Pre-Emptive Donor-Derived Innate Immune Cell Add-Back after Haploidentical Hematopoietic Stem Cell Transplantation to Reduce High Rate of Infection, Gvhd, and Non-Relapse Mortality

Abstract

<h3>Introduction</h3> Post-transplant cyclophosphamide has allowed alloHSCT using haploidentical donors. PTCy is very effective at reducing GVHD-causing T cells, but it has the unwanted effect of eliminating Natural Killer cells. We have developed a new reduced-intensity haploHSCT transplant conditioning regimen based on an a regimen developed for fully-matched donors with lymphoma: bendamustine 130 mg/m2 IV daily, and fludarabine 30 mg/m2 IV daily, for 3 days, +/- rituximab. We made additional modifications designed to improve NK immune recovery: 1.) no mycophenolate, 2.) no routine G-CSF, 3.) early tacrolimus taper starting on day +60, 4.) pre-emptive NK-enriched donor lymphocyte infusion on Day +8. <h3>Objectives</h3> Conduct a prospective clinical trial to evaluate the safety of bendamustine-fludarabine conditioning, PTCy, NK cell add-back, and short course tacrolimus for patients with myeloma or lymphoma undergoing haploHSCT. Assess clinical outcomes over the first year after transplantation. Efficacy Endpoints: Death or engraftment failure at D+30, death or severe chronic extensive GVHD at D+100. Test rate of survival, engraftment, and GVHD. Measure reconstitution of adaptive and innate lymphocyte subsets. Measure NK KIR repertoire recovery and assess for ‘missing self'. <h3>Methods</h3> This is a Phase I, single center, single cohort, open-label, proof-of-concept clinical trial to evaluate the safety of the BFRHaplo regimen (Figure 1) and preemptive CD56-selected DLI following PTCy for adults with myeloma or lymphoma. <h3>Results</h3> We have safety data on six patients (Table 1). Recovery of neutrophils and platelets is prompt. No primary or secondary graft failures have occurred. No patients have developed Grade III-IV or steroid-refractory acute GVHD. No organ toxicities, and no alkylator-alkylator toxicity from bendamustine – PTCy, have been observed. No instances of either veno-occlusive disease or transplant-related thrombotic microangiopathy, and no deaths, serious infections, or re-hospitalizations. One patient relapsed and is alive without GVHD receiving salvage therapy. We used single-step CD56 selection to prepare CD56-enriched donor lymphocyte infusions (Table 2). The one-step CD56 selection method has the attractive property of preserving CD3+/CD56+ cells, including NK/T and gdT. The target cell dose (> 1 million CD56+ cells/kg and < 1 million T cells/kg) was achieved for all patients. <h3>Conclusion</h3> The trial will establish whether BFRHaplo, and the infusion of cytotoxic NK and some T cells (< 1million/kg) without mycophenolate, is safe. Completion of this Phase I trial will lead to double-blind, placebo- controlled studies to assess the efficacy of CD56-selected immune cell add-back after PTCy in reducing the high rate of infection, GVHD, and mortality following haploidentical stem cell transplantation.