Risk Factors for Graft Failure and Survival after Reduced Intensity (RIC) Conditioning Allogeneic Hematopoietic Cell Transplantation (HCT) for Myelofibrosis

Reduced intensity conditioning (RIC) HSCT is a potentially curative therapy for Myelofibrosis (MF), but graft failure is a major cause of treatment failure. We evaluated the outcomes and risk factors for graft failure and survival in patients undergoing RIC HSCT. We performed a retrospective review of all patients receiving a first RIC HSCT for MF at Dana Farber Cancer Institute/Brigham and Women's Hospital between January 1, 2000 and December 31, 2012.  Primary graft failure (PGF) was defined as the inability to achieve an ANC greater than 0.5x10⁹/L for three consecutive days. Secondary failure was defined as achievement of WBC engraftment with subsequent decline in chimerism to < 50%, or need for donor lymphocyte infusion (DLI) or second HSCT. An event was defined as primary or secondary graft failure or relapse. Median age of the cohort (n= 40) was 62 years (44-73). The RIC regimens included fludarabine/IV busulfan 3.2 mg/kg (Flu/Bu1) (24), fludarabine/IV busulfan 6.4 mg/kg (Flu/Bu2) (15), or fludarabine/melphalan (1). A majority of patients received tacrolimus, sirolimus and methotrexate (24) for GVHD prophylaxis.  Nine patients received ATG as part of the conditioning.   All received PBSC except one who received a dUCBT. Thirty-four patients received 10/10 matched transplants from related or unrelated donors. Eighteen patients (45%) experienced graft failure including one patient with PGF. 22.5% of all patients had D30 and 35% had D100 chimerism<50%. Unplanned DLI were needed in 12/40 (30%) patients. Seven patients (17.5%) ultimately needed a second transplant for persistent disease and/or poor chimerism.  Grade II-IV acute GVHD incidence at D180 was 18%. Chronic GVHD incidence at 2 years was 27%. With median follow-up of 28 months, the 2-year EFS and OS were 29% and 51%. Based on univariate analysis, use of ATG (p=0.03), female recipient gender (p=0.03), and WBC <5K at transplant (p=0.016) were associated with longer EFS, while predictors for superior OS were absence of circulating blasts (p=0.004), low platelet count (p=0.011) and unrelated donor (p=0.03). DIPSS score and spleen size did not predict for EFS or OS. There was a trend toward improved 2-year OS in patients who received Flu/Bu2 compared to those who received Flu/Bu1 (53% vs. 21%, p= 0.10).  We developed a prognostic score based on factors found to be significant on univariate analysis. Based on this composite score incorporating 1 point for platelet count >100x10⁹/L, blast count >5%, and non-MUD donor, the 2-year EFS was 49% for score<=1 and 12% for score>=2 (p=0.0017); the 2-year OS was 67% for score<=1 and 21% for score>=2 (p=0.0003) (Figure 1). RIC HSCT using low dose Flu/Bu is associated with a high incidence of mixed chimerism and late graft failure necessitating frequent unplanned DLI or second HSCT.  The incidence of graft failure may be mitigated by increasing the intensity of the conditioning regimen or addition of ATG.

Figure 1.