Results of Phase II Clinical Trial MPD-RC 101: Allogeneic Hematopoietic Stem Cell Transplantation Conditioned with Fludarabine/Melphalan in Patients with Myelofibrosis

Abstract 1750

The Myeloproliferative Disorder-Research Consortium (MPD-RC) designed the first US prospective phase II study of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with primary myelofibrosis (PMF) or MF secondary to essential thrombocythemia (ET-MF) or polycythemia vera (PV-MF). Between May 2007 and March 2011, 66 patients were entered into the MPD-RC 101 study. Thirty-two patients received an allogeneic HSCT from a related and 34 patients from an unrelated donor. In the two groups diagnoses were: PMF: 44%, 74%; ET-MF: 47%, 12% and PV-MF: 9%, 15%, respectively. A reduced intensity regimen with fludarabine/melphalan (FluMel) ± ATG was used. Of 66 patients, 63 were at intermediate/high risk according to Lille score system and 3 patients were at low risk but had thrombocytopenia. Recipients of related and unrelated HSCT were comparable with respect to age (median: 54 vs 55 years), gender (M/F 19/13 vs 19/15), Lille score intermediate (63% vs 68%) or high risk (28% vs 32%) and time from diagnosis to transplant (median, range: 16, 1–247 vs 20, 2–341 months). At the time of transplant, 66% and 82% of patients in the related and unrelated cohorts had splenomegaly and 19% and 15% had previous splenectomy. Jak-2 V617F mutation was present in 38% and 50% and an abnormal karyotype was detected in 56% and 59% of patients with known status, respectively. Bone marrow stem cells were utilized in 19% of related and 9% of unrelated transplants, while in the remaining cases patients received peripheral blood stem cell (PBSC) grafts. Donor compatibility was assessed by molecular typing for HLA A, B, C, DRB1 and DQB1 antigens; inclusion criteria allowed enrollment with maximum 1 antigen mismatched donor. Thirty of 32 transplants (94%) in the related cohort and 25/36 (74%) in the unrelated cohort were fully matched. In transplants from related donor, engraftment of neutrophils and platelets occurred in 31/32 patients, One patient in this group experienced a secondary graft failure. In contrast, among patients in the unrelated group only 26/34 (76%) patients engrafted and of these 4 had a secondary graft failure post transplant. Median time to neutrophils > 0.5 × 10⁹/L and platelets >20 × 10⁹/L engraftment was: day 22 and day 28 in the related, and day 18 and day 28 in the unrelated cohort, respectively. Acute GVHD grade II-IV was observed in 37% related (grade III-IV: 12%) and in 42% unrelated transplants (grade III-IV: 21%). Based on the International Working Group criteria, in patients who were followed for at least 6 months there were 7 CR, 8 PR, and 11 CI among the 28 patients in the related group, and 5 CR, 1 PR, and 5 CI among the 16 patients in the unrelated group. After a median follow-up for survivors of 24 months, 25 patients (78%) in the related group are alive, 6 patients (18%) died for causes related to transplant (GVHD n=3, cardiac toxicity n=1, renal failure n=1, secondary cancer n=1) and 1 (3%) for progression of disease. In the unrelated group, 15 patients (44%) are alive at 12 months follow-up for survivors, 18 patients (53%) died for causes related to transplant and 1 patient (3%) due to relapse. Median survival time has not been reached in the related transplant group and is 7 months in the unrelated group (hazard ratio 4.2, 95% CI: 1.7–10.1, p<0.001). Survival in unrelated transplants was not associated with HLA matching, diagnosis, or the presence of Jak-2 mutation. In this prospective study a reduced intensity allogeneic HSCT with Flu/Mel regimen was very effective in patients with myelofibrosis transplanted from related donors. In unrelated transplants, a high rate of primary or secondary graft failure led to a high rate of transplant-related-mortality. For these patients a different conditioning regimen may be required.