Attainment of Minimal Residual Disease Negative State Is Crucial for Successful Outcome of Reduced Intensity Conditioning Allogeneic Stem Cell Transplantation in Advanced Chronic Lymphocytic Leukemia (CLL).
Authors: Andritsos Leslie , Hamadani Mehdi , Heerema Nyla A. , Benson Don , Hofmeister Craig C. , Blum William , Flynn Joseph , Jones Jeffrey Alan , Elder Patrick , Lin Thomas S. , Lozanski Gerard , Byrd John C. , Devine Steven 
Published: April 2020

Abstract
Allogeneic hematopoietic stem cell transplantation (ASCT) may produce long-term remissions in patients with CLL, however toxicity has limited the success of myeloablative regimens. We pursued a strategy of reduced intensity conditioning (RIC) allogeneic stem cell transplantation (ASCT) in patients (pts) with heavily pretreated relapsed and/or refractory CLL. Twenty-seven pts with advanced CLL underwent ASCT following RIC at our institution between March 2002 and May 2008. There were 20 male and 7 female pts with a median age of 52 years (range 43–69 yrs).Median number of prior therapies was 3 (range 2–11). 26 pts (96%) had previously received fludarabine (F) based chemotherapy. 55% (n=15) had chemorefractory disease. Karyotype assessment by FISH (Fluorescent in situ hybridization) revealed high-risk cytogenetics in 55% (n=15) of the pts (−17p13.1 or −11q22–23). Donors were matched siblings (n=14) or unrelated volunteers (n=13). Stem cell source was peripheral blood (n=26) or bone marrow (n=1). Minimal residual disease (MRD) was assessed with 4-color flow cytometry on bone marrow biopsy specimens posttransplantation. Conditioning regimens included F/TBI/Campath (n=8), F/Busulfan with (n=9) or without ATG (n=6), and F/Cyclophosphamide (n=4). GVHD prophylaxis consisted of tacrolimus/MMF (n=8) or tacrolimus/methotrexate (n=19). All pts engrafted neutrophils and platelets promptly (median 16 and 20 days, respectively). Following allografting 15 pts (55%) achieved complete remission (CR), while 5 were in partial remission (PR). Overall response rate (CR+PR) was 74%. 13 pts (48%) in CR were MRD negative. Among pts with chemorefractory disease the overall response rate was 73%, with 8 pts achieving CR (7 MRD negative). Compared to pts with high-risk cytogenetics, those with low-risk cytogenetics were more likely achieve MRD negative state (58% vs. 40%). No impact of conditioning regimen or development of chronic GVHD with MRD negative state was seen. Rates of grade II–IV and III–IV acute GVHD were 55% (n=15) and 11% (n=3) respectively. 19 pts (70%) developed chronic GVHD, while extensive chronic GVHD was seen 37% (n=10). Cumulative incidence of relapse was 25%. 4 pts underwent DLI at relapse. Two of these pts remain in CR at +15 months post DLI. A fifth patient received DLI to successfully eradicate MRD. The median follow-up of surviving patients is 15 months (range 3–70 months). Day 100 and overall non-relapse mortality was 0% and 11% (n=3) respectively. At last followup 7 pts have died. Causes of death included disease progression=4, GVHD=1, second malignancy=1, and hepatic failure=1. Rates of overall survival (OS) and progression free survival (PFS) at 2 years are 61% and 41% respectively. On univariate analysis donor type, remission at transplant, and number of prior therapies were not associated with OS or PFS. Pts with high-risk cytogenetics by FISH showed trends towards worse OS (31% vs. 75%; p-value=0.13) and PFS (21% vs. 57%; p-value=0.09). Pts younger than 55yrs had superior OS (p-value=0.05) and PFS (0.005). Pts achieving MRD negative state had superior PFS (57% vs. 29%; p-value=0.01), and trends toward improved OS (67% vs. 57%; p-value=0.13). PFS advantage in MRD negative pts persisted even after adjusting for cytogenetic riskcategories. On multivariate analysis only MRD negative state remained significant for superior PFS (p-value=0.01; 95% CI 0.008–0.61). In conclusion, RIC regimens for ASCT in CLL are associated with low TRM, and approximately half of pts were able to achieved MRD negative status. These pts experienced durable remissions, regardless of cytogenetic risk status. Novel strategies promoting elimination of MRD following allografting, especially in high-risk CLL pts, are warranted.