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Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia.

ABSTRACT: IL-2 is a natural, T cell-derived cytokine that stimulates the cytotoxic functions of T and natural killer cells. IL-2 monotherapy has been evaluated in several randomized clinical trials (RCTs) for remission maintenance in patients with acute myeloid leukemia (AML) in first complete remission (CR1), and none demonstrated a significant benefit of IL-2 monotherapy. The objective of this meta-analysis was to reliably determine IL-2 efficacy by combining all available individual patient data (IPD) from 5 RCTs (N = 905) and summary data from a sixth RCT (N = 550). Hazard ratios (HRs) were estimated using Cox regression models stratified by trial, with HR < 1 indicating treatment benefit. Combined IPD showed no benefit of IL-2 over no treatment in terms of leukemia-free survival (HR = 0.97; P = .74) or overall survival (HR = 1.08; P = .39). Analyses including the sixth RCT yielded qualitatively identical results (leukemia-free survival HR = 0.96, P = .52; overall survival HR = 1.06; P = .46). No significant heterogeneity was found between the trials. Prespecified subset analyses showed no interaction between the lack of IL-2 effect and any factor, including age, sex, baseline performance status, karyotype, AML subtype, and time from achievement of CR1 to initiation of maintenance therapy. We conclude that IL-2 alone is not an effective remission maintenance therapy for AML patients in CR1.

SUBMITTER: Buyse M

PROVIDER: S-EPMC3539044 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia.

Buyse Marc M Squifflet Pierre P Lange Beverly J BJ Alonzo Todd A TA Larson Richard A RA Kolitz Jonathan E JE George Stephen L SL Bloomfield Clara D CD Castaigne Sylvie S Chevret Sylvie S Blaise Didier D Maraninchi Dominique D Lucchesi Kathryn J KJ Burzykowski Tomasz T

Blood 20110425 26

IL-2 is a natural, T cell-derived cytokine that stimulates the cytotoxic functions of T and natural killer cells. IL-2 monotherapy has been evaluated in several randomized clinical trials (RCTs) for remission maintenance in patients with acute myeloid leukemia (AML) in first complete remission (CR1), and none demonstrated a significant benefit of IL-2 monotherapy. The objective of this meta-analysis was to reliably determine IL-2 efficacy by combining all available individual patient data (IPD) ...[more]

PMID: 21518931

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Project description:Before the era of tyrosine kinase inhibitors (TKIs), interferon-alpha (IFN-?) was the treatment of choice in chronic myeloid leukemia (CML). Curiously, some IFN-? treated patients were able to discontinue therapy without disease progression. The aim of this project was to study the immunomodulatory effects of IFN-? in CML patients in prolonged remission and isolate biological markers predicting response. Due to rarity of patients on IFN-? monotherapy, a relatively small cohort of patients still on treatment (IFN-ON, n?=?10, median therapy duration 11.8 years) or had discontinued IFN-? therapy but remained in remission for >2 years (IFN-OFF, n?=?9) were studied. The lymphocyte immunophenotype was analyzed with a comprehensive flow cytometry panel and plasma cytokine levels were measured with multiplex bead-based assay. In addition, the clonality status of different lymphocyte subpopulations was analyzed by TCR ?/? rearrangement assay. Median NK-cell absolute number and proportion from lymphocytes in blood was higher in IFN-OFF patients as compared to IFN-ON patients or controls (0.42, 0.19, 0.21×10(9)/L; 26%, 12%, 11%, respectively, p<0.001). The proportion of CD8+ T-cells was significantly increased in both patient groups and a larger proportion of T-cells expressed CD45RO. Most (95%) patients had significant numbers of oligoclonal lymphocytes characterized by T-cell receptor ?/? rearrangements. Strikingly, in the majority of patients (79%) a distinct clonal V?9 gene rearrangement was observed residing in ??(+) T-cell population. Similar unique clonality pattern was not observed in TKI treated CML patients. Plasma eotaxin and MCP-1 cytokines were significantly increased in IFN-OFF patients. Despite the limited number of patients, our data indicates that IFN-? treated CML patients in remission have increased numbers of NK-cells and clonal ??(+) T-cells and a unique plasma cytokine profile. These factors may relate to anti-leukemic effects of IFN-? in this specific group of patients and account for prolonged therapy responses even after drug discontinuation.

Project description:BackgroundData from a randomized multinational phase 3 trial of 320 adults with acute myeloid leukemia (AML) demonstrated that maintenance therapy with 3-week cycles of histamine dihydrochloride plus low-dose interleukin-2 (HDC/IL-2) for up to 18 months significantly improved leukemia-free survival (LFS) but lacked power to detect an overall survival (OS) difference.PurposeTo assess the consistency of treatment benefit across patient subsets and the robustness of data with respect to trial centers and endpoints.MethodsForest plots were constructed with hazard ratios (HRs) of HDC/IL-2 treatment effects versus no treatment (control) for prospectively defined patient subsets. Inconsistency coefficients (I²) and interaction tests (X²) were used to detect any differences in benefit among subsets. Robustness of results to the elimination of individual study centers was performed using "leave-one-center-out" analyses. Associations between treatment effects on the endpoints were evaluated using weighted linear regression between HRs for LFS and OS estimated within countries.ResultsThe benefit of HDC/IL-2 over controls was statistically consistent across all subsets defined by baseline prognostic variables. I² and P-values of X² ranged from 0.00 to 0.51 and 0.14 to 0.91, respectively. Treatment effects were statistically significant in 14 of 28 subsets analyzed. The "leave-one-center-out" analysis confirmed that no single center dominated (P-values ranged from 0.004 to 0.020 [mean 0.009]). The HRs representing the HDC/IL-2 effects on LFS and OS were strongly correlated at the country level (R² = 0.84).LimitationsSmall sample sizes in some of the subsets analyzed.ConclusionsThese analyses confirm the consistency and robustness of the HDC/IL-2 effect as compared with no treatment. LFS may be an acceptable surrogate for OS in future AML trials. Analyses of consistency and robustness may aid interpretation of data from multicenter trials, especially in populations with rare diseases, when the size of randomized clinical trials is limited.Trial registrationClinicalTrials.gov: NCT00003991.

Dataset Information

Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia.

Publications

Individual patient data meta-analysis of randomized trials evaluating IL-2 monotherapy as remission maintenance therapy in acute myeloid leukemia.

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