Reduced-Intensity or Myeloablative Allogeneic Hematopoietic Cell Transplantation for Myelofibrosis: A Side-By-Side Systematic Review/Meta-Analysis

Background: Despite availability of novel therapies, namely JAK inhibitors and immunomodulatory agents, for treatment of myelofibrosis, the disease remains incurable unless eligible patients are offered an allogeneic hematopoietic cell transplant (allo-HCT). Available data supporting allo-HCT in myelofibrosis are limited to single-arm prospective or retrospective studies (including data from registries) or single-center case series. No randomized controlled trial (RCT) has ever been conducted comparing the impact of dose-intensity of the conditioning regimen on post-transplant outcomes in patients with myelofibrosis. Accordingly, we performed a systematic review/meta-analysis of the published literature using PubMed and EMBASE from date of inception until 12/16/2015. We restricted inclusion criteria to studies published only as peer-reviewed manuscripts which included more than 10 patients.

Patients and methods: Our search strategy identified 907 publications, but only 29 (n=2,128 patients) met our inclusion criteria. Data were collected on treatment benefits (overall response rate (ORR), complete (CR) or partial response (PR), overall survival (OS)) and harms (grade 2-4 acute graft-versus-host disease (GVHD), 3-4 acute GVHD, chronic GVHD, non-relapse mortality (NRM), and graft failure) whenever available. We also assessed outcomes based on disease-risk stratification whenever possible. For the purposes of our analysis, low-risk encompassed (low-risk Lille/Dupriez/DIPSS), intermediate-risk (intermediate-risk Lille/Dupriez/int-1 DIPSS), and high-risk (high-risk Lille/Dupriez/Int-2 or high-DIPSS). All results are reported as pooled proportions.

Results: When using reduced-intensity conditioning (RIC) regimens, 7 prospective (n=281 patients) and 11 retrospective (n=532 patients) studies were identified. Pooled (rates) outcomes of RIC prospective studies were as follow: ORR=65% (95%CI=26-95%), CR=51% (95%CI=18-84%), OS= 69% (95%CI=58-80%), grade 2-4 acute GVHD= 37% (95%CI=27-48%), grade 3-4 acute GVHD= 22% (95%CI=7-44%), chronic GVHD= 38% (95%CI=22-55%), NRM= 23% (95%CI=12-37%), and graft failure= 6% (95%CI=1-12%). Pooled outcomes of RIC retrospective studies were as follow: ORR= 100% (95%CI=86-100%), CR=100% (95%CI=86-100%), OS= 51% (95%CI=43-58%), grade 2-4 acute GVHD= 35% (95%CI=30-39%), grade 3-4 acute GVHD=19% (95%CI=11-29%), chronic GVHD= 47% (95%CI=41-52%), NRM= 20% (95%CI=13-27%), and graft failure= 15% (95%CI=9-22%). For myeloablative conditioning (MAC) regimens, 0 prospective and 5 retrospective (n=132 patients) studies were identified. Outcomes were as follow: ORR= 40% (95%CI=21-61%), CR=40% (95%CI=21-61%), OS=56% (95%CI=42-70%), grade 2-4 acute GVHD= 46% (95%CI=26-66%), grade 3-4 acute GVHD=13% (95%CI=4-26%), chronic GVHD= 57% (95%CI=26-86%), NRM= 26% (95%CI=16-38%), and graft failure= 9% (95%CI=0-32%). Furthermore, Survival outcomes based on disease-risk stratification showed OS rates of 78% (95%CI=69-86%) for low-risk, 60% (95%CI=48-70%) for intermediate-risk, and 42% (95%CI=36-48%) for high-risk cases.

Conclusions: Notwithstanding the need of a RCT to help better understand the effect of dose-intensity of allo-HCT regimens (RIC vs. MAC) on outcomes, this systematic review/meta-analysis highlights encouraging OS rates of 51-69% when using RIC regimens with resulting pooled NRM rates of 20-23%. Rates of grade 2-4 acute and chronic GVHD appear, unsurprisingly, lower with RIC regimens; but high rates of graft failure remain a serious concern in myelofibrosis regardless of the intensity of the conditioning regimen.