Faculty Opinions recommendation of A phase II study of 5-azacitidine for patients with primary and post-essential thrombocythemia/polycythemia vera myelofibrosis.

Abstract Recombinant human IFN-α has been the mainstay of therapy for patients with Philadelphia chromosome-negative myeloproliferative disorders for many years. However, the response rates of IFN-α therapy have been frequently challenged by high dropout rates due to side effects and inconvenient subcutaneous dosing schedules. Accordingly, we design a phase II study to evaluate the efficacy and safety of natural human IFN-α administered by the oral mucosal route in patients (pts) with essential thrombocythemia (ET) or polycythemia vera (PV). Pts were eligible if they had failed (inability to normalize platelet count in ET, or to reduce the frequency of phlebotomy or splenomegaly by 50% in PV, after 6 months of therapy with hydroxyurea (HU) and anagrelide (AG)), were intolerant to HU and AG, or refused to receive standard cytoreductive therapy. HU or AG therapy had to be stopped at least 3 weeks prior to start of oral IFN-α. Prior exposure to IFN-α was not allowed. Oral IFN-α was administered at 150 IU three times daily as a lozenge. A total of 14 pts (8 PV, 6 ET) have been treated. Median age was 57 (range, 32 to 79), time from diagnosis to oral IFN-α therapy 2 months (range, 0 to 32), Hb 14.2 gm/dL (range, 11.2 to 15.4), WBC 9.75 ×109/L, (range, 5.6 to 17.3), platelets 812 ×109/L (range, 360 to 1389). Five patients were previously treated with HU, four with AG, and 3 with imatinib mesylate. Six pts with PV had received phlebotomies and 2 presented with marked splenomegaly. The JAK2 V617F mutation was detected in 10 of 11 evaluated pts and 2 of 14 pts (14%) had abnormal cytogenetics. All 14 pts are evaluable for response and toxicity. No responses have been observed among any of the 14 pts treated. Ten (71%) pts discontinued oral IFN-α therapy due to lack of response (n=9) or disease progression (n=1, elevation of platelets), and 4 are currently on therapy. Duration of therapy varied: 2.5 months = 2 pts, 3 months = 6 pts, 4 months = 4 pts, 6 months = 2 pts. Therapy with oral IFN-α was very well tolerated: grade 1 headache was noted in 2 pts, and grade 1 paresthesia in 1 pt. We conclude that oral IFN-α is very well tolerated but has no activity in the treatment of pts with ET or PV at the dose and schedule employed in this study.

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Phase II Study of CEP701, an Orally Available JAK2 Inhibitor, in Patients with Primary Myelofibrosis and Post Polycythemia Vera/Essential Thrombocythemia Myelofibrosis.

Blood ◽

10.1182/blood.v110.11.3543.3543 ◽

2007 ◽

Vol 110 (11) ◽

pp. 3543-3543 ◽

Cited By ~ 8

Author(s):

Srdan Verstovsek ◽

Ayalew Tefferi ◽

Steven Kornblau ◽

Deborah Thomas ◽

Jorge Cortes ◽

...

Keyword(s):

Tyrosine Kinase ◽

Polycythemia Vera ◽

Phase Ii ◽

Essential Thrombocythemia ◽

Phase Ii Study ◽

Subcutaneous Administration ◽

Jak2 V617f ◽

Primary Myelofibrosis ◽

Common Mutation ◽

Tyrosine Kinase 2

Polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF) are myeloproliferative disorders (MPDs) associated with activating mutations of Janus tyrosine kinase 2 (JAK2) gene. The most common mutation, JAK2 V617F, has been reported in ∼97% of patients with PV, ∼50% with ET, and ∼50% with PMF. The resultant JAK2 protein is continuously autophosporylated and therefore always active. It is believed that this mutated tyrosine kinase contributes to the existence and progression of MPDs. CEP701 is an orally available potent low nanomolar inhibitor of wild type and mutated JAK2 tyrosine kinase in enzymatic and cellular assays. Significant inhibition (growth stasis) was observed following CEP-701 subcutaneous administration to V617F-mutated JAK2-dependent HEL.92 xenografts grown in immunocompromised mice. These results indicate that CEP-701 is an attractive candidate for clinical evaluation in patients with MPD carrying a mutated, constitutively activated JAK2. CEP701 is also a potent inhibitor of FLT3 and is being evaluated as FLT3 inhibitor in Phase II/III studies in patients with acute myeloid leukemia, at the starting dose of 80mg PO BID. We designed a Phase II study of CEP701, at the dose of 80 mg PO BID, in patients with PMF and post PV/ET MF, who harbor JAK2 V617F mutation. Eleven patients have been treated so far, seven males, median age 56 years (range, 38–69), median 3 prior therapies (range 0–6); 7 with abnormal cytogenetics; 8 with enlarged spleen (2 had splenectomy); 4 with enlarged liver; 5 transfusion dependent. Five patients have been followed for at least 1 month and have had stable disease. Response will be evaluated using International Working Group for MF Consensus Response Criteria. JAK2 V617F allele burden is being measured monthly. Except for Grade 2 nausea in one patient, no toxicities have been noted so far. Updated results will be presented at the meeting.

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Evaluation of plitidepsin in patients with primary myelofibrosis and post polycythemia vera/essential thrombocythemia myelofibrosis: results of preclinical studies and a phase II clinical trial

Blood Cancer Journal ◽

10.1038/bcj.2015.5 ◽

2015 ◽

Vol 5 (3) ◽

pp. e286-e286 ◽

Cited By ~ 6

Author(s):

A Pardanani ◽

A Tefferi ◽

P Guglielmelli ◽

C Bogani ◽

N Bartalucci ◽

...

Keyword(s):

Clinical Trial ◽

Polycythemia Vera ◽

Phase Ii ◽

Essential Thrombocythemia ◽

Primary Myelofibrosis ◽

Phase Ii Clinical Trial ◽

Preclinical Studies

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A phase II study of vorinostat (MK-0683) in patients with primary myelofibrosis and post-polycythemia vera myelofibrosis

Haematologica ◽

10.3324/haematol.2013.096669 ◽

2014 ◽

Vol 99 (1) ◽

pp. e5-e7 ◽

Cited By ~ 20

Author(s):

C. L. Andersen ◽

N. B. Mortensen ◽

T. W. Klausen ◽

H. Vestergaard ◽

O. W. Bjerrum ◽

...

Keyword(s):

Polycythemia Vera ◽

Phase Ii ◽

Phase Ii Study ◽

Primary Myelofibrosis

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A Phase II Study of the HDAC Inhibitor Givinostat In Combination with Hydroxyurea In Patients with Polycythemia Vera Resistant to Hydroxyurea Monotherapy

Blood ◽

10.1182/blood.v118.21.1748.1748 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1748-1748 ◽

Cited By ~ 7

Author(s):

Alessandro Rambaldi ◽

Guido Finazzi ◽

Alessandro M. Vannucchi ◽

Vincenzo Martinelli ◽

Francesco Rodeghiero ◽

...

Keyword(s):

Polycythemia Vera ◽

Phase Ii ◽

Hdac Inhibitor ◽

Phase Ii Study ◽

Jak2v617f Mutation ◽

Response Criteria ◽

Weekly Dose ◽

Daily Dose ◽

Group A ◽

Group B

Abstract Abstract 1748 Background and purpose. Several agents inhibiting the JAK2V617F mutation are actively investigated in patients with polycythemia vera (PV) and other chronic myeloproliferative neoplasms (MPN) with promising results. Givinostat, an HDAC inhibitor, specifically inhibits proliferation of cells bearing the JAK2V617F mutation and has shown significant activity with good tolerability in clinical studies in MPN patients. The aim of the present study was to evaluate safety and efficacy of two oral doses of Givinostat (50 or 100 mg daily) in combination with hydroxyurea (HU) in PV patients. Methods. In this multicenter, randomized, open-label, phase II study, we treated 44 patients with JAK2V617F positive PV, non-responders (NR) to the maximum tolerated doses of HU monotherapy for at least 3 months. The clinical -hematological response criteria developed by the European LeukemiaNet (ELN) consensus conference (complete and partial response) were used to assess the primary endpoint after 12 weeks of treatment. Recruited patients were randomly assigned to receive Givinostat (50 or 100 mg/die) in combination with the maximum tolerated dose of HU. After week 12, NR patients increased the initial daily dose of Givinostat by 50 mg, while responders continued Givinostat at the initial daily dose. Overall, the treatment lasted up to a maximum of 24 cumulative weeks of drug administration. Results. Baseline demographic and hematological parameters were balanced between the two randomized groups. The mean weekly dose of HU at baseline was 6.75 (range 1.75–14) and 6.25 (1–14) grams and was reduced during the study to 6.25 (range 1.75–14) and 5.75 (0.75-12.25) grams, in the 50 (group A) and 100 mg (group B) Givinostat groups, respectively. Safety. The combination of Givinostat and HU was well tolerated. Only five out of 44 evaluable patients dropped-out before week 12, respectively 2 in group A and 3 in group B. Reasons for treatment discontinuation were grade 2 thrombocytopenia and iperkalemia in group A and panic attack, withdrawal of consent and investigator decision due to safety reason (detection of familiar cardiac disorder unknown at recruitment) in group B. Only two grade 3 not drug related adverse events (AEs) were observed (hyperkalemia and platelet count increase), both occurring in group B. The most frequent grade 2 AEs were thrombocytopenia (4 cases, two in each group), leukopenia (2 cases both in group B) and diarrhea (2 cases, one in each group). Efficacy. Complete (CR) plus partial (PR) response according to ELN response criteria was observed in 50% and 45% of patients in group A and B respectively. Moreover, a notable control of itching was observed at week 12 in most of the 21 evaluable patients affected by severe itching (grade ≥ 2) at baseline. Seven out of 11 (64%) and 8 out of 10 (80%) patients had a complete itching relief, in group A and B respectively. Conclusions. The combined use of Givinostat and HU is well tolerated and about 50% of patients resistant to HU monotherapy achieved an overall ELN response (PR or CR). At week 12 no differences were found in the two randomized arms in term of hematological responses and itching relief. Givinostat confirms to be active in PV through the control of myeloproliferation and of some specific clinical needs, such as severe itching. Completed clinical and molecular data (after 24 cumulative weeks of treatment) will be presented at the meeting. Disclosures: Rambaldi: Italfarmaco S.p.A.: Consultancy, Honoraria. Vannucchi:Italfarmaco S.p.A.: Consultancy, Honoraria. Barbui:Italfarmaco S.p.A.: Consultancy, Honoraria.

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