Prognosis of graft failure patients is dismal, and another transplant is the sole option for long-term survival. Currently, there is no consensus concerning the best option for treating patients undergoing primary graft failure and finding a new donor within an acceptable delay is challenging. In the last years, haploidentical transplants with post-transplant cyclophosphamide (PT-Cy) have shown acceptable results in the treatment of many hematological diseases, including some cases of graft failure.

To address the interest of haploidentical transplants as a salvage option in this context, we retrospectively collected and analyzed data from 26 primary graft failure (PGF) patients transplanted between 2011 and 2017 in 15 centers belonging to the Francophone Society for Bone Marrow Transplantation and Cellular Therapy (SFGM-TC). Inclusion criteria were the occurrence of PGF defined as non-achievement of a minimum absolute neutrophil count of 500/μL without evidence of disease relapse at D+28 after transplantation and the use of a haploidentical transplantation with PT-Cy as graft-versus-host-disease (GvHD) prophylaxis.

Continuous variables are presented as medians and inter-quartile range. They were compared between groups using the Wilcoxon rank sum. Categorical variables are presented with counts and percentages and were compared using the Fisher exact test. All tests were 2-sided, and a p-value below 0.05 was considered to be significant. Analyses were performed using the R statistical platform (version 3.4.1). This study was performed according to the Declaration of Helsinki and was approved by the SFGM-TC scientific council.

Nineteen patients had a diagnosis of myeloid malignancy (8 acute myeloid leukemias, 4 myelodysplastic syndromes, 4 myeloproliferative neoplasms, 1 unclassified myeloid disorder), 3 had a lymphoid neoplasm, and 4 had a bone marrow failure syndrome (2 acquired and 2 congenital). Twenty-four patients had previously received an allogeneic transplantation, and 2 had already failed two previous allogeneic transplants. Male/female ratio was 2.25. Median age at haploidentical transplant was 42 years (2-58). Fifteen patients received peripheral blood as stem cell source, and 11 received bone marrow. Eleven transplants were female to male. Twelve patients received an ABO-matched graft, 6 had a major ABO-incompatibility, 7 a minor incompatibility and one missing data. The median number of infused CD34+ cells was 5.2 x106/kg (1.2 - 12.5). There was no ex-vivomanipulation of cells. CMV matching was available for 22 transplantations, of which 6 were high-risk (seropositive recipient with a seronegative donor).

Fludarabine-based reduced intensity conditioning was used in all but one patient who received clofarabine + 4Gy TBI. Twenty patients received TBI 2Gy. Three patients received ATG. Fourteen patients received the Baltimore regimen (53%). The median delay between the previous and the salvage transplantation was 77 days (39-1161).

All patients received PT-Cy associated with cyclosporine, and 24 patients also received MMF for GvHD prophylaxis.

Median follow up was 487 (16-2010) days. The cumulative incidence (CI) of neutrophil recovery at day 30 was 81%, and the median time to neutrophil engraftment was 19 (13-34) days. Four patients (15%) presented primary graft failure and died within a median time of 5 (3-8) weeks after transplantation of infectious complications.

Cumulative incidence of grade II-IV aGvHD at day-100 was 13%, and 1-year CI of cGvHD was 32%. One-year CI of relapse was 16%. Overall survival was 58% at 1 year (Figure 1; confidence interval: 39-85). Among the 22 patients who engrafted, 6 patients died. HSCT complications accounted for 80% of the causes of deaths (4 multiorgan failure, 1 GvHD, 1 interstitial pneumonitis, 1 bacterial infection, 1 post-transplant lymphoproliferative disorder).

To the best of our knowledge, this is the first cohort describing the outcomes of haploidentical transplants with PT-Cy rescuing patients with primary graft failure.

Our cohort presents promising outcomes in a particularly challenging situation, suggesting that haploidentical transplants with PT-Cy might appear as a valid salvage strategy for patients with PGF. Prospective well-designed trials are urgently needed before the inclusion of Haplo-PT-Cy in the treatment strategy of patients with PGF.

Disclosures

Mohty:MaaT Pharma: Consultancy, Honoraria. Peffault De Latour:Pfizer Inc.: Consultancy, Honoraria, Research Funding; Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Author notes

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Asterisk with author names denotes non-ASH members.