relapse with either MDS or AML. The relapsed disease often shows evidence of clonal evolution in its immunophenotype and/or cytogenetic profile toward a more aggressive disease. Approaches to post-HCT relapse remain heterogenous but HMA is beneficial.

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Schuck, Anna, Ariane Dienst, Kathrin Nachtkamp, Pia Verena Schmidt, Esther Schuler, Roland Fenk, Mustafa Kondakci i in. "Disease Characteristics, Treatment and Outcome of Patients with Myelodysplastic Syndromes Relapsing after Allogeneic Stem Cell Transplantation". Blood 126, nr 23 (3.12.2015): 3167. http://dx.doi.org/10.1182/blood.v126.23.3167.3167.

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Abstract Background and Rationale: Allogeneic stem cell transplantation (allo-SCT) has a curative potential in patients (pts) with MDS. While non-relapse mortality (NRM) has been continuously reduced during the years, relapse incidence remained almost unchanged. As a consequence relapse remains the major cause of treatment failure and is associated with a poor prognosis. Although a better knowledge about relapse biology and kinetics could eventually help to optimize post-transplant maintenance or salvage therapies and to define intervals for minimal residual disease (MRD) monitoring, so far only a few studies exclusively focused on relapse patterns in MDS. Material and Methods: To address this in detail, we retrospectively analyzed data of 140 pts (median age: 58 y, 23-72) with MDS (n=125) or secondary AML (sAML, n=15), who had received a first allo-SCT from a related (29%) or unrelated (71%) donor at our center between 2001 and 2014. Fifty pts (36%) relapsed after allo-SCT and were therefore included in this study focusing on relapse characteristics, treatment strategies and outcome. In pts with sequential cytogenetic analyses available we also compared karyotypes pre-transplant and at relapse in order to track clonal evolution. Results: Overall, hematological relapse was diagnosed in 46 pts (92%), while 4 pts (8%) had a molecular relapse. Median time to relapse was 248 days (range: 53-3349) with the great majority of relapses occurring within the first 3 years (1st year: 62%; 2nd year: 84%; 3rd year: 94%). Only 3 pts (6%) relapsed beyond the 3rd year. To identify predictors for early relapse we compared those pts (defined by an interval between transplant and relapse <248 days) with those pts who relapsed late (>248 days). Hereby, we identified a longer interval between diagnosis and transplant (p=0.0122) and the use of intensive chemotherapy prior transplant (p=0.0209) as predictors for early relapse. Pre-transplant blast count (p=0.07), disease progression prior transplant (p=0.08) and presence of poor/very poor risk cytogenetics according to IPSS-R (p=0.08) also tended to predict early relapse. Sequential cytogenetic analyses revealed that 18 of 30 pts (60%) carried a karyotype at relapse with at least 1 of the abnormalities present before allo-SCT suggesting a common clonal origin. In 12 (40%) of these pts cytogenetic results before allo-SCT and at relapse were identical, while in 6 pts (20%) additional aberrations were detected. In the remaining 12 pts (40%) we observed new cytogenetic aberrations (n=7) or even evolution of a complex karyotype (n=5) indicating clonal evolution or the emergence of a previously undetectable clone. Following relapse, the majority of pts (n=36) received at least one salvage therapy, while 9 pts received BSC only (missing n=5). Salvage therapies consisted of hypomethylating agents (n=32, 31 Aza, 1 DAC) +/- DLI, intensive chemotherapy (n=1), DLI only (n=1) and 2nd allo-SCT (n=2). In contrast to previous studies, time between allo-SCT and relapse here predicted response to hypomethylating agents as indicated by a significantly higher CR rate in pts with late relapse (CR rates: all pts: 37,5%; late relapse 62,5% vs. early relapse 12,5%, p=0.0091). With a median follow-up of 43 months, 14 pts (28%) are currently alive and in remission. Median overall survival (OS) of the entire group was 273 d (range:3-2717) and 2-year OS rate 33%. Median survival and 2-year OS rate were significantly higher in pts with late relapse compared to those with early relapse (1435 vs.169 d; 55% vs.10%; p=0.0036). Conclusion: Relapses mostly occur within the first 3 years after allo-SCT arguing in favor for stringent MRD monitoring and post-transplant interventions during this interval. Pts with a longer time to transplant or need for induction therapy are at risk for early relapse, and the interval from allo-SCT until relapse represents a crucial factor to predict response to salvage therapy and survival. Cytogenetic patterns at relapse suggest that MDS relapses can arise from original clones but also frequently due to emergence of new clones. Disclosures Gattermann: Novartis: Honoraria, Research Funding.

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Epperla, Narendranath, Namrata Shah, Kristin Richardson, Jonathan Kapke, George Carrum, Parameswaran Hari, Mehdi Hamadani, Sai Ravi Pingali, Reem Karmali i Timothy S. Fenske. "Impact of Routine Surveillance Imaging on Outcomes in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Undergoing Autologous Hematopoietic Cell Transplantation (auto-HCT)". Blood 126, nr 23 (3.12.2015): 4360. http://dx.doi.org/10.1182/blood.v126.23.4360.4360.

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Abstract Background It is common for diffuse large B-cell lymphoma (DLBCL) patients following autologous hematopoietic transplant (auto-HCT) to undergo surveillance imaging to monitor for lymphoma progression/relapse. Although a standard at most centers, this practice is not evidence-based, has not been shown to improve survival, and may pose a risk to patients due to radiation exposure. We studied DLBCL patients who underwent auto-HCT at three transplant centers to define how many surveillance imaging studies were obtained, how often relapses were detected by surveillance imaging versus clinically (based on signs, symptoms or laboratory findings), and whether survival was improved if relapse was detected by imaging versus clinically. Methods DLBCL patients who underwent auto-HCT during 2000-2013 were identified using clinical databases. Pre-transplant patient and disease characteristics were collected. Progression-free survival (PFS) and overall survival (OS) were determined. Patients were classified as having "radiographic" or "clinical" relapses. PFS and OS were compared for these two groups. Results A total of 209 patients with DLBCL who underwent auto-HCT between 2000 and 2013 were identified. There was insufficient follow-up information on 15 patients and hence only 194 patients were evaluable. Of these, 22 patients relapsed or progressed prior to or at their initial post-transplant disease assessment (day 100 evaluation). The remaining 172 patients were then analyzed to determine which patients relapsed and how relapses were detected. 48 patients relapsed at a median time of 287 days post-transplant. Of these patients, 14 (29%) had relapse detected clinically and 34 (71%) had relapse detected by surveillance imaging. Comparing the radiographic and clinically detected groups, median PFS post auto-HCT was 218 vs 402 days respectively (p= 0.49, log rank test, Figure 1) and median survival post auto-HCT was 643 vs 615 days respectively (p= 0.44, log rank test, Figure 1). For patients who never relapsed after auto-HCT, a median of 4 surveillance imaging studies were performed (with median follow up of 3.0 years post-transplant). Conclusions In DLBCL patients post auto-HCT, the majority of relapses were detected by surveillance imaging. However, the survival of patients with relapse detected by surveillance imaging was not superior to those whose relapse was detected clinically. Given this, combined with the radiation exposure and cost associated with surveillance imaging, the practice of surveillance imaging post auto-HCT appears to have limited utility in DLBCL. Disclosures Hari: Janssen: Consultancy; Novartis: Consultancy; Spectrum: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy; BMS: Consultancy. Hamadani:Takeda: Research Funding; Cellerant: Consultancy; Celgene: Consultancy; MedImmune: Consultancy. Fenske:Celgene: Honoraria; Pharmacyclics: Honoraria; Seattle Genetics: Honoraria; Millennium/Takeda: Research Funding.

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Marinescu, Elena-Cristina, Horia Bumbea, Iuliana Iordan, Ion Dumitru, Dan Soare, Cristina Ciufu i Mihaela Gaman. "The Philadelphia Chromosome, from Negative to Positive: A Case Report of Relapsed Acute Lymphoblastic Leukemia following Allogeneic Stem Cell Transplantation". Medicina 59, nr 4 (28.03.2023): 671. http://dx.doi.org/10.3390/medicina59040671.

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Relapsed acute lymphoblastic leukemia (ALL) represents a continuous challenge for the clinician. Despite recent advances in treatment, the risk of relapse remains significant. The clinical, biological, cytogenetic, and molecular characteristics may be different at the time of relapse. Current comprehensive genome sequencing studies suggest that most relapsed patients, especially those with late relapses, acquire new genetic abnormalities, usually within a minor clone that emerges after ALL diagnosis. We report the case of a 23-year-old young woman diagnosed with Philadelphia chromosome-negative B cell acute lymphoblastic leukemia. The patient underwent allogeneic stem cell transplantation (allo-HSCT) after complete remission. Despite having favorable prognostic factors at diagnosis, the disease relapsed early after allo-HSCT. The cytogenetic and molecular exams at relapse were positive for the Philadelphia chromosome, respectively for the Bcr-Abl transcript. What exactly led to the recurrence of this disease in a more aggressive cytogenetic and molecular form, although there were no predictive elements at diagnosis?

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