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Hôpital-Camfrout, France

Heiblig M.,Center Hospitalier Lyon Sud | Sobh M.,Center Hospitalier Lyon Sud | Nicolini F.E.,Center Hospitalier Lyon Sud | Nicolini F.E.,French Institute of Health and Medical Research | Nicolini F.E.,French group of CML Fi LMC group
Leukemia Research | Year: 2014

The treatment of chronic myelogenous leukemia (CML) has been revolutionized by the introduction of tyrosine kinase inhibitors (TKI), however, with the exception of ponatinib, none of the existing licensed agents seem to eradicate the reservoir of Philadelphia positive stem cells, thus sustaining the disease over time, and retaining activity in cells and patients harboring an ABL T315I mutation. Omacetaxine mepesuccinate (OMA), formerly known as homoharringtonine, is a cephalotaxus alkaloid derivative and an inhibitor of protein synthesis without tyrosine kinase activity developed 35 years ago by Chinese investigators in the treatment of leukemia. This compound demonstrates specific activity in CML and has been recently commercialized in the U.S. for the treatment of patients in chronic or accelerated phase CML with resistance and/or intolerance to two or more tyrosine kinase inhibitors or harboring a T315I ABL mutation. CML patients with a T315I mutation experienced poor overall survival rates in the pre-ponatinib era (median for CP CML 24 months). Recent studies demonstrate the activity of OMA even in such a poor prognosis population. We hereby detail the development of OMA as an effective agent in CML in these patients. © 2014 Elsevier Ltd.

Nicolini F.E.,Center Hospitalier Lyon Sud | Nicolini F.E.,French Institute of Health and Medical Research | Nicolini F.E.,French group of CML Fi LMC group | Etienne G.,Institute Bergonie | And 35 more authors.
The Lancet Haematology | Year: 2015

Background: Nilotinib is now recommended for patients with newly diagnosed chronic myeloid leukaemia in chronic phase and leads to important rates of molecular response 4.5 log (MR4.5), allowing the prospect of therapy cessation. However, most patients do not reach this criterion and nilotinib is taken for lengthy periods, resulting in chronic or late-onset adverse events. Nilotinib combined with interferon might further increase rates of MR4.5, avoid late sideeffects, and allow therapy cessation. In a phase 2 trial we aimed to assess the feasibility, safety, and deep molecular response of the combination of nilotinib (600 mg daily) and peginterferon alfa-2a in newly diagnosed patients with chronic-phase chronic myeloid leukaemia (CML). Methods: In a non-randomised, open-label, phase 2 trial, we enrolled adult patients (age ≥18 years) without any organ failure who had BCR-ABL-positive, chronic-phase CML, at diagnosis. After a priming procedure with 90 μg per week of peginterferon alfa-2a alone for a month, we gave patients peginterferon alfa-2a 45 μg per week combined with nilotinib 600 mg daily until 24 months after interferon initiation. The primary endpoint was the cumulative incidence of MR4.5 at 12 months after initiation of peginterferon alfa-2a. Data were analysed by a modifi ed intention-to-treat principle. This trial is registered at the European Clinical Trials Database (EudraCT), number 2010-019786-28. Findings: Between March 24, 2011, and Sept 27, 2011, we enrolled 42 patients. One patient withdrew consent before receiving any study treatment so was excluded from analysis; 41 patients received treatment with peginterferon alfa-2a and nilotinib. At 12 months, seven (17%) patients had achieved MR4.5. Haematological and hepatic adverse events were frequent-with grade 3-4 neutropenias occurring in ten (24%) patients, grade 3-4 thrombocytopenias occurring in ten (24%) patients, grade 3-4 cholestatic events occurring in seven (17%) patients, and grade 3-4 elevations in aspartate aminotransferase or alanine aminotransferase occurring in three (7% patients-particularly during the fi rst 3 months. However, 30 (73%) patients remained on interferon therapy at 1 year. Three grade 3-4 cardiac events (7% of patients, all coronary stenoses) occurred at later timepoints. Interpretation: The combination of peginterferon alfa-2a resulted in good molecular responses in patients. Despite substantial toxic eff ects, most patients remained on the study drugs for more than a year. This combination should now be tested in a randomised controlled trial.

Nicolini F.E.,Hopital edouard Herriot | Nicolini F.E.,French group of CML Fi LMC group | Nicolini F.E.,European Group for Blood and Marrow Transplantation | Basak G.W.,European Group for Blood and Marrow Transplantation | And 27 more authors.
Blood | Year: 2011

T315I + Philadelphia chromosome-positive leukemias are inherently resistant to all licensed tyrosine kinase inhibitors, and therapeutic options remain limited.We report the outcome of allogeneic stem cell transplantation in 64 patients with documented BCR-ABL T315I mutations. Median follow-up was 52 months from mutation detection and 26 months from transplantation. At transplantation, 51.5% of patients with chronic myeloid leukemia were in the chronic phase and 4.5% were in advanced phases. Median overall survival after transplantation was 10.3 months (range 5.7 months to not reached [ie, still alive]) for those with chronic myeloid leukemia in the blast phase and 7.4 months (range 1.4 months to not reached [ie, still alive]) for those with Philadelphia chromosome-positive acute lymphoblastic leukemia but has not yet been reached for those in the chronic and accelerated phases of chronic myeloid leukemia. The occurrence of chronic GVHD had a positive impact on overall survival (P ∇ .047). Transplant-related mortality rates were low. Multivariate analysis identified only blast phase at transplantation (hazard ratio 3.68, P ∇ .0011) and unrelated stem cell donor (hazard ratio 2.98, P ∇ .011) as unfavorable factors. We conclude that allogeneic stem cell transplantation represents a valuable therapeutic tool for eligible patients with BCR-ABL T315I mutation, a tool that may or may not be replaced by third-generation tyrosine kinase inhibitors. © 2011 by The American Society of Hematology.

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