Publications by authors named "Myriam Labopin"

302 Publications

Second allogeneic haematopoietic cell transplantation using HLA-matched unrelated versus T-cell replete haploidentical donor and survival in relapsed acute myeloid leukaemia.

Br J Haematol 2021 Apr 10. Epub 2021 Apr 10.

Department of Hematology, Hôpital Saint Antoine, Sorbonne University and INSERM UMRs 938, Paris, France.

Optimal donor choice for a second allogeneic haematopoietic cell transplant (allo-HCT) in relapsed acute myeloid leukaemia (AML) remains unknown. We compared overall survival (OS) using registry data from the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT) involving 455 adults who received a second allo-HCT from a human leucocyte antigen (HLA)-matched unrelated (MUD) (n = 320) or a haploidentical (n = 135) donor. Eligibility criteria required adults aged ≥18 years who received a second allo-HCT for treating AML relapse between 2005 and 2019. The primary end-point was OS. There was no statistically significant difference in the median (interquartile range) age between the groups, MUD 46 (35-58) versus haploidentical 44 (33-53) years (P = 0·07). The median OS was not different between the MUD and the haploidentical groups (10 vs. 11 months, P = 0·57). Similarly, the 2-year OS was 31% for the MUD and 29% for the haploidentical donor groups. The OS was worse if the procedure was performed with active AML [hazard ratio (HR) 1·42, 95% confidence interval (CI) 1·07-1·89; P = 0·02]. Conversely, a longer time from first allo-HCT to relapse (>13·2 months) was associated with better OS (HR 0·50, 95% CI 0·37-0·69; P < 0·0001). The results of the present analysis limit the ability to recommend one donor type over another when considering a second allo-HCT for relapsed AML. Our findings highlight that best OS is achieved when receiving the second allo-HCT in complete remission.
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http://dx.doi.org/10.1111/bjh.17426DOI Listing
April 2021

Improved Outcomes of Haploidentical Hematopoietic Cell Transplantation with Total Body Irradiation-Based Myeloablative Conditioning in Acute Lymphoblastic Leukemia.

Transplant Cell Ther 2021 Feb 11;27(2):171.e1-171.e8. Epub 2020 Dec 11.

Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France; European Society for Blood and Marrow Transplantation Paris Study Office/CEREST-TC, Paris, France.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI)-based versus chemotherapy (CT)-based MAC regimens in patients with acute lymphoblastic leukemia (ALL). The study included 427 patients who underwent first haplo-HCT with post-transplantation cyclophosphamide (PTCy), following TBI-based (n = 188; 44%) or CT-based (n = 239; 56%) MAC. The median patient age was 32 years. Fludarabine-TBI (72%) and thiotepa-busulfan-fludarabine (65%) were the most frequently used TBI- and CT-based regimens, respectively. In the TBI and CT cohorts, 2-year leukemia-free survival (LFS) was 45% versus 37% (P = .05), overall survival (OS) was 51% versus 47% (P = .18), relapse incidence (RI) was 34% versus 32% (P = .44), and nonrelapse mortality (NRM) was 21% versus 31% (P < .01). In the multivariate analysis, TBI was associated with lower NRM (hazard ratio [HR], 0.53; 95% confidence interval [CI], 0.33 to 0.86; P = .01), better LFS (HR, 0.71; 95% CI, 0.52 to 0.98; P =.04), and increased risk for grade II-IV acute graft-versus-host disease (GVHD) (HR, 1.59; 95% CI, 1.08 to 2.34; P = .02) compared with CT-based MAC. The type of conditioning regimen did not impact RI, chronic GVHD, OS, or GVHD-free, relapse-free survival after adjusting for transplantation-related variables. TBI-based MAC was associated with lower NRM and better LFS compared with CT-based MAC in patients with ALL after haplo-HCT/PTCy.
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http://dx.doi.org/10.1016/j.jtct.2020.10.008DOI Listing
February 2021

Outcome of haploidentical versus matched sibling donors in hematopoietic stem cell transplantation for adult patients with acute lymphoblastic leukemia: a study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

J Hematol Oncol 2021 Apr 1;14(1):53. Epub 2021 Apr 1.

Department of Haematology, Saint Antoine Hospital, INSERM UMR 938, Sorbonne University, Paris, France.

Background: Non-T-cell depleted haploidentical hematopoietic stem cell transplantation (HaploSCT) is being increasingly used in acute lymphoblastic leukemia (ALL) with improving patient outcomes. We have recently reported that outcomes of adult patients (pts) with ALL in complete remission (CR) receiving HaploSCT are comparable to unrelated donor transplants. We now compared HaploSCT and matched sibling donor (MSD) transplants in pts with ALL.

Aim: To assess transplantation outcomes of HaploSCT and MSD transplants in pts with ALL in CR.

Methods: We retrospectively analyzed adult patients (≥ 18 years) with ALL who underwent their first allogeneic stem cell transplantation (alloSCT) in first or second CR between 2012 and 2018, either from a T cell replete Haplo or MSD donor, and whose data were reported to the Acute Leukemia Working Party (ALWP) of the European Society for Blood and Marrow Transplantation (EBMT). Multivariate analysis (MVA) adjusting for differences between the groups was performed using the Cox proportional hazards regression model. Propensity score matching was also performed to reduce confounding effects.

Results: The analysis comprised 2304 patients: HaploSCT-413; MSD-1891. Median follow-up was 25 months. Median age was 37 (range 18-75) and 38 (18-76) years in HaploSCT and MSD, respectively. HaploSCT patients were transplanted more recently than those transplanted from MSD (2016 vs 2015, p < 0.0001). A higher rate of HaploSCT was in CR2 (33.4% vs 16.7%, p < 0.0001), respectively, and fewer received myeloablative conditioning (68% vs 83.2%, p < 0.0001). Cytomegalovirus (CMV) seropositivity was lower in HaploSCT patients (22% vs 28%, p = 0.01) and donors (27.1% vs 33%, p < 0.02), and a higher proportion of the HaploSCTs were performed using a bone marrow (BM) graft (46.2% vs 18.6%, p < 0.0001). The 2 groups did not differ with regard to gender, Karnofsky performance status score, ALL phenotype, Philadelphia chromosome (Ph) positivity and pre-alloSCT measurable residual disease (MRD). Graft versus host disease (GVHD) prophylaxis was mainly post-transplant cyclophosphamide (PTCy) based (92.7%) in the HaploSCT setting, while it was mostly pharmacologic in the setting of MSD (18.7% received ATG). Cumulative incidence of engraftment at day 60 was higher in MSD transplants compared to HaploSCT (98.7% vs 96.3%, p = 0.001), respectively. Day 180 incidence of acute (a) GVHD II-IV and III-IV was higher in HaploSCT vs. MSD: 36.3% vs 28.9% (p = 0.002 and 15.2% vs 10.5% (p = 0.005), respectively. Conversely, the 2-year chronic (c) GVHD and extensive cGVHD were 32% vs 38.8% (p = 0.009) and 11.9% vs 19.5% (p = 0.001) in HaploSCT vs MSD, respectively. Main causes of death were leukemia (31.8% vs 45%), infection (33.1% vs 19.7%) and GVHD (16.6% vs 19.7%) for HaploSCT and MSD, respectively. Two-year relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS) and GVHD-free, relapse-free survival (GRFS) were 26% vs 31.6%, 22.9% vs 13%, 51% vs 55.4%, 58.8% vs 67.4% and 40.6% vs 39% for HaploSCT and MSD, respectively. In the MVA, RI was significantly lower in HaploSCT in comparison with MSD, hazard ratio (HR) = 0.66 (95% CI 0.52-0.83, p = 0.004), while NRM was significantly higher, HR = 1.9 (95% CI 1.43-2.53, p < 0.0001). aGVHD grade II-IV and grade III-IV were higher in HaploSCT than in MSD HR = 1.53 (95% CI 1.23-1.9, p = 0.0002) and HR = 1.54 (95% CI 1.1-2.15, p = 0.011), respectively. Extensive cGVHD was lower in HaploSCT compared with MSD, HR = 0.61 (95% CI 0.43-0.88, p = 0.007), while total cGVHD did not differ significantly, HR = 0.94 (95% CI 0.74-1.18, p = 0.58). LFS, OS and GRFS did not differ significantly between the 2 transplant groups, HR = 0.96 (95% CI 0.81-1.14, p = 0.66); HR = 1.18 (95% CI 0.96-1.43, p = 0.11) and HR = 0.93 (95% CI 0.79-1.09, p = 0.37), respectively. These results were confirmed in a matched-pair analysis.

Conclusions: Outcomes of adult patients with ALL in CR receiving alloSCT from haploidentical donors are not significantly different from those receiving transplants from MSD in terms of LFS, OS and GRFS.
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http://dx.doi.org/10.1186/s13045-021-01065-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017786PMC
April 2021

Outcome of T-cell-replete haploidentical stem cell transplantation improves with time in adults with acute lymphoblastic leukemia: A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Cancer 2021 Mar 19. Epub 2021 Mar 19.

European Society for Blood and Marrow Transplantation Acute Leukemia Working Party, St Anthony Hospital, Paris, France.

Background: The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with posttransplantation cyclophosphamide prophylaxis is gaining traction in patients with acute lymphoblastic leukemia (ALL).

Methods: The Acute Leukemia Working Party/European Society for Blood and Marrow Transplantation registry was used to evaluate the outcomes of adult patients with ALL who underwent haplo-HCT during 2011 through 2015 and compared them with the outcomes of those who underwent transplantation during 2016 through 2018.

Results: The analysis consisted of 195 patients, including 79 who underwent transplantation during 2011 through 2015 and 116 who underwent transplantation during 2016 through 2018. Overall, the 2-year leukemia-free survival and relapse incidence rates were 56.5% and 21%, respectively. The 100-day incidence of grade 2 through 4 acute graft-vs-host disease (GVHD) was 34.5%. The rates of nonrelapse mortality (NRM) and overall survival (OS) were 22.5% and 64.7%, respectively. Patients who underwent transplantation during 2016 through 2018 experienced improved rates of leukemia-free survival (64.9% vs 47.3%; P = .019) and OS (75.5% vs 53.5%; P = .006). Patients who underwent transplantation during 2016 through 2018 developed more grade 2 through 4 acute GVHD (42% vs 26.4%; P = .047). The incidence of relapse, GVHD-free/relapse-free survival, grade 3 and 4 acute GVHD, chronic GVHD, and extensive chronic GVHD did not differ significantly between groups. In multivariate analysis, more recently transplanted patients had a significantly reduced risk of NRM (hazard ratio, 0.44; 95% CI, 0.22-0.89; P = .022) and improved OS (hazard ratio, 0.47; 95% CI, 0.26-0.86; P = .014). A comparable analysis of patients who had acute myeloid leukemia during the same timeframes did not reveal any statistically significant differences in any outcomes.

Conclusions: The outcome of adult patients with ALL who receive posttransplant cyclophosphamide has improved over time, with an impressive 2-year OS of 75% and, most recently, an NRM rate of only 17%.
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http://dx.doi.org/10.1002/cncr.33522DOI Listing
March 2021

Prognostic factors for neutrophil engraftment after haploidentical cell transplantation with PT-Cy in patients with acute myeloid leukemia in complete remission, on behalf of the ALWP-EBMT.

Bone Marrow Transplant 2021 Mar 5. Epub 2021 Mar 5.

Department of Haematology and EBMT Paris Study Office/CEREST-TC, Saint Antoine Hospital, Paris, France.

The use of haplo-HCT with posttransplant cyclophosphamide (PT-Cy) is a new standard in the treatment of hematological diseases. A paucity of data exists on risk factors for engraftment failure in haplo-HCT with PT-Cy. We analyzed 1939 adults with acute myeloid leukemia (AML) who received a first haplo-HCT from 2010 to 2019. Status at haplo-HCT was first complete remission (CR1) in 72.5% of patients, secondary AML was reported in 9.9%. Median follow-up was 24.4 months and median age at haplo-HCT was 51 years. Stem cell source was bone marrow (BM) in 42% and peripheral blood stem cell (PBSC) in 58%, and 64% of patients received a myeloablative conditioning (MAC) regimen. Cumulative incidence of primary graft failure (GF) was 6%; GF was reported in 110 patients and 54 died before day +30 with no sign of cell recovery. Overall, 33 patients underwent a second HCT in a median time of 45 days and 13 were alive at last follow-up, the 2-year overall survival (OS) after second HCT being 32.4%. In multivariate analysis, factors independently associated with the risk of nonengraftment were: secondary AML (HR 1.30, p = 0.003), use of RIC (HR 1.22, p < 0.001), and use of BM (HR 1.21, p < 0.001). At 2 years, leukemia-free survival (LFS) and OS for the entire population was 55.2% (95% CI: 52.6-57.6) and 60.9% (95% CI: 58.4-63.3), respectively. Incidence of GF after haplo-HCT with PT-Cy is lower than reported T-cell-depleted haplo-HCT. Optimization of conditioning regimen and graft source should be considered for reducing the risk of GF in haplo-HCT recipients using PT-Cy.
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http://dx.doi.org/10.1038/s41409-021-01248-3DOI Listing
March 2021

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.

Lancet Haematol 2021 Mar;8(3):e205-e215

Hematology Division, Chaim Sheba Medical Center, Tel Aviv University, Ramat Gan, Israel.

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.
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http://dx.doi.org/10.1016/S2352-3026(20)30394-XDOI Listing
March 2021

Allogeneic hematopoietic stem cell transplantation for adult patients with t(4;11)(q21;q23) KMT2A/AFF1 B-cell precursor acute lymphoblastic leukemia in first complete remission: impact of pretransplant measurable residual disease (MRD) status. An analysis from the Acute Leukemia Working Party of the EBMT.

Leukemia 2021 Feb 4. Epub 2021 Feb 4.

EBMT Paris Study Office, Department of Hematology and Cell Therapy, Hôpital Saint-Antoine, Paris, France.

Adult B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with t(4;11)(q21;q23);KMT2A/AFF1 is a poor-prognosis entity. This registry-based study was aimed to analyze outcome of patients with t(4;11) BCP-ALL treated with allogeneic hematopoietic stem cell transplantation (alloHSCT) in first complete remission (CR1) between 2000 and 2017, focusing on the impact of measurable residual disease (MRD) at the time of transplant. Among 151 patients (median age, 38) allotransplanted from either HLA-matched siblings or unrelated donors, leukemia-free survival (LFS) and overall survival (OS) at 2 years were 51% and 60%, whereas relapse incidence (RI) and non-relapse mortality (NRM) were 30% and 20%, respectively. These results were comparable to a cohort of contemporary patients with diploid normal karyotype (NK) BCP-ALL with equivalent inclusion criteria (n = 567). Among patients with evaluable MRD pre-alloHSCT, a negative status was the strongest beneficial factor influencing LFS (hazard ratio [HR] = 0.2, p < 0.001), OS (HR = 0.14, p < 0.001), RI (HR = 0.23, p = 0.001), and NRM (HR = 0.16, p = 0.002), with a similar outcome to MRD-negative NK BCP-ALL patients. In contrast, among patients with detectable pretransplant MRD, outcome in t(4;11) BCP-ALL was inferior to NK BCP-ALL (LFS: 27% vs. 50%, p = 0.02). These results support indication of alloHSCT in CR1 for t(4;11) BCP-ALL patients, provided a negative MRD status is achieved. Conversely, pre-alloHSCT additional therapy is warranted in MRD-positive patients.
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http://dx.doi.org/10.1038/s41375-021-01135-2DOI Listing
February 2021

Systematic reviews in hematopoietic cell transplantation and cellular therapy: considerations and guidance from the American Society for Transplantation and Cellular Therapy, European Society for Blood and Marrow Transplantation, and the Center for International Blood and Marrow Transplant Research late effects and quality of life working committee.

Bone Marrow Transplant 2021 Apr 29;56(4):786-797. Epub 2021 Jan 29.

Center for International Blood and Marrow Transplant Research, Milwaukee, WI, USA.

Systematic reviews apply rigorous methodologies to address a pre-specified, clearly formulated clinical research question. The conclusion that results is often cited to more robustly inform decision-making by clinicians, third-party payers and managed care organizations about the clinical question of interest. While systematic reviews provide a rigorous standard, they may be unfeasible when the task is to create general disease-focused guidelines comprised of multiple clinical practice questions versus a single major clinical practice question. Collaborating transplantation and cellular therapy societal committees also recognize that the quantity and or quality of reference sources may be insufficient for a meaningful systematic review. As the conduct of systematic reviews has evolved over time in terms of grading systems, reporting requirements and use of technology, here we provide current guidance in methodologies, resources for reviewers, and approaches to overcome challenges in conducting systematic reviews in transplantation and cellular therapy.
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http://dx.doi.org/10.1038/s41409-020-01199-1DOI Listing
April 2021

Hematopoietic stem cell transplantation for adults with relapsed acute promyelocytic leukemia in second complete remission.

Bone Marrow Transplant 2020 Dec 15. Epub 2020 Dec 15.

Hôpital Saint Antoine, Sorbonne University, Department of Hematology, Paris, France.

We retrospectively compared outcomes of a large series of adult patients with APL in CR2 receiving alloHSCT (n = 228) or autoHSCT (n = 341) reported to the European Society for Blood and Marrow Transplantation from January 2004 to December 2018. The 2-year cumulative incidence of non-relapse mortality was significantly higher for alloHSCT 17.3% (95% CI 12.5-22.8) compared with autoHSCT 2.7% (95% CI 1.2-5) (p = 0.001), while differences in relapse rate were not significant (28% versus 22.9%; p = 0.28). Leukemia-free survival (LFS) and overall survival (OS) favored autoHSCT with 74.5% (95% CI 69-79.2) and 82.4% (95% CI 77.3-86.5) compared with alloHSCT with 54.7% (95% CI 47.5-61.3) (p = 0.001) and 64.3% (95% CI 57.2-70.6), respectively (p = 0.001 and p = 0.001). Multivariable analysis showed significantly worse LFS after alloHSCT (HR 0.49; 95% CI 0.37-0.67; p < 0.0001), older age (p = 0.001), and shorter time from diagnosis to transplant (p = 0.00015). Similar results were obtained for OS. The study shows that autoHSCT resulted in better survival outcomes (LFS and OS) for APL in CR2. These results were mainly due to reduced NRM in the autoHSCT as compared to alloHSCT.
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http://dx.doi.org/10.1038/s41409-020-01162-0DOI Listing
December 2020

Second- and third-generation tyrosine kinase inhibitors for Philadelphia-positive adult acute lymphoblastic leukemia relapsing post allogeneic stem cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party.

Bone Marrow Transplant 2020 Dec 9. Epub 2020 Dec 9.

Service d'Hématologie et de Thérapie cellulaire, Hôpital Saint Antoine, ALWP Office (EBMT), Paris, France.

Second- and third-generation tyrosine kinase inhibitors (TKI) play an important role in the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, data on feasibility and efficacy of using these drugs for persisting or relapsed Ph + ALL after allogeneic stem cell transplantation (alloSCT) are scarce. Based on the EBMT Acute Leukemia Working Party registry, we evaluated the use of second-/third-generation TKI in 140 patients with Ph + ALL, suffering from measurable residual disease (MRD, n = 6), molecular relapse (MRel, n = 23), or hematological relapse (HRel, n = 111) following alloSCT. Treatment included dasatinib in 104, nilotinib in 18, or ponatinib in 18 patients. Forty-nine patients received TKI monotherapy, while 91 received additional treatment. Toxicity of second-/third-generation TKI post alloSCT was comparable to pretransplant use and could be managed with dose reduction or temporary discontinuation. Response rates were 71% (overall) and 61% (following TKI monotherapy). For the entire cohort, 2- and 5-year overall survival (OS) was 49% and 33%, respectively. OS was comparable among patients treated for persisting MRD/MRel and HRel. Among patients treated with TKI monotherapy, 2- and 5-year OS was 38% and 33%, respectively. The data underscore that second-/third-generation TKI are important compounds for the management of active Ph + ALL post alloSCT.
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http://dx.doi.org/10.1038/s41409-020-01173-xDOI Listing
December 2020

Comparison of mycophenolate mofetil and calcineurin inhibitor versus calcineurin inhibitor-based graft-versus-host-disease prophylaxis for matched unrelated donor transplant in acute myeloid leukemia. A study from the ALWP of the EBMT.

Bone Marrow Transplant 2020 Nov 28. Epub 2020 Nov 28.

Sorbonne University, Service d'Hématologie Clinique et Thérapie cellulaire, Hôpital Saint-Antoine, INSERM UMRs 938, Paris, France.

The association of Cyclosporine A (CsA) and mycophenolate mofetil (MMF) has increased in the setting of reduced intensity conditioning (RIC). Nevertheless, the use of CsA or CsA+MMF has not been reported in a large and uniform cohort. We analyzed 497 patients with acute myeloid leukemia in complete remission (CR) who underwent matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). All patients received a fludarabine busulfan RIC regimen and anti-thymocyte globulin (ATG) with either CsA alone or in combination with MMF. The cumulative incidence (CI) of grade II-IV acute GvHD was 27% (95% CI 21-33%) for CsA and 33% (95% CI 27-38%) for CsA+MMF (p = 0.25). The 2-year CI of chronic GvHD was 38% (95% CI 31-45%) and 33% (95% CI 28-39%) for the CsA and the CsA+MMF group, respectively (p = 0.26). On multivariate analysis, no statistically significant differences with respect to relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), acute and chronic GvHD were found between the two groups, also when conducting a subgroup analysis in peripheral blood stem cells (PBSC) recipients. Our results support the importance of randomized trial to identify patients who could benefit from the addition of MMF in MUD HSCT.
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http://dx.doi.org/10.1038/s41409-020-01155-zDOI Listing
November 2020

Allogeneic stem cell transplant in patients with acute myeloid leukemia and karnofsky performance status score less than or equal to 80%: A study from the acute leukemia working party of the European Society for Blood and Marrow Transplantation (EBMT).

Cancer Med 2021 Jan 26;10(1):23-33. Epub 2020 Nov 26.

EBMT Paris Study Office, Saint Antoine Hospital, Paris, France.

Limited data are currently available on the outcome of patients with acute myeloid leukemia (AML) undergoing allogeneic stem cell transplantation (allo-SCT) with a reduced performance status. We herein present the results of a registry study on 2,936 AML patients undergoing allo-SCT in first remission (CR1) with a Karnofsky Performance Status (KPS) score less than or equal to 80%. Two-year leukemia-free survival (LFS), overall survival (OS) and graft-versus-host disease (GVHD)-free, and relapse-free survival (GRFS) rates were 54%, 59%, and 41%, respectively. In multivariable analysis, patients with a KPS score = 80% had lower non-relapse mortality (NRM) and superior OS in comparison to patients with a KPS score <80% (p < 0.001). In the subgroup of patients with a KPS score =80%, a reduced-intensity conditioning (RIC) regimen was associated with an increased risk of relapse (p = 0.002) and lower GRFS (p < 0.001) compared to myeloablative conditioning (MAC). Differently, in patients with a KPS score <80%, a RIC regimen resulted in lower NRM (p < 0.001), whereas relapse incidence did not differ, thus leading to an improved GRFS (p = 0.008) as compared to MAC. A transplant from a matched sibling donor (MSD) was associated with a reduced incidence of grade III-IV acute GVHD (p < 0.01) and NRM (p < 0.01) in comparison to other donor types. In conclusion, allo-SCT appears feasible in AML patients with a jeopardized KPS score. Survival is significantly affected by the conditioning intensity, which should be adjusted according to the severity of KPS impairment.
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http://dx.doi.org/10.1002/cam4.3593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826477PMC
January 2021

Allogeneic HCT for adults with B-cell precursor acute lymphoblastic leukemia harboring IKZF1 gene mutations. A study by the Acute Leukemia Working Party of the EBMT.

Bone Marrow Transplant 2020 Nov 25. Epub 2020 Nov 25.

Department of Hematology, Hospital Saint Antoine, Paris, France.

The presence of IKZF1 gene mutations is associated with poor prognosis of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). The goal of this retrospective study was to evaluate outcome of allogeneic hematopoietic cell transplantation (allo-HCT) in this population. Ninety-five patients transplanted in first (n = 75) or second (n = 20) complete remission (CR) from either HLA-matched sibling (n = 32), unrelated (n = 47) or haploidentical (n = 16) donor were included in the analysis. The probabilities of the overall survival (OS) and leukemia-free survival (LFS) at 2 years were 55% and 47%, respectively. Relapse incidence (RI) was 32% while non-relapse mortality (NRM), 21%. The incidence of grade II-IV acute graft-versus-host disease (GVHD) and chronic GVHD was 34% and 30%, respectively. The probability of GVHD and relapse-free survival (GRFS) was 35%. In a multivariate analysis positive minimal residual disease (MRD) status was associated with decreased chance of LFS (HR = 3.15, p = 0.004) and OS (HR = 2.37, p = 0.049) as well as increased risk of relapse (HR = 5.87, p = 0.003). Disease stage (CR2 vs. CR1) affected all, LFS, OS, GRFS, RI, and NRM. Results of allo-HCT for patients with BCP-ALL and IKZF1 mutations are generally improving, however, individuals with detectable MRD have poor prognosis and require additional intervention prior to transplantation.
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http://dx.doi.org/10.1038/s41409-020-01139-zDOI Listing
November 2020

Underdiagnosed veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) as a major cause of multi-organ failure in acute leukemia transplant patients: an analysis from the EBMT Acute Leukemia Working Party.

Bone Marrow Transplant 2021 Apr 18;56(4):917-927. Epub 2020 Nov 18.

Sorbonne University, Department of Clinical Hematology and Cellular Therapy, Saint Antoine Hospital, INSERM UMR 938, Paris, France.

Allogeneic hematopoietic cell transplantation (alloHCT) is a complex, potentially fatal therapy featuring a myriad of complications. Triggering event(s) of such complications vary significantly, but often a so-called "multi-organ failure" (MOF) is reported as the leading cause of death. The identification of the exact trigger of MOF is critical towards early and disease-specific intervention to improve outcome. We examined data from 202 alloHCT patients reported to have died of MOF from the EBMT registry aiming to determine their exact cause of death focusing on veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) due to its life-threatening, often difficult to capture yet preventable nature. We identified a total of 70 patients (35%) for whom VOD/SOS could be considered as trigger for MOF and leading cause of death, among which 48 (69%) were previously undiagnosed. Multivariate analysis highlighted history of hepatic comorbidity or gentuzumab use and disease status beyond CR1 as the only significant factors predictive of VOD/SOS incidence (OR = 6.6; p = 0.001 and OR = 3.3; p = 0.004 respectively). VOD/SOS-related MOF was widely under-reported, accounting for 27% of deaths attributed to MOF of unknown origin without a previous VOD/SOS diagnosis. Our results suggest most missed cases developed late VOD/SOS beyond 21 days post-alloHCT, highlighting the importance of the newly revised EBMT criteria.
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http://dx.doi.org/10.1038/s41409-020-01135-3DOI Listing
April 2021

Comparison of Haploidentical Bone Marrow versus Matched Unrelated Donor Peripheral Blood Stem Cell Transplantation with Posttransplant Cyclophosphamide in Patients with Acute Leukemia.

Clin Cancer Res 2021 Feb 4;27(3):843-851. Epub 2020 Nov 4.

Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, AP-HP, Sorbonne University, and INSERM UMRs 938, Paris, France.

Purpose: Posttransplant cyclophosphamide (PTCy) is increasingly being utilized as a principle GvHD prophylaxis strategy in allogeneic hematopoietic cell transplantation (allo-HCT). A haploidentical (haplo) or matched unrelated donor (UD) is a valid option 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, = 401) versus UD mobilized peripheral blood stem cells (UD-PB, = 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 ( < 0.01). Myeloablative conditioning was used in 64.6% and 42.7% of haplo-BM and UD-PB patients, respectively ( < 0.01). Cumulative incidence of neutrophil engraftment at day 30 was 87% in haplo-BM versus 94% in UD-PB, respectively ( = 0.21). In the multivariate analysis, the risk of grade 2-4 acute GvHD (HR = 0.53, = 0.01) and chronic GvHD (HR = 0.50, = 0.02) was significantly lower in the haplo-BM group compared with the UD-PB group. There was no significant difference between the study groups with respect to relapse incidence, nonrelapse mortality, leukemia-fee survival, overall survival, or GvHD-free and relapse-free survival.

Conclusions: The use of a haplo donor with a BM graft resulted in a lower incidence of GvHD compared with a UD-PB stem cell graft in the setting of PTCy for patients with acute leukemia. However, differences in GvHD did not translate into a difference in survival outcomes. Based upon these data, UD-PB or haplo-BM should be considered equally acceptable sources for allo-HCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-2809DOI Listing
February 2021

Post-transplantation cyclophosphamide versus antithymocyte globulin in patients with acute myeloid leukemia undergoing allogeneic stem cell transplantation from HLA-identical sibling donors: A retrospective analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Cancer 2021 Jan 29;127(2):209-218. Epub 2020 Oct 29.

Hematology Department, Hôpital Saint Antoine, Service d'Hématologie et Thérapie Cellulaire, Paris, France.

Background: Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Addition of antithymocyte globulin (ATG) or post-transplantation cyclophosphamide (PTCY) to standard immunosuppressive agents reduces GVHD in different donor settings.

Methods: We compared the outcomes of adults with acute myeloid leukemia undergoing allo-HSCT from HLA-identical sibling donors after the use of PTCY (n = 197) or ATG (n = 1913).

Results: Patients in the PTCY group were younger than those in the ATG group (median age, 47 vs 54 years; P < .01). Peripheral blood was the most frequently used stem cell source, being significantly more frequent in the ATG group than in the PTCY group (95% vs 70% P < .01). The conditioning regimen was more frequently myeloablative in the PTCY group than in the ATG group (59% vs 48%; P < .01). Time to neutrophil engraftment was shorter in the ATG group than in the PTCY group (17 vs 20 days; P < .01). No differences were observed according to the other transplantation outcomes, except for chronic GVHD of all grades and extensive chronic GVHD at 2 years, which were significantly lower in the ATG group compared with the PTCY group (P < .02).

Conclusion: PTCY is feasible in an HLA-identical sibling setting, and despite similar outcomes, ATG may be associated with lower incidence of chronic GVHD.
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http://dx.doi.org/10.1002/cncr.33255DOI Listing
January 2021

Haematopoietic stem cell transplantation in adult soft-tissue sarcoma: an analysis from the European Society for Blood and Marrow Transplantation.

ESMO Open 2020 10;5(5):e000860

Internal Medicine and Medical Therapy, Università degli Studi di Pavia, Pavia, Lombardia, Italy.

Background: The role of high-dose chemotherapy with autologous stem cell transplantation (ASCT) in the treatment of soft-tissue sarcoma (STS) remains an unsettled issue. Prospective clinical trials failed to prove a benefit of the procedure but were limited by small and heterogeneous patient cohorts. Thus, it is unknown if ASCT may be a valuable treatment option in specific patient subgroups.

Methods: The purpose of this study was to investigate the value of ASCT according to histological subtype in STS patients who were registered in the European Society for Blood and Marrow Transplantation database between 1996 and 2016.

Results: Median progression-free (PFS) and overall survival (OS) in the entire cohort of 338 patients were 8.3 and 19.8 months, respectively, and PFS and OS at 5 years were 13% and 25%, respectively. Analysis of outcomes in different subgroups showed that younger age, better remission status before transplantation and melphalan-based preparative regimen were predictive of benefit from ASCT, whereas histology and grading had no statistically significant impact.

Conclusions: Outcomes after ASCT compared favorably to those of recent trials on conventional chemotherapies and targeted therapies in STS, including histology-tailored approaches. ASCT, thus, should be reinvestigated in clinical trials focusing on defined patient subgroups.
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http://dx.doi.org/10.1136/esmoopen-2020-000860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590345PMC
October 2020

Evaluation of six different types of sequential conditioning regimens for allogeneic stem cell transplantation in relapsed/refractory acute myelogenous leukemia - a study of the Acute Leukemia Working Party of the EBMT.

Leuk Lymphoma 2021 02 11;62(2):399-409. Epub 2020 Oct 11.

Department of Hematology and Cell Therapy, Hopital Saint-Antoine, Paris, France.

The Acute Leukemia Working Party (ALWP) of the EBMT assessed the outcome of allogeneic stem cell transplantation (alloSCT) in patients with relapsed/refractory AML (r/rAML) evaluating six sequential conditioning regimens (SR) groups. A total of 2132 patients were included. LFS at 2 years was 28.9%, 33.6%, 35.3%, 20.6%, 24.4%, and 27% for the FLAMSA-TBI4, FLAMSA-Chemo, Mel-Flu-TBI8, Mel-Treo-Flu, Thio-ETO-Cy-Bu2-Flu, and Clo-ARAC-(Bu2/TBI4)-Cy groups, respectively. In patients <55 years of age Mel-Flu-TBI8 had the best LFS, which was statistically significant only in comparison to the Mel-Treo-Flu group, while in patients ≥55 years LFS was best with FLAMSA-Chemo without significant differences compared to FLAMSA-TBI4 and Mel-Flu-TBI8. Furthermore, best NRM rates were obtained with the two FLAMSA regimens groups. Our study suggests that in younger (<55 years) patients a more intense regimen might be used whereas in older (≥55 years) patients the focus might be more on tolerability.
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http://dx.doi.org/10.1080/10428194.2020.1827248DOI Listing
February 2021

Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia.

Bone Marrow Transplant 2021 Mar 6;56(3):622-634. Epub 2020 Oct 6.

Department of Haematology and EBMT Paris Study Office/CEREST-TC, Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France.

We compared transplant outcomes of 708 acute myeloid leukemia (AML) patients receiving haploidentical allogeneic hematopoietic-cell transplantation using thiotepa/busulfan/fludarabine (TBF) conditioning with posttransplant cyclophosphamide (ptCy), to 2083 patients receiving matched unrelated donor (MUD) transplantation using fludarabine/busulfan (FB) conditioning and in vivo T-cell depletion. For intermediate cytogenetic risk AML transplanted in first complete remission (CR1), multivariate analysis revealed that haplo-TBF significantly increased nonrelapse mortality (NRM) (HR 2.1; p = 0.0006) but did not affect relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), or graft-versus-host disease-free, relapse-free survival (GRFS). For high cytogenetic risk AML transplanted in CR1, haplo-TBF significantly increased NRM (HR = 2.7; p = 0.02), decreased RI (HR = 0.45; p = 0.03) but had no influence on LFS, OS, or GRFS. For AML transplanted in CR2, haplo-TBF significantly increased NRM (HR = 2.36; p = 0.008), decreased RI (HR = 0.38; p = 0.005), but had no influence on LFS, OS, or GRFS. Finally, for AML patients transplanted with active disease, haplo-TBF had no influence on transplant outcomes. In conclusion, compared to MUD-FB, haplo-TBF increased NRM, reduced RI in high-risk AML in CR, resulting in similar LFS, OS, and GRFS. These results comparing two different approaches support the use of a haploidentical family donor for high-risk AML patients lacking a matched sibling donor.
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http://dx.doi.org/10.1038/s41409-020-01074-zDOI Listing
March 2021

High-dose post-transplant cyclophosphamide impairs γδ T-cell reconstitution after haploidentical haematopoietic stem cell transplantation using low-dose antithymocyte globulin and peripheral blood stem cell graft.

Clin Transl Immunology 2020 23;9(9):e1171. Epub 2020 Sep 23.

INSERM, Centre de Recherche Saint-Antoine (CRSA) Sorbonne Université Paris France.

Objectives: Haploidentical haematopoietic cell transplantation (Haplo-HCT) using peripheral blood stem cell (PBSC) grafts and post-transplant cyclophosphamide (PTCy) is being increasingly used; however, data on immunological reconstitution (IR) are still scarce.

Methods: This retrospective study evaluated T-cell immunological reconstitution in 106 adult patients who underwent allogeneic haematopoietic cell transplantation for haematologic malignancies between 2013 and 2016.

Results: At D30, while conventional T cells reached similar median counts in Haplo-HCT recipients ( = 19) and controls ( = 87), γδ and Vδ2 T-cell median counts were significantly lower in Haplo-HCT recipients and it persists at least until D360 for Vδ2 T cells. PTCy induces a significant reduction in early γδ and Vδ2 T-cell proliferation at D  7. At one year, the rate of increase in Epstein-Barr virus (EBV) viral load was significantly higher in Haplo-HCT recipients as compared to controls (61% versus 34%,  = 0.02). In multivariate analysis, a higher γδ T-cell count (> 4.63 μL) at D30 was the only independent parameter significantly associated with a reduced risk of increase in EBV viral load (RR 0.34; 95% CI, 0.15-0.76,  = 0.009).

Conclusion: Immunological reconstitution of γδ T cells is significantly delayed after Haplo-HCT using PTCy and low-dose ATG and is associated with an increased risk of increase in EBV viral load.
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http://dx.doi.org/10.1002/cti2.1171DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511259PMC
September 2020

Evaluation of Trends and Prognosis Over Time in Patients with AML Relapsing After Allogeneic Hematopoietic Cell Transplant Reveals Improved Survival for Young Patients in Recent Years.

Clin Cancer Res 2020 Dec 28;26(24):6475-6482. Epub 2020 Sep 28.

Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, INSERM UMR 938 and Sorbonne University, Paris, France.

Purpose: Relapsed acute myeloid leukemia (AML) post allogeneic hematopoietic cell transplantation (allo-HCT) has a dismal prognosis.

Experimental Design: To assess prognosis of patients with recurrent AML post allo-HCT over time, we analyzed European Society for Blood and Marrow Transplantation registry data of 8,162 adult patients with AML who relapsed between 2000 and 2018 after allo-HCT performed in first complete remission from matched sibling, unrelated, or haploidentical donors.

Results: The 2-year overall survival (OS) rate from relapse was 17%. For 3,630 patients, <50 years of age, the 2-year OS continuously increased from 16% between 2000 and 2004 to 18% for 2005-2009, to 21% for 2010-2014, and to 26% for 2015-2018 ( = 0.001). Improvement over time was noted both after relapse within and beyond 6 months from allo-HCT. On multivariate analysis among patients <50 years of age, OS was positively affected by a later year of relapse (baseline: 2000-2004; HR, 0.82; < 0.02 for 2010-2014 and HR, 0.72; = 0.0002 for 2015-2018), good performance status, favorable cytogenetics, and longer time from transplant to relapse, but negatively affected by increasing age. In contrast, among 4,532 patients, >50 years of age, the year of relapse had no influence on OS (16% for 2000-2004 and 14% for 2015-2018; = 0.56). Regarding treatment, encouraging results were observed after second allo-HCT, which was performed within 2 years after relapse in 17% of the entire cohort, resulting in a 2-year OS of 30.7%.

Conclusions: Outcome after posttransplant relapse among younger patients has improved significantly in recent years, likely reflecting, among other factors, the efficacy of posttransplant salvage including second allo-HCT.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-3134DOI Listing
December 2020

Nutritional support in stem cell transplantation programs: Results from a multicenter survey of nurses on behalf of the Nurses Group and Transplant Complications Working Party of the European Society for Blood and Marrow Transplantation and the Gruppo Italiano Trapianto di Midollo Osseo.

Nutrition 2020 Nov - Dec;79-80:110998. Epub 2020 Aug 28.

Division of Hemato-Oncology, European Institute of Oncology IRCCS, Milan, Italy.

Objectives: Malnutrition in patients undergoing hematopoietic stem cell transplant (HSCT) can develop rapidly without appropriate nutritional support and affect morbidity and mortality. Guidance to monitor and manage nutrition status is described within the literature; however, whether this is applied in clinical practice is unclear.

Methods: This paper describes a cross-sectional survey to explore current practice approaches in nutrition support management and adherence to international guidelines.

Results: A total of 108 nurses from 108 centers across 16 countries replied to the questionnaire. A significant variation was observed regarding the availability of documents supporting the monitoring and management of nutrition status, application of recommendations, and nutritional practices.

Discussion: The findings revealed that country was the most important factor influencing the differences in practice; however, significant differences were also observed based on patient age group (pediatrics vs. adults), department composition (hematology + HSCT unit vs. HSCT unit alone), and availability of nutrition health care professionals. Behavioral differences regarding nutritional practice approaches could be indicative of differences in knowledge or subject awareness, as well as a reflection of diversity across health care system policies.

Conclusions: Guideline dissemination and raising awareness through educational campaigns are suggested approaches to improve health care professionals' knowledge and sensitivity to this important topic.
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http://dx.doi.org/10.1016/j.nut.2020.110998DOI Listing
August 2020

The impact of cytogenetic risk on the outcomes of allogeneic hematopoietic cell transplantation in patients with relapsed/refractory acute myeloid leukemia: On behalf of the acute leukemia working party (ALWP) of the European group for blood and marrow transplantation (EBMT).

Am J Hematol 2021 01 8;96(1):40-50. Epub 2020 Oct 8.

Hematology Department, Hôpital Saint Antoine, Service d'Hématologie et Thérapie Cellulaire, Paris, France.

Karyotypic analysis at time of diagnosis has an important value in determining initial response to treatment, remission duration and overall survival (OS) in acute myeloid leukemia (AML). Less is known about its value before allogeneic hematopoietic cell transplantation (allo-HCT) in patients transplanted with active disease, either relapsed or primary refractory (Rel-Ref) AML. We explored the impact of cytogenetic risk (stratification according to MRC-UK) in 2089 patients with either Ref (n = 972) or Rel AML (n = 1117) transplanted during the period 2000-2017. Overall, 154 patients had a favorable risk, 1283 had an intermediate risk and 652 had an adverse cytogenetic risk. Median follow-up was 49 months. Compared to the favorable risk group, intermediate and adverse risk patients were associated with worse leukemia-free survival and OS and also with a higher incidence of relapse. In a subgroup analysis of patients in the intermediate risk group harboring Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD), this remained an important prognostic factor, being associated with worse outcomes. When analyzing patients according to the intensity of the conditioning regimen, no differences were observed for the main transplant outcomes. In conclusion, in patients diagnosed with AML and transplanted with active disease, karyotype remains an important prognostic factor, allowing splitting patients into different risk groups according to their cytogenetics. Similarly, FLT3-ITD mutation also remains a negative prognostic factor in this population.
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http://dx.doi.org/10.1002/ajh.26000DOI Listing
January 2021

Total body irradiation + fludarabine compared to busulfan + fludarabine as "reduced-toxicity conditioning" for patients with acute myeloid leukemia treated with allogeneic hematopoietic cell transplantation in first complete remission: a study by the Acute Leukemia Working Party of the EBMT.

Bone Marrow Transplant 2021 Feb 5;56(2):481-491. Epub 2020 Sep 5.

Department of Hematology, Hospital Saint Antoine, Paris, France.

The optimal conditioning for patients with acute myeloid leukemia in first complete remission treated with allogeneic hematopoietic cell transplantation (allo-HCT) has not been defined so far. In this retrospective study, we compared two "reduced-toxicity" regimens: intravenous busulfan at a total dose of 9.6 mg/kg (3 days) + fludarabine (Bu3/Flu) and total body irradiation at a dose of 8 Gy + fludarabine (TBI8Gy/Flu). In the entire study cohort (n = 518), the probabilities of overall survival (OS), leukemia-free survival (LFS), relapse and non-relapse mortality (NRM) at 2 years for Bu3/Flu and TBI8Gy/Flu were 62% vs. 72.5% (p = 0.051), 59.5% vs. 65% (p = 0.15), 30% vs. 20% (p = 0.01), and 10% vs. 14% (p = 0.18), respectively. In multivariate model for patients <50 years old, TBI8Gy/Flu was associated with improved LFS (hazard ratio (HR) = 0.5, p = 0.04), OS (HR = 0.31, p = 0.004), and survival free from both graft-versus-host disease and relapse (HR = 0.55, p = 0.03), as well as tendency to reduced risk of relapse (HR = 0.53, p = 0.08). Among patients aged 50 years or older the use of TBI8Gy/Flu was associated with increased incidence of NRM (HR = 3.9, p = 0.0009), with no significant impact on other outcome measures. We conclude that the use of TBI8Gy/Flu as "reduced-toxicity" regimen may be advised in younger patients with AML referred for allo-HCT.
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http://dx.doi.org/10.1038/s41409-020-01050-7DOI Listing
February 2021

Better leukemia-free survival with allogeneic than with autologous HCT in AML patients with isolated trisomy 8: a study from the ALWP of the EBMT.

Bone Marrow Transplant 2021 Feb 4;56(2):461-469. Epub 2020 Sep 4.

EBMT Paris Study Office/CEREST-TC, Paris, France.

The indication for performing an allogeneic hematopoietic stem cell transplantation (allo-HCT) in patients with isolated trisomy 8 AML in first complete remission (CR) is still debated. Here, we compared outcomes of such patients given either allo-HCT or autologous (auto)-HCT. Inclusion criteria consisted of adult patients with de novo AML, isolated trisomy 8, first HCT between 2000 and 2018, CR1 at transplantation, and either auto-HCT or allo-HCT with a HLA-identical sibling donor (MSD) or a 10/10 HLA-matched unrelated donor (UD 10/10). A total of 401 patients met the inclusion criteria. They underwent an auto-HCT (n = 81), allo-HCT with a MSD (n = 186) or allo-HCT with a 10/10 UD (n = 134). At 3 years, relapse incidence, nonrelapse mortality and leukemia-free survival (LFS) were 59%, 5%, and 37%, respectively, in auto-HCT recipients; 31% (P < 0.001), 14% (P = 0.04), and 55% (P = 0.033), respectively, in MSD recipients and 29% (P < 0.001), 13% (P = 0.15), and 59% (P = 0.03), respectively, in UD 10/10 recipients. In multivariate analysis, in comparison to auto-HCT, MSD and UD 10/10 were associated with a lower risk of relapse (HR = 0.47, P < 0.001 and HR = 0.40, P < 0.001, respectively) translating to better LFS (HR = 0.69, P = 0.04 and HR = 0.60, P = 0.03, respectively). There was also a similar trend for overall survival (HR = 0.73, P = 0.12 and HR = 0.65, P = 0.08).
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http://dx.doi.org/10.1038/s41409-020-01051-6DOI Listing
February 2021

Gemtuzumab Ozogamicin Combined With Intensive Chemotherapy in Patients With Acute Myeloid Leukemia Relapsing After Allogenic Stem Cell Transplantation.

Clin Lymphoma Myeloma Leuk 2020 Dec 6;20(12):791-796. Epub 2020 Jul 6.

Service d'Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Sorbonne Université, INSERM UMRs 938, Paris, France.

Background: More than one-third of patients with acute myeloid leukemia (AML) will relapse after allogenic hematopoietic cell transplant (allo-HCT). The main challenge is to overcome disease resistance to achieve a new complete remission while avoiding excessive toxicity. Gemtuzumab ozogamicin (GO), a conjugate of calicheamicin linked to the humanized monoclonal anti-CD33 antibody, has been used for refractory or relapsed AML with promising response rates, but liver toxicity of GO has long been considered a limiting factor.

Patients And Methods: We included 18 consecutive patients with AML relapsing after a first allo-HCT and treated with fractioned GO (fGO) and intensive chemotherapy. The median age was 40 years (range, 18-65).

Results: The overall response rate was 72% (13/18), including 7 complete remissions. No death was attributed to treatment toxicity. The main liver toxicity was transient and consisted of transaminase level elevation and hyperbilirubinemia. No cases of veno-occlusive disease were observed after the GO treatment. From the time of salvage treatment initiation, 1- and 2-year OS rates were 54% (95% confidence interval, 28%-74%) and 42% (95% confidence interval, 19%-63%), respectively.

Conclusions: Our study suggests the feasibility, efficacy, and safety of an fGO-based salvage regimen combined with intensive chemotherapy in patients with CD33+ AML in the case of early relapse after an allo-HCT.
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http://dx.doi.org/10.1016/j.clml.2020.07.001DOI Listing
December 2020

Measurable residual disease (MRD) testing for acute leukemia in EBMT transplant centers: a survey on behalf of the ALWP of the EBMT.

Bone Marrow Transplant 2021 Jan 28;56(1):218-224. Epub 2020 Jul 28.

EBMT Paris Study Office/CEREST-TC, Paris, France.

Detectable measurable residual disease (MRD) is a key prognostic factor in both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) patients. Thus, we conducted a survey in EBMT transplant centers focusing on pre- and post-allo-HCT MRD. One hundred and six centers from 29 countries responded. One hundred had a formal strategy for routine MRD assessment, 91 for both ALL and AML. For ALL (n = 95), assessing MRD has been routine practice starting from 2010 (range, 1990-2019). Techniques used for MRD assessment consisted of PCR techniques alone (n = 27), multiparameter flow cytometry (MFC, n = 16), both techniques (n = 43), next-generation sequencing (NGS) + PCR (n = 2), or PCR + MFC + NGS (n = 7). The majority of centers assessed MRD every 2-3 months for 2 (range, 1-until relapse) years. For AML, assessing MRD was routine in 92 centers starting in 2010 (range 1990-2019). Assessment of MRD was by PCR (n = 23), MFC (n = 13), both PCR and MFC (n = 39), both PCR and NGS (n = 3), and by all three techniques (n = 14). The majority assesses MRD for AML every 2-3 months for 2 (range, 1-until relapse) years. This survey is the first step in the aim to include MRD status as a routine registry capture parameter in acute leukemia.
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http://dx.doi.org/10.1038/s41409-020-01005-yDOI Listing
January 2021

FLAMSA-Based Reduced-Intensity Conditioning versus Myeloablative Conditioning in Younger Patients with Relapsed/Refractory Acute Myeloid Leukemia with Active Disease at the Time of Allogeneic Stem Cell Transplantation: An Analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2020 11 24;26(11):2165-2173. Epub 2020 Jul 24.

Department of Clinical Hematology and Cell Therapy, Hôpital Saint-Antoine, AP-HP, Sorbonne University, INSERM UMR 938, Paris, France.

The use of myeloablative conditioning (MAC) in the setting of active relapsed/refractory (R/R) acute myeloid leukemia (AML) has been hindered by high historical rates of nonrelapse mortality (NRM). FLAMSA (fludarabine, Ara-C, and amsacrine) chemotherapy (CT) followed by reduced-intensity conditioning (RIC) has been proposed as an effective and potentially safer alternative in this scenario. As improvements in supportive care have contributed to decreasing NRM rates after MAC, a comparative reassessment of these two strategies was performed. This was a registry-based analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation. Eligibility criteria included age 18 to 50 years, primary refractory, first or second relapsed active AML, first allogeneic stem cell transplantation from a matched sibling donor (MSD) or an unrelated donor (UD) performed between 2005 and 2018, MAC or FLAMSA-RIC. A total of 1018 patients were included. The median patient age was 39 years (range, 18 to 50). Two hundred and fifty-eight patients received busulfan (Bu)/cyclophosphamide (Cy), 314 received Cy/total body irradiation (TBI), 318 received FLAMSA-TBI, and 128 received FLAMSA-CT. The median duration of follow-up was 50 months. In univariate analysis, the 2-year relapse incidence (RI) (54%; 95% confidence interval (CI), 50%-57%), leukemia-free survival (LFS) (30%; 95% CI, 27%-33%), and refined graft-versus-host disease-free, relapse-free survival (GRFS) (21%; 95% CI, 18%-24%) were not significantly different between cohorts. Lower 2-year NRM was observed in the FLAMSA-CT group (7% versus 16% in Bu/Cy, 19% in Cy/TBI, and 18% in FLAMSA-TBI; P = .04), as well as increased 2-year overall survival (OS) (50% versus 33% in Bu/Cy, 34% in Cy/TBI, and 36% in FLAMSA-TBI; P = .03). These results were maintained in the multivariate analysis (hazard ratio [HR] for NRM: .40, P = .01; HR for OS: .65, P = .01; Bu/Cy as reference). These data suggest that FLAMSA-CT may be a preferred conditioning regimen in patients with active R/R AML due to lower NRM. Yet, the high relapse rates observed in our analyses emphasize the need for novel therapeutic strategies in this clinical setting.
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http://dx.doi.org/10.1016/j.bbmt.2020.07.020DOI Listing
November 2020

Impact of total body irradiation- vs chemotherapy-based myeloablative conditioning on outcomes of haploidentical hematopoietic cell transplantation for acute myelogenous leukemia.

Am J Hematol 2020 Jul 13. Epub 2020 Jul 13.

Saint Antoine Hospital, INSERM UMR 938, Université Pierre et Marie Curie, Paris, France and EBMT Paris study office / CEREST-TC, Paris, France.

The optimal myeloablative conditioning (MAC) for patients undergoing haploidentical hematopoietic cell transplantation (haplo-HCT) is unknown. We studied the outcomes of total body irradiation (TBI) vs chemotherapy (CT) based MAC regimens in acute myeloid leukemia (AML) patients. The study included 1008 patients who underwent first haplo-HCT with post-transplant cyclophosphamide, following TBI (N = 89, 9%) or CT (n = 919, 91%) based MAC. Patients in the TBI cohort were younger (median age, 38 vs 47 years, P < .01) and more likely to receive BM graft (57% vs 43%, P = .01). Two-year overall chronic GVHD (cGVHD) incidence was 42% vs 27% (P < .01) and extensive cGVHD incidence was 9% vs 12% (P = .33) in TBI and CT cohorts, respectively. Graft failure was reported in two (2%) TBI- and 65 (7%) CT-MAC recipients (P = .08). Death from veno-occlusive disease was reported in one (3%) TBI and 11 (3%) CT patients who died during the study period. In the multivariate analysis, TBI was associated with increased risk for overall cGVHD (hazard ratio = 1.95, 95% confidence interval:1.2-3.1, P < .01) compared to CT-based MAC. The choice of conditioning regimen did not impact relapse incidence, leukemia-free survival, non-relapse mortality, overall survival or GVHD-relapse-free survival in multivariate analysis. In conclusion, major transplant outcomes were not statistically different between TBI-based MAC and CT-based MAC in patients with AML after haplo-HCT/PTCy.
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http://dx.doi.org/10.1002/ajh.25934DOI Listing
July 2020

Timing of Post-Transplantation Cyclophosphamide Administration in Haploidentical Transplantation: A Comparative Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Biol Blood Marrow Transplant 2020 10 6;26(10):1915-1922. Epub 2020 Jul 6.

Hematology Department, Service d'Hématologie et Thérapie Cellulaire, Hôpital Saint Antoine, Paris, France; Sorbonne Universités, INSERM, Centre de Recherche Saint-Antoine, UPMC Univ Paris 06, Paris, France; European Society for Blood and Marrow Transplantation, Paris, France.

The timing of immunosuppressive therapy used in combination with post-transplantation cyclophosphamide (PTCY) in haploidentical hematopoietic stem cell transplant (haplo-HSCT) is not standardized. We evaluated the schedules of immunosuppression therapy after haplo-HSCT in 509 patients with acute leukemia receiving PTCY on days +3 and +4 along with tacrolimus (group 1; n = 215), with cyclosporine A (CSA) and mycophenolate mofetil (MMF) from day +5 (group 2; n = 170), or CSA + MMF from day 0 or 1 with PTCY on days +3 and +5 (group 3; n = 124). Compared with the other 2 groups, patients in group 3 were younger (median age, 46 years; P = .02) and more often received bone marrow (77%; P < .01) and a regimen containing thiotepa, fludarabine, and busulfan (84%; P< .01). At 2 years, overall survival was 44% was in group 1, 48% in group 2, and 59% in group 3 (P= .15); leukemia-free survival (LFS) was 43%, 46%, and 53% (P= .05); and refined graft-versus-host disease-free, relapse-free survival (rGRFS) was 33%, 39%, and 36% (P = .02). The incidence of grade II-IV acute GVHD was 25% in group 1, 39% in group 2, and 18% in group 3 (P< .01); incidence of chronic GVHD was 25%, 21%, and 24% (P= .50); relapse incidence was 36%, 37%, and 26% (P= .02); and nonrelapse mortality was 26%, 20%, and 21% (P= .35). On multivariate analysis, early start of immunosuppression therapy at day +1 followed by PTCY was associated with a better LFS (hazard ratio [HR], .58; P= .02) and improved rGRFS (HR, .62; P = .02). In this study, the timing of immunosuppression influenced the outcomes of haplo-HSCT with PTCY. An early start of CSA + MMF with PTCY administered on days +3 and +5 improves LFS and rGRFS.
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http://dx.doi.org/10.1016/j.bbmt.2020.06.026DOI Listing
October 2020