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1.
The Clinical Significance of BCR-ABL1 Mutations in Patients With Philadelphia Chromosome-Positive Chronic Myeloid Leukemia Who Underwent Allogeneic Hematopoietic Cell Transplantation
Tachibana, T., Kondo, T., Uchida, N., Doki, N., Takada, S., Takahashi, S., Yano, S., Mori, T., Kohno, A., Kimura, T., et al
Transplantation and Cellular Therapy. 2022;28(6):321.e1-321.e8
Abstract
The global standard therapy for chronic myeloid leukemia (CML) is tyrosine kinase inhibitors (TKIs). One of the causes of therapeutic resistance to some TKIs corresponds to point mutations in the BCR-ABL1 fusion gene. Allogeneic hematopoietic cell transplantation (HCT) is a treatment option for high-risk CML, including TKI resistance. Although BCR-ABL1 point mutations comprise a major factor in the assessment of the indications for HCT, there is limited evidence for their significance in relation to transplant outcomes. This study aimed to evaluate the profiles and transplant outcomes of BCR-ABL1 mutations in allografted patients with CML. The retrospective study used a nationwide registry data including adult patients with CML who underwent their first HCT between 2006 and 2016. The inclusion criterion was the evaluation of the status of the BCR-ABL1 mutation before HCT. The cohort included 315 patients with a median age of 44 years (range 16-70 years). Point mutations were detected in 152 patients, of which 101 (66%) harbored T315I mutations and 51 harbored mutations other than T315I (non-T315I). With a median follow-up period of 38 months (range 2-114 months), overall survival (OS) at 3 years was worse in the mutation group than in the no-mutation group (53% versus 71%; P = .002), which was validated by multivariate analysis (hazard ratio [HR] = 1.50; 95% confidence interval [CI], 1.0-2.2; P = .038); this difference was remarkable in the chronic phase of CML. OS in the non-T315I group was significantly worse than that in the no-mutation group (HR = 1.69; 95% CI, 1.0-2.8; P = .035). The nationwide study has successfully evaluated the BCR-ABL1 mutational profile and its outcomes in patients with CML who received HCT. The mortality risk was significantly higher in patients with the BCR-ABL1 mutation than in patients without the mutation. These findings would be useful to understand the clinical significance of various BCR-ABL1 mutations in CML and provide insight into the on mid need for treatment strategies for cases of CML with BCR-ABL1 mutations.
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2.
Prognostic Factors for Outcomes of Allogeneic HSCT for Children and Adolescents/Young Adults with CML in the TKI Era
Shimada, H., Tanizawa, A., Kondo, T., Nagamura-Inoue, T., Yasui, M., Tojo, A., Muramatsu, H., Eto, T., Doki, N., Tanaka, M., et al
Transplantation and cellular therapy. 2022
Abstract
BACKGROUND The breakthrough effects of tyrosine kinase inhibitors (TKIs) have lessened indications for allogeneic hematopoietic stem cell transplantation (HSCT) in chronic myeloid leukemia (CML). However, HSCT is still attractive for children and adolescents/young adults (AYAs) requiring lifelong TKI therapy. Nevertheless, little has been reported on the outcomes of large clinical studies of HSCT targeting these age groups. OBJECTIVE This study aimed to identify prognostic factors for the outcomes of HSCT, including reduced-intensity conditioning (RIC)-HSCT, for children and AYAs with CML in the TKI era. STUDY DESIGN We performed a registry analysis for 200 patients with CML aged <30 years who underwent pretransplant TKI therapy from the observational nationwide database established by the Japanese Society for Transplantation and Cellular Therapy. The patients received bone marrow (BM), peripheral blood (PB), or cord blood (CB) from either related or unrelated donors. The indication for HSCT for individual patients was determined by the institution according to European LeukemiaNet recommendations and other guidelines. RESULTS The 5-year overall survival (OS) rates for patients with chronic phase (CP) (n = 124), accelerated phase (AP) (n = 23), and blastic phase (BP) (n = 53) at diagnosis were 82.8%, 71.1%, and 73.3%, respectively, with no significant difference (P = 0.3293). The strongest predictor of engraftment was transplant source, with CB (hazard ratio [HR], 0.33) and PB (HR, 2.00) (compared with BM) being independent unfavorable and favorable predictors, respectively. Transplant source was also an independent predictor of chronic GVHD, with PB (HR, 1.81) and CB (HR, 0.39) (compared with BM) being unfavorable and favorable predictors, respectively. The strongest predictor of OS rate for patients with CP at diagnosis was disease phase at HSCT, with second or greater CP, AP, or BP (HR, 2.81) (compared with first CP [CP1]) being an unfavorable predictor. In addition, patients with CP at diagnosis who had major and complete molecular responses at HSCT had excellent outcomes, with 5-year OS rates of 100% and 94.4%, respectively. The 5-year OS rate was compared between RIC (n = 31) and myeloablative conditioning (MAC) (n = 58) in patients with CP1, both of which were 89.3%, with no significant difference (P = 0.9440). On univariate analysis for the RIC cohort with CP at diagnosis, the age at HSCT (HR, 1.27) (increase per year) and the time from diagnosis to HSCT (HR, 1.83) (increase per year) were significant predictors for OS. CONCLUSIONS Our study demonstrates that RIC may be an appropriate alternative to MAC for children and AYAs with CP1. As for the transplant source, we recommend first selecting BM because of a higher engraftment rate compared to CB and a lower incidence of chronic GVHD compared to PB. Although HSCT in the status of a major molecular response is desirable, it is not advisable to continue TKI pointlessly long because age at HSCT and timing of HSCT are prognostic factors that determine survival. The decision to perform RIC-HSCT instead of continuing TKI should be carefully made, considering the possibility of transplant-related complications.
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3.
Investigations of methods for multiple time-to-event endpoints: A chronic myeloid leukemia data analysis
Wu, H., Hou, Y., Chen, Z.
Journal of evaluation in clinical practice. 2022
Abstract
BACKGROUND In randomized controlled trials, multiple time-to-event endpoints are commonly used to determine treatment effects. However, choosing an appropriate method to address multiple endpoints, according to different purposes of clinical practice, is a challenge for researchers. METHODS We applied single endpoint, composite endpoint and win ratio analysis to chronic myeloid leukemia (CML) data to illustrate the distinctions with different multiple endpoints, including relapse, recovery and death after transplantation. RESULTS Regarding relapse and death, the hazard ratio in single endpoint analysis (HR(s) ) were 1.281 (95% CI: 1.061-1.546) and hazard ratio in composite endpoint analysis (HR(c) ) were 1.286 (95% CI: 1.112-1.486) and 1/WR (win ratio) was 1.292 (95% CI: 1.115-1.497) indicated a similar negative effect for non-prophylaxis patients. However, when considering recovery and death, the corresponding HR(s) = 1.280 (95% CI: 1.056-1.552) may not be enough to describe the effect on death with nonproportional hazards (p < 0.05), and for the composite endpoint analysis, the HR(c) = 0.828 (95% CI: 0.740-0.926) cannot quantify and interpret the clinical effect on the composite endpoint with the combination of recovery and death, while the 1/WR = 1.351 (95% CI: 1.207-1.513) showed an unfavourable effect for non-prophylaxis patients CONCLUSIONS When dealing with multiple endpoints, single endpoints, researchers may choose single endpoints, composite endpoints and WR analysis due to different clinical applications and purposes. However, both single and composite endpoint analyses are hazard-based measures, and thus, the proportional hazards assumption should be considered. Moreover, composite endpoint analysis should be applied for endpoints with similar clinical meanings but not opposing implications. Win ratio analysis can be considered for different clinical importance of multiple endpoints, but the meaning of 'winner' needs to be specified for desired or undesired endpoints.
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4.
Risk factors for outcome after allogeneic stem cell transplantation in patients with advanced phase CML
Niederwieser, C., Morozova, E., Zubarovskaya, L., Zabelina, T., Klyuchnikov, E., Janson, D., Wolschke, C., Christopeit, M., Ayuk, F., Moiseev, I., et al
Bone marrow transplantation. 2021
Abstract
Allogeneic hematopoietic stem-cell transplantation (HSCT) remains the only curative option for patients with advanced chronic myeloid leukemia (CML). However, outcome is dismal and of short follow-up. The objective of the study was to determine long-term outcome and risk factors in patients with a history of CML Blast Crisis (BC; n?=?96) or accelerated phase (n?=?51) transplanted between 1990 and 2018. At transplant, patients had a median age of 39 (range 7-76) years and were in =CP2 (n?=?70), in AP (n?=?40) or in BC (n?=?37) with a diagnosis-HSCT interval of median 1.9 (range 0.3-24.4) years. Overall survival (OS) amounted 34% (95% CI 22-46) and progression-free survival (PFS) 26% (95% CI 16-36) at 15 years. Adverse risk factors for OS and PFS were low CD34(+) count in the graft, donor age (>36 years) and BC. Cumulative incidence of Non-Relapse Mortality (NRM) was 28% (95% CI 18-38) and of relapse (RI) 43% (95% CI 33-53) at 15 years. PB-HSCT and HSCT after 2008 were favorable prognostic factors for NRM, while family donor and patient age >39 years were independently associated with higher RI. HSCT resulted in long-term OS in patients with advanced CML. OS was improved in non-BC patients, with donors =36 years and with higher CD34(+) dose in the graft.
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5.
Long-term survival benefit after allogeneic hematopoietic cell transplantation in chronic myelomonocytic leukemia
Gagelmann, N., Bogdanov, R., Stölzel, F., Rautenberg, C., Panagiota, V., Becker, H., Radujkovic, A., Luft, T., Christopeit, M., Finke, J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2020
Abstract
The critical question in the management of chronic myelomonocytic leukemia (CMML) is which patients may benefit from allogeneic hematopoietic cell transplantation (allo-HCT). Using ad hoc statistical analysis, we designed a multicenter retrospective study to determine outcomes in 261 patients =70 years at diagnosis who received allo-HCT (n=119) compared with patients who did not (n=142) according to the current CMML-specific prognostic scoring system (CPSS). Categorizing patients as lower (CPSS low/intermediate-1) and higher risk (intermediate-2/high) showed significantly improved outcome after transplant in higher risk patients, with a 37% reduced hazard for death. However, while higher CPSS was associated with worse outcome in the nontransplant group, the score was of limited utility for posttransplant risk stratification. This study may further support the potentially beneficial role of allo-HCT in terms of long-term survival in higher risk patients but also underlines the need for transplant-specific risk assessment. Recognizing limitations of retrospective comparisons, larger and prospective comparisons are needed to further refine the indication for allo-HCT and thus counseling of CMML patients.
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6.
Prognostic impact and timing considerations for allogeneic hematopoietic stem cell transplantation in chronic myelomonocytic leukemia
Pophali, P., Matin, A., Mangaonkar, A. A., Carr, R., Binder, M., Al-Kali, A., Begna, K. H., Reichard, K. K., Alkhateeb, H., Shah, M. V., et al
Blood cancer journal. 2020;10(11):121
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7.
Impact of clinical, cytogenetic, and molecular profiles on long-term survival after transplantation in patients with chronic myelomonocytic leukemia
Woo, J., Choi, D. R., Storer, B. E., Yeung, C., Halpern, A. B., Salit, R. B., Sorror, M. L., Woolston, D. W., Monahan, T., Scott, B. L., et al
Haematologica. 2019
Abstract
Chronic myelomonocytic leukemia is a heterogeneous group of clonal hematopoietic malignancies with variable clinical and molecular features. We analyzed long term results of allogeneic hematopoietic cell transplantation in patients with chronic myelomonocytic leukemia and determined clinical and molecular risk factors associated with outcomes. Data on 129 patients, aged 7-74 (median 55) years, at various stages of the disease and transplanted from related or unrelated donors were analyzed. In 52 patients somatic mutations present pre-hematopoietic cell transplantation were determined using a panel of 75 genes. Progression-free survival at 10 years was 29%. The major cause of death was relapse (32%), which was significantly associated with adverse cytogenetics (hazard ratio 3.77, p = 0.0002), Chronic myelomonocytic leukemia Prognostic Scoring System (hazard ratio 14.3, p = 0.01), and MD Anderson prognostic scores (hazard ratio = 9.4, p=0.005). Mortality was associated with high-risk cytogenetics (hazard ratio 1.88, p = 0.01) and high hematopoietic cell transplantation comorbidity index (score ≥ 4: hazard ratio 1.99, p = 0.01). High overall mutation burden (≥ 10 mutations, hazard ratio = 3.4, p = 0.02), and ≥ 4 mutated epigenetic regulatory genes (hazard ratio 5.4, p=0.003) were linked to relapse. Unsupervised clustering of the correlation matrix revealed distinct high-risk groups with unique associations of mutations and clinical features. Chronic myelomonocytic leukemia with high mutation burden appeared to be distinct from high-risk groups defined by complex cytogenetics. New transplant strategies must be developed that may target specific disease sub-groups, stratified by molecular profiling and clinical risk factors.
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8.
Extramedullary relapse of leukemia after allogeneic hematopoietic stem cell transplantation: A retrospective study
Xie, N., Zhou, J., Zhang, Y., Yu, F., Song, Y.
Medicine. 2019;98(19):e15584
Abstract
Extramedullary relapse (EMR) rarely occurs after allogeneic hematopoietic stem cell transplantation (HSCT) in leukemia. This study was to investigate the clinical characteristics of EMR.We retrospectively investigated 316 consecutive patients undergoing HSCT for acute leukemia or chronic myeloid leukemia (CML) at 2 institutions between January 2012 and February 2017. Furthermore, we analyzed and compared the risk factors and outcomes between EMR and bone marrow relapse (BMR).The 5-year cumulative incidence of EMR was 14.1%. The EMR incidence in acute myeloid leukemia, lymphoblastic leukemia, and CML was 17.5%, 18.9%, and 5.3%, respectively. CML had a lower EMR incidence rate. Compared to the BMR group, the EMR group had a longer median relapse-free time (10.5 months vs 5 months, P = .02), and the EMR group had a higher incidence rate of chronic graft-versus-host disease (50.0% vs 20.9%, P = .009). EMR had better estimated 3-year survival rates post-HSCT, and post-relapse, than did BMR (39.5% vs 9.5%, P < .001, and 21.9% vs 10.8%, P = .001). Multivariate analysis identified that adverse cytogenetics (hazard ratio [HR] = 9.034, P < .001) and extramedullary leukemia before HSCT (HR = 2.685, P = .027) were the independent risk factors for EMR after HSCT. In the EMR group, patients who achieved complete remission (CR) had a significantly better, estimated 3-year survival than did patients who did not achieve CR (38.4% vs 14.3%, P = .014).EMR is a significant contributor to mortality after HSCT, which appears to be resistant to most of the current therapies. Establishing effective strategies for EMR is important in improving outcomes after HSCT.
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9.
BCR-ABL1 transcripts (MR4.5) at post-transplant 3 months as an early predictor for long-term outcomes in chronic myeloid leukemia
Lee, S. E., Choi, S. Y., Kim, S. H., Song, H. Y., Yoo, H. L., Lee, M. Y., Kang, K. H., Hwang, H. J., Jang, E. J., Kim, D. W.
Korean Journal of Internal Medicine. 2017;32(1):125-136
Abstract
BACKGROUND/AIMS: The aim of this study was to identify the role of BCR-ABL1 transcript level as a predictor for post-transplant relapse and outcome in patients who underwent allogeneic stem cell transplantation (SCT) for chronic phase (CP) chronic myeloid leukemia (CML). METHODS Of 101 patients receiving allograft in CML CP, 85 had available quantitative reverse transcriptase polymerase chain reaction data at post-transplant 3 months. These patients were divided into two groups according to molecular response (MR4.5), defined as a BCR-ABL1 transcript level < 0.0032% on the international scale, at 3 months based on receiver operating characteristic curve analysis of relapse. RESULTS The 4-year overall survival and event-free survival (EFS) were 80.6% and 57.3%, respectively, and the cumulative incidence of relapse at 4 years was 29.6% after a median follow-up of 126.4 months. We performed multivariate analyses including potential variables to evaluate the early predictive role of MR4.5 at 3 months and found that MR4.5 at 3 months was associated with a higher EFS (p = 0.028) and showed a trend for a lower relapse rate (p = 0.089). CONCLUSIONS our results imply that frequent molecular monitoring and immune suppressive therapy modulation are required for patients without reduction of BCR-ABL1 transcripts to this level after SCT.
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10.
Clinical impact of pretransplant use of multiple tyrosine kinase inhibitors on the outcome of allogeneic hematopoietic stem cell transplantation for chronic myelogenous leukemia
Kondo, T., Nagamura-Inoue, T., Tojo, A., Nagamura, F., Uchida, N., Nakamae, H., Fukuda, T., Mori, T., Yano, S., Kurokawa, M., et al
American Journal of Hematology. 2017;92(9):902-908
Abstract
Tyrosine kinase inhibitors (TKIs) are widely used to treat patients with chronic myelogenous leukemia in the chronic phase (CML-CP), and outcomes of TKI treatment for patients with CML-CP have been excellent. Since multiple TKIs are currently available, second-line or third-line TKI therapy is considered for patients who are intolerant of or resistant to the previous TKI treatment. Therefore, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered only for patients with disease progression or for patients after treatment failure with multiple TKIs. To reflect the current clinical situation of patients with CML-CP, we tried to clarify whether prior TKI treatment affects the outcome of allo-HSCT. Data from 237 patients for whom the number of pretransplant TKIs varied from one to three were used for analysis. Before allo-HSCT, 153 patients were treated with one TKI, 49 patients were treated with two TKIs and 35 patients were treated with three TKIs. In addition to conventional risk factors, i.e., disease status at transplantation and patient's age, the use of three TKIs before transplantation was identified as a significant adverse factor for prognosis. Nonrelapse mortality rate was higher in patients treated with three TKIs than in patients treated with one or two TKIs. Our results suggest that allo-HSCT could be considered for young patients with CML-CP who manifest resistance to second-line TKI therapy and who have an appropriate donor.