Etiology and Spectrum of Non-Relapse Mortality after Reduced Intensity Allogeneic Hematopoietic Stem Cell Transplantation in Adults with Myeloid Neoplasms

Background: Reduced-intensity conditioning (RIC) provides graft-versus-disease effect with less treatment related toxicity, making allogeneic hematopoietic stem cell transplantation (HSCT) available to more recipients.  The objective was to describe the etiology and spectrum of non-relapse mortality (NRM) following RIC HSCT for myeloid neoplasms.

Methods:  After due IRB approval, consecutive patients, who underwent RIC HSCT for myeloid neoplasms between 2000 and 2014 at Mayo Clinic, Rochester were identified.  RIC regimens were Melphalan/Fludarabine or Busulfan/Fludarabine. Graft-versus-host disease (GVHD) prophylaxis was per institutional standards. Cause of mortality was retrospectively analyzed through clinical documentation.

Results:  200 patients, 125 (63%) males, median age 60 (range, 18 to 72) underwent RIC HSCT for myeloid neoplasms (AML, 59% [77% in CR]; MDS, 30% [52% without excess blasts]; myelofibrosis, 7.5%; and CML 3.5%). At last follow-up, 102 (51%) patients had died. Median follow-up was 14 months (range, 0-111).  Of the 102 patients, 41 (40%) patients had disease relapse (AML, 28 [61% in prior CR]; MDS, 11[72% with prior excess blasts]); and myelofibrosis, 2 (5 %).

NRM was documented in 59 (58%) of 102 patients that had died and 2 patients were lost to follow-up.  In 54 (92%) of the 59 patients, death was attributed to transplant-related complications (sepsis, 11 [20%]; multiple organ dysfunction syndrome (MODS) and sepsis, 10 [19%]; respiratory failure secondary to infection, 5 [9%]; acute GVHD, 9 [17%]; chronic GVHD, 12 [22%]; intracranial hemorrhage from thrombocytopenia, 4 [7%]; diffuse alveolar hemorrhage, 2 [4%]; and graft failure, 1 [2%]).  Amongst acute GVHD deaths (67% grade 4- all GI GVHD), CMV infection and steroid-induced myopathy contributed to death. In patients with chronic GVHD (83%  severe), associated causes of death included respiratory failure from obliterative bronchiolitis, encephalopathy, and MODS from transplant-associated microangiopathy.

The remaining 5 NRM patients died of non-transplant related complications;  unrelated malignancies (4) and traumatic intracranial hemorrhage (1).

Conclusion: Although RIC increases access to transplant for otherwise ineligible patients, it still poses significant mortality risk from disease relapse (20%) and transplant-related complications (27%).  No cases of sinusoidal obstruction syndrome were seen in our series.