Non-myeloablative allogeneic hematopoietic cell transplantation following fludarabine plus 2 Gy TBI or ATG plus 8 Gy TLI: a phase II randomized study from the Belgian Hematological Society

Abstract

BackgroundFew studies thus far have compared head-to-head different non-myelooablative conditioning regimens for allogeneic hematopoietic cell transplantation (allo-HCT).MethodsHere, we report the results of a phase II multicenter randomized study comparing non-myeloablative allo-HCT from HLA-identical siblings (n = 54) or from 10/10 HLA-matched unrelated donors (n = 40) with either fludarabine plus 2 Gy total body irradiation (Flu-TBI arm; n = 49) or 8 Gy TLI + anti-thymocyte globulin (TLI-ATG arm; n = 45) conditioning.ResultsThe 180-day cumulative incidences of grade II-IV acute GVHD (primary endpoint) were 12.2% versus 8.9% in Flu-TBI and TLI-ATG patients, respectively (P = 0.5). Two-year cumulative incidences of moderate/severe chronic GVHD were 40.8% versus 17.8% in Flu-TBI and TLI-ATG patients, respectively (P = 0.017). Five Flu-TBI patients and 10 TLI-ATG patients received pre-emptive DLI for low donor chimerism levels, while 1 Flu-TBI patient and 5 TLI-ATG patients (including 2 patients given prior pre-emptive DLIs) received a second HCT for poor graft function, graft rejection, or disease progression. Four-year cumulative incidences of relapse/progression were 22% and 50% in Flu-TBI and TLI-ATG patients, respectively (P = 0.017). Four-year cumulative incidences of nonrelapse mortality were 24% and 13% in Flu-TBI and TLI-ATG patients, respectively (P = 0.5). Finally, 4-year overall (OS) and progression-free survivals (PFS) were 53% and 54%, respectively, in the Flu-TBI arm, versus 54% (P = 0.9) and 37% (P = 0.12), respectively, in the TLI-ATG arm.ConclusionsIn comparison to patients included in the Flu-TBI arm, patients included in the TLI-ATG arm had lower incidence of chronic GVHD, higher incidence of relapse and similar OS.Trial registrationThe study was registered on ClinicalTrial.gov (NCT00603954) and EUDRACT (2010-024297-19).Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0098-9) contains supplementary material, which is available to authorized users.

Immune Recovery after Allogeneic Hematopoietic Stem Cell Transplantation Following Flu-TBI versus TLI-ATG Conditioning

“…Indeed, following both HLAhaploidentical and HLA-matched HCT, faster immune reconstitution has been associated with lower relapse rates and better survival (7,48), while favoring Treg homeostasis improved steroid-refractory chronic GVHD (41). In the current study, we compared immune recovery in a cohort of 53 patients included in a prospective multicenter randomized study comparing two widely used nonmyeloablative conditioning regimens (25). The main findings of the current analyses are discussed below.…”

“…The study was registered in clinicaltrial.gov (NCT00603954). The clinical results of the study (including the data from the 94 patients) have been reported elsewhere (25).…”

HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity

“…30 A previous multicenter randomized phase II study from Belgium comparing TLI-ATG to low-dose TBI-fludarabine in patients with HLA-matched donors showed similar outcomes with higher rates of NRM and GVHD in the TBI-fludarabine arm, higher rates of relapse in the TLI-ATG arm, and equivalent OS at 4 years. 31 Our data also compare favorably to other RIC regimens incorporating posttransplant cyclophosphamide (PT CY) or bortezomib for GVHD prophylaxis. Gaballa et al 32 used PT CY in combination with a RIC regimen of fludarabine, melphalan, and thiotepa in the setting of 9 of 10 MMUD HCT and haploidentical HCT and reported NRM rates at 1 year of 31% and 21%, respectively; acute GVHD grade II-IV at day 1100 rates of 33% and 28%, respectively, and grade III-IV rates of 13% and 3%, respectively; chronic GVHD rates at 2 years of 19% and 24%, respectively; and relapse rates at 1 year of 25% and 19%, respectively.…”

“…Male donor, male recipient 23 (32) 70 (36) Male donor, female recipient 14 (19) 50 (26) Female donor, male recipient 22 (31) 41 (21) Female donor, female recipient 13 (18) 32 (17) CMV serologic status Donor and/or recipient seropositive 54 (75) 130 (67) Donor and recipient seronegative 18 (25) 63 (33) Data are presented as n (%) unless otherwise indicated. *Other B-cell non-Hodgkin lymphoma includes 1 patient with nodal marginal zone lymphoma and 1 patient with lymphoplasmacytic lymphoma.…”

“…Prior autologous transplantation 9/36 (25) 34/104 (33) Myeloid malignancies 36 (50) 89 (46) Acute myeloid leukemia 23 (32) 59 (31) De novo acute myeloid leukemia 15 (21) 40 (21) Secondary acute myeloid leukemia ‡ 8 (11) 19 (10) Myelodysplastic syndrome and myeloproliferative neoplasms 8 (11) 27 (14) Chronic myeloid leukemia 5 (7) 3 (2) Prior autologous transplantation 2/36 (6) 0/89 (0) …”