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A Simple Prognostic System in Myelofibrosis Patients Undergoing Allogeneic Stem Cell Transplant: A CIBMTR/EBMT analysis
Tamari, R., McLornan, D. P., Ahn, K. W., Estrada-Merly, N., Hernandez-Boluda, J. C., Giralt, S. A., Palmer, J. M., Gale, R. P., DeFilipp, Z., Marks, D., et al
Blood advances. 2023
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Editor's Choice
Abstract
To develop a prognostic model for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HCT) for myelofibrosis (MF). We examined 623 patients undergoing allo-HCT between 2000 - 2016 in the USA (CIBMTR cohort). A Cox multivariable model was used to identify factors prognostic of mortality. A weighted score using these factors was assigned to patients transplanted in Europe (EBMT cohort) (n = 623). Age above 50 (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98 -1.96), and HLA matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with increased hazard of death and were assigned 1 point. Hemoglobin lower than 100g/L at time of transplant (HR, 1.63; 95% CI, 1.2- 2.19), and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25- 2.52), were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points) and high score (5 points) were 69% (95% CI, 61% -76 %), 51 % (95% CI, 46% -56.4 %), and 34% (95% CI, 21% - 49%), respectively (P. < 0.001). Increasing score was predictive of increased transplant related mortality (TRM) (P .0017) but not for relapse (P. 0.12). The derived score was predictive for OS (P. < 0.001) and TRM (P. 0.002) but not relapse (P. 17) in the EBMT cohort as well. The proposed system was prognostic of survival in two large cohorts, CIBMTR and EBMT, and can easily be applied by clinicians consulting patients with MF on transplant outcomes.
PICO Summary
Population
Adults aged 40 or over undergoing allogeneic transplantation for myelofibrosis and reported to the CIBMTR or EBMT registries (n=1246)
Intervention
Cox regression model of prognostic factors developed with patients from the CIBMTR registry (n=623)
Comparison
Validation of the model using a cohort from the EBMT registry (n=623)
Outcome
Age above 50 (hazard ratio [HR], 1.39; 95% confidence interval [CI], 0.98 -1.96), and HLA matched unrelated donor (HR, 1.29; 95% CI, 0.98-1.7) were associated with increased hazard of death and were assigned 1 point. Hemoglobin lower than 100g/L at time of transplant (HR, 1.63; 95% CI, 1.2- 2.19), and a mismatched unrelated donor (HR, 1.78; 95% CI, 1.25- 2.52), were assigned 2 points. The 3-year overall survival (OS) in patients with a low (1-2 points), intermediate (3-4 points) and high score (5 points) were 69% (95% CI, 61% -76 %), 51 % (95% CI, 46% -56.4 %), and 34% (95% CI, 21% - 49%), respectively. Increasing score was predictive of increased transplant related mortality (TRM) but not for relapse. The derived score was predictive for OS and TRM but not relapse in the EBMT cohort as well.
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Fludarabine/TBI 8 Gy versus fludarabine/treosulfan conditioning in patients with AML in first complete remission: a study from the Acute Leukemia Working Party of the EBMT
Bug, G., Labopin, M., Niittyvuopio, R., Stelljes, M., Reinhardt, H. C., Hilgendorf, I., Kröger, N., Kaare, A., Bethge, W., Schäfer-Eckart, K., et al
Bone marrow transplantation. 2023
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Abstract
The optimal reduced intensity conditioning (RIC) regimen is a matter of debate. We retrospectively compared conditioning with fludarabine plus fractionated total body irradiation of 8 Gy (FluTBI) and fludarabine plus treosulfan 30, 36 or 42 g/m(2) (FluTreo) in 754 patients with AML above the age of 40 years undergoing an allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission (CR). After balancing patient characteristics by propensity score matching of 115 patients in each group, FluTBI was associated with a significantly lower probability of relapse compared to FluTreo (18.3% vs. 34.7%, p = 0.018) which was counteracted by a higher non-relapse mortality (NRM, 16.8% vs. 5.3%, p = 0.02). Thus, overall survival and graft-versus-host disease-free and relapse-free survival at 2 years were similar between groups (OS 66.9% vs. 67.8%, GRFS 50.3% vs. 45.6%). Univariate analysis by age group demonstrated a higher NRM exclusively in patients ≥55 years of age treated with FluTBI compared to FluTreo (27.6% vs. 5.8%, p = 0.02), while a similarly low NRM was observed in patients <55 years in both groups (6.0% vs. 4.7%, p = ns). We conclude that both conditioning regimens are effective and safe, but FluTBI may better be reserved for younger patients below the age of 55 years.
PICO Summary
Population
Adults above the age of 40 years with AML, undergoing an allogeneic hematopoietic stem cell transplant (HSCT) in first complete remission and reported to the EBMT registry (n=754, pair matched to produce a population of 230)
Intervention
Conditioning with fludarabine plus fractionated total body irradiation of 8 Gy (FluTB, n=115)
Comparison
Conditioning with fludarabine plus treosulfan 30, 36 or 42 g/m(2) (FluTreo, n=115)
Outcome
After balancing patient characteristics by propensity score matching of 115 patients in each group, FluTBI was associated with a significantly lower probability of relapse compared to FluTreo (18.3% vs. 34.7%) which was counteracted by a higher non-relapse mortality (NRM, 16.8% vs. 5.3%). Thus, overall survival and graft-versus-host disease-free and relapse-free survival at 2 years were similar between groups (OS 66.9% vs. 67.8%, GRFS 50.3% vs. 45.6%). Univariate analysis by age group demonstrated a higher NRM exclusively in patients ≥55 years of age treated with FluTBI compared to FluTreo (27.6% vs. 5.8%), while a similarly low NRM was observed in patients <55 years in both groups (6.0% vs. 4.7%).
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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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4.
Impact of conditioning regimen intensity on outcomes of second allogeneic hematopoietic cell transplantation for secondary acute myelogenous leukemia
Nagler, A., Peczynski, C., Dholaria, B., Labopin, M., Valerius, T., Dreger, P., Kröger, N., Reinhardt, H. C., Finke, J., Franke, G. N., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Limited data is available on factors impacting the outcomes of second hematopoietic cell transplantation (HCT2) in patients with secondary acute myeloid leukemia (sAML). This study aimed to assess HCT2 outcome for sAML comparing reduced-intensity (RIC) to myeloablative (MAC) conditioning. Two hundred and fifteen patients were included: RIC (n = 134), MAC (n = 81). The median follow-up was 41.1 (95% CI: 26.7-69.3) and 28.5 (95% CI: 23.9-75.4) months, respectively. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. MVA showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26-0.8, p = 0.006)] and improved LFS [HR = 0.62 (95% CI, 0.39-0.98, p = 0.042)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52-2.5, p = 0.74)], overall survival (OS) [HR = 0.72 (95% CI, 0.44-1.17, p = 0.18)] or GRFS [HR = 0.89 (95% CI, 0.59-1.36, p = 0.6)]. In conclusion, MAC was associated with a lower RI and superior LFS. These results support the use of MAC for eligible patients with sAML who are being considered for HCT2.
PICO Summary
Population
Adult patients with relapsed secondary acute leukaemia (sAML) receiving a second hematopoietic cell transplant (HCT2) from mulitple centre registries across Europe (n=215)
Intervention
Reduced-intensity pre-HCT2 conditioning (RIC, n=134)
Comparison
Myeloablative pre-HCT2 conditioning (MAC, n=81)
Outcome
Median follow-up was 41.1 (RIC, 95% CI: 26.7-69.3) and 28.5 (MAC, 95% CI: 23.9-75.4) months. At two years, the relapse incidence (RI) was 58.3% versus 51.1% in RIC and MAC, respectively. The 2-year leukemia free survival (LFS) was 26.6% versus 26%, and the graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) was 16.4% versus 12.1%, while OS was 31.4% and 39.7%, for RIC and MAC respectively. Multivariate analysis showed a significantly lower RI [hazard ratio (HR) = 0.46 (95% CI, 0.26-0.8)] and improved LFS [HR = 0.62 (95% CI, 0.39-0.98)] with MAC versus RIC. The choice of conditioning regimen did not impact non-relapse mortality [HR = 1.14 (95% CI, 0.52-2.5)], overall survival (OS) [HR = 0.72 (95% CI, 0.44-1.17)] or GRFS [HR = 0.89 (95% CI, 0.59-1.36)].
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5.
Total body irradiation plus fludarabine versus thiotepa, busulfan plus fludarabine as a myeloablative conditioning for adults with acute lymphoblastic leukemia treated with haploidentical hematopoietic cell transplantation. A study by the Acute Leukemia Working Party of the EBMT
Swoboda, R., Labopin, M., Giebel, S., Angelucci, E., Arat, M., Aljurf, M., Sica, S., Pavlu, J., Socié, G., Bernasconi, P., et al
Bone marrow transplantation. 2022
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Editor's Choice
Abstract
Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.
PICO Summary
Population
Adults with acute lymphoblastic leukemia (ALL) treated with haploidentical (n=haematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide (n=236)
Intervention
Fludarabine + total body irradiation conditioning (Flu-TBI, n=117)
Comparison
Thiotepa + iv. busulfan + fludarabine conditioning (TBF, n=119)
Outcome
In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%). There was a tendency towards reduced incidence of relapse after TBF. Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34) but an increased risk of relapse (HR = 2.59) without significant effect on survival and graft-versus-host disease.
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Development and validation of a disease risk stratification system for patients with haematological malignancies: a retrospective cohort study of the European Society for Blood and Marrow Transplantation registry
Shouval, R., Fein, J. A., Labopin, M., Cho, C., Bazarbachi, A., Baron, F., Bug, G., Ciceri, F., Corbacioglu, S., Galimard, J. E., et al
The Lancet. Haematology. 2021;8(3):e205-e215
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Editor's Choice
Abstract
BACKGROUND Diagnosis and remission status at the time of allogeneic haematopoietic stem-cell transplantation (HSCT) are the principal determinants of overall survival following transplantation. We sought to develop a contemporary disease-risk stratification system (DRSS) that accounts for heterogeneous transplantation indications. METHODS In this retrospective cohort study we included 55 histology and remission status combinations across haematological malignancies, including acute leukaemia, lymphoma, multiple myeloma, and myeloproliferative and myelodysplastic disorders. A total of 47?265 adult patients (aged =18 years) who received an allogeneic HSCT between Jan 1, 2012, and Dec 31, 2016, and were reported to the European Society for Blood and Marrow Transplantation registry were included. We divided EBMT patients into derivation (n=25?534), tuning (n=18?365), and geographical validation (n=3366) cohorts. Disease combinations were ranked in a multivariable Cox regression for overall survival in the derivation cohort, cutoff for risk groups were evaluated for the tuning cohort, and the selected system was tested on the geographical validation cohort. An independent single-centre US cohort of 660 patients transplanted between Jan 1, 2010, and Dec 31, 2015 was used to externally validate the results. FINDINGS The DRSS model stratified patients in the derivation cohort (median follow-up was 2·1 years [IQR 1·0-3·2]) into five risk groups with increasing mortality risk: low risk (reference group), intermediate-1 (hazard ratio for overall survival 1·26 [95% CI 1·17-1·36], p<0·0001), intermediate-2 (1·53 [1·42-1·66], p<0·0001), high (2·03 [1·86-2·22], p<0·0001), and very high (2·87 [2·63-3·13], p<0·0001). DRSS levels were also associated with a stepwise increase in risk across the tuning and geographical validation cohort. In the external validation cohort (median follow-up was 5·7 years [IQR 4·5-7·1]), the DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34 [95% CI 1·04-1·74], p=0·025), high risk (HR 2·03 [95% CI 1·39-2·95], p=0·00023) and very-high risk (HR 2·26 [95% CI 1·62-3·15], p<0·0001) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14?041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% (95% CI 61·2-62·9) for these 14?041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4-54·0; very high risk patients) to 73·1% (70·1-76·2; low risk patients). INTERPRETATION The DRSS is a novel risk stratification tool including disease features related to histology, genetic profile, and treatment response. The model should serve as a benchmark for future studies. This system facilitates the interpretation and analysis of studies with heterogeneous cohorts, promoting trial-design with more inclusive populations. FUNDING The Varda and Boaz Dotan Research Center for Hemato-Oncology Research, Tel Aviv University.
PICO Summary
Population
Adults with haematological malignancies who received an allogeneic HSCT reported to the European Society for Blood and Marrow Transplantation registry (n=47,265)
Intervention
Disease Risk Stratification System (DRSS)
Comparison
Disease Risk Index (DRI)
Outcome
The DRSS scheme separated patients into 4 risk groups associated with increasing risk of mortality: intermediate-2 risk (hazard ratio [HR] 1·34), high risk (HR 2·03]) and very-high risk (HR 2·26) patients compared with the low risk and intermediate-1 risk group (reference group). Across all cohorts, between 64% and 65% of patients were categorised as having intermediate-risk disease by a previous prognostic system (ie, the disease-risk index [DRI]). The DRSS reclassified these intermediate-risk DRI patients, with 855 (6%) low risk, 7111 (51%) intermediate-1 risk, 5700 (41%) intermediate-2 risk, and 375 (3%) high risk or very high risk of 14,041 patients in a subanalysis combining the tuning and internal geographic validation cohorts. The DRI projected 2-year overall survival was 62·1% for these 14,041 patients, while the DRSS reclassified them into finer prognostic groups with overall survival ranging from 45·7% (37·4-54·0; very high risk patients) to 73·1% (70·1-76·2; low risk patients).
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Allogeneic hematopoietic cell transplantation with cord blood versus mismatched unrelated donor with post-transplant cyclophosphamide in acute myeloid leukemia
Dholaria, B., Labopin, M., Sanz, J., Ruggeri, A., Cornelissen, J., Labussière-Wallet, H., Blaise, D., Forcade, E., Chevallier, P., Grassi, A., et al
Journal of hematology & oncology. 2021;14(1):76
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Editor's Choice
Abstract
BACKGROUND Allogeneic hematopoietic cell transplantation (allo-HCT) using a mismatched unrelated donor (MMUD) and cord blood transplantation (CBT) are valid alternatives for patients without a fully human leukocyte antigen (HLA)-matched donor. Here, we compared the allo-HCT outcomes of CBT versus single-allele-mismatched MMUD allo-HCT with post-transplant cyclophosphamide (PTCy) in acute myeloid leukemia. METHODS Patients who underwent a first CBT without PTCy (N?=?902) or allo-HCT from a (HLA 9/10) MMUD with PTCy (N?=?280) were included in the study. A multivariate regression analysis was performed for the whole population. A matched-pair analysis was carried out by propensity score-based 1:1 matching of patients (177 pairs) with known cytogenetic risk. RESULTS The incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% (p?=?0.07) and 15% versus 11% (p?=?0.16) for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%, p?0.01) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%, p?0.01) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR?=?2.09, 95% CI 1.46-2.99, p?0.0001), and relapse (HR?=?1.35, 95% CI 1-1.83, p?=?0.05), which resulted in worse leukemia-free survival (LFS) (HR?=?1.68, 95% CI 1.34-2.12, p?0.0001), overall survival (OS) (HR?=?1.7, 95% CI 1.33-2.17, p?0.0001), and GVHD-free, relapse-free survival (GRFS) (HR?=?1.49, 95% CI 1.21-1.83, p?0.0001) compared to MMUD. The risk of grade II-IV acute GVHD (p?=?0.052) and chronic GVHD (p?=?0.69) did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis. CONCLUSIONS CBT was associated with lower LFS, OS, and GRFS due to higher NRM, compared to MMUD allo-HCT with PTCy. In the absence of a fully matched donor, 9/10 MMUD with PTCy may be preferred over CBT.
PICO Summary
Population
Patients with acute myeloid leukaemia (n=1182)
Intervention
First cord blood transplant without post-transplant cyclophosphamide (CBT, n=902)
Comparison
Allogeneic haematopoietic stem cell transplantation usinga mismatched unrelated donor with post-transplant cyclophosphamide (MMUD, n=280)
Outcome
The incidence of grade II-IV and grade III-IV acute graft-versus-host disease (GVHD) at 6 months was 36% versus 32% and 15% versus 11% for CBT and MMUD cohorts, respectively. CBT was associated with a higher incidence of graft failure (11% vs. 4%) and higher 2-year non-relapse mortality (NRM) (30% vs. 16%) compared to MMUD. In the multivariate analysis, CBT was associated with a higher risk of, NRM (HR=2.09), and relapse (HR=1.35), which resulted in worse leukemia-free survival (LFS) (HR=1.68), overall survival (OS) (HR=1.7), and GVHD-free, relapse-free survival (GRFS) (HR=1.49) compared to MMUD. The risk of grade II-IV acute GVHD and chronic GVHD did not differ significantly between the cohorts. These results were confirmed in a matched-pair analysis.
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8.
Fludarabine and Melphalan Compared with Reduced Doses of Busulfan and Fludarabine Improves Transplant Outcomes in Older MDS Patients
Oran, B., Ahn, K. W., Fretham, C., Beitinjaneh, A., Bashey, A., Pawarode, A., Wirk, B., Scott, B. L., Savani, B. N., Bredeson, C., et al
Transplantation and cellular therapy. 2021
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Editor's Choice
Abstract
Reduced-intensity conditioning (RIC) regimens developed to extend allogeneic stem cell transplantation (HSCT) to older patients have resulted in encouraging outcomes. We aimed to compare the two most commonly used RIC regimens, intravenous use of fludarabine with busulfan (FluBu) and fludarabine with melphalan (FluMel), in myelodysplastic syndrome (MDS). Through CIBMTR, we identified 1045 MDS patients aged = 60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor using RIC. CIBMTR's definition of RIC was used: a regimen that incorporated an intravenous busulfan total dose = 7.2 mg/kg, or a low-dose melphalan total dose of = 150 mg/m(2). The two groups, FluBu (n=697) and FluMel (n=448), were comparable for disease and transplant-related characteristics except for the more frequent use of anti-thymocyte globulin or alemtuzumab in the FluBu group (39% vs. 31%). The median age was 67 in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% vs. 44% (p=0.0001). Transplant-related mortality (TRM) was higher with FluMel compared with FluBu (26% vs. 16%, p=0.0001). Since the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 40% at 1 year, p=0.02, and 35% vs. 27% at 3 years, p=0.01). Overall survival (OS) was comparable at 1 year (63% vs. 61%, p=0.4) but significantly improved with FluMel compared with FluBu at 3 years (46% vs. 39%, p=0.03). Our results suggest that FluMel is associated with superior DFS compared with FluBu due to reduced RI in older MDS patients.
PICO Summary
Population
Patients with myelodysplastic syndrome aged >/=60 years who underwent first HSCT with a matched related or matched (8/8) unrelated donor, and were reported to the CIBMTR registry (n=1045)
Intervention
Reduced intensity regimen incorporating an intravenous busulfan total dose = 7.2 mg/kg (FluBu, n=697)
Comparison
Reduced intensity regimen incorporating a low-dose melphalan total dose of = 150 mg/m(2) (FluMel, n=448)
Outcome
The two groups were comparable for disease and transplant-related characteristics except for the more frequent use of anti-thymocyte globulin or alemtuzumab in the FluBu group (39% vs. 31%). The median age was 67 in both groups. FluMel was associated with a reduced relapse incidence (RI) compared with FluBu, with a 1-year adjusted incidence of 26% vs. 44%. Transplant-related mortality (TRM) was higher with FluMel compared with FluBu (26% vs. 16%). Since the magnitude of improvement with FluMel in RI was greater than the improvement in TRM with FluBu, disease-free survival (DFS) was improved at 1-year and beyond with FluMel compared with FluBu (48% vs. 40% at 1 year, and 35% vs. 27% at 3 years). Overall survival (OS) was comparable at 1 year (63% vs. 61%) but significantly improved with FluMel compared with FluBu at 3 years (46% vs. 39%). Our results suggest that FluMel is associated with superior DFS compared with FluBu due to reduced RI in older MDS patients.
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9.
The outcome of two or more HLA loci mismatched unrelated donor hematopoietic cell transplantation for acute leukemia: an ALWP of the EBMT study
Nagler, A., Dholaria, B., Labopin, M., Bruno, B., Rambaldi, A., Pioltelli, P., La Nasa, G., Socie, G., Mielke, S., Ruggeri, M., et al
Bone marrow transplantation. 2020
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Editor's Choice
Abstract
A mismatched unrelated (MMUD) donor represents an alternative therapeutic option for patients who need allogeneic hematopoietic cell transplantation (allo-HCT) and do not have a human leukocyte antigen (HLA) matched donor. We studied outcomes of patients with acute leukemia transplanted from ≥2 HLA allele MMUD. The study population consisted of 465 patients. The median follow-up period was 63 and 75 months in the AML and ALL groups, respectively. The incidence of grade II-IV and grade III-IV acute (a) graft-versus-host disease (GVHD) during the first 100 days was 37% and 16%, respectively. Total and extensive chronic (c) GVHD rates at 2 years were 38% and 17%, respectively. In the entire population, the 5-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival and refined GVHD-free, relapse-free survival (GRFS) was 33%, 31%, 37%, 41%, and 27%, respectively. In the multivariate analysis, HLA-DR mismatch was a poor prognostic factor, giving a significantly higher NRM [hazard ratio (HR), 1.67, p = 0.02]; poorer LFS (HR, 1.42, p = 0.03); OS (HR, 1.46, p = 0.03) and higher aGVHD grade II-IV (HR, 1.46, p = 0.05). In this study, allo-HCT from ≤6/8 HLA allele MMUD in acute leukemia patients resulted in acceptable LFS and refined GRFS. HLA-DR mismatch was a poor prognostic factor.
PICO Summary
Population
Patients with acute leukaemia (n=465, of which AML n=320, ALL n=145)
Intervention
Transplantation with >/=2 HLA allele mismatched unrelated donor
Comparison
None
Outcome
The incidence of grade II-IV and grade III-IV acute (a) graft-versus-host disease (GVHD) during the first 100 days was 37% in AML patients and 16% in ALL patients. Total and extensive chronic (c) GVHD rates at 2 years were 38% and 17%, respectively. In the entire population, the 5-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival and refined GVHD-free, relapse-free survival (GRFS) was 33%, 31%, 37%, 41%, and 27%, respectively. In the multivariate analysis, HLA-DR mismatch was a poor prognostic factor, giving a significantly higher NRM [hazard ratio (HR), 1.67]; poorer LFS (HR, 1.42); OS (HR, 1.46) and higher aGVHD grade II-IV (HR, 1.46).
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10.
Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Post-transplant Cyclophosphamide in Patients with Acute Leukemia
Nagler, A., Labopin, M., Dholaria, B., Angelucci, E., Afanasyev, B., Cornelissen, J. J., Sica, S., Meijer, E., Ciceri, F., Van Gorkom, G., et al
Clinical cancer research : an official journal of the American Association for Cancer Research. 2020
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Full text
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Editor's Choice
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) is increasingly being utilized as a principle graft-versus-host disease (GvHD) prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) are valid options in the absence of a matched related donor. EXPERIMENTAL DESIGN We compared the outcomes of patients with acute leukemia who underwent haplo bone marrow (haplo-BM, N=401) versus UD mobilized peripheral blood stem cells (UD-PB, N=192) transplantation in the setting of PTCy. RESULTS The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively (p<0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively (p<0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively (p =0.21). In the multivariate analysis, the risk of grade II-IV acute GvHD (HR=0.53, p=0.01) and chronic GvHD (HR=0.50, p=0.02) was significantly lower in the haplo-BM group compared to the UD-PB group. There was no significant difference between the study groups, with respect to relapse incidence, non-relapse mortality, leukemia-fee survival, overall survival or, GvHD-free, relapse-free survival. CONCLUSION The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared to a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into the difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
PICO Summary
Population
Patients with acute leukaemia (n=593)
Intervention
Haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PTCy) (haplo-BM, n=401)
Comparison
Matched unrelated donor transplantation with mobilised peripheral blood stem cells (UD-PB, n=192)
Outcome
The median follow-up duration was 36 months in the haplo-BM group and 16.6 months in the UD-PB group, respectively. Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively. Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively. In the multivariate analysis, the risk of grade II-IV acute GvHD and chronic GvHD was significantly lower in the haplo-BM group compared to the UD-PB group. There was no significant difference between the study groups, with respect to relapse incidence, non-relapse mortality, leukemia-fee survival, overall survival or, GvHD-free, relapse-free survival.