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Association between the choice of the conditioning regimen and outcomes of allogeneic hematopoietic cell transplantation for myelofibrosis
Murthy, G. S. G., Kim, S., Estrada-Merly, N., Abid, M. B., Aljurf, M., Assal, A., Badar, T., Badawy, S. M., Ballen, K., Beitinjaneh, A., et al
Haematologica. 2023
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Editor's Choice
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only curative treatment for myelofibrosis. However, the optimal conditioning regimen either with reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) is not well known. Using the Center for International Blood and Marrow Transplant Research database, we identified adults aged ≥18 years with myelofibrosis undergoing allo-HCT between 2008-2019 and analyzed the outcomes separately in the RIC and MAC cohorts based on the conditioning regimens used. Among 872 eligible patients, 493 underwent allo-HCT using RIC (Fludarabine/busulfan=166, Fludarabine/melphalan=327) and 379 using MAC (Fludarabine/busulfan=247, Busulfan/cyclophosphamide=132). In multivariable analysis with RIC, Fludarabine/melphalan was associated with inferior overall survival (HR 1.80, 95% CI 1.15-2.81, p=0.009), higher early non-relapse mortality (HR 1.81, 95% CI 1.12-2.91, p=0.01) and higher acute graft versus host disease (GVHD) (grade II-IV- HR 1.45, 95% CI 1.03-2.03, p=0.03; grade III-IV HR 2.21, 95%CI 1.28-3.83, p=0.004) compared to Fludarabine/busulfan. In the MAC setting, Busulfan/cyclophosphamide was associated with a higher acute GVHD (grade II-IV HR 2.33, 95% CI 1.67-3.25, p<0.001; grade III-IV HR 2.31, 95% CI 1.52-3.52, p<0.001) and inferior GVHD-free relapse-free survival (GRFS) (HR 1.94, 95% CI 1.49-2.53, p<0.001) as compared to Fludarabine/busulfan. Hence, our study suggests that Fludarabine/busulfan is associated with better outcomes in RIC (better overall survival, lower early non-relapse mortality, lower acute GVHD) and MAC (lower acute GVHD and better GRFS) in myelofibrosis.
PICO Summary
Population
Adults with myelofibrosis undergoing allogeneic HSCT between 2008-2019 and reported to the CIBMTR database (n=872)
Intervention
Reduced intensity conditioning (RIC) regimens (n=493): fludarabine/busulfan (n=166) or fludarabine/melphalan (n=327)
Comparison
Myeloablative conditioning (MAC) regimens (n=379): fludarabine/busulfan (n=247) or busulfan/cyclophosphamide (n=132).
Outcome
In multivariable analysis with RIC, fludarabine/melphalan was associated with inferior overall survival (HR 1.80, 95% CI 1.15-2.81), higher early non-relapse mortality (HR 1.81, 95% CI 1.12-2.91,) and higher acute graft versus host disease (GVHD) (grade II-IV- HR 1.45, 95% CI 1.03-2.03; grade III-IV HR 2.21, 95%CI 1.28-3.83) compared to fludarabine/busulfan. In the MAC setting, busulfan/cyclophosphamide was associated with a higher acute GVHD (grade II-IV HR 2.33, 95% CI 1.67-3.25; grade III-IV HR 2.31, 95% CI 1.52-3.52) and inferior GVHD-free relapse-free survival (GRFS) (HR 1.94, 95% CI 1.49-2.53) as compared to fludarabine/busulfan.
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Reduced intensity hematopoietic stem cell transplantation for myelofibrosis in accelerated-phase
Gagelmann, N., Wolschke, C., Salit, R. B., Schroeder, T., Ditschkowski, M., Panagiota, V., Cassinat, B., Thol, F., Badbaran, A., Robin, M., et al
Blood advances. 2022
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Abstract
Accelerated-phase (AP) myelofibrosis, currently defined by circulating blasts 10-19%, usually confers very high risk for progression and poor outcome. The outcome of hematopoietic stem cell transplantation for AP myelofibrosis has not been evaluated yet. We analyzed the outcome of 349 clinically and genetically annotated patients with primary or secondary myelofibrosis undergoing reduced intensity transplantation, of whom 35 had AP myelofibrosis. In comparison with chronic-phase (CP, <10% blasts), median leukocyte counts were higher, more patients had constitutional symptoms, and RAS mutations were detected more frequently in the AP group. After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% (95% confidence interval, 49-81%) versus 64% (95% confidence interval, 59-69%) for the CP group (P=0.91), and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% confidence interval, 32-67%) versus 55% (95% confidence interval, 50-61%) for the CP group (P=0.65). Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% confidence interval, 24-35%; P=0.25) for the CP group. In terms of relapse, 5-year incidence was 30% (95% confidence interval, 14-46%) for the AP group versus 15% (95% confidence interval, 11-19%) for the CP group (P=0.02). Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts. In conclusion, reduced intensity transplantation showed excellent survival but higher relapse for AP myelofibrosis.
PICO Summary
Population
People with primary or secondary myelofibrosis in four centres in France, Germany and USA (n=349)
Intervention
Reduced intensity conditioning and allogeneic transplantation in accelerated phase (AP, n=35)
Comparison
Reduced intensity conditioning and allogeneic transplantation in chronic phase (CP, n=314)
Outcome
After a median follow-up of 5.9 years, estimated 5-year overall survival was 65% in the AP group (95% confidence interval, 49-81%) versus 64% (95% CI, 59-69%) for the CP group, and median overall survival was not reached. In terms of relapse-free survival, estimated 5-year outcome for the AP group was 49% (95% CI, 32-67%) versus 55% (95% CI, 50-61%) for the CP group. Estimated 5-year non-relapse mortality was 20% (95% CI, 8-33%) for the AP group versus 30% (95% CI, 24-35%) for the CP group. In terms of relapse, 5-year incidence was 30% (95% CI, 14-46%) for the AP group versus 15% (95% CI, 11-19%) for the CP group. Results were confirmed in multivariable analysis and propensity score matching. Increase in circulating blasts was associated with increased risk for relapse, showing strongest increase in risk for ≥10% blasts.
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Reduced-intensity conditioning versus myeloablative conditioning allogeneic stem cell transplantation for patients with myelofibrosis
Kim, D. H., Seo, J., Shin, D. Y., Koh, Y., Hong, J., Kim, I., Yoon, S. S., Byun, J. M.
Blood research. 2022
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (alloSCT) is the sole curative option for myelofibrosis (MF). However, it is unknown as to which of the two, myeloablative conditioning (MAC) or reduced-intensity conditioning (RIC), is a better preconditioning regimen. METHODS Twenty-five patients with MF were treated with alloSCT, 12 of whom underwent RIC. Baseline characteristics, response to alloSCT, adverse events, including graft-versus-host disease (GVHD), and survival outcomes were reviewed. RESULTS There was no difference in the neutrophil engraftment rate and time to engraftment between MAC vs. RIC. The time to platelet engraftment was significantly longer in the MAC group (median, 112.8 vs. 28.8 days for MAC vs. RIC, respectively, P=0.049). RIC was more advantageous in terms of achieving complete chimerism (38.5% vs. 83.3%, P=0.041). The incidence of acute GVHD was 84.6% (11 of 13) and 58.3% (7 of 12) in the MAC and RIC groups, respectively. The cumulative incidence of grade III-IV acute GVHD was significantly higher in the MAC group than in the RIC group (P=0.03). No significant differences were observed in progression-free and overall survival. The 17-month probability of progression-free survival was 38.4% [95% confidence interval (CI), 19.3-76.5] vs. 47.6% (95% CI, 25.7-88.2) (P=0.21), and that of overall survival was 53.8% (95% CI, 32.5-89.1) vs. 48.6% (95% CI, 26.8-88.3) (P=0.85) for MAC vs. RIC, respectively. CONCLUSION RIC offers a significant advantage over MAC, even in younger patients with MF undergoing alloSCT, in terms of cell engraftment, rate of complete chimerism achievement, and incidence of acute GVHD.
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Reduced Intensity Conditioning Allogeneic Transplant with Dual T-cell Depletion in Myelofibrosis
Salas, M. Q., Lam, W., Datt Law, A., Kim, D. D. H., Michelis, F. V., Loach, D., Al-Shaibani, Z., Howard Lipton, J., Kumar, R., Mattsson, J., et al
European journal of haematology. 2019
Abstract
BACKGROUND There remains a significant mortality in recipients with MF who undergo allogeneic stem cell transplant (allo-HSCT). The combination of anti-thymoglobulin (ATG) and post-transplant cyclophosphamide (PTCy) provides good control of graft versus host disease (GVHD) when peripheral blood stem cell grafts are used. METHODS We report the outcome of 37 recipients with myelofibrosis who underwent reduced intensity conditioning (RIC) allo-HSCT with ATG and PTCy. Median follow-up was 16.4 months. RESULTS Nine (24.3%) recipients received 10/10 MRD grafts, 17 (45.9%) 10/10 MUD grafts, 4 (10.8%) 9/10 MUD grafts and 7 (18.9%) haploidentical donor grafts. Six (16.3%) patients had graft failure. The cumulative incidence of grade II-IV and grade III-IV aGVHD at day +100 and moderate/severe chronic GVHD at 1 year were: 13.5%, 5.4%, and 17%. There were no deaths secondary to GVHD. One-year overall survival (OS), relapse-free survival (RFS),non-relapse mortality (NRM) and GVHD-Free/RFS (GRFS) were respectively: 74.4%, 71.3%, 23% and 43.3% . Those recipients who had worse KPS ≤80% had worse OS and RFS. CONCLUSION RIC allo-HSCT with ATG and PTCy results in high OS and RFS in patients with myelofibrosis and absence of mortality secondary to GVHD. Further investigations are required to reduce NRM and graft failure rates.
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5.
Comparison of reduced intensity conditioning regimens used in patients undergoing hematopoietic stem cell transplantation for myelofibrosis
Jain, T., Kunze, K. L., Temkit, M., Partain, D. K., Patnaik, M. S., Slack, J. L., Khera, N., Hogan, W. J., Roy, V., Noel, P., et al
Bone Marrow Transplantation. 2019;54(2):204-211
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Abstract
The aim of this study is to compare clinical outcomes of patients who underwent allogeneic stem cell transplantation (HCT) for myelofibrosis with reduced intensity conditioning (RIC) using either Busulfan Fludarabine (BuFlu), Fludarabine Bis-chlorethyl-nitroso-urea/ carmustine Melphalan (FBM) or Fludarabine Melphalan (FluMel) regimens. Sixty-one patients were identified who underwent HCT with one of these RIC regimens. Overall survival (OS) was not different in the 3 groups. However, 100% donor chimerism was seen in more frequently at day +30 and day +100 in patients who received FBM or FluMel than BuFlu, in both CD3 and CD33 fractions. For instance, 100% donor chimerism in CD33 fraction was present in 100% patients in FBM cohort, 90% in FluMel cohort while 44% in BuFlu cohort at day +100. Acute graft-versus host disease, grade 2-4 and grade 3-4, was not statistically different in the 3 groups (BuFlu 47 and 35%, FBM 68 and 27%, FluMel 68 and 46%; p = 0.31 and 0.45). Relapses and non-relapse mortality was also not statistically significantly different. Our study shows similar OS with these 3 RIC regimens in myelofibrosis; although donor chimerism at day +30 and day +100 was better in patients who received FBM and FluMel.
Clinical Commentary
What is known?
NIHMS1698054
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
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6.
Reduced intensity allogeneic stem cell transplantation for younger patients with myelofibrosis
Mannina, D., Zabelina, T., Wolschke, C., Heinzelmann, M., Triviai, I., Christopeit, M., Badbaran, A., Bonmann, S., von Pein, U. M., Janson, D., et al
British journal of haematology. 2019
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Editor's Choice
Abstract
Allogeneic stem cell transplantation (alloSCT) is a curative procedure for myelofibrosis. Elderly people are mainly affected, limiting the feasibility of myeloablative regimens. The introduction of reduced-intensity conditioning (RIC) made alloSCT feasible for older patients. Nevertheless, the incidence of myelofibrosis is not negligible in young patients, who are theoretically able to tolerate high-intensity therapy. Very few data are available about the efficacy of RIC-alloSCT in younger myelofibrosis patients. This study included 56 transplanted patients aged <55 years. Only 30% had a human leucocyte antigen (HLA)-matched sibling donor, the others were transplanted from a fully-matched (36%) or partially-matched (34%) unrelated donor. All transplants were conditioned according the European Society for Blood and Marrow Transplantation protocol: busulfan-fludarabine + anti-thymocyte globulin, followed by ciclosporin and mycophenolate. One patient experienced primary graft failure. Incidence of graft-versus-host disease grade II-IV was 44% (grade III/IV 23%). One-year non-relapse mortality was 7% and the 5-year cumulative incidence of relapse was 19%. After a median follow-up of 8.6 years, the estimated 5-year progression-free survival and overall survival (OS) was 68% and 82%, respectively. Patients with fully-matched donor had a 5-year OS of 92%, in contrast to 68% for those with a mismatched donor (P = 0.03). The most important outcome-determining factor is donor HLA-matching. In conclusion, RIC-alloSCT ensures optimal engraftment and low relapse rate in younger myelofibrosis patients, enabling the possibility of cure in this group.
PICO Summary
Population
Patients under the age of 55 with myelofibrosis (n=56)
Intervention
Allogeneic stem cell transplantation with reduced intensity conditioning
Comparison
None
Outcome
One-year non-relapse mortality was 7% and the 5-year cumulative incidence of relapse was 19%. After a median follow-up of 8.6 years, the estimated 5-year progression-free survival and overall survival (OS) was 68% and 82%, respectively. Patients with fully-matched donor had a 5-year OS of 92%, in contrast to 68% for those with a mismatched donor.
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Ruxolitinib Therapy Followed by Reduced Intensity Conditioning for Hematopoietic Cell Transplantation for Myelofibrosis - Myeloproliferative Disorders Research Consortium 114 study
Gupta, V., Kosiorek, H. E., Mead, A., Klisovic, R. B., Galvin, J. P., Berenzon, D., Yacoub, A., Viswabandya, A., Mesa, R. A., Goldberg, J., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018
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Editor's Choice
Abstract
We evaluated the feasibility of ruxolitinib therapy followed by a reduced intensity conditioning (RIC) regimen for myelofibrosis (MF) patients undergoing transplant in a two stage Simon phase II trial. The aims were to decrease the incidence of graft failure (GF) and non-relapse mortality (NRM) in comparison to previous Myeloproliferative Disorders Research consortium 101 study. The plan was to enrol 11 patients each in related donor (RD), and unrelated donor (URD) arms, with trial termination if ≥3 failures (GF or death by day +100 post-transplant) or ≥6 failures occurred in the RD and URD arm, respectively. A total of 21 patients were enrolled (RD, 7; URD, 14). The RD arm did not meet the pre-determined criteria for proceeding to stage II. Although the URD arm met the criteria for stage II, the study was terminated due to poor accrual and significant failures. F Of the 19 patients undergoing transplant, ruxolitinib was tapered successfully in each patient without significant side effects, and 9 patients (47%) had significant decrease in symptom burden. The cumulative incidences of GF, NRM, acute and chronic graft-versus-host disease at 24 months were 16%, 28%, 64% and 76%, respectively. On an intention to treat basis, the 2-year overall survival (OS) for RD and URD arms was 51% and 70%, respectively. Ruxolitinib can be integrated as pre-transplant treatment for MF patients, and a tapering strategy prior to transplant is safe, allowing patients to commence conditioning therapy with a reduced symptom burden. However, GF and NRM remain significant. The trial is registered at www.clinicaltrials.gov (NCT01790295).
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Outcome after Transplantation According to Reduced-Intensity Conditioning Regimen in Patients Undergoing Transplantation for Myelofibrosis
Robin, M., Porcher, R., Wolschke, C., Sicre de Fontbrune, F., Alchalby, H., Christopeit, M., Cassinat, B., Zabelina, T., Peffault de Latour, R., Ayuk, F., et al
Biology of Blood & Marrow Transplantation. 2016;22(7):1206-11
Abstract
Allogeneic hematopoietic stem cell transplantation remains the sole curative option for myelofibrosis. Many transplantation recipients receive a reduced-intensity conditioning (RIC) regimen owing to age or comorbidities; however, there is little published evidence to guide the choice of RIC regimen. In this study, we compared outcomes in patients who received 1 of 2 frequently used RIC regimens for patients with myelofibrosis: fludarabine-busulfan (FB) and fludarabine-melphalan (FM). A total of 160 patients underwent a RIC allograft procedure (FB group, n = 105; FM group, n = 55). We have developed a complex statistical model involving weighting and adjustment to permit comparison between these 2 groups. After weighting, the incidence of acute graft-versus-host disease (GVHD) was 62% in the FM group and 31% in the FB group (P = .001), and the corresponding incidence of chronic GVHD was 49% and 53%, respectively. The 7-year progression-free survival was were 52% in the FM group versus 33% in the FB group, and the 7-year overall survival rate 52% in the FM group versus 59% in the FB group. Nonrelapse mortality (NRM) was 43% in the FM group and 31% in the FB group. Multivariable analyses revealed no significant differences in PFS between the 2 groups; however, the relapse rate was significantly lower in the FM group (hazard ratio, 9.21; P = .008), whereas a trend toward reduced NRM was seen in the FB group (hazard ratio, 0.51; P = .068). In conclusion, both regimens appear to be efficient in mediating disease control and can be used to successfully condition patients with myelofibrosis. The FM regimen appears to induce more NRM than the FB regimen, but with augmented control of disease, leading to comparable overall survival rates for both regimens. Copyright © 2016 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
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Incidence and risk factors of poor graft function after allogeneic stem cell transplantation for myelofibrosis
Alchalby, H., Yunus, D. R., Zabelina, T., Ayuk, F., Kroger, N.
Bone Marrow Transplantation. 2016;51(9):1223-7
Abstract
Allogeneic hematopoieteic stem cell transplantation (HSCT) is the only curative treatment for myelofibrosis (MF), but it is still associated with significant risks and complications. One of these complications is poor graft function, but incidence and risk factors have not been studied yet. We retrospectively studied a cohort of 100 patients with primary MF or post-ET/PV MF who received a reduced-intensity HSCT in our center. The cumulative incidence of primary leukocyte engraftment was 98%. The cumulative incidence of poor graft function was 17% and all of the cases occurred before day 100 after HSCT at a median of 49 days (range 24-99 days). In the univariate analysis, age as continuous parameter (P=0.05; hazard ratio 1042) and persistence of significant splenomegaly (defined as palpable splenomegaly of 10cm under costal margin) at d+30 after HSCT (33% vs 12%; P=0.05) showed an increased cumulative incidence of poor graft function. In conclusion, the incidence of poor graft function after HSCT for MF is rather high, but did not influence survival. Persistence of splenomegaly after transplantation is a significant factor for poor graft function in myelofibrosis patients. Whether therapeutic reduction of splenomegaly before HSCT would result in a lower incidence of poor graft function should be investigated in future studies.