Phase I/II study of the deacetylase inhibitor panobinostat after allogeneic stem cell transplantation in patients with high-risk MDS or AML (PANOBEST trial)

Bug, Gesine; Burchert, Andreas; Em, Wagner; Kröger, Nicolaus; Berg, Tobias; Güller, Saskia; Metzelder, Stephan; Wolf, Andrea; Hünecke, S; Bader, Peter; Schetelig, Johannes; Serve, Hubert; Ottmann, Oliver G.

doi:10.1038/leu.2017.242

Cited by 78 publications

(50 citation statements)

References 15 publications

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“…Until the article is received, the median overall survival (OS) and relapse-free survival have not been reached after a median follow-up of 22 months [79]. This result was also consistent with another phase Ia/II panobinostat clinical trial, whose panobinostat-related G3/4 adverse events included thrombocytopenia (41.5%), fatigue (21%), and neutropenia (21%) [94].…”

Section: Hdac6 Inhibitorssupporting

confidence: 69%

Histone deacetylase 6 in cancer

et al. 2018

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Histone acetylation and deacetylation are important epigenetic mechanisms that regulate gene expression and transcription. Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family that not only participates in histone acetylation and deacetylation but also targets several nonhistone substrates, such as α-tubulin, cortactin, and heat shock protein 90 (HSP90), to regulate cell proliferation, metastasis, invasion, and mitosis in tumors. Furthermore, HDAC6 also upregulates several critical factors in the immune system, such as program death receptor-1 (PD-1) and program death receptor ligand-1 (PD-L1) receptor, which are the main targets for cancer immunotherapy. Several selective HDAC6 inhibitors are currently in clinical trials for cancer treatment and bring hope for patients with malignant tumors. A fuller understanding of HDAC6 as a critical regulator of many cellular pathways will help further the development of targeted anti-HDAC6 therapies. Here, we review the unique features of HDAC6 and its role in cancer, which make HDAC6 an appealing drug target.

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Section: Hdac6 Inhibitorssupporting

confidence: 69%

Histone deacetylase 6 in cancer

et al. 2018

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“…Given the limited number of patients and the lack of a control arm, a definitive ranking of outcome results is of course difficult so far but they suggested a potential benefit impact. Panobinostat, a potent inhibitor of deacetylases, maintenance post-HSCT was reported to be feasible and associated with a low relapse rate [47]. Sorafenib maintenance has been recently reported in 27 patients with FTL3-ITD+ with encouraging results [48].…”

Section: Discussionmentioning

confidence: 99%

Comparison of matched sibling donors versus unrelated donors in allogeneic stem cell transplantation for primary refractory acute myeloid leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT

et al. 2017

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BackgroundPrimary refractory acute myeloid leukemia (PRF-AML) is associated with a dismal prognosis. Allogeneic stem cell transplantation (HSCT) in active disease is an alternative therapeutic strategy. The increased availability of unrelated donors together with the significant reduction in transplant-related mortality in recent years have opened the possibility for transplantation to a larger number of patients with PRF-AML. Moreover, transplant from unrelated donors may be associated with stronger graft-mediated anti-leukemic effect in comparison to transplantations from HLA-matched sibling donor, which may be of importance in the setting of PRF-AML.MethodsThe current study aimed to address the issue of HSCT for PRF-AML and to compare the outcomes of HSCT from matched sibling donors (n = 660) versus unrelated donors (n = 381), for patients with PRF-AML between 2000 and 2013. The Kaplan-Meier estimator, the cumulative incidence function, and Cox proportional hazards regression models were used where appropriate.ResultsHSCT provide patients with PRF-AML a 2-year leukemia-free survival and overall survival of about 25 and 30%, respectively. In multivariate analysis, two predictive factors, cytogenetics and time from diagnosis to transplant, were associated with lower leukemia-free survival, whereas Karnofsky performance status at transplant ≥90% was associated with better leukemia-free survival (LFS). Concerning relapse incidence, cytogenetics and time from diagnosis to transplant were associated with increased relapse. Reduced intensity conditioning regimen was the only factor associated with lower non-relapse mortality.ConclusionsHSCT was able to rescue about one quarter of the patients with PRF-AML. The donor type did not have any impact on PRF patients’ outcomes. In contrast, time to transplant was a major prognostic factor for LFS. For patients with PRF-AML who do not have a matched sibling donor, HSCT from an unrelated donor is a suitable option, and therefore, initiation of an early search for allocating a suitable donor is indicated.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-017-0498-8) contains supplementary material, which is available to authorized users.

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“…The 2-year DFS was 74%. 77 A number of phase 1 and 2 studies are evaluating FLT3 inhibitors (NCT02400255, NCT01398501, NCT01578109, and NCT02723435), HMAs (NCT01835587, NCT01835587, NCT02124174, NCT01995578, NCT02204020, and NCT01700673), lenalidomide (NCT02038153), antibody-drug conjugates such as SGN-CD33A (NCT02326584), and HDACs (NCT01451268) as maintenance after allo-HCT. In addition, a randomized phase 2 study (NCT01773395), currently enrolling participants, is comparing posttransplant outcomes in patients with AML (not in CR before allo-HCT) randomly assigned to receive placebo vs GVAX.…”

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confidence: 99%

“…The post-allo-HCT setting may represent a unique situation in which maintenance can, at least theoretically, contribute to cure by maintaining the disease burden in a minimal state until the immunologic effect of graft-versus-leukemia becomes dominant, potentially resulting in eradication of residual disease. Although no maintenance RCT has yet been performed in the post-HCT setting, a number of earlyphase studies have been performed to assess safety and feasibility of maintenance therapy after allo-HCT using HMAs, 68-72 FLT3 inhibitors, [73][74][75][76] histone deacetylase (HDAC) inhibitors, 77 and lenalidomaide. 78 In the largest of these trials, 42 patients with high-risk myelodysplastic syndrome (n 5 5) or AML (n 5 37) in CR after reduced-intensity allo-HCT were treated with the HDAC inhibitor panobinostat using 2 different schedules; 67% of patients received transplantation in active disease.…”

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confidence: 99%