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Non-T-depleted haploidentical transplantation with post-transplant cyclophosphamide in patients with secondary versus de novo AML in first complete remission: a study from the ALWP/EBMT
Nagler, A., Labopin, M., Blaise, D., Raiola, A. M., Corral, L. L., Bramanti, S., Sica, S., Kwon, M., Koc, Y., Pavlu, J., et al
Journal of hematology & oncology. 2023;16(1):58
Abstract
We compared outcomes of adult patients with secondary acute myeloid leukemia (sAML) versus de novo AML after non-T-depleted haploidentical stem cell transplant (HaploSCT) with post-transplant cyclophosphamide (PTCy). Seventeen hundred and eleven AML patients (sAML-231, de novo-1480) in first complete remission transplanted from 2010 to 2021, were included. Patients with de novo AML were younger, median age 55.8 versus 60.8 years, p < 0.0001, had better transplantation comorbidity index (HCT-CI) ≥ 3 21.3% versus 40.8%, p < 0.0001 and Karnofsky performance status (KPS) with KPS ≥ 90 in 78% versus 68.5%, respectively, p = 0.002. The two patient groups did not differ with respect to gender, cytomegalovirus serostatus, and cell source. Median time from diagnosis to HaploSCT was 5.2 versus 4.9 months, respectively, p = 0.005. Fewer sAML patients received myeloablative conditioning 35.1% versus 50.1%, p < 0.0001. Two hundred and eleven sAML and 410 de novo AML patients were included in the matched-pair analysis matching two de novo AML with each sAML. No significant difference was observed in any transplantation outcome parameter between the sAML versus de novo AML groups. Two-year non-relapse mortality and relapse incidence did not differ with HaploSCT for de novo versus sAML; 21.4% versus 21%, hazard ratio (HR) = 0.98, p = 0.9 and 23.4% versus 20.6%, HR = 0.92, p = 0.67, respectively. Two-year leukemia-free survival, overall survival, and graft-versus-host disease (GVHD)-free, relapse-free survival were also not different between the de novo AML and sAML groups 55.2% versus 58.4%, HR = 0.95, p = 0.67; 61.4% versus 66.4%, HR = 0.91, p = 0.51 and 46.3% versus 48.2%, HR = 0.92, p = 0.48, respectively. Similarly, the incidence of engraftment as well as acute and chronic GVHD was similar between the 2 cohorts. In conclusion, HaploSCT with PTCy may be able to overcome the bad prognosis of sAML as results are not significantly different to those of HaploSCT in de novo AML.
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2.
Matched related versus unrelated versus haploidentical donors for allogeneic transplantation in AML patients achieving first complete remission after two induction courses: a study from the ALWP/EBMT
Nagler, A., Labopin, M., Mielke, S., Passweg, J., Blaise, D., Gedde-Dahl, T., Cornelissen, J. J., Salmenniemi, U., Yakoub-Agha, I., Reményi, P., et al
Bone marrow transplantation. 2023;58(7):791-800
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Editor's Choice
Abstract
We compared transplants (HSCT) from matched related siblings (MSD) with those from matched 10/10 and mismatched 9/10 unrelated (UD) and T-replete haploidentical (Haplo) donors in acute myeloid leukemia (AML) in first complete remission (CR1) achieved after two inductions, a known poor prognostic factor. One thousand two hundred and ninety-five patients were included: MSD (n = 428), UD 10/10 (n = 554), UD 9/10 (n = 135), and Haplo (n = 178). Acute GVHD II-IV was higher in all groups compared to MSD. Extensive chronic (c) GVHD was significantly higher in UD 9/10 (HR = 2.52; 95% CI 1.55-4.11, p = 0.0002) and UD 10/10 (HR = 1.48; 95% CI 1.03-2.13, p = 0.036) and cGVHD all grades were higher in UD 9/10 vs MSD (HR = 1.77; 95% CI 1.26-2.49, p = 0.0009). Non-relapse mortality was higher in all groups compared to MSD. Relapse incidence, leukemia-free, and overall survival did not differ significantly between donor types. Finally, GVHD-free relapse-free survival was lower in HSCT from UD 9/10 (HR = 1.56, 95% CI 1.20-2.03, p = 0.0009) but not in those from UD 10/10 (HR = 1.13, p = 0.22) and Haplo donors (HR = 1.12, p = 0.43) compared to MSD. In conclusion, in AML patients undergoing HSCT in CR1 achieved after two induction courses 10/10 UD and Haplo but not 9/10 UD donors are comparable alternatives to MSD.
PICO Summary
Population
Adults with acute myeloid leukemia (AML) in first complete remission (CR1) achieved after two inductions (n=1295)
Intervention
Allo-HSCT from matched related sibling donor (MSD, n=428)
Comparison
Matched 10/10 unrelated donor (UD 10/10 n=554), Mismatched 9/10 unrelated (UD 9/10, n=135) or T-replete haploidentical (Haplo, n=178)
Outcome
Acute GVHD II-IV was higher in all groups compared to MSD. Extensive chronic (c) GVHD was significantly higher in UD 9/10 (HR = 2.52; 95% CI 1.55-4.11) and UD 10/10 (HR = 1.48; 95% CI 1.03-2.13) and cGVHD all grades were higher in UD 9/10 vs MSD (HR = 1.77; 95% CI 1.26-2.49). Non-relapse mortality was higher in all groups compared to MSD. Relapse incidence, leukemia-free, and overall survival did not differ significantly between donor types. Finally, GVHD-free relapse-free survival was lower in HSCT from UD 9/10 (HR = 1.56, 95% CI 1.20-2.03) but not in those from UD 10/10 (HR = 1.13) and Haplo donors (HR = 1.12) compared to MSD
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Post-transplant cyclophosphamide-based graft-versus-host disease prophylaxis in HLA-matched and haploidentical donor transplants for patients with Hodgkin lymphoma: a comparative study of the LWP EBMT.: GVHD prophylaxis for patients with Hodgkin lymphoma
Montoro, J., Boumendil, A., Finel, H., Bramanti, S., Castagna, L., Blaise, D., Dominietto, A., Kulagin, A., Yakoub-Agha, I., Tbakhi, A., et al
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Post-transplant cyclophosphamide (PTCy) has emerged as a promising approach for preventing graft-versus-host disease (GVHD) in allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, there is a lack of studies examining the impact of this GVHD prophylaxis when different donor types are used in patients with Hodgkin lymphoma (HL). OBJECTIVE To compare the outcomes of patients with HL undergoing HSCT from both HLA-matched donors, which include matched sibling donors (MSD) and matched unrelated donors (MUD), and haploidentical donors, using PTCy as GVHD prophylaxis approach in all cohorts. STUDY DESIGN We retrospectively compared transplant outcomes of allo-HSCT from 166 HLA-matched donors (96 siblings and 70 unrelated) and 694 haploidentical donors using PTCy-based GVHD prophylaxis in patients with HL registered in the EBMT database from 2010 to 2020. RESULTS Haploidentical transplantation showed significantly lower platelet engraftment (86% vs 94%, p<0.001) and higher rates of grades II-IV acute GVHD (24% vs 34%, p=0.01) compared to HLA-matched transplantation. The 2-year cumulative incidence of non-relapse mortality (NRM) was significantly lower in the HLA-matched cohort compared to haploidentical cohort (10% vs 18%, p=0.02), resulting in a higher overall survival (OS) rate (82% vs 70%, p=0.002). There were no significant differences observed in terms of relapse, progression-free survival, or GVHD-free relapse-free survival between the groups. In multivariable analysis, haploidentical transplantation was associated with an increased risk of grades II-IV acute GVHD, NRM, and worse OS compared to HLA-matched transplantation. CONCLUSIONS Our findings suggest that, in the context of PTCy-based GVHD prophylaxis, transplantation from HLA-matched donors appears to be a more favorable option compared to haploidentical transplantation.
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GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT
Baron, F., Labopin, M., Tischer, J., Raiola, A. M., Vydra, J., Blaise, D., Chiusolo, P., Stölzel, F., Fanin, R., Chevallier, P., et al
Journal of hematology & oncology. 2023;16(1):10
Abstract
The association between graft-versus-host disease (GVHD) occurrence and acute myeloid leukemia (AML) relapse in patients treated with HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis has remained debated. Here, we addressed this issue in patients with active AML at transplantation. 2-year cumulative incidences of relapse and leukemia-free survival (LFS) were 49% and 32.3%, respectively. There were no associations between acute nor chronic GVHD of any grade and lower relapse incidence. However, grade I acute GVHD was associated with better LFS (HR = 0.71, 95% CI 0.51-0.99, P = 0.04). In contrast, grade III-IV acute (HR = 3.09, 95% CI 1.87-5.12, P < 0.0001) as well as extensive chronic (HR = 3.3, 95% CI 1.81-6.04, P = 0.0001) GVHD correlated with higher nonrelapse mortality leading to lower LFS (HR = 1.36, 95% CI 0.99-1.86, P = 0.056 and HR = 1.97, 95% CI 1.35-2.89, P = 0.0004, respectively). In conclusion, these data suggest a dissociation of graft-versus-leukemia effects from GVHD in patients with active AML treated with PTCy-based Haplo-HCT.
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5.
Thiotepa-busulfan-fludarabine Compared to Treosulfan-based Conditioning for Haploidentical Transplant With Posttransplant Cyclophosphamide in Patients With Acute Myeloid Leukemia in Remission: A Study From the Acute Leukemia Working Party of the EBMT
Saraceni, F., Labopin, M., Raiola, A. M., Blaise, D., Reményi, P., Sorà, F., Pavlu, J., Bramanti, S., Busca, A., Berceanu, A., et al
HemaSphere. 2023;7(10):e952
Abstract
We conducted a registry analysis including adult acute myeloid leukemia (AML) patients in remission who had received thiotepa, busulfan, and fludarabine (TBF) or treosulfan-based (Treo) conditioning for haplo-hematopoietic stem cell transplant (HSCT) with posttransplant cyclophosphamide (PTCy) between 2010 and 2020. A total of 1123 patients met the inclusion criteria (968 received TBF and 155 received Treo). A 1:1 matched-pair analysis was performed on 142 TBF and 142 Treo patients. In the Treo group, 68% of patients received treosulfan at a dose ≥36 g/m(2) and 54% of patients received a second alkylator (thiotepa or melphalan). We observed a trend toward increased incidence of grade II-IV acute (a) graft-versus-host disease (GVHD) at 180 days in the TBF group compared with Treo (29% versus 20%; P = 0.08), while incidence of grade III-IV aGVHD was not statistically different. Similarly, the incidence of chronic (c) GVHD was not statistically different in the 2 groups. Incidence of nonrelapse mortality at 2 years was 19% in TBF and 14% in Treo (P = 0.4). Relapse incidence at 2 years was not statistically different in the 2 groups (16% and 18% in TBF and Treo, respectively; P = 0.9). Leukemia-free survival, overall survival, and GVHD-free, relapse-free survival was 65% versus 68% (P = 0.6), 73% versus 76% (P = 0.5), and 54% versus 53% (P = 0.8) in TBF versus Treo, respectively. In conclusion, we did not find a significant difference between the 2 conditioning in the present study; Treo and TBF represent 2 valid alternative regimens for haplo-HSCT with PTCy for AML in remission.
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6.
Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS
Michel, C., Robin, M., Morisset, S., Blaise, D., Maertens, J., Chevalier, P., Castilla-Llorente, C., Forcade, E., Ceballos, P., Yakoug-Agha, I., et al
Bone marrow transplantation. 2023;58(5):534-543
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Editor's Choice
Abstract
Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.
PICO Summary
Population
Patients with higher-risk MDS undergoing allogeneic transplant in centres in France (n=266)
Intervention
HLA-matched sibling donor (MSD, n=79), HLA-matched unrelated donor (MUD, n=139)
Comparison
and HLA haploidentical donor (HID, n=48)
Outcome
The overall survival was significantly different between the three groups with a better OS observed in the MUD group. This observation could be explained by a higher progression-free survival with MUD. The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group. However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]) and a MSD ([sHR]: 0.56 [0.28-1.11]).
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7.
Similar outcomes following non-first-degree and first-degree related donor haploidentical hematopoietic cell transplantation for acute leukemia patients in complete remission: a study from the Global Committee and the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation
Ye, Y., Labopin, M., Chen, J., Gulbas, Z., Zhang, X., Koc, Y., Blaise, D., Ciceri, F., Polge, E., Houhou, M., et al
Journal of Hematology & Oncology. 2023;16(1):25
Abstract
There are situations where non-first-degree (NFD) related donors have to be considered as alternatives to first-degree (FD) related donors for haploidentical hematopoietic cell transplantation (HAPLO). However, the efficacy of these NFD related transplants remains uncertain. All consecutive adult patients (≥ 18 years) with acute myelogenous leukemia (AML) or acute lymphocytic leukemia (ALL) in CR who underwent a first HAPLO between 2010 and 2021 in the European Society for Blood and Marrow Transplantation (EBMT) registry were analyzed. Exact matching and propensity score matching was used. The NFD-to-FD ratio was 1:3. 2703 patients (AML: n = 2047; ALL: n = 656) in CR received a first HAPLO from either NFD (n = 154) or FD (n = 2549) related donors in 177 EBMT centers. 123 NFD and 324 FD HAPLO were included for analysis after matching. Median patient age was 35.6 and 37.2 for the NFD and FD cohorts, respectively. Both cohorts reached good engraftment rates (NFD: 95.7% vs. FD, 95.6%; p = 0.78). The 2-year relapse incidence (NFD, 21.1% vs. FD, 22.6%; p = 0.84) and non-relapse mortality (NRM) (NFD, 13.2% vs. FD, 17.7%; p = 0.33) were not significantly different. The 2-year overall survival (OS) (NFD, 71.8% vs. FD, 68.3%; p = 0.56), leukemia-free survival (LFS) (NFD, 65.7% vs. FD, 59.7%; p = 0.6) and graft-versus-host disease (GVHD)-free, relapse-free survival (GRFS) (NFD, 50.9% vs. FD, 47.8%; p = 0.69) also showed no significant differences. The two cohorts showed no difference in terms of cumulative day 180 grade II-IV, grade III-IV acute GVHD, 2-year cumulative incidences of chronic and extensive chronic GVHD. For HAPLO in patients with acute leukemia, NFD related donors could be equivalent substitutions when FD related donors are not available.
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Significance of Degree of HLA Disparity Using T-cell Replete Peripheral Blood Stem Cells From Haploidentical Donors With Posttransplantation Cyclophosphamide in AML in First Complete Hematologic Remission: A Study of the Acute Leukemia Working Party of the EBMT
Kharfan-Dabaja, M. A., Labopin, M., Ayala, E., Bazarbachi, A., Blaise, D., Vydra, J., Bramanti, S., Itälä-Remes, M., Schmid, C., Busca, A., et al
HemaSphere. 2023;7(7):e920
Abstract
Availability of haploidentical donors has broadened utilization of allogeneic hematopoietic cell transplantation (allo-HCT). Peripheral blood stem cells (PBSC) are being used with increased frequency in haploidentical allo-HCT. We evaluated extent of HLA disparity (2-3/8 versus 4/8 HLA antigen mismatches) on post-allograft outcomes when using T-cell replete PBSC from haploidentical donors for acute myeloid leukemia in first complete remission. Primary objectives entailed assessing cumulative incidence of grade 2-4 acute graft-versus-host disease (GVHD) and chronic GVHD (any grade). A total of 645 patients received a haploidentical allo-HCT from a donor with either 2-3 of 8 HLA antigen mismatches (n = 180) or with 4 of 8 HLA antigen mismatches (n = 465). Presence of 2-3 of 8 versus 4 of 8 HLA mismatches did not affect the incidence of acute GVHD (grade 2-4) and chronic GVHD (any grade). Overall survival (OS), leukemia-free survival (LFS) relapse incidence (RI), nonrelapse mortality and the composite endpoint of GVHD-free relapse-free survival were also similar among the groups. Pertaining to HLA-B leader matching effect, our analysis did not discern any difference in aforementioned post-allograft outcomes for this variable. However, in univariate analysis, absence of an antigen mismatch in HLA-DPB1 showed a trend for better OS. Notwithstanding inherent limitations associated with registry data, our results did not show an advantage of selecting a haploidentical donor with 2-3 of 8 HLA antigen mismatches over one with 4 of 8 HLA antigen mismatches when using PBSC as the cell source. Adverse cytogenetics remains a major adverse determinant of inferior OS and LFS and a higher RI. Using reduced-intensity conditioning yielded worse OS and LFS.
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Peripheral blood haploidentical hematopoietic cell transplantation for patients aged 70 years and over with acute myeloid leukemia or high-risk myelodysplastic syndrome
Harbi, S., Brac de la Perriere, L., Bouchacourt, B., Garciaz, S., Pagliardini, T., Calmels, B., Cecile, M., Lefloch, A. C., Hicheri, Y., Hospital, M. A., et al
Bone marrow transplantation. 2023
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Editor's Choice
Abstract
Haploidentical stem cell transplantation (Haplo-SCT) using non-myeloablative conditioning regimen (NMAC) has extended the feasibility of allogeneic transplantation, notably in older patients. However, there is few data specifically focusing on patients aged 70 years and over with AML and MDS. Thus the benefit of transplantation in this population is still debated. Here we report our single center experience of peripheral blood Haplo-SCT with NMAC and post-transplantation cyclophosphamide in AML and MDS patients aged 70 years and over. We analyzed 50 patients (27 AML, 23 MDS) with a median age of 72 years (70-77), 12/50 (24%) with active disease at Haplo-SCT. Cumulative incidence of grade 3-4 acute and moderate or severe chronic GVHD were 6% and 25%, respectively. Non-relapse mortality (NRM) at day +100 was 0%. NRM, relapse, PFS and OS at 3 years were 16%, 18%, 66%, and 69%, respectively. Among patients who were disease free at 2 years post Haplo-SCT, 88% are living without immunosuppressive treatment. Peripheral blood Haplo-SCT is feasible in selected AML/MDS patients over 70 years, without any early NRM. It produces long-term disease control and survival. Thus, age by itself should not be considered as a formal barrier to Haplo-SCT.
PICO Summary
Population
Adults aged 70 years and over with acute myeloid leukaemia or myelodysplastic syndromes, from a single centre in France (n=50)
Intervention
Haploidentical transplant with 12/50 (24%) having active disease at time of transplant
Comparison
None
Outcome
Cumulative incidence of grade 3-4 acute and moderate or severe chronic GVHD were 6% and 25%, respectively. Non-relapse mortality (NRM) at day +100 was 0%. NRM, relapse, PFS and OS at 3 years were 16%, 18%, 66%, and 69%, respectively. Among patients who were disease free at 2 years post Haplo-SCT, 88% are living without immunosuppressive treatment. Peripheral blood Haplo-SCT is feasible in selected AML/MDS patients over 70 years, without any early NRM.
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10.
Comparison of outcomes after unrelated double-unit cord blood and haploidentical peripheral blood stem cell transplantation in adults with acute myeloid leukemia, a study on behalf of Eurocord and ALWP-EBMT
Ruggeri, A., Galimard, J. E., Labopin, M., Rafii, H., Blaise, D., Ciceri, F., Diez-Martin, J. L., Cornelissen, J., Chevallier, P., Sanchez-Guijo, F., et al
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Unmanipulated haploidentical stem cell transplantation with post-transplant cyclophosphamide as graft-versus-host disease (GVHD) prophylaxis (Haplo-PTCY) and unrelated double-unit umbilical cord blood transplant (dUCBT) are feasible options to treat patients with high risk acute myeloid leukemia (AML). OBJECTIVES The aim of our study was to compare outcomes after dUCBT and Haplo-HCT using PBSC in adult patients with AML in complete remission (CR) transplanted in European Society for Blood and Marrow Transplantation (EBMT) affiliated centers. STUDY DESIGN In a population of adults with de novo AML in first or second CR, we compared outcomes after dUCBT (n=165) and after Haplo-PTCY PBSC (n=544) performed between January 2013 and December 2018. Patients receiving in-vivo antithymocyte globuline (ATG), Campath, or ex-vivo T-cell depletion were excluded. RESULTS Median follow-up was 33 months for Haplo-PTCY and 52 months for dUCBT. No statically significant differences were observed between the two approaches in grade-II-IV acute-GVHD (hazard ratio [HR]=1.31, p=0.18), and grade-III-IV (HR=1.17, p=0.56) or in chronic-GVHD (HR=0.86, p=0.48) or relapse (HR=1.07, p=0.77), non-relapse mortality (NRM; HR=0.94, p=0.77), leukemia-free survival (LFS; HR=0.99, p=0.95) and overall survival (OS; HR=0.99, p=0.97) when comparing dUCBT with Haplo-PTCY. Favourable cytogenetic risk was the only factor predictive of lower relapse incidence. Younger age at transplant was associated with lower NRM and higher LFS and OS. CONCLUSION Both dUCBT and Haplo-PTCY with PBSC can be considered as valid approaches for adult AML patients in complete remission. New strategies should be investigated in both settings to define the most appropriate conditioning regimen and potentially, to decrease relapse incidence and NRM through better immune reconstitution and optimal supportive care.
PICO Summary
Population
Adults with acute myeloid leukaemia having first allogeneic transplant, and reported to the EBMT or Eurocord registries (n=709)
Intervention
Double cord blood transplantation (dUCBT, n=165)
Comparison
Haploidentical transplant with post-transplant cyclophosphosphamide (Haplo-PTCY, n=544)
Outcome
No statistically significant differences were observed between the two approaches in grade-II-IV acute-GVHD (hazard ratio [HR]=1.31), and grade-III-IV (HR=1.17) or in chronic-GVHD (HR=0.86) or relapse (HR=1.07), non-relapse mortality (NRM; HR=0.94), leukemia-free survival (LFS; HR=0.99) and overall survival (OS; HR=0.99) when comparing dUCBT with Haplo-PTCY. Favourable cytogenetic risk was the only factor predictive of lower relapse incidence. Younger age at transplant was associated with lower NRM and higher LFS and OS.