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Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome.

ABSTRACT: Chronic lymphocytic leukemia (CLL) remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced-intensity (RIC) and 32 with myeloablative conditioning (MAC) between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up of 5.9 years in surviving patients, the 5-year overall survival (OS) for the entire cohort is 63% for RIC regimens and 49% for MAC regimens (P=0.18). The risk of death declined significantly starting in 2004, and we found that 5-year OS for HSCT between 2004 and 2009 was 83% for RIC regimens compared with 47% for MAC regimens (P=0.003). For RIC transplantation, we developed a prognostic model based on predictors of progression-free survival (PFS), specifically remission status, lactate dehydrogenase, comorbidity score and lymphocyte count, and found 5-year PFS to be 83% for Score 0, 63% for Score 1, 24% for Score 2 and 6% for Score ?3 (P<0.0001). We conclude that RIC HSCT for CLL in the current era is associated with excellent long-term PFS and OS, and, as potentially curative therapy, should be considered early in the disease course of relapsed high-risk CLL patients.

SUBMITTER: Brown JR

PROVIDER: S-EPMC3519975 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome.

Brown J R JR Kim H T HT Armand P P Cutler C C Fisher D C DC Ho V V Koreth J J Ritz J J Wu C C Antin J H JH Soiffer R J RJ Gribben J G JG Alyea E P EP

Leukemia 20120814 2

Chronic lymphocytic leukemia (CLL) remains incurable with chemoimmunotherapy, and allogeneic hematopoietic stem cell transplantation (HSCT) offers the potential for cure. We assessed the outcomes of 108 CLL patients undergoing first allogeneic HSCTs, 76 with reduced-intensity (RIC) and 32 with myeloablative conditioning (MAC) between 1998 and 2009 at Dana-Farber Cancer Institute. With median follow-up of 5.9 years in surviving patients, the 5-year overall survival (OS) for the entire cohort is 6 ...[more]

PMID: 22955330

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Project description:BackgroundThe graft-versus-leukemia effect is able to induce clinical responses in patients with chronic lymphocytic leukemia treated with a reduced intensity conditioning regimen, followed by allogeneic stem cell transplantation. We investigated whether molecular remissions could be attained after reduced intensity conditioning and allogeneic stem cell transplantation in patients with relapsed chronic lymphocytic leukemia and whether the assessment of minimal residual disease might be used to predict the clinical outcome.Design and methodsMinimal residual disease was monitored by polymerase chain reaction using the immunoglobulin heavy-chain gene rearrangement as a molecular marker in 29 relapsed patients who achieved complete remission following reduced intensity conditioning and allogeneic stem cell transplantation. A nested-polymerase chain reaction with patient-specific primers derived from complementarity determining regions (CDR2 and CDR3) was carried out in all the patients. Real-time polymerase chain reaction was performed in patients whose nested reaction gave positive or mixed results.ResultsThree patterns of minimal residual disease were observed: negative (31%), mixed (24%), and always positive (45%). The cumulative incidence of relapse according to the minimal residual disease status at 6 and 12 months after transplantation was significantly different between polymerase chain reaction-negative and -positive patients (p=0.031 and p=0.04, respectively). Two-year disease-free survival was 93% and 46% for polymerase chain reaction-negative and -positive patients at 6 months after transplantation, respectively (p=0.012). Similarly, 2-year disease-free survival was 100% and 57% for polymerase chain reaction-negative and -positive patients at 12 months, respectively (p=0.037). No clinical or biological factors were predictive of the achievement of polymerase chain reaction negativity after allogeneic stem cell transplantation. Graft-versus-host disease was more frequent in patients who did not relapse (p=0.04). Quantitative monitoring of minimal residual disease was able to identify polymerase chain reaction-positive patients with a higher risk of relapse.ConclusionsThese findings demonstrate that relapsed patients can achieve molecular remission after reduced intensity conditioning and allogeneic stem cell transplantation and suggest a minimal residual disease-driven intervention that might be useful to prevent overt hematologic relapse.

Project description:BackgroundPatients with refractory/relapsed (r/r) acute B lymphocytic leukemia (B-ALL) can achieve complete response (CR) after chimeric antigen receptor T-cell (CAR-T) therapy, but recurrence occurs in the short term. To reduce recurrence and improve survival, CAR-T therapy followed by transplantation is a feasible option. We analyzed the long-term follow-up outcomes and the risk factors for allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CR by CAR-T therapy in this study.MethodsA total of 144 patients who underwent allo-HSCT after CAR-T therapy in our hospital were enrolled in this study. Target gene analysis was performed in 137 r/r B-ALL patients receiving allo-HSCT after CR by CAR-T therapy. Among the 137 patients, 87 were evaluated for germline predisposition gene mutations, and 92 were evaluated for tumor somatic gene mutations using NGS. The clinical factors, germline predisposition gene and somatic gene mutations associated with the prognosis of patients receiving transplantation after CAR-T therapy were analyzed using univariate Cox regression. Factors related to disease-free survival (DFS) and overall survival (OS) were analyzed using multivariate Cox regression analysis.ResultsIn 137 r/r B-ALL patients, the 2-year cumulative incidence of recurrence (CIR), OS and DFS in patients receiving allo-HSCT after CAR-T therapy was 31.5%, 71.4%, and 60.5%, respectively. The 2-year OS and DFS in MRD-negative patients were 80.9% and 69.3%, respectively. Univariate Cox analysis showed that pretransplant MRD positivity, fungal infection, germline EP300 mutation and somatic TP53 mutation were associated with a poor prognosis after transplantation; a TBI-based regimen was a protective factor for survival and recurrence after transplantation. Multivariate Cox regression analysis showed that the TBI-based regimen was an independent protective factor for DFS, fungal infection and MRD positivity were independent risk factors for DFS, and tumor somatic TP53 mutation and germline EP300 mutation were independent risk factors for DFS and OS.ConclusionGermline EP300 mutation and tumor somatic TP53 mutation are poor prognostic factors for posttransplant recurrence and survival in r/r B-ALL patients achieving CR after CAR-T therapy. The prognostic risk factors should be considered in adjusting treatment strategies to improve the efficacy of clinical diagnosis and treatment.

Dataset Information

Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome.

Publications

Long-term follow-up of reduced-intensity allogeneic stem cell transplantation for chronic lymphocytic leukemia: prognostic model to predict outcome.

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