Abstract
Introduction: Primary refractory or relapsing acute myeloid leukemia (R/R-AML) has very poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) may be the only chance of cure. Therefore a suitable donor should be rapidly searched for, in this setting. In those patients (pts) lacking an HLA-matched sibling donor (MSD), mismatched family donor (haploidentical, Haplo) may represent a valid and rapidly available option.
Methods: Herein, we compared the outcomes of pts with R/R-AML undergoing first HSCT from either a MSD (n=1654) or Haplo (n=389) in the period 2007-2015. The Haplo group included pts receiving a T-repleted graft with post-transplant cyclophosphamide (PTCY, n=278), in vivo T-cell depletion (TCD, n=95), or both (n=16).
Results: Median age at HSCT was 52 (range 18-74) years. Median follow-up was 16 and 22 months for MSD and Haplo recipients, respectively (p=0.11). At time of HSCT, 41% and 56% presented a primary refractory AML in Haplo and MSD groups, respectively (p<0.01). Compared to MSD, Haplo HSCT were performed more recently (median year 2013 versus 2011, p<0.01) with a higher number of pts having a poor Karnofsky performance status (22% versus 16%, p<0.01) and a positive serology for CMV (83% versus 71%, p<0.001) at time of HSCT, respectively. The latter also had more frequently undergone a previous autologous HSCT (8% vs 3%, p<0.01), had a longer interval from diagnosis to HSCT (7 versus 5 months, p<0.01), received more frequently bone marrow as stem cell source (47% vs 8%, p<0.01), a reduced intensity conditioning regimen ( 50% vs 43%, p<0.03), and a graft from a male donor (59% versus 53%, p<0.03) as compared to MSD recipients. Compared to Haplo, cumulative incidence (CI) of neutrophil engraftment was higher (93% versus 83%, p<0.01) and associated to a shorter median time to engraftment (15 versus 18 days, p<0.01) in MSD recipients. According to donor type, no differences were found in univariate analysis for the CI of grade II-IV acute graft-versus host disease (aGVHD)(28% versus 27%, p=0.37), while a lower CI of chronic GVHD (cGVHD) (27% versus 42%, p<0.01) and extensive cGVHD (12% and 19%, p<0.01) was observed in HSCT from Haplo compared to MSD, respectively. At two years, overall survival (OS) was 25% and 32% (p<0.01), leukemia-free survival (LFS) 19% and 27% (p<0.01) and GVHD/relapse-free survival (GRFS) 18% and 26% (p<0.01) in HSCT from Haplo and MSD, respectively. Relapse incidence (RI) was similar following HSCT from Haplo and MSD (50% vs 51%, p=0.60), while non-relapse mortality (NRM) was higher for Haplo transplants (31% vs 22% in HSCT from MSD, p<0.001), respectively. In a multivariate analysis adjusted for the differences between the two groups, Haplo HSCT was associated with lower OS (HR 1.19, p<0.04), LFS (HR 1.17, p<0.05) and GRFS (HR 1.22, p<0.02). Higher grade II-IV aGVHD was observed in Haplo recipients. Neither cGVHD (any grade) nor RI differed according to donor type (p=ns). Compared to MSD, Haplo recipients experienced a higher NRM (HR 1.4, p<0.02) mainly related to a higher incidence of infections (41% versus 25%, p<0.01). Regardless of donor type, age as a continuous variable was associated with lower RI (HR 0.99, p<0.01), lower OS (HR 1.01, p<0.01) and higher NRM (HR 1.02, p<0.01). The use of peripheral blood as stem cell source was independently associated with a higher risk of cGVHD (HR 1.64, p<0.01).
Conclusions: Our results indicate that for pts with R/R-AML outcome is better with HSCT from a MSD compared to unmanipulated Haplo donor, mainly due to the higher NRM associated with transplants from Haplo and most probably related to a higher incidence of infections and grade II-IV aGVHD. Chronic GVHD as well as RI are similar, indicating once again that despite the broader HLA disparities with Haplo HSCT the graft versus leukemia effect is probably not stronger than after HSCT from MSD (Ringden O, on behalf of the ALWP; Leukemia 2016). In the absence of a MSD, Haplo HSCT may represent a valid alternative, with nearly one quarter of the R/R-AML pts surviving at 2 years from transplant. Future goals in the Haplo setting should be to reduce NRM and rate of infections in order to further improve outcomes.
Ciceri: GSK: Other: B-thalassemia gene therapy was developed by Fondazione Telethon and Ospedale San Raffaele and has been inlicenced by GSK that provides funding for the clinical trial, Research Funding. Mohty: Sanofi: Honoraria, Speakers Bureau.
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