Allogeneic Hematopoietic Cell Transplantation (HCT) with Nonmyeloablative Conditioning after Failed Myeloablative HCT: Factors Affecting Outcomes.
Authors: Baron Frederic , Storb R. , Storer B. , Maloney D. , Maris M. , Niederwieser D. , Shizuru J. , Chauncey T. , Bruno B. , Forman S. , McSweeney P. , Maziarz R. , Pulsipher M. , Agura E. , Sorror M. , Wade J. , Sandmaier B. 
Published: April 2020

We describe data from 147 consecutive patients (median age, 46; range, 9–73 yrs) who had failed myeloablative conventional autologous (n=135), allogeneic (n=10), or syngeneic (n = 2) HCT, and were given HLA-matched related (MRD) (n=62) or unrelated (URD) (n=85) HCT after conditioning with 2 Gy TBI with or without 90 mg/m2 of fludarabine with the aim of identifying predictive factors for HCT outcomes. Postgrafting immunosuppression consisted of cyclosporine (CSP) and mycophenolate mofetil (MMF). Median times between failed HCT and nonmyeloablative HCT were 22 (range, 3–128) months for MRD recipients and 25 (range, 4–222) months for URD recipients, respectively. Median follow-up for surviving patients was 27 (range, 7–66) months. Comorbidities at HCT were scored according to the HCT-specific comorbidity index (HCT-CI, Sorror et al. Blood 2005). Sustained engraftment was achieved in 141 patients, while 6 (5 URD and 1 MRD) rejected their grafts 13 to 1123 days after HCT. Median donor T-cell chimerism levels on days 28, 56, 84, 180 and 365 after HCT were 95%, 97%, 97%, 99% and 100%, respectively. Grades II, III and IV acute GVHD were seen in 36%, 15%, and 5% of MRD recipients, and 48%, 8%, and 7% of URD recipients, respectively. Extensive chronic GVHD occurred in 47% of MRD recipients and 57% of URD recipients. Three-yr probabilities of nonrelapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) were 31%, 48%, 22% and 32% in MRD recipients and 34%, 37%, 29% and 42% in URD recipients, respectively. The best outcomes were observed in patients with non-Hodgkin lymphoma (NHL), while patients with multiple myeloma and Hodgkin disease had poor outcomes due to high incidences of relapse/progression (Table 1). Pre-transplant factors associated with better PFS in multivariate analyses were chemosensitive malignancy (CR/PR) (P=0.0009), absence of comorbidity (HCT-CI score 0) (P=0.02), and URD (P=0.03). Pre-transplant factors associated with better OS in multivariate analyses were chemosensitive malignancy (CR/PR) at HCT (P=0.02), and absence of comorbidity (HCT-CI score 0) at HCT (P=0.008). In time-dependent analyses, grade II-IV acute GVHD was associated with increased NRM (HR=2.56, P=0.008), and a trend for increased risk of overall mortality (HR 1.53, P=0.07), while chronic GVHD was associated with a lower risk of relapse (HR 0.47, P=0.05) and no increase in overall mortality (HR 0.84, P=0.53). In conclusion, encouraging outcomes could be achieved with nonmyeloablative conditioning in selected patients having failed high-dose HCT, particularly in patients with NHL. Results with URD were as least as good than those with MRD, suggesting that this approach should not be restricted to patients with a MRD.

Table 1: Survival according to diagnosis OS @ 3 yrs PFS @ 3 yrs NHL-MCL (n=14) 64% 57% NHL-Indolent (n=12) 56% 56% NHL-Aggressive (n=24) 40% 36% Hodgkin Disease (n=35) 33% 9% CML/AML/MDS (n=35) 31% 27% Multiple myleoma (n=22) 26% 0% Other (n=5) 27% 30%