A Novel Reduced Intensity Conditioning Regimen for Patients with High Risk Hematologic Malignancies Undergoing Conventional Allogeneic Stem Cell Transplantation

Introduction: Reduced intensity conditioning (RIC) allows older patients and those with comorbidities to undergo allogeneic hematopoietic stem cell transplantation. In an effort to balance the risks of transplant-related mortality (TRM) associated with high-dose myeloablative (MA) conditioning against the risk of relapse after non-myeloablative (NMA) conditioning in cord blood transplantation (CBT), we investigated CBT using a novel RIC regimen of cyclophosphamide 50mg/kg, fludarabine 150mg/m², thiotepa 10mg/kg and 400 cGy total body irradiation (Cy50/Flu150/Thio10/TBI400), with favorable results (Ponce et al, BBMT 2013). We now report outcomes of allograft using this conditioning regimen and adult donors.

Methods: Twenty consecutive patients (median age 51 years, range 27-69) underwent Cy50/Flu150/Thio10/TBI400 conditioning for the treatment of AML (CR1 = 2, CRi = 2, relapse = 2), ALL (CR2=1, PR=1) CMML (CR = 1, PR = 1), NHL (CR1 = 2, CR2 = 1, CR3 = 1, refractory = 5) and plasmacytoid dendritic neoplasm (n = 1). Most (n = 16) had high-risk disease and a median HCT-CI of 1 (range 0-7). All patients received unmodified peripheral blood stem cell transplants (9 HLA-matched related, 9 HLA-matched unrelated, and 2 HLA-mismatched unrelated donors). Graft-versus-host disease (GVHD) prophylaxis was with tacrolimus/methotrexate (MTX) (n = 5), ortacrolimus/sirolimus with MTX (n = 12) or without MTX (n = 3). One recipient of a mismatched graft also received anti-thymocyte globulin.

Results: All patients engrafted with a median time to neutrophil engraftment of 12 days (range 9-19).  The cumulative incidence of day 100 grade II acute GVHD was 30% (95%CI: 12-51) with no patient having grade III-IV disease. At 2 years, 42% (95%CI: 19-64) of patients had developed chronic GVHD of whom 2 patients had moderate and 2 had severe disease. Two-year TRM was 23% (95%CI: 6-46) with 2 patients dying of GVHD and 2 from organ toxicity.  With a median follow-up of survivors of 19.4 months (range 4.1-59.1 months), the 1 and 2-year overall survival (OS) are 74% (95%CI: 48-88) and 59% (95%CI: 32-79), and 1 and 2-year progression-free survival (PFS) are 68% (95%CI: 43-85) and 53% (95%CI: 27-74), respectively.

Conclusion: Adult donor allograft after Cy50/Flu150/Thio10/TBI400 conditioning is associated with high rates of engraftment, acceptable TRM, and promising OS and PFS in patients with high-risk hematologic malignancies. This regimen is an alternative to both high-dose MA and NMA conditioning and warrants further prospective investigation.

Figure 1.