Treatment-related mortality and graft-versus-leukemia activity after allogeneic stem cell transplantation for chronic lymphocytic leukemia using intensity-reduced conditioning

Abstract

Allogeneic stem cell transplantation (SCT) using reduced-intensity conditioning (RIC) has potential to be a promising treatment of aggressive chronic lymphocytic leukemia (CLL). Since available clinical data obtained with this novel approach are very limited, we have performed a survey on this issue. Data of 77 patients were collected from 29 European Group for Blood and Marrow Transplantation centers. Median age was 54 (30-66) years, and the median number of previous chemotherapy regimens was 3 (0-8). HLA-identical sibling donors were used in 81% of the cases. Moderate conditioning regimens (mainly low-dose total body irradiation (TBI) or fludarabine-cyclophosphamide combinations) were administered to 56% of the patients, whereas the remainder received more intense conditioning consisting of fludarabine-busulfan or high-dose melphalan combinations. In 40% of the patients, in vivo T-cell depletion (TCD) with anti-thymocyte globulin or CAMPATH-1H was part of the conditioning regimen. Cumulative treatment-related mortality (TRM) was 18% (95% CI 9; 27) after 12 months. Complete chimerism as well as best response was not achieved immediately post-transplant but took a median of 3 months to develop. The 2-year probability of relapse was 31% (95% CI 18; 44), with no event occurring later than 12 months post transplant in the absence of TCD. With one exception, relapses were not observed after onset of chronic graft-versus-host disease. Event-free and overall survival at 24 months were 56% (95% CI 43; 69) and 72% (95% CI 61; 83), respectively. The median follow-up was 18 (1-44) months. Donor lymphocyte infusions or secondary transplants were performed in 19 patients with insufficient disease control and/or incomplete donor chimerism post-transplant, leading to a response in seven patients (37%). Preliminary multivariate analysis identified less than PR at transplant (hazard ratio (HR) 3.5; P&<0.01) and alternative donor (HR 3.1; P=0.02) as significant risk factors for relapse, whereas number of previous regimens >2 (HR 5.4; P=0.03), TBI (HR 2.5; P=0.05), and alternative donor (HR 2.3; P=0.08) were risk factors for survival. We conclude that RIC might favorably influence the outcome after allogeneic SCT for CLL by reducing TRM while preserving graft-versus leukemia activity.

Chronic Lymphocytic Leukemia: Recent Advances in Diagnosis and Treatment

“…Further proof of a GVL effect is demonstrated by the induction of complete remission of CLL in many patients with persistent disease following the administration of donor leukocyte infusion [65]. Finally, allotransplant recipients experiencing chronic graft-versus-host disease (GVHD) have a significantly lower risk for CLL relapse than patients experiencing no GVHD [66].…”

Efficacy of cisplatin-based immunochemotherapy plus alloSCT in high-risk chronic lymphocytic leukemia: final results of a prospective multicenter phase 2 HOVON study

“…[1][2][3][4][5][6] Evidence for a GvL effect comes from the observation that responses can occur after discontinuation of immunosuppression, [7][8][9] after donor lymphocyte infusion 10,11 and after onset of chronic GvHD (cGvHD). 7,[12][13][14] AlloSCT overcomes the poor prognostic impact of fludarabine refractoriness and the presence of deletion(17p)[del (17p)], [1][2][3]8,15,16 and the GvL effect seems to be preserved after reduced intensity conditioning. 1,8,15,16 Therefore, alloSCT was proposed for patients with poor survival with non-transplant treatments: (1) purine analog refractory/relapsing (R/R) o12 months, or (2) R/R o2 years after purine-analog-based combination therapy or (3) del(17p)/ TP53 abnormalities present (EBMT Transplant Consensus on alloSCT in CLL).…”

“…7,[12][13][14] AlloSCT overcomes the poor prognostic impact of fludarabine refractoriness and the presence of deletion(17p)[del (17p)], [1][2][3]8,15,16 and the GvL effect seems to be preserved after reduced intensity conditioning. 1,8,15,16 Therefore, alloSCT was proposed for patients with poor survival with non-transplant treatments: (1) purine analog refractory/relapsing (R/R) o12 months, or (2) R/R o2 years after purine-analog-based combination therapy or (3) del(17p)/ TP53 abnormalities present (EBMT Transplant Consensus on alloSCT in CLL). 17 High disease burden and chemorefractory disease at the time of alloSCT have been identified as negative predictors of PFS.…”

Comparing efficacy of reduced-toxicity allogeneic hematopoietic cell transplantation with conventional chemo-(immuno) therapy in patients with relapsed or refractory CLL: a Markov decision analysis

“…The following search strategy was used to identify potential studies: ((((('Leukemia, Lymphocytic Table 2). 18,[46][47][48][49][50][51][52][53][54] From the primary articles identified, the probabilities of each outcome of interest were abstracted and summarized as a pooled estimate using random-effects meta-analysis. The resultant pooled estimate was used to define transition probabilities in the model.…”