Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM)

Thépot, Sylvain; Itzykson, Raphaël; Seegers, Valérie; Raffoux, Emmanuel; Quesnel, Bruno; Chaït, Yasmine; Sorin, Lucile; Dreyfus, François; Cluzeau, Thomas; Delaunay, Jacques; Sanhès, Laurence; Éclache, Virginie; Dartigeas, Caroline; Turlure, Pascal; Harel, Stéphanie; Salanoubat, Célia; Kiladjian, Jean‐Jacques; Fenaux, Pierre; Adès, Lionel

doi:10.1182/blood-2010-03-274811

Cited by 143 publications

(89 citation statements)

References 34 publications

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“…40 Thepot et al evaluated the use of azacitidine in 54 patients with AML or myelodysplastic syndrome secondary to MPN, finding an overall response rate and complete remission rate of 52% and 24%, respectively, with a median overall survival of 11 months. 41 However, in AML patients, the complete remission rate (including complete remission with incomplete count recovery) was only 11%. As in our study, the duration of response was short (9 months); nonetheless azacitidine still represents another promising treatment strategy for patients in this high-risk group, either as a bridge to an allogeneic SCT or for symptomatic improvement.…”

Section: Discussionmentioning

confidence: 99%

A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

et al. 2013

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© F e r r a t a S t o r t i F o u n d a t i o nand children, and revealed the potentiation of cytarabine cytotoxicity ex vivo. [27][28][29][30] Preclinical studies demonstrated that triapine administration was associated with decreases in intracellular circulating leukemic blast dNTP pools with subsequent inhibition of DNA synthesis. 16 On the basis of these data, we conducted a phase I clinical trial of triapine followed by escalating doses of fludarabine in adults with relapsed and refractory acute leukemias, high-risk myelodysplastic syndrome, or transformed MPN including CMML. 31 We tested two schedules: schedule A, consisting of daily doses of triapine at 105 mg/m 2 over 4 h for 5 days followed by a 30-min infusion of fludarabine within 1 h of completion of triapine, and schedule B, consisting of triapine at 200 mg/m 2 over 24 h followed by fludarabine for 5 days. There were no dose-limiting toxicities in this study; however, the dose of fludarabine (30 mg/m 2 daily) was not further escalated due to concern about neurotoxicity. Schedule A (triapine 105 mg/m 2 daily) led to a 21% complete remission + partial remission rate, with the majority of responses being in patients with underlying MPN (29% response rate in MPN). In contrast, schedule B (triapine 200 mg/m 2 over 24 h) did not lead to any clinical responses.Given the promising results of schedule A, we designed and conducted a phase II study of triapine 105 mg/m 2 daily followed by fludarabine 30 mg/m 2 daily for 5 days in 37 patients with aggressive MPN and secondary, transformed AML. We confirm our previous findings that this combination of agents is clinically active in accelerated MPN and secondary AML derived from MPNs, and further identify the JAK2 V617F mutation as a potential predictor of response to sequential ribonucleotide reductase inhibition. Methods PatientsBetween August 2006 and November 2010, 37 adults with pathological confirmation of accelerated MPN (>5% blasts in bone marrow, new onset/worsening myelofibrosis, new onset or >25% increase in hepatomegaly/splenomegaly, or new onset/worsening constitutional symptoms), CML-BC, CMML (>5% blasts), or secondary AML, arising from a preexisting MPN or CMML, defined by standard criteria, 32 were entered on study at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center. This study was approved by the Johns Hopkins Medical Institutional Review Board. Treatment planTriapine was administered as a 4-h intravenous infusion daily for 5 consecutive days at a dose of 105 mg/m 2 /day. Fludarabine 30 mg/m 2 /day was administered as a 30-min intravenous infusion daily, beginning within 1 h of completion of the triapine infusion, on each of the 5 consecutive days. Each cycle was 21 days in duration. Patients were eligible to receive additional cycles of treatment until disease progression or toxicity. Measurement of toxicitiesNon-hematologic toxicities were graded according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. Treatment of tria...

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Section: Discussionmentioning

confidence: 99%

A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

et al. 2013

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“…[85][86][87][88] Current efforts are investigating diverse agents, including hypomethylating agents, JAK and MEK inhibitors, BCL-X L and BCL-2 inhibitors and clofarabine. [89][90][91][92][93][94] IMPACT OF THE TRANSPLANT-PROCEDURE-AND DONOR-RELATED FACTORS Several prospective multicenter studies have now confirmed the usefulness of RIC-SCT using related or unrelated donors for younger and older patients with MF. In a large retrospective European Group for Blood and Marrow Transplantation study, outcomes from 250 consecutive patients (median age 56 years) with PPV-MF (n = 120) or PET-MF (n = 130) who received allo-SCT, either in MF 'chronic' phase (n = 193) or MF transformed to AML (n = 57), were analyzed.…”

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

confidence: 97%

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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“…There is no convincing evidence that medical therapies prolong survival in PMF-BP. However, following the encouraging results of azacitidine in high risk MDS, a recent study evaluated its efficacy in transformed MPN (Thepot et al, 2010). An overall response rate of 38% was reported, including 4/7 cases of transformed PMF with a resultant median survival of 8 months.…”

Section: Blast Phase Of Myelofibrosismentioning

confidence: 99%

Guideline for the diagnosis and management of myelofibrosis

et al. 2012

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SummaryThe guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK-based medical experts, together with a contribution from a single expert from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato-oncology Task Forces of the British Committee for Standards in Haematology (BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the 'GRADE' system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post-polycythaemic myelofibrosis (post-PV MF) and post-thrombocythemic myelofibrosis (post-ET MF) in both adult and paediatric patients.

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Treatment of progression of Philadelphia-negative myeloproliferative neoplasms to myelodysplastic syndrome or acute myeloid leukemia by azacitidine: a report on 54 cases on the behalf of the Groupe Francophone des Myelodysplasies (GFM)

Abstract: Transformation of Philadelphia (Ph)-negative myeloproliferative neoplasms (MPNs

Cited by 143 publications

References 34 publications

A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

A phase II trial of sequential ribonucleotide reductase inhibition in aggressive myeloproliferative neoplasms

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

Guideline for the diagnosis and management of myelofibrosis

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