Autologous Hematopoietic Stem Cell Infusion for Myelosuppression after Bcma-CART Therapy in Relapsed Myeloma Patients
Authors: Lin Quande , Han Lu , Zhou Jian , Liu Lina , Liu Yuzhang , Yu Fengkuan , Zhang YangLi , Zuo Wenli , Zhou Keshu , Fang Baijun , Gao Quanli , Wei Xudong , Liu Delong , Song Yongping 
Published: November 2019

Abstract
Background:
The adoption of B cell mature antigen (BCMA) targeted chimeric antigen receptor (CAR) T cells is demonstrating promise prospects in refractory relapsed multiple myeloma (RRMM), however the persistent severe myelosuppression remains a serious complication. Autologous hematopoietic stem cell infusion facilitates the recovery of hematopoietic function and has contributed to efficacy and safety in clinical trials with BCMA-specific CAR T cells. In this phase I clinical study of BCMA-specific CAR T cell therapy for RRMM, we applied autologous hematopoietic stem cell(auto-HSC) infusion to promote the hematopoietic recovery which may improve the efficacy of CAR T therapy.
Methods:
Eligible relapsed or treatment refractory MM patients had received lymphodepleting chemotherapy of FC regimen((Fludarabine 25 mg/m2 daily for 3 days, Cyclophosphamide 500 mg/m2 daily for 2 days)) before infusion of BCMA CAR T cells at a dose of 1.0×107 cells. We performed autologous hematopoietic stem cell infusion (2.1-3.6×108/kg for MNC cells and 1.8-2.6×106/kg for CD34+ cells) in patients with Ⅳ degree of myelosuppression sustained more than 30 days, and observe hematopoietic recovery of the patient.
Results:
A total of 23 patients developed grade Ⅳ myelosuppression. Seven of patients suffered grade Ⅳ myelosuppression for more than 30 days received autologous hematopoietic stem cell infusion, and all 7 patients recovered hematopoietic within 14 days after stem cell reinfusion. Patient 1 had myelosuppression after CART therapy, which was characterized by severe thrombocytopenia and manifested as bleeding. Auto-HSCs were infused on the 37th day after CART cell therapy. Hematopoiesis gradually recovered 4 days after infusion, platelets increased and returned to normal 13 days after auto-HSCs infusion. Patient 2 and 5 developed granulocytopenia after CART therapy. They were infused auto-HSCs on the 32nd and 33rd day after CART cell therapy respectively. Leukocytes of patient 2 and patients 5 gradually increased 2 days and 3 days after infusion, returned to normal 7 days and 9 days after auto-HSCs infusion, respectively. Patient 3 and 4 suffered IV degree of myelosuppression, referred as leukopenia, anemia and thrombocytopenia. Stem cell was infused on day 31st and 33rd after CART therapy, erythrocyte and platelet increased 3 days after reinfusion for patient 3, as for patient 4, erythrocyte and platelets increased 3 days and 5 days after infusion, respectively. Patient 6 developed severe pancytopenia, auto-HSCs were infused on 32 days after CART therapy, leukocytes gradually increased 3 days after infusion. Leukocyte and platelet increased to normal 6 and 11 days after stem cell infusion. Patient 7 is an elderly relapse who intend to receive auto-HSCT, however, owing to his advanced age, CART therapy was preferred. Grade IV myelosuppression occurred after CART cell infusion, patient had undergone neutropenia and severe. Auto-HSCs was infused on the 32nd day after CART cell therapy, granulocyte and erythrocyte gradually increased 5days after infusion, recovered 9 daysand14days after stem cell infusion.
Conclusions:
Our results demonstrate application of autologous stem cells in the CAR-T therapy, whose effect was similar to the role of hematopoietic stem cell infusion in transplantation after high-dose chemotherapy, which could promote the reconstruction of bone marrow hematopoietic, avoid serious infection and hemorrhage. It suggests that autologous stem cell infusion is also a worthwhile option when patients suffer from severe and sustained myelosuppression after treatment with CAR-T cells.

Disclosures
No relevant conflicts of interest to declare.