A Two-Year Follow-Up Of a Prospective Study Of Intensified Conditioning Regimen With High-Dose-Etoposide Allogeneic Hematopoietic Stem Cell Transplantation For Adult Acute Lymphoblastic Leukemia In China
Authors: Zhou Hongsheng , Fan Zhiping , Huang Fen , Zhang Yu , Dai Min , Xu Na , Yu Guopan , Xu Dan , Jiang Qianli , Sun Jing , Liu Qifa 
Published: October 2019

Background
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a major role for improving the outcome of adult acute lymphoblastic leukemia (ALL), especially for high-risk and refractory/relapsed patients. Intensified conditioning allo-HSCT is based on the hypothesis that intensifying condition regimen could overcome resistance, reduce tumor burden, and most importantly, spare enough time for slow-growing graft-versus-leukemia (GVL) effect and immune reconstitution to finally get rid of minimal residual disease (MRD).

Patient and Methods
A single-center, open-label, prospective study of intensified conditioning regimen with high-dose-etoposide allo-HSCT for adult ALL in China was performed from 2011 to 2013 in Nanfang hospital according to HDE-ALL-2011 (NCT01457040).

Results
A total of 97 patients were enrolled, including 36 female and 61 male, a median age of 25 years old (range 11-54). The molecular cytogenetics make-up consisted of 33 Ph-positive cases, 2 cases of MLL-rearranged cases. Of the whole cohort, 34 of 97 cases (35.1%) were refractory and/or relapsed patients. Forty-seven patients (48.4%) received HLA-matched sibling allo-HSCT, 26 patients (26.8%) underwent HLA-matched unrelated donor transplantation, 13 patients (13.4%) received HLA-haploidentical allo-HSCT and 11 patients (11.3%) received HLA-mismatched sibling transplantation. Ninety-four patients (96.9%) achieved complete engraftment and full-donor chimerism with a median of 14 days for neutrophils (0.5G/L) and 15 days for platelet (20G/L) and three patients failed to obtain engraftment. Forty patients (40.0%) received a median of 1 time (range 1-4) pre-emptive and/or MRD-guided donor lymphocyte infusion (DLI) from 2 or 3 months after transplantation. Acute III-IV grade graft-versus-host disease (GVHD) occurred in 15 patients, including 4 cases of DLI-induced GVHD, as 9 cases occurred in matched-sibling allo-HSCT group (9/47, 19.1%), 3 cases in MUD allo-HSCT (3/26, 11.5%) and 3 cases in HLA-haploidentical/mismatched allo-HSCT group (3/24, 12.5%). Twelve patients with III-IV GVHD attained durable complete remission with cyclosporine A, tacrolimus, methylprednisolone, cyclophosphamide, methotrexate, anti-CD25 antibody and mesenchymal stem cells (MSC). The overall incidence of EBV viremia was 23.7% (n=23) and 47.8% percent (n=11) of 23 patients received rituximab preemptive therapy. Six patients (6.2%) developed EBV-related post-transplant lymphoproliferative disorders (PTLD) and durable complete remission was achieved after integrated treatment with reduction in immunosuppression, rituximab-containing chemotherapies and donor-lymphocyte-infusion. CMV viremia occurred in 23.7% patients and 6 patient progressed to CMV-related interstitial pneumonia (IP, n=6), which accounted for 27.2% of transplantation-related mortality (TRM), followed by 18.2% of rapidly progressive brochiolitis obliterans (BO) after donor lymphocyte infusion (n=4), severe GVHD (n=3, 13.6%), diffuse alveolar hemorrhage(n=2, 9.1%), sinusoidal obstruction syndrome/venoocclusive disease (SOS/VOD, n=2, 9.1%), engraftment dysfunction (n=1, 4.5%), mitochondrial encephalopathy (n=1, 4.5%), thrombotic microangiopathy (TMA, n=1, 4.5%), infection (n=1, 4.5%) and myocardial infarction (n=1, 4.5%). With 2 year of Kaplan-Meier estimate of potential follow-up (KM-PF), 9 out of 97 patients relapsed after transplantation and died of primary disease. The 2-year overall survival of the whole cohort was 60.1%, with no significant difference (p=0.624) between patients in complete remission (59.3%) and refractory/relapsed patients (61.5%) before transplantation.

Conclusions
Intensified conditioning regimen with high-dose-etoposide allo-HSCT (HDE-ALL-2011) yielded a promising result, especially for high-risk and refractory/relapsed ALL, but it still deserves a better optimal balance between immuno/myelo-suppression and EBV/CMV-related complications, DLI and DLI-related side effects to reduce TRM.

Disclosures:
Zhou: Guangzhou Pearl River of Science & Technology New Star (No. 2011J2200069 to HS.Zhou): Research Funding. Liu:It was supported by 863 Program (No. 2011AA020105), National Public Health Grand Research Foundation (Grant No. 201202017): Research Funding; National Natural Science Foundation of China (Grant No.81000231, No.81270647) and Science and Technology Program of Guangzhou of China (11A72121174).: Research Funding.