High incidence of impaired graft function after allogeneic HSCT for myelofibrosis, and successful utilization of stem cell boost

Abstract

Abstract For myelofibrosis (MF) patient's undergoing hematopoietic stem cell transplant (HSCT) engraftment failure is a life-threatening challenge, largely due to primary graft failure (PGF) and/or prolonged poor graft function (PGFxn). Although medical management of MF patients has improved with the introduction of JAK2 inhibitors, HSCT remains the only potentially curative option. In this single center retrospective analysis, we studied a cohort of 50 consecutive patients with primary MF or secondary MF (post ET/PV) who underwent allogeneic HSCT at our institution between 2012 and 2023. PGF was defined according to the CIBMTR definition as failure to achieve a sustained ANC ≥ 500/uL by posttransplant day 30. We defined PGFxn as prolonged platelet transfusion dependence and/or growth factor dependence necessitating a CD-34 selected stem cell boost (SCB). Survival outcomes were censored at 2 yrs post-transplant to avoid time bias.  The median age at transplant of 63.5 years (range 35-74 years). The cohort was predominantly male (n=28; 56%), Caucasian (n=41; 82%) and most had JAK2 mutated (n=36, 72%) primary MF (n=47; 94%). The median Dynamic International Prognostic Scoring System (DIPSS) score at transplant was 2 (Intermediate-1 risk). The majority of patients received a JAK2 inhibitor prior to transplant (80%, n=40). The graft source was peripheral blood stem cells for 45 patients (90%), and bone marrow for 5 patients (10%). Reduced intensity conditioning (RIC) regimens were used in 38 cases (76%), and myeloablative regimens in 12 cases (24%). Donors included matched unrelated donors in 28 cases (56%), matched related donors in 15 (30%), mismatched unrelated donors in 6 (12%), and a haploidentical related donor in 1 case (2%). GVHD prophylaxis consisted of MTX/tacrolimus-based regimens (n=35; 70%), post-transplant cyclophosphamide (PTCy)-based prophylaxis (n=9; 18%) or other regimens (n=6; 12%). Eight patients (16%) met criteria for PGF, and 5 additional patients (10%) had PGFxn for which they received a CD-34 selected stem cell boost.  Primary Graft Failure Group (n=8): All patients had donor predominant chimerism in blood and/or marrow. Two PGF patients received early SCB (on days 93 and 151 post-transplant) with subsequent improvement in hematopoiesis, and both survived beyond 2 yrs post-transplant. One patient received a second transplant from a different donor and died shortly thereafter without engraftment. Among patients with PGF, 3 patients (37.5%) died before posttransplant day 100 with cause of death being infection. The 2-year OS of the PGF group was 40%. Poor Graft Function Group (n=5): All patients had donor predominant chimerism in blood and/or marrow. PGFxn patients all received a SCB at a median of post-transplant day 99 (day range 34-141), and all had improvement in hematopoietic function. 2 year OS for the PGFxn group was 75%.    Predictive Factors for Impaired Graft Function: In univariate analysis, the only significant associations with either PGF or PGFxn were DIPSS score >3 (p=0.026), and PTCy based GVHD prophylaxis [p=0.019; OR = 7.07, 95% CI: 1.57-31.86]. Notably, graft source, HLA matching and conditioning intensity were not predictive of impaired graft function in our series.  Conclusion: These findings confirm previous observations that impaired graft function is relatively common after allogeneic transplantation for MF. Our data suggests that PGF and PGFxn may be associated with advanced disease burden reflected by the higher DIPSS scores, as well as the use of PTCy-based GVHD prophylaxis. SCB was used as a rescue intervention in both PGF and PGFxn groups, with generally favorable outcomes. Unfortunately, the feasibility of arranging a prompt SCB can be challenging, particularly with registry donors. Further analyses of larger data sets are warranted to inform selection of the best GVHD prophylaxis strategies as well as optimization of selection criteria for earlier consideration of stem cell boost in this challenging patient population.