Abstract
Background: With PTCy as GVHD prophylaxis, outcomes of NMA haplo and matched BMT are similar, and relapse rather than toxicity is the leading cause of treatment failure. Early discontinuation of IS may augment a graft-versus-tumor effect and permit early implementation of strategies to reduce relapse, but may increase GVHD. We present a completed, prospective single-center trial of stopping tacrolimus (tacro) 3 or 4 months earlier than our Day (D) 180 standard after NMA haplo BMT (ClinicalTrials.gov: NCT01342289). Methods: From 8/2011-11/2015,105 evaluable patients (pts) with hematologic malignancies received NMA haplo BMT on this trial. The primary objective was to evaluate the feasibility and safety of reduced-duration tacro, stopping tacro without taper before D 180.Transplant criteria included age ≤ 75, ECOG PS ≤ 2, LVEF ≥ 35%, FEV1 and FVC ≥ 40% predicted, transaminases < 5 x ULN and no prior allogeneic BMT. All received Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete bone marrow. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and tacro from D 5. Pretransplantation, pts were assigned to stop tacro early if eligible, contingent on having ≥ 5% donor T cells at ~D 56 onward, no relapse and no grade 2-4 acute or significant chronic GVHD. Tacro was first planned through D 90 (n=47), then through D 60 (n=55). A D 120 cohort (n=3) enrolled while D 90 safety data were maturing. For pts ineligible for planned early tacro cessation, IS was individualized and continued to at least D 180. Monitoring rules declared reduced IS feasible if ≥ 33% of pts stopped tacro early as planned. Safety stopping rules for early tacro cessation were based on ≥ 65% probability of a ≥ 20% incidence of grade 3-4 acute plus severe chronic GVHD, ≥ 10% nonrelapse mortality (NRM) or ≥ 5% graft failure, measured from the tacro stop date to ~D 180. Historical data from 212 haplo transplants at our center using the same regimen but tacro until D 180 informed safety risk calculations. Results: Of the 105 pts (median age 61, range 13-74), the most common diagnoses were acute leukemia (50%), MDS (17%), NHL (16%) and HL (8%). By refined Disease Risk Index, 11% were low risk, 70% intermediate and 19% high. Shortened IS was feasible in 63 pts (60%) overall. Ineligibility for shortened IS was due most commonly to GVHD, followed by low donor chimerism or graft failure and early relapse. Of the 47 pts in the D 90 cohort (median follow-up 44 months), 23 (49%) stopped tacro early as planned. Safety stopping criteria were not met. Of these 23 pts, 16 (70%) had no safety events before D 180, 5 (22%) developed grade 2 acute GVHD (1 complicated by severe chronic GVHD) and 2 (9%) developed grade 3-4 acute GVHD. Of the 55 pts in the D 60 cohort (median follow-up 14 months), 38 (69%) stopped tacro early as planned, and safety stopping criteria were likewise not met. Of these 38 pts, 25 (66%) had no safety events before D 180, 1 developed graft failure, 9 (24%) developed grade 2 acute GVHD and 3 (8%) developed grade 3-4 acute GVHD. GVHD outcomes by cohort relative to historical outcomes are shown in Figures A and B. In both cohorts, the D 180 CuI of grade 2-4 acute GVHD was < 40% and was < 10% for grade 3-4 acute GVHD and NRM. The 1-year CuI of any chronic GVHD was 11% for the D 90 arm and 13% for the D 60 arm (12% historically). The 1-year probabilities of PFS, OS and GVHD-free relapse-free survival (GRFS, Figure C) were 40%, 59% and 27% respectively for the D 90 arm and 63%, 77% and 53% respectively for the D 60 arm. Conclusion: These data suggest that reduced-duration tacro is feasible and carries an acceptable safety profile in pts receiving NMA haplo BMT with PTCy. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with tacro until D 180. A larger prospective study is needed to define the optimal duration of IS that balances GVHD risk and relapse risk. However, these data show that many pts (60% in this trial) can discontinue tacro without taper well before D 180. There is even a suggestion of improved PFS and GRFS in the D 60 arm compared to the D 90 arm, although the trial was not powered for these endpoints. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early tacro cessation, provides an ideal setting to incorporate novel posttransplantation approaches for relapse reduction.
No relevant conflicts of interest to declare.
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