Publications by authors named "Mohamad Mohty"

597 Publications

A phase 2a randomized clinical trial of intravenous vedolizumab for the treatment of steroid-refractory intestinal acute graft-versus-host disease.

Bone Marrow Transplant 2021 Jun 9. Epub 2021 Jun 9.

Hematopoietic Cell Transplant and Cellular Therapy Program, Massachusetts General Hospital, Boston, MA, USA.

Steroid-refractory (SR) acute graft-versus-host disease (aGvHD) remains a significant complication after allogeneic hematopoietic cell transplantation. Systemic corticosteroids are first-line therapy for aGvHD, but apart from ruxolitinib, there are no approved treatments for SR aGvHD. Vedolizumab is approved for treatment of ulcerative colitis and Crohn's disease, and may be effective for treatment of SR intestinal aGvHD. We conducted a phase 2a trial (NCT02993783) to evaluate the clinical efficacy, tolerability, and safety of vedolizumab 300 and 600 mg for SR intestinal aGvHD. This study was terminated before full enrollment was completed because early results failed to demonstrate positive proof-of-concept in efficacy. Before termination, 17 participants had enrolled and an early response in intestinal aGvHD was observed in 11 and eight participants at days 15 and 28, respectively. All adverse events observed were consistent with those expected in a population with SR intestinal aGvHD. Overall, vedolizumab did not meet the primary efficacy endpoint (overall response at day 28), likely owing to premature study drug discontinuation, lack of efficacy, and the competing risks inherent with a population with advanced SR intestinal aGvHD. Nevertheless, this study provides valuable insights into the considerations needed when conducting studies in patients with SR intestinal aGvHD.
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http://dx.doi.org/10.1038/s41409-021-01356-0DOI Listing
June 2021

A multicentre, multinational, prospective, observational registry study of defibrotide in patients diagnosed with veno-occlusive disease/sinusoidal obstruction syndrome after haematopoietic cell transplantation: an EBMT study.

Bone Marrow Transplant 2021 May 31. Epub 2021 May 31.

Department of Hematology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Severe hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a potentially life-threatening complication of haematopoietic cell transplantation (HCT). This multinational, prospective, observational study (NCT03032016), performed by the EBMT, enrolled patients treated with defibrotide from April 2015 to July 2018. This analysis focused on defibrotide-treated patients with VOD/SOS post-HCT. The primary endpoint was incidence of serious adverse events (SAEs) of interest up to 12 months post-HCT in patients with severe VOD/SOS. Overall, 104 defibrotide-treated patients with VOD/SOS post-HCT were enrolled: 62 had severe VOD/SOS and comprised the primary study population, including 36 with multi-organ dysfunction/failure (MOD/MOF). SAEs of interest occurred in 20 of 62 (32%) severe VOD/SOS patients; the most common by category were infection (24%) and bleeding (13%). In patients with severe VOD/SOS, the Kaplan-Meier-estimated Day 100 survival rate was 73% (95% CI: 60%, 82%) with VOD/SOS resolution by Day 100 in 45 of 62 (73%) patients. MOD/MOF resolved in 19 of 36 (53%) patients with MOD/MOF at VOD/SOS diagnosis. Results from this multicentre registry study build on prior defibrotide studies supporting the utility of defibrotide for the treatment of VOD/SOS post-HCT. These results provide additional real-world evidence of the effectiveness and safety of defibrotide in patients with VOD/SOS post-HCT.
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http://dx.doi.org/10.1038/s41409-021-01265-2DOI Listing
May 2021

Allogeneic stem cell transplantation for AML patients with RUNX1 mutation in first complete remission: a study on behalf of the acute leukemia working party of the EBMT.

Bone Marrow Transplant 2021 May 31. Epub 2021 May 31.

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

Acute myeloid leukemia with runt-related transcription factor 1 gene mutation (RUNX1+ AML) is associated with inferior response rates and outcome after conventional chemotherapy. We performed a retrospective, registry-based analysis to elucidate the prognostic value of RUNX1 mutation after allogeneic stem cell transplantation (alloSCT). All consecutive adults undergoing alloSCT for AML in first complete remission (CR1) between 2013 and 2019 with complete information on conventional cytogenetics and RUNX1 mutational status were included. Endpoints of interest were cumulative relapse incidence, non-relapse mortality, overall and leukemia-free survival (OS/LFS), and GvHD-free/relapse-free survival. A total of 674 patients (183 RUNX1+, 491 RUNX1-) were identified, with >85% presenting as de novo AML. Median follow-up was 16.4 (RUNX1+) and 21.9 (RUNX1-) months. Survival rates showed no difference between RUNX1+ and RUNX1- patients either in univariate or multivariate analysis (2-year OS: 67.7 vs. 66.1%, p = 0.7; 2-year LFS: 61.1 vs. 60.8%, p = 0.62). Multivariate analysis identified age, donor type and poor cytogenetics as risk factors for inferior outcome. Among patients with RUNX+ AML, older age, reduced intensity conditioning and minimal residual disease at alloSCT predicted inferior outcome. Our data provide evidence that the negative influence of RUNX1 mutations in patients with AML can be overcome by transplantation in CR1.
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http://dx.doi.org/10.1038/s41409-021-01322-wDOI Listing
May 2021

Post-transplant cyclophosphamide containing regimens after matched sibling, matched unrelated and haploidentical donor transplants in patients with acute lymphoblastic leukemia in first complete remission, a comparative study of the ALWP of the EBMT.

J Hematol Oncol 2021 May 28;14(1):84. Epub 2021 May 28.

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

Background: There is no information on the impact of donor type in allogeneic hematopoietic stem cell transplantation (HCT) using homogeneous graft-versus-host (GVHD) prophylaxis with post-transplant cyclophosphamide (PTCy) in acute lymphoblastic leukemia (ALL).

Methods: We retrospectively analyzed outcomes of adult patients with ALL in CR1 that had received HCT with PTCy as GVHD prophylaxis from HLA-matched sibling (MSD) (n = 78), matched unrelated (MUD) (n = 94) and haploidentical family (Haplo) (n = 297) donors registered in the EBMT database between 2010 and 2018. The median follow-up period of the entire cohort was 2.2 years.

Results: Median age of patients was 38 years (range 18-76). Compared to MSD and MUD, Haplo patients received peripheral blood less frequently. For Haplo, MUD, and MSD, the cumulative incidence of 100-day acute GVHD grade II-IV and III-IV, and 2-year chronic and extensive chronic GVHD were 32%, 41%, and 34% (p = 0.4); 13%, 15%, and 15% (p = 0.8); 35%, 50%, and 42% (p = 0.01); and 11%, 17%, and 21% (p = 0.2), respectively. At 2 years, the cumulative incidence of relapse and non-relapse mortality was 20%, 20%, and 28% (p = 0.8); and 21%, 18%, and 21% (p = 0.8) for Haplo, MUD, and MSD, respectively. The leukemia-free survival, overall survival and GVHD-free, relapse-free survival for Haplo, MUD, and MSD was 59%, 62%, and 51% (p = 0.8); 66%, 69%, and 62% (p = 0.8); and 46%, 44%, and 35% (p = 0.9), respectively. On multivariable analysis, transplant outcomes did not differ significantly between donor types. TBI-based conditioning was associated with better LFS.

Conclusions: Donor type did not significantly affect transplant outcome in patient with ALL receiving SCT with PTCy.
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http://dx.doi.org/10.1186/s13045-021-01094-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161915PMC
May 2021

Outbreak of OXA-48-producing Enterobacterales in a haematological ward associated with an uncommon environmental reservoir, France, 2016 to 2019.

Euro Surveill 2021 05;26(21)

Unité INSERM S-1139, Université de Paris, Faculté de Pharmacie, Paris, France.

The hospital water environment, including the wastewater drainage system, is increasingly reported as a potential reservoir for carbapenemase-producing Enterobacterales (CPE). We investigated a persistent outbreak of OXA-48 CPE (primarily ) in a haematological ward of a French teaching hospital by epidemiological, microbiological and environmental methods. Between January 2016 and June 2019, we detected 37 new OXA-48 CPE-colonised and/or ‑infected patients in the haematological ward. In October 2017, a unit dedicated to CPE-colonised and/or ‑infected patients was created. Eleven additional sporadic acquisitions were identified after this date without any obvious epidemiological link between patients, except in one case. Environmental investigations of the haematological ward (June-August 2018) identified seven of 74 toilets and one of 39 drains positive for OXA-48 CPE (seven , one , one ). Whole genome comparisons identified a clonal dissemination of OXA-48-producing from the hospital environment to patients. In addition to strict routine infection control measures, an intensive cleaning programme was performed (descaling and bleaching) and all toilet bowls and tanks were changed. These additional measures helped to contain the outbreak. This study highlights that toilets can be a possible source of transmission of OXA-48 CPE.
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http://dx.doi.org/10.2807/1560-7917.ES.2021.26.21.2000118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161731PMC
May 2021

Gut microbiota diversity after autologous fecal microbiota transfer in acute myeloid leukemia patients.

Nat Commun 2021 05 25;12(1):3084. Epub 2021 May 25.

Service d'hématologie clinique et de thérapie cellulaire, Hôpital Saint Antoine, APHP, Sorbonne Université, INSERM UMRs 938, Paris, France.

Acute myeloid leukemia (AML) intensive chemotherapy combined with broad-spectrum antibiotics, leads to gut microbiota dysbiosis promoting pathological conditions and an increased incidence of complications. Here we report findings from a phase II single-arm, multicenter study evaluating autologous fecal microbiota transfer (AFMT) in 25 AML patients treated with intensive chemotherapy and antibiotics (ClinicalTrials.gov number: NCT02928523). The co-primary outcomes of the study are to evaluate the efficacy of AFMT in dysbiosis correction and multidrug-resistant bacteria eradication. The main secondary outcomes are to define a dysbiosis biosignature, to evaluate the effect of dysbiosis correction on patient clinical status, to assess the short and mid-term safety of AFMT in this immunocompromised population, and to evaluate the feasibility of the AFMT procedure and acceptability by the patient. Intensive induction chemotherapy induces a dramatic decrease of α-diversity indices, and a microbial dysbiosis with a significant shift of the microbial communities and domination of pro-inflammatory families. After AFMT treatment, α-diversity indices return to their initial mean levels and the similarity index shows the restoration of microbial communities. The trial meets pre-specified endpoints. AFMT appears to be safe and may be effective for gut microbiota restoration in AML patients receiving intensive chemotherapy and antibiotics, with an excellent gut microbiota reconstruction based on both richness and diversity indices at the species level.
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http://dx.doi.org/10.1038/s41467-021-23376-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8149453PMC
May 2021

Comparison of non-first-degree related donors and first-degree related donors in haploidentical HSCT: a multi-centre retrospective analysis.

Bone Marrow Transplant 2021 May 24. Epub 2021 May 24.

Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

The transplant outcomes of non-first-degree (NFD) related donors in haploidentical haematopoietic stem cell transplantation (haplo-HSCT) remain unclear. This multi-centre analysis compared NFD and first-degree (FD) related donors in haplo-HSCT using a low-dose anti-T-lymphocyte globulin/G-CSF-mobilised peripheral blood stem cell graft-based regimen. Ninety-nine patients (33 NFD; 66 FD) were included. All patients achieved myeloid and platelet engraftment. The 100-day cumulative incidence (CI) of aGVHD, 2-year CIs of relapse, cGVHD, and NRM, and 2-year probabilities of OS and GRFS were comparable between the two cohorts. In multivariate analysis, donor type (NFD vs. FD) had no impact on OS, PFS, GRFS, incidences of relapse, grade II-IV aGVHD or moderate-severe cGVHD. Older donor age was associated with a higher incidence of grade II-IV aGVHD (HR, 1.64, p = 0.03), moderate-severe cGVHD (HR, 1.92, p = 0.01) and worse GRFS (HR, 1.40, p = 0.02). A lower level of donor-recipient HLA matching was associated with a higher incidence of moderate-severe cGVHD (HR, 4.07, p = 0.02), and disease at complete remission was associated with better OS (HR, 0.21, p = 0.01) and PFS (HR, 0.3, p = 0.03). In conclusion, NFD donors may serve as feasible alternatives when FD donors are not available for haplo-HSCT.
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http://dx.doi.org/10.1038/s41409-021-01352-4DOI Listing
May 2021

Comprehensive Review of AL amyloidosis: some practical recommendations.

Blood Cancer J 2021 May 18;11(5):97. Epub 2021 May 18.

Department of Clinical Hematology and Cellular Therapy, Saint-Antoine Hospital, AP-HP, Sorbonne University, and INSERM, Saint-Antoine Research Centre, Paris, France.

Amyloid light chain (AL) amyloidosis is among the more common and more severe of the amyloidoses usually involving the slow proliferation of a bone-marrow-residing plasma cell (PC) clone and the secretion of unstable immunoglobulin-free light chains (FLC) that infiltrate peripheral tissues and result in detrimental end-organ damage. Disease presentation is rather vague, and the hallmark of treatment is early diagnosis before irreversible end-organ damage. Once diagnosed, treatment decision is transplant-driven whereby ~20% of patients are eligible for autologous stem cell transplantation (ASCT) with or without bortezomib-based induction. In the setting of ASCT-ineligibility, bortezomib plays a central role in upfront treatment with the recent addition of daratumumab to the current emerging standard of care. In general, management of AL amyloidosis is aimed at achieving deep, durable responses with very close monitoring for early detection of relapse/refractory disease. This article provides a comprehensive review of the management of patients with AL amyloidosis including goals of therapy, current treatment guidelines in the setting of both ASCT-eligibility and ineligibility, treatment response monitoring recommendations, toxicity management, and treatment of relapse/refractory disease.
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http://dx.doi.org/10.1038/s41408-021-00486-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8130794PMC
May 2021

Measurable residual disease status and outcome of transplant in acute myeloid leukemia in second complete remission: a study by the acute leukemia working party of the EBMT.

Blood Cancer J 2021 May 12;11(5):88. Epub 2021 May 12.

Hematology Division, Chaim Sheba Medical Center, Tel Hashomer, Israel.

Measurable residual disease (MRD) prior to hematopoietic cell transplant (HCT) for acute myeloid leukemia (AML) in first complete morphological remission (CR1) is an independent predictor of outcome, but few studies address CR2. This analysis by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation registry assessed HCT outcomes by declared MRD status in a cohort of 1042 adult patients with AML CR2 at HCT. Patients were transplanted 2006-2016 from human leukocyte antigen (HLA) matched siblings (n = 719) or HLA 10/10 matched unrelated donors (n = 293). Conditioning was myeloablative (n = 610) or reduced-intensity (n = 432) and 566 patients (54%) had in-vivo T cell depletion. At HCT, 749 patients (72%) were MRD negative (MRD NEG) and 293 (28%) were MRD positive (MRD POS). Time from diagnosis to HCT was longer in MRD NEG than MRD POS patients (18 vs. 16 months (P < 0.001). Two-year relapse rates were 24% (95% CI, 21-28) and 40% (95% CI, 34-46) in MRD NEG and MRD POS groups (P < 0.001), respectively. Leukemia-free survival (LFS) was 57% (53-61) and 46% (40-52%), respectively (P = 0.001), but there was no difference in terms of overall survival. Prognostic factors for relapse and LFS were MRD NEG status, good risk cytogenetics, and longer time from diagnosis to HCT. In-vivo T cell depletion predicted relapse.
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http://dx.doi.org/10.1038/s41408-021-00479-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8116335PMC
May 2021

Feasibility and Outcomes of a Third Allogeneic Hematopoietic Stem Cell Transplantation: A Retrospective Analysis from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Transplant Cell Ther 2021 May 6;27(5):408.e1-408.e6. Epub 2021 Feb 6.

Hématologie Clinique et Thérapie Cellulaire, Hôpital Saint-Antoine, Paris, France.

Few therapeutic options are available for patients with acute myeloid or lymphoblastic leukemia (AML/ALL) relapsing after a second allogeneic stem cell transplantation (alloSCT2). In selected patients a third allogeneic stem cell transplantation (alloSCT3) has been used, but no detailed analysis is available so far. The European Society for Blood and Marrow Transplantation (EBMT) registry was screened for patients with acute leukemia (AL) receiving alloSCT3 from an identical or alternative donor to treat AL in either haematological relapse or disease persistence after alloSCT2 between 2001 and 2018. Feasibility, efficacy, outcome, and risk factors of this approach were analyzed retrospectively. Forty-five patients (median age, 37 years, range 12-71) with AML (n=34) or ALL (n=11) were identified. Eleven patients received alloSCT3 in complete remission (CR), 34 had active disease. Fifteen patients were transplanted from the same donor at all three transplants, 30 patients had at least 2 different donors. Between alloSCT2 and alloSCT3, the donor was changed in 25 patients. After alloSCT3, 38 patients engrafted, and 26 achieved CR or CR with incomplete hematological reconstitution (CRi). Acute graft-versus-host disease (GvHD) grade II-IV was observed in 19%, chronic GvHD occurred in 13%. After 1-year, cumulative incidences of leukemia relapse and non-relapse mortality were 47% and 42%, respectively. Median progression free and overall survival (PFS/OS) from alloSCT3 were 2.5 and 4 months, respectively, 1-year PFS and OS were 11% and 20%,. Outcome was improved in patients with at least one donor change (1-year PFS/OS: 17%/30%), further factors for better outcome included an unrelated donor for alloSCT3, Karnofsky performance score >80, and more recent year of alloSCT3. Only patients with AML achieved >1 year OS. In conclusion, results after a third alloSCT are poor, limiting this procedure to few, highly selected patients. Recurrent relapses of acute leukemia after alloSCT remain an unmet therapeutic need.
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http://dx.doi.org/10.1016/j.jtct.2021.01.025DOI Listing
May 2021

Increasing Donor Options in Allogenic Hematopoietic Cell Transplantation.

J Clin Oncol 2021 Jun 4;39(18):1951-1954. Epub 2021 May 4.

Sorbonne University, INSERM, UMRs 938, Paris, France.

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http://dx.doi.org/10.1200/JCO.21.00622DOI Listing
June 2021

Allogeneic hematopoietic cell transplantation with cord blood versus mismatched unrelated donor with post-transplant cyclophosphamide in acute myeloid leukemia.

J Hematol Oncol 2021 May 3;14(1):76. Epub 2021 May 3.

EBMT ALWP Office, Hôpital Saint-Antoine, Paris, France.

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.
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http://dx.doi.org/10.1186/s13045-021-01086-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8094558PMC
May 2021

Comparing outcomes of a second allogeneic hematopoietic cell transplant using HLA-matched unrelated versus T-cell replete haploidentical donors in relapsed acute lymphoblastic leukemia: a study of the Acute Leukemia Working Party of EBMT.

Bone Marrow Transplant 2021 Apr 30. Epub 2021 Apr 30.

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

Optimal donor choice for a second allogeneic hematopoietic cell transplant (allo-HCT) in relapsed acute lymphoblastic leukemia (ALL) remains undefined. We compared outcomes using HLA-matched unrelated donors (MUD) versus haploidentical donors in this population. Primary endpoint was overall survival (OS). The MUD allo-HCT group comprised 104 patients (male = 56, 54%), median age 36 years, mostly (76%) with B-cell phenotype in complete remission (CR) (CR2/CR3 + = 76, 73%). The 61 patients (male = 38, 62%) in the haploidentical group were younger, median age 30 years (p = 0.002), had mostly (79%) a B-cell phenotype and the majority were also in CR at time of the second allo-HCT (CR2/CR3 + = 40, 66%). Peripheral blood stem cells was the most common cell source in both, but a significantly higher number in the haploidentical group received bone marrow cells (26% vs. 4%, p < 0.0001). A haploidentical donor second allo-HCT had a 1.5-fold higher 2-year OS (49% vs. 31%), albeit not statistically significant (p = 0.13). A longer time from first allo-HCT to relapse was associated with improved OS, leukemia-free survival, graft-versus-host disease-free-relapse-free survival, and lower cumulative incidences of relapse and non-relapse mortality. Results suggest no major OS difference when choosing either a MUD or haploidentical donor for ALL patients needing a second allo-HCT.
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http://dx.doi.org/10.1038/s41409-021-01317-7DOI Listing
April 2021

The evolving role of allogeneic haematopoietic cell transplantation in the era of chimaeric antigen receptor T-cell therapy.

Br J Haematol 2021 Jun 29;193(6):1060-1075. Epub 2021 Apr 29.

EBMT ALWP Office Hôpital Saint-Antoine, Paris, France.

Chimaeric antigen receptor T-cell (CAR T) therapy has revolutionized the management of many haematological malignancies. It is associated with impressive disease responses in relapsed or refractory high-grade B-cell non-Hodgkin lymphoma (B-NHL) and acute lymphoblastic leukaemia (B-ALL) with durable remissions in a subset of patients. Historically, haematopoietic cell transplantation (HCT) has been the standard consolidation strategy for many of these patients who are now being treated with CAR T. Relapses are frequent after CD19 CAR T therapy in B-ALL and consolidation with allogeneic HCT (allo-HCT) may improve survival of patients with high-risk disease. There appears to be a clear difference in B-ALL outcomes between paediatric and adult patients, with the latter having a much higher risk of relapse after CAR T therapy. Late relapses are infrequent in patients with B-NHL and consolidation with allo-HCT may not be needed in patients who achieve a complete remission after CAR T therapy. Future registry-based and prospective studies will hopefully provide the needed data in the future to risk-stratify the recipients of CAR T therapy. Meanwhile, we provide guidance on patient selection and practical issues with performing allo-HCT after CAR T therapy.
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http://dx.doi.org/10.1111/bjh.17460DOI Listing
June 2021

Allogeneic haematopoietic cell transplantation for myelofibrosis: a real-life perspective.

Br J Haematol 2021 Apr 21. Epub 2021 Apr 21.

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

Myelofibrosis (MF) is a clonal stem cell neoplasm with heterogeneous clinical phenotypes and well-established molecular drivers. Allogeneic haematopoietic stem cell transplantation (HSCT) offers an important curative treatment option for primary MF and post-essential thrombocythaemia/polycythaemia vera MF or secondary MF. With a disease course that varies from indolent to highly progressive, we are now able to stratify risk of mortality through various tools including patient-related clinical characteristics as well as molecular genetic profile. Owing to the high risk of mortality and morbidity associated with HSCT for patients with myelofibrosis, it is important to improve patient selection for transplant. Our primary goal is to comprehensively define our understanding of current practices including the role of Janus Kinase (JAK) inhibitors, to present the data behind transplantation before and after leukaemic transformation, and to introduce novel personalization of MF treatment with a proposed clinical-molecular prognostic model to help elucidate a timepoint optimal for consideration of HSCT.
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http://dx.doi.org/10.1111/bjh.17469DOI Listing
April 2021

Outcome after hematopoietic stem cell transplantation in patients with extranodal natural killer/T-Cell lymphoma, nasal type: A French study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC).

Am J Hematol 2021 07 3;96(7):834-845. Epub 2021 May 3.

Department of Hematology, Inserm U1163, IMAGINE Institute, Paris University, Necker Hospital, Paris, France.

We evaluated the outcome of 65 French patients with Extranodal NK/T-cell lymphoma, nasal type (ENKTL) undergoing hematopoietic stem cell transplantation (HSCT) (19 allogeneic and 46 autologous). Fifty-four patients (83%), most of which receiving L-asparaginase (L-aspa) containing regimens (81%), achieved complete or partial response at time of HCST. After a median follow-up of 79.9 months, 4-years progression-free survival (PFS) and overall survival (OS) were similar in both autologous and allogeneic groups (PFS: 34% vs. 26%, p = .12 and OS: 52% vs. 53%, p = .74). Response status at HSCT was the major independent prognostic factor on survival (OS: HR: 4.013 [1.137; 14.16], p = .031 and PFS: HR: 5.231 [1.625; 16.838], p = .006). As compared to control patients receiving chemotherapy and/or radiotherapy containing regimens only, upfront HSCT did not improve the outcome of responder patients, including those treated by L-aspa. However, it tends to provide survival benefit for relapsed patients with initial high-risk clinical features who achieved second remission. Whereas the place of HSCT in upfront therapy has still to be clarified, these data confirm that HSCT should be considered for consolidation in selected patients with relapsed ENKTL. Based on a large non Asian ENKTL cohort since the L-aspa era, this study provides some insight into the survival patterns of ENKTL patients with HSCT in the Western hemisphere and may give future direction for the next clinical trial design.
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http://dx.doi.org/10.1002/ajh.26200DOI Listing
July 2021

Nutritional Supplements and Complementary/Alternative Medications in Patients With Hematologic Diseases and Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 Jun 14;27(6):467-473. Epub 2021 Mar 14.

APHP, Hôpital Saint Antoine, Service d'Hématologie Clinique et de Thérapie cellulaire, Paris, France; Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine (CRSA), Paris, France. Electronic address:

This perspective article discusses the various practices classified as complementary and alternative medicine (CAM) and reviews the benefits and uncertainties with respect to nutritional supplements in patients with hematological disease. It considers the high prevalence of CAM use especially among cancer survivors, particularly patients with hematologic malignancies and allogeneic stem cell transplant survivors, many of whom believe (because of extensive advertising) that supplements are anticancer/antitoxic agents, despite the paucity of evidence to support any benefit and the enormous cost to the individual. CAM constitutes various practices and nutritional behaviors including prayers, relaxation, spiritual healing, nutritional supplements, meditation, religious counseling, massage, and support groups. We highlighted the current literature regarding CAM practices and focused our discussion on the omnipresent nutritional supplements in particular to further expound on their benefits and adverse effects. As the number of survivors after HSCT increases over the next several years along with prevalence of CAM use, it becomes imperative to ascertain any beneficial potential, as well as toxicities associated with CAM use in this population.
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http://dx.doi.org/10.1016/j.jtct.2021.03.011DOI Listing
June 2021

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 May 10;193(3):592-601. 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
May 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

Role of D(T)PACE-based regimens as treatment of multiple myeloma with extramedullary relapse or refractory disease.

Leuk Lymphoma 2021 Apr 1:1-7. Epub 2021 Apr 1.

Service d'Hématologie et thérapie cellulaire, Hôpital Saint-Antoine, AP-HP, Paris, France.

In multiple myeloma, atypical forms with extramedullary involvement exhibit poor survival. The poly-chemotherapeutic regimen D(T)-PACE has shown high activity in relapsed or refractory multiple myeloma. In this large monocentric retrospective study, we addressed the activity of D(T)-PACE-based regimens in 43 heavily pretreated patients with relapsed/refractory multiple myeloma and extramedullary disease.Median age at initiation was 57 years. Four patients had a t(4;14) translocation, 3 had a t(11;14) translocation and 7 had a del(17p). Extramedullary sites were mostly the skin (15 patients), central nervous system (10 patients), and thorax or abdomen (10 patients each). Overall response was achieved in 25 (58%) patients, including 6 (14%) with a complete response. Median progression-free survival was 5.0 months. Median overall survival was 9.0 months. Fourteen patients subsequently underwent stem-cell transplantation. Cytogenetics had no impact on response rate, overall survival and progression-free survival.In the era of several new immunotherapies, D(T)-PACE-based regimens still remain a useful treatment option for a selected group of heavily pretreated myeloma patients.
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http://dx.doi.org/10.1080/10428194.2021.1907373DOI Listing
April 2021

Worldwide Network for Blood and Marrow Transplantation (WBMT) Recommendations Regarding Essential Medications Required To Establish An Early Stage Hematopoietic Cell Transplantation Program.

Transplant Cell Ther 2021 Mar 16;27(3):267.e1-267.e5. Epub 2020 Dec 16.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota.

Establishing a hematopoietic cell transplantation (HCT) program is complex. Planning is essential while establishing such a program to overcome the expected challenges. Authorities involved in HCT program establishment will need to coordinate the efforts between the different departments required to start up the program. One essential department is pharmacy and the medications required. To help facilitate this, the Worldwide Network for Blood and Marrow Transplantation organized a structured survey to address the essential medications required to start up an HCT program. A group of senior physicians and pharmacists prepared a list of the medications used at the different phases of transplantation. These drugs were then rated by a questionnaire using a scale of necessity based on the stage of development of the transplant program. The questionnaire was sent to 30 physicians, in different parts of the world, who have between 5 and 40 years of experience in autologous and/or allogeneic transplantation. This group of experts scored each medication on a 7-point scale, ranging from an absolute requirement (score of 1) to not required (score of 7). The results are presented here to help guide the prioritization of required medications.
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http://dx.doi.org/10.1016/j.jtct.2020.12.015DOI Listing
March 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

Let's reconstitute microbiota diversity.

Blood 2021 Mar;137(11):1442-1444

Sorbonne Université.

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http://dx.doi.org/10.1182/blood.2020009963DOI Listing
March 2021

Expert review on soft-tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations.

Br J Haematol 2021 Mar 16. Epub 2021 Mar 16.

Berlín, Germany.

In this review, two types of soft-tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high-risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor-based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor-based regimen such as lenalidomide-bortezomib-dexamethasone (RVD) may be the best option, while for those eligible for high-dose therapy a myeloma/lymphoma-like regimen such as bortezomib, thalidomide and dexamethasone (VTD)-RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high-unmet need population.
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http://dx.doi.org/10.1111/bjh.17338DOI Listing
March 2021

How Do We Manage Hematopoietic Cell Transplant during the SARS-CoV-2 Pandemic?

Acta Haematol 2021 Mar 9:1-7. Epub 2021 Mar 9.

Institute of Hematology, Zhejiang University, Hangzhou, Zhejiang Province, China,

Patients receiving a hematopoietic cell transplant are thought to be at increased risk of infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and coronavirus infectious disease 2019. Transplant activities at our center continue, and notably, no patient has been infected with SARS-CoV-2. Indeed, social distancing, masking, and education for patients and donors are major pillars of prevention. We recommend potential transplant recipients and donors to be tested for SARS-CoV-2 with qRT-PCR, serum antibody detection, and a lung CT scan pretransplant. If possible, stem cells from HLA-matched unrelated donors by local processing laboratories should be cryopreserved and shipped before initiating pretransplant conditioning. An alternative HLA-haplotype-matched related donor should be identified and evaluated as a backup. The interval immediately after discharge is the time of greatest risk for SARS-CoV-2 infection because of travel and exposure to infected persons. We recommend self-isolation and minimal contact with family members. Nonessential clinic visits should be deferred or substituted with telemedicine consultations if possible. These recommendations are based on our experience at a major transplant center in China. Although some recommendations are evidence based, other recommendations are not and warrant validation in controlled trials.
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http://dx.doi.org/10.1159/000513036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018218PMC
March 2021

Venetoclax does not impair activated T-cell proliferation.

Bone Marrow Transplant 2021 Mar 8. Epub 2021 Mar 8.

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

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http://dx.doi.org/10.1038/s41409-021-01245-6DOI 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