Flu/Mel/TBI Peripheral Blood Haploidentical Stem Cell Transplantation with Post-Transplant Cyclophosphamide and Bortezomib (Cy2Bor3): A Pilot Study

Bortezomib (Bor) can inhibit dendritic cell proliferation and blocks the expression of coreceptors CD80, CD86 and other favorable immunomodulatory effects that prevent GVHD and enhance immune reconstitution. However, this was dose- and time-dependent in mice. When bor is started later post-transplant (days 5–7) or given early and then continued with the delayed administration, there was increased GVHD-dependent morbidity and gut toxicity. Others reported the addition of Bor on days 0 and +3 with post-transplant cyclophosphamide (PTCY) in MRD, with addition of ATG for MUD, and in another study with PTCy and Abatacept with or without ATG. Here we report the safety outcome of incorporating the addition of 3 doses of Bor to PTCy in the setting of peripheral blood (PB) haploidentical stem cell transplantation (Haplo-SCT). Methods: This is a single center open label pilot study. Eligible patients received Fludarabine, Melphalan, and TBI 200 cGy followed by haplo-SCT and PTCY. Bor was administered at 1.3mg/m2 on day+1, +4 and +7. Tacrolimus and mycophenolate were started on day+5. Safety analysis was performed after 9 patients were enrolled. Results: Patients enrolled were 2 females and 7 males. 6 African America, 4 Caucasian and 1 Hispanic. Median age was 58 (26-68 Donors were 3 brothers, 4 sons, 1 mother and 1 sister. Disease risk index was high in 3, intermediate in 5, and low in 1. Five patients had AML, and two had ALL with Myeloma (MM), one had B ALL involving CNS, and one had CML. CMV recipient status was negative in two and positive in 7. HCT-CI was 0-6. Median CD34 and CD3 infused were 4.36 × 106 and 1.7 × 108/kg recipient respectively. Six patients had cytokine release syndrome (CRS) with ASTCT grade of 1. Four patients had neutropenic fever, and one patient had engraftment fever. Median neutrophils and platelets engraftment were 16 and 26 days respectively. Chimerism post SCT was ≥99% donor at day 30 for all patients. No graft failure. Median time to follow up is 1494 days. Two patients died, one had high DRI with history of 3 inductions died of relapse, and one died of fungal infection. All other patients are alive and off any IS. Acute GVHD grade II developed in 1 patient, none had grade III-IV. Moderate chronic GVHD developed in one patient, none had severe cGVHD, Fig 1. Two patients had reactivation of CMV, 2 had EBV, one had adenovirus, 3 had HHV6, all resolved. At 1 year for 7 evaluable patients IgG were >400 mg/dl and CD4 > 200 cells/ul. Conclusions: Cy2Bor3 post PB Haplo-SCT was well tolerated in this small number of patients. Bor did not affect engraftment. We did not observe high grade CRS, and only low rates and grades of GVHD. Viral reactivations were observed in these high risk and heavily pre-treated patients but were manageable and did not affect patients’ outcomes. These results are encouraging. The trial is ongoing. (ClinicalTrials.gov ID: NCT03850366)