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Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells.

ABSTRACT: Post-consolidation immunotherapy with histamine dihydrochloride and interleukin-2 has been shown to improve leukemia-free survival in acute myeloid leukemia in a phase III trial. For this study, treatment efficacy was determined among 145 trial patients with morphological forms of acute myeloid leukemia as defined by the French-American-British classification. Leukemia-free survival was strongly improved in M4/M5 (myelomonocytic/monocytic) leukemia but not in M2 (myeloblastic) leukemia. We also analyzed histamine H(2) receptor expression by leukemic cells recovered from 26 newly diagnosed patients. H(2) receptors were typically absent from M2 cells but frequently expressed by M4/M5 cells. M4/M5 cells, but not M2 cells, produced reactive oxygen species that triggered apoptosis in adjacent natural killer cells. These events were significantly inhibited by histamine dihydrochloride. Our data demonstrate the presence of functional histamine H(2) receptors on human AML cells and suggest that expression of these receptors by leukemic cells may impact on the effectiveness of histamine-based immunotherapy.

SUBMITTER: Aurelius J

PROVIDER: S-EPMC3590096 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells.

Aurelius Johan J Martner Anna A Brune Mats M Palmqvist Lars L Hansson Markus M Hellstrand Kristoffer K Thoren Fredrik B FB

Haematologica 20120611 12

Post-consolidation immunotherapy with histamine dihydrochloride and interleukin-2 has been shown to improve leukemia-free survival in acute myeloid leukemia in a phase III trial. For this study, treatment efficacy was determined among 145 trial patients with morphological forms of acute myeloid leukemia as defined by the French-American-British classification. Leukemia-free survival was strongly improved in M4/M5 (myelomonocytic/monocytic) leukemia but not in M2 (myeloblastic) leukemia. We also ...[more]

PMID: 22689678

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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.

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Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells.

Publications

Remission maintenance in acute myeloid leukemia: impact of functional histamine H2 receptors expressed by leukemic cells.

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