A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post‐polycythaemia vera/essential thrombocythaemia myelofibrosis (post‐PV/ET MF)

Mascarenhas, John; Lü, Min; Li, Timmy; Petersen, Bruce; Hochman, Tsivia; Najfeld, Vesna; Goldberg, Judith D.; Hoffman, Ronald

doi:10.1111/bjh.12220

Cited by 70 publications

(54 citation statements)

References 18 publications

(22 reference statements)

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“…91 A phase 1 study of the drug used alone in MF demonstrated clinical effects at low doses given during a long period of time with minimal adverse effects. 92 There are currently 2 phase 1/2 trials assessing the safety and tolerability of the combination of panobinostat and ruxolitinib (Table 2). In vitro, givinostat inhibits the clonogenic potential of JAK2V617F-mutated progenitor cells at concentrations 10 times lower than JAK2 wild-type cells, 93 and in a phase 2a study of patients with ET/PV, clinical activity was observed in about half.…”

Section: Hdacimentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

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There has been a major revolution in the management of patients with myeloproliferative neoplasms (MPN), and in particular those with myelofibrosis and extensive splenomegaly and symptomatic burden, after the introduction of the JAK1 and JAK2 inhibitor ruxolitinib. The drug also has been approved as second-line therapy for polycythemia vera (PV). However, the therapeutic armamentarium for MPN is still largely inadequate for coping with patients’ major unmet needs, which include normalization of life span (myelofibrosis and some patients with PV), reduction of cardiovascular complications (mainly PV and essential thrombocythemia), prevention of hematological progression, and improved quality of life (all MPN). In fact, none of the available drugs has shown clear evidence of disease-modifying activity, even if some patients treated with interferon and ruxolitinib showed reduction of mutated allele burden, and ruxolitinib might extend survival of patients with higher-risk myelofibrosis. Raised awareness of the molecular abnormalities and cellular pathways involved in the pathogenesis of MPN is facilitating the development of clinical trials with novel target drugs, either alone or in combination with ruxolitinib. Although for most of these molecules a convincing preclinical rationale was provided, the results of early phase 1 and 2 clinical trials have been quite disappointing to date, and toxicities sometimes have been limiting. In this review, we critically illustrate the current landscape of novel therapies that are under evaluation for patients with MPN on the basis of current guidelines, patient risk stratification criteria, and previous experience, looking ahead to the chance of a cure for these disorders.

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Section: Hdacimentioning

confidence: 99%

Emerging treatments for classical myeloproliferative neoplasms

Vannucchi

Harrison

2017

Blood

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“…Several pilot clinical studies suggest clinical activity in both early and late phases of the disease. [59][60][61][62][63] These agents also have the potential to harness an immunomodulatory effect that could synergize with the GVL effect, making them of additional interest. 64,65 The notion of administering these agents at a lower dose/intensity to harness their immunomodulatory effects, which include the upregulation of cancer testis antigens and augmentation of T-regulatory cells, following allo-SCT is additionally attractive.…”

Section: Impact Of Targeting the Jak/signal Transducers And Activatormentioning

confidence: 99%

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

Tamari

Mughal

Rondelli

et al. 2015

Bone Marrow Transplant

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At present, allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only curative treatment for patients with myelofibrosis (MF). Unfortunately a significant proportion of candidate patients are considered transplant ineligible due to their poor general condition and advanced age at time of diagnosis. The approval of the first JAK inhibitor, Ruxolitinib, for patients with advanced MF in 2011 has had a qualified impact on the treatment algorithm. The drug affords substantial improvement in MF-associated symptoms and splenomegaly but no major effect on the natural history. There has, therefore, been considerable support to assess the drug’s candidacy in the peri-transplant period. The drug’s precise impact on clinical outcome following allo-SCT is currently not known; nor is the drug’s long term efficacy and safety known. Considering the rarity of MF and the small proportion of patients who are undergoing allo-SCT, well designed collaborative efforts are required. In order to address some of the principal challenges, an expert panel of laboratory and clinical experts in this field was established, and an independent workshop held during the 54th American Society of Hematology’s meeting in New Orleans, USA, on 6th December 2013 and the European Hematology Association meeting in Milan, Italy on 13th June 2014. This document summarizes the results of these efforts.

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“…More recently, recently shown that treatment of JAK2 V617F knock-in mice with the pan-deacetylase inhibitor vorinostat led to a reduction in splenomegaly, aberrant blood counts, and mutant allele burden (29). Encouragingly, anemia responses, as well as reduction of mutant allele burden and bone marrow fibrosis, have been observed in some patients with myelofibrosis treated with the pan-deacetylase inhibitor panobinostat (13)(14)(15). In terms of promising combination strategies, preclinical studies have shown that sequential treatment of CD34 þ cells from patients with myelofibrosis with the hypomethylating agent 5-aza-2 0 -deoxycytidine followed by the deacetylase inhibitor trichostatin A was capable of correcting aberrant CXCR4 expression and trafficking behavior of the mutant clone (30).…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, combination strategies with JAK inhibitors could also be aimed at addressing biologic pathways and processes that may cooperate with aberrant JAK signaling. Along these lines, the immunomodulatory drug lenalidomide plus prednisone (12) and the deacetylase inhibitor panobinostat (13)(14)(15) have shown promising activity in terms of diseasemodifying potential, evidenced by anemia responses, reduction of mutant allele burden, and reversal of bone marrow fibrosis in some patients with myelofibrosis, thus representing potentially appealing combination partners for JAK inhibitors.…”

Section: Introductionmentioning

confidence: 99%

JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease

Evrot

Ebel

Romanet

et al. 2013

Clinical Cancer Research

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Purpose: The myeloproliferative neoplasm myelofibrosis is characterized by frequent deregulation of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling, and JAK inhibitors were shown to reduce splenomegaly and ameliorate disease-related symptoms. However, the mutant clone and bone marrow fibrosis persist in the majority of patients. Using preclinical models, we explored whether JAK and pan-deacetylase inhibitor combination yielded additional benefits.Experimental Design: The combination of the JAK1/2 inhibitor ruxolitinib and panobinostat was investigated using two different mouse models of JAK2 V617F -driven disease. A Ba/F3 JAK2 V617F cell-driven leukemic disease model was used to identify tolerated and efficacious doses. The drugs were then evaluated alone and in combination in a mouse model of myeloproliferative neoplasm-like disease based on transplantation of bone marrow transduced with a retrovirus expressing JAK2 V617F . Exposures were determined in blood and tissues, and phosphorylated STAT5 and acetylated histone H3 pharmacodynamic readouts were assessed in spleen and bone marrow. Histologic analysis was conducted on spleen and bone marrow, including staining of reticulin fibers in the latter organ.Results: The combination of ruxolitinib and panobinostat was found to have a more profound effect on splenomegaly, as well as on bone marrow and spleen histology, compared with either agent alone, and the analysis of pharmacodynamic readouts showed that ruxolitinib and panobinostat have nonoverlapping and complementary effects.Conclusion: Combining JAK1/2 and pan-deacetylase inhibitors was fairly well tolerated and resulted in improved efficacy in mouse models of JAK2 V617F -driven disease compared with the single agents. Thus, the combination of ruxolitinib and panobinostat may represent a promising novel therapeutic modality for myeloproliferative neoplasms.

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A phase I study of panobinostat (LBH589) in patients with primary myelofibrosis (PMF) and post‐polycythaemia vera/essential thrombocythaemia myelofibrosis (post‐PV/ET MF)

Cited by 70 publications

References 18 publications

Emerging treatments for classical myeloproliferative neoplasms

Emerging treatments for classical myeloproliferative neoplasms

Allo-SCT for myelofibrosis: reversing the chronic phase in the JAK inhibitor era?

JAK1/2 and Pan-Deacetylase Inhibitor Combination Therapy Yields Improved Efficacy in Preclinical Mouse Models of JAK2V617F-Driven Disease

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