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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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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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3.
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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High leukemia-free survival after TBI-based conditioning and mycophenolate mofetil-containing immunosuppression in patients allografted for chronic myelomonocytic leukemia: a single-center experience
Radujkovic, A., Hegenbart, U., Muller-Tidow, C., Herfarth, K., Dreger, P., Luft, T.
Annals of hematology. 2020
Abstract
This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6-8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P < 0.001 and HR 0.41, P = 0.030, respectively). After stratification according to conditioning and GVHD prophylaxis into four groups (TBI-MMF [n = 17], TBI-MTX [n = 16], alkylator-MMF [n = 6], alkylator-MTX [n = 5]), TBI-MMF was associated with improved overall survival (OS) and LFS (P = 0.001 and P < 0.001, respectively). Patient and disease characteristics did not differ between the groups. The associations of TBI-based conditioning and MMF with prolonged LFS were observed across the CMML (n = 29), secondary AML (n = 15), and UD allograft (n = 34) subgroups. In summary, our study suggests that allografting based on intermediate-dose TBI conditioning and MMF-containing GVHD prophylaxis is associated with increased disease control in CMML. Larger (registry-based) studies are warranted to confirm our findings.
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Multiple tyrosine kinase inhibitors before allogeneic stem cell transplantation for chronic myeloid leukemia: toxicity and efficacy in a single center experience
Helbig, G., Duda, K., Krzemien, H., Wlodarczyk, M., Kata, D., Wieczorkiewicz-Kabut, A.
Polish archives of internal medicine. 2020
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Efficacy and influencing factors of allogeneic hematopoietic stem cell transplantation in treatment of 71 children with leukemia
Zhang, B. L., Zhou, J., Lyu, T. X., Gui, R. R., Zu, Y. L., Yu, F. K., Zhao, H. F., Li, Z., Wang, J., Zhang, Y. L., et al
Chinese medical journal. 2019;132(7):860-864
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Myeloablative vs reduced-intensity conditioning allogeneic hematopoietic cell transplantation for chronic myeloid leukemia
Chhabra, S., Ahn, K. W., Hu, Z. H., Jain, S., Assal, A., Cerny, J., Copelan, E. A., Daly, A., DeFilipp, Z., Gadalla, S. M., et al
Blood advances. 2018;2(21):2922-2936
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.
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Reduced-intensity allogeneic hematopoietic stem cell transplantation combined with imatinib has comparable event-free survival and overall survival to long-term imatinib treatment in young patients with chronic myeloid leukemia
Zhao, Y., Wang, J., Luo, Y., Shi, J., Zheng, W., Tan, Y., Cai, Z., Huang, H.
Annals of Hematology. 2017;96(8):1353-1360
Abstract
The relative merits of reduced intensity hematopoietic stem cell transplantation (RIST) for chronic myeloid leukemia (CML) in the first chronic phase (CP) in imatinib era have not been evaluated. The study was designed to compare the outcomes of combination therapy of RIST plus imatinib (RIST + IM) vs. imatinib (IM) alone for young patients with early CP (ECP) and late CP (LCP). Of the patients, 130 were non-randomly assigned to treatment with IM alone (n = 88) or RIST + IM (n = 42). The 10-year overall survival (OS) and event-free survival (EFS) were comparable between RIST + IM and IM groups. LCP, high Sokal score, and no complete cytogenetic response at 3 months were adverse prognostic factors for survival, but only the time from diagnosis to IM was an independent predictor after multivariate analysis. For ECP, IM was similar to RIST + IM, with 10-year EFS rates of 77.2 vs. 81.6% (p = 0.876) and OS rates of 93.8 vs. 87.9% (p = 0.102), respectively. For LCP, both treatments resulted in similar survival, but more patients in the imatinib group experienced events (10-year EFS 40.8 vs. 66.7%, p = 0.047). The patients with higher EBMT risk scores had an inferior survival than those with lower scores (69.2 vs. 92.9%, p = 0.04). We concluded that RIST + IM was comparable to IM in terms of OS and EFS. However, RIST + IM was more affordable than IM alone in a 10-year scale. Thus, RIST + IM could be considered as an alternative treatment option, especially when the patients have low EBMT risk scores and demand a definite cure for CML.
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Splenic irradiation before hematopoietic stem cell transplantation for chronic myeloid leukemia: long-term follow-up of a prospective randomized study
Gratwohl, A., Iacobelli, S., Bootsman, N., van Biezen, A., Baldomero, H., Arcese, W., Arnold, R., Bron, D., Cordonnier, C., Ernst, P., et al
Annals of Hematology. 2016;95(6):967-72
Abstract
In the context of discussions on the reproducibility of clinical studies, we reanalyzed a prospective randomized study on the role of splenic irradiation as adjunct to the conditioning for hematopoietic stem cell transplantation (HSCT) for chronic myeloid leukemia (CML). Between 1986 and 1989, a total of 229 patients with CML were randomized; of these, 225 (98 %; 112 with, 113 without splenic irradiation) could be identified in the database and their survival updated. Results confirmed the early findings with no significant differences in all measured endpoints (overall survival at 25 years: 42.7 %, 32.0-52.4 % vs 52.9 %, 43.2-62.6 %; p=0.355, log rank test). Additional splenic irradiation failed to reduce relapse incidence. It did not increase non-relapse mortality nor the risk of late secondary malignancies. Comforting are the long-term results from this predefined consecutive cohort of patients: more than 60 % were alive at plus 25 years when they were transplanted with a low European Society for Blood and Marrow Transplantation (EBMT) risk sore. This needs to be considered today when treatment options are discussed for patients who failed initial tyrosine kinase inhibitor therapy and have an available low risk HLA-identical donor.