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1.
Allogeneic stem cell transplantation for children and adolescents/young adults with de novo blastic phase chronic myeloid leukemia in the tyrosine kinase inhibitor era
Ishida, H., Shimada, H., Tanizawa, A., Shimazu, Y., Tachibana, T., Doki, N., Ara, T., Matsuo, Y., Nara, M., Toubai, T., et al
American journal of hematology. 2023
Abstract
The analysis of 165 children and adolescents/young adults with de novo blastic phase chronic myeloid leukemia showed disease status at hematopoietic stem cell transplantation was a strong prognostic factor and clearly separated the patient outcomes.
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2.
The Impact of Pretransplant Use of Tyrosine Kinase Inhibitors on Allogeneic Stem Cell Transplantation in Patients with Chronic Myeloid Leukemia-A Single-institution Retrospective Study
Fujita, S., Kasahara, H., Kato, J., Koda, Y., Shiroshita, K., Yamaguchi, K., Okayama, M., Abe, R., Kikuchi, T., Shimizu, T., et al
Internal medicine (Tokyo, Japan). 2023
Abstract
Objective Chronic myeloid leukemia (CML) is a malignant hematological disorder, and allogeneic stem cell transplantation (allo-SCT) was its only curative treatment until the introduction of tyrosine kinase inhibitors (TKIs). Allo-SCT is still considered for CML patients who are resistant to TKIs and in an advanced phase. Currently, second- and third-generation (2/3 G) TKIs are typically incorporated into the first-line treatment of CML. However, the impact of 2/3 G TKIs on subsequent allo-SCT remains unclear. We therefore evaluated the effect of 2/3 G TKIs on allo-SCT. Methods We retrospectively evaluated the effect of pretransplant therapy with TKIs on the outcome of allo-SCT for CML using clinical data at our institution. Patients or Materials Thirty-two CML patients who received their first allo-SCT procedure at our institute from 2001 to 2020 were included. We divided the patients into three subgroups based on TKI treatment before allo-SCT. Patients receiving no TKIs, only imatinib (IM), and 2/3 G TKIs were classified into the Non-TKI, IM, and 2/3 G TKI groups, respectively. Results In a univariate analysis, the pretransplant use of 2/3 G TKIs was significantly associated with a higher 5-year overall survival (91.7%) and relapse-free survival (75.0%) than the use of IM (37.5% and 12.5%) in patients presenting with or progressing to the advanced phase. In addition, pretransplant use of 2/3 G TKIs did not increase the incidence of graft-versus-host disease (GVHD). Conclusions We demonstrated that the pretransplant use of 2/3 G TKIs was safe and improved the outcome of CML patients who presented with or progressed to the advanced phase without increasing the frequency of GVHD.
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3.
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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4.
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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5.
The new generation tyrosine kinase inhibitor improves the survival of chronic myeloid leukemia patients after allogeneic stem cell transplantation
Shimazu, Y., Murata, M., Kondo, T., Minami, Y., Tachibana, T., Doki, N., Uchida, N., Ozawa, Y., Yano, S., Fukuda, T., et al
Hematological oncology. 2022
Abstract
The introduction of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) treatment has dramatically improved the prognosis of CML patients and reduced the number of patients receiving allogeneic stem cell transplantation (allo-SCT). However, the impact of the newest-generation TKIs on the overall survival (OS) after allo-SCT has not been well described. To investigate the beneficial effects of TKIs on the prognosis after allo-SCT, we conducted a retrospective observational study using the Transplant Registry Unified Management Program database in Japan. We analyzed 1,188 patients (male/female: 738/450; median age: 44 years; range: 16-75) who underwent their first allo-SCT between January 2001 and December 2018. We divided the patients into two groups according to the TKI treatment used before allo-SCT: group 1 was treated with the 1(st) generation TKI imatinib; group 2 was treated with the 2(nd) generation TKIs nilotinib, dasatinib, or bosutinib and/or the 3(rd) generation TKI ponatinib. We compared the post allo-SCT OS between the two groups. The 3-year OS rates (95%CI) of groups 1 and 2 were 59.3% (54.8-63.5%) and 65.8% (61.6-69.6%), respectively (p=0.017). Multivariate analysis confirmed that group 2 had superior OS after allo-SCT compared to group 1 (p=0.002). Other factors associated with superior prognosis were age ≤65, performance status (PS) 0/1, a 6/6 HLA-matched donor and chronic-phase (CP) disease status at allo-SCT. A subgroup analysis showed poor prognoses for patients who could not obtain a molecular response before allo-SCT and patients with positive T315I mutation in the BCR/ABL gene. In group 2, early allo-SCT was correlated with superior OS in patients with a blast-crisis disease status at allo-SCT (p=0.001). The cumulative incidence of non-relapse mortality rate significantly decreased in group 2 (p=0.0005). The post allo-SCT OS was improved both by pre- and post-management of allo-SCT and by the introduction of newer TKIs. This article is protected by copyright. All rights reserved.
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6.
CD34-selected allogeneic hematopoietic cell transplantation for chronic myeloid leukemia in the tyrosine kinase era
Vaughn, J. L., Brown, S., Papadopoulos, E. B., Jakubowski, A. A., Tamari, R., Giralt, S. A., Ponce, D. M., Cho, C., Perales, M. A., Shaffer, B. C., et al
Bone marrow transplantation. 2022
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7.
Allogeneic hematopoietic cell transplantation in patients with CML chronic phase in the era of third generation tyrosine kinase inhibitors: a retrospective study by the Chronic Malignancies Working Party of the EBMT
Chalandon, Y., Sbianchi, G., Gras, L., Koster, L., Apperley, J., Byrne, J., Salmenniemi, U., Sengeloev, H., Aljurf, M., Helbig, G., et al
American journal of hematology. 2022
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Editor's Choice
Abstract
Following the introduction of tyrosine kinase inhibitors (TKI), the number of patients undergoing allogeneic haematopoietic cell transplantation (allo-HCT) for chronic phase (CP) CML has dramatically decreased. Imatinib was the 1(st) TKI introduced to the clinical arena, predominantly utilised in the 1(st) line setting. In cases of insufficient response, resistance or intolerance, CML patients can subsequently be treated with either a 2(nd) or 3(rd) generation TKI. Between 2006 and 2016, we analyzed the impact of the use of 1, 2 or 3 TKI prior to allo-HCT for CP CML in 904 patients. A total of 323-, 371- and 210 patients had 1, 2 or 3 TKI prior to transplant respectively; imatinib (n=778), dasatinib (n=508), nilotinib (n=353), bosutinib (n=12) and ponatinib (n=44). The majority had imatinib as first TKI (n=747, 96%). Transplants were performed in CP1, n=549, CP2, n=306, and CP3, n=49. With a median follow-up of 52 months, 5-year OS for the entire population was 64.4% (95% CI 60.9-67.9 %), PFS 50% (95% CI 46.3-53.7%), RI 28.7% (95% CI 25.4-32.0%) and NRM 21.3% (95% CI 18.3-24.2%). No difference in OS, PFS, RI or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI (p=ns). Significant factors influencing OS and PFS were >CP1 vs CP1 and Karnofsky performance (KPS) score > 80 vs ≤80, highlighting CP1 patients undergoing allo-HCT have improved survival compared to >CP1 and the importance of careful allo-HCT candidate selection. This article is protected by copyright. All rights reserved.
PICO Summary
Population
Adults, identified from the EBMT registry who had chronic myeloid leukaemia and received tyrosine kinase inhibitor (TKI) therapy prior to first allogeneic transplant (n=904)
Intervention
1 TKI prior to transplant (n=323)
Comparison
2 TKI prior to transplant (n=371); 3 TKI prior to transplant (n=210)
Outcome
With a median follow-up of 52 months, 5-year overall survival (OS) for the entire population was 64.4% (95% CI 60.9-67.9 %), Progression free survival (PFS) 50% (95% CI 46.3-53.7%), relapse incidence (RI) 28.7% (95% CI 25.4-32.0%) and non-relapse mortality (NRM) 21.3% (95% CI 18.3-24.2%). No difference in OS, PFS, RI or NRM was evident related to the number of TKI prior to allo-HCT or to the type of TKI. Significant factors influencing OS and PFS were chronic phase (CP) >1 vs CP1 and Karnofsky performance score > 80 vs </=80.
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A Systematic Literature Review of the Economic Evaluations of Treatments for Patients with Chronic Myeloid Leukemia
Agrawal, R., Vieira, J., Ryan, J., Negi, H., Rajput, T., Corbin, R., Viana, R.
PharmacoEconomics. 2022
Abstract
BACKGROUND AND OBJECTIVES The management of chronic myeloid leukemia is associated with an extensive economic burden, and as novel interventions are being tested in this disease, understanding the comparative effectiveness is of interest. Findings and conclusions of this important issue continue to evolve with improvements in clinical research and economic understanding. This systematic literature review aims to conduct a comprehensive assessment of economic evaluations in chronic phase chronic myeloid leukemia. METHODS Embase(®), MEDLINE(®), and the National Health Service Economic Evaluation Database were searched on 4 July, 2022 to identify economic evaluations of chronic myeloid leukemia. Health technology assessment websites and key conference proceedings were also searched. Economic evaluations comparing treatment options in adult patients with chronic phase chronic myeloid leukemia were included. The quality of the studies were assessed using Drummond's checklists. RESULTS The search retrieved 47 studies and 16 health technology assessments that fulfilled the eligibility criteria. Most were cost-utility analyses (23 studies and 11 health technology assessments) and were from the USA (n = 15) and China (n = 7). Twenty-seven studies and six health technology assessments included only patients with chronic phase chronic myeloid leukemia. Most models had a Markov structure, a 1 year to lifetime time horizon, and a 1-month cycle length. Commonly assessed treatments were various tyrosine kinase inhibitors (imatinib, nilotinib, dasatinib, bosutinib, and ponatinib) and other interventions such as interferon-α, hydroxyurea, and allogeneic stem cell transplant. CONCLUSIONS In patients with newly diagnosed chronic myeloid leukemia, imatinib regimens were cost effective, mostly owing to the availability of generics. Nilotinib and dasatinib were generally cost effective as second-line agents for patients who were resistant or intolerant to imatinib. Though progress has been made to better characterize the cost effectiveness of first-line and second-line chronic myeloid leukemia therapies, the paucity of published cost-effectiveness studies of third-line treatments increases the uncertainty associated with economic evaluations of later lines of therapy.
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Outcomes and toxicity of allogeneic hematopoietic cell transplantation in chronic myeloid leukemia patients previously treated with second-generation tyrosine kinase inhibitors: a prospective non-interventional study from the Chronic Malignancy Working Party of the EBMT
Masouridi-Levrat, S., Olavarria, E., Iacobelli, S., Aljurf, M., Morozova, E., Niittyvuopio, R., Sengeloev, H., Reményi, P., Helbig, G., Browne, P., et al
Bone marrow transplantation. 2021
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) remains a treatment option for patients with chronic myeloid leukemia (CML) who fail to respond to tyrosine kinase inhibitors (TKIs). While imatinib seems to have no adverse impact on outcomes after transplant, little is known on the effects of prior use of second-generation TKI (2GTKI). We present the results of a prospective non-interventional study performed by the EBMT on 383 consecutive CML patients previously treated with dasatinib or nilotinib undergoing allo-HCT from 2009 to 2013. The median age was 45 years (18-68). Disease status at transplant was CP1 in 139 patients (38%), AP or >CP1 in 163 (45%), and BC in 59 (16%). The choice of 2GTKI was: 40% dasatinib, 17% nilotinib, and 43% a sequential treatment of dasatinib and nilotinib with or without bosutinib/ponatinib. With a median follow-up of 37 months (1-77), 8% of patients developed either primary or secondary graft failure, 34% acute and 60% chronic GvHD. There were no differences in post-transplant complications between the three different 2GTKI subgroups. Non-relapse mortality was 18% and 24% at 12 months and at 5 years, respectively. Relapse incidence was 36%, overall survival 56% and relapse-free survival 40% at 5 years. No differences in post-transplant outcomes were found between the three different 2GTKI subgroups. This prospective study demonstrates the feasibility of allo-HCT in patients previously treated with 2GTKI with a post-transplant complications rate comparable to that of TKI-naive or imatinib-treated patients.
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10.
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.