Showing papers by "Francois-Xavier Mahon published in 2016"

The concept of treatment-free remission in chronic myeloid leukemia

Abstract: The advent of tyrosine kinase inhibitors (TKI) into the management of patients with chronic myeloid leukemia (CML) has profoundly improved prognosis. Survival of responders is approaching that of the general population but lifelong treatment is still recommended. In several trials, TKI treatment has been stopped successfully in approximately half of the patients with deep molecular response. This has prompted the development of a new concept in the evaluation of CML patients known as 'treatment-free remission'. The future in CML treatment will be to define criteria for the safe and most promising discontinuation of TKI on one hand, and, on the other, to increase the number of patients available for such an attempt. Until safe criteria have been defined, discontinuation of therapy is still experimental and should be restricted to clinical trials or registries. This review will provide an overview of current knowledge as well as an outlook on future challenges.

Development and evaluation of a secondary reference panel for BCR-ABL1 quantification on the International Scale

Abstract: Molecular monitoring of chronic myeloid leukemia patients using robust BCR-ABL1 tests standardized to the International Scale (IS) is key to proper disease management, especially when treatment cessation is considered. Most laboratories currently use a time-consuming sample exchange process with reference laboratories for IS calibration. A World Health Organization (WHO) BCR-ABL1 reference panel was developed (MR(1)-MR(4)), but access to the material is limited. In this study, we describe the development of the first cell-based secondary reference panel that is traceable to and faithfully replicates the WHO panel, with an additional MR(4.5) level. The secondary panel was calibrated to IS using digital PCR with ABL1, BCR and GUSB as reference genes and evaluated by 44 laboratories worldwide. Interestingly, we found that >40% of BCR-ABL1 assays showed signs of inadequate optimization such as poor linearity and suboptimal PCR efficiency. Nonetheless, when optimized sample inputs were used, >60% demonstrated satisfactory IS accuracy, precision and/or MR(4.5) sensitivity, and 58% obtained IS conversion factors from the secondary reference concordant with their current values. Correlation analysis indicated no significant alterations in %BCR-ABL1 results caused by different assay configurations. More assays achieved good precision and/or sensitivity than IS accuracy, indicating the need for better IS calibration mechanisms.

Deep molecular responses for treatment-free remission in chronic myeloid leukemia.

Abstract: Several clinical trials have demonstrated that some patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieve sustained deep molecular responses on tyrosine kinase inhibitor (TKI) therapy can safely suspend therapy and attempt treatment-free remission (TFR). Many TFR studies to date have enrolled imatinib-treated patients; however, the feasibility of TFR following nilotinib or dasatinib has also been demonstrated. In this review, we discuss available data from TFR trials and what these data reveal about the molecular biology of TFR. With an increasing number of ongoing TFR clinical trials, TFR may become an achievable goal for patients with CML-CP.

Personalized daily doses of imatinib by therapeutic drug monitoring increase the rates of molecular responses in patients with Chronic Myeloid Leukemia - Final results of the randomized Optim imatinib study: Co-028

Abstract: ![Graphic][1] Background Imatinib mesylate (IM) at 400 mg/d remains a standard for first line therapy in patients (pts) with newly diagnosed chronic phase CML (CP-CML). A sub analysis of the IRIS study (Larson et al. Blood, 2008) demonstrated that pts with high IM trough levels achieved higher rates of major molecular response (MMR). The level of 1000 ng/ml was established as the [C]min value threshold to predict molecular response (Picard et al. Blood, 2007). We conducted a randomized trial to evaluate the value of IM dose optimization based on the monitoring of [C]min levels in newly diagnosed CP-CML pts (OPTIM-imatinib trial, EudraCT number 2008-006854-17). Patients and Methods Pts diagnosed with CP- CML for less than 3 months, not previously treated or treated with IM for less than 3 months were eligible and treated with IM 400 mg/d. IM [C]min was determined by chromatography-tandem mass-mass spectrometry 15 days after enrollment. Pts with a [C]min < 1000 ng/ml were randomized between a dose-increase strategy aiming to reach the threshold of 1000 ng/ml (arm A1) versus standard IM management (arm A2). Pts with [C]min levels ≥1000 ng/ml were observed (arm A3). All pts were managed according to the ELN 2009 recommendations (amended with ELN 2013 recommendations). IM [C]min levels were assessed monthly in A1 and A2 and every 3 months in A3. BCR-ABLIS was assessed every 3 months. The primary end-point was MMR rates at 12 months. Results One hundred thirty nine pts were enrolled. Median follow-up was 31 months. Median age was 64y (25 to 88y), sex ratio (M/F) was 1.4 and Sokal score distribution was 21%, 41% and 38% for high, intermediate and low categories respectively, equally distributed in the 3 arms. In 6 pts the initial [C]min was not assessed (3 were intolerant and 3 declined the dosage). Thus 133 pts were studied. In 86 pts (65%), initial [C]min value was < 1000 ng/ml. These pts were randomized between A1 (43 pts) and A2 (43 pts). [C]min was ≥1000 ng/ml in the 47 remaining pts followed in A3. Table 1 shows the significant improvement of the median IM [C]min after dose adjustment in A1 ( p<0.0001 ) as compared to standard management in A2. Correspondingly, IM daily dose increased in A1 (p<0.0001) to reach a mean value of 600 mg/d. In the experimental A1 arm, the distribution of IM doses at 12 months was 13% for 500 mg/d, 30% for 600 mg/d, 34% for 800 mg/d whereas 16% of the pts remained at 400 mg/d and 7% were dose decreased at 300 mg/d. During follow-up, a similar proportion of pts with AE was observed in A1 (58%) and A2 (51%). Eight SAE related to IM were equally distributed in A1, A2 and A3. Cumulative incidences of treatment discontinuation were comparable in the 3 arms (overall, 18.8% by 12 months and 34.1% by 24 months). Reasons for discontinuation were not similar in A1 and A2 with a trend for more treatment failures in A2 as compared to A1 (60% versus 18%, p=0.08 ). At 12 months, MMR was achieved in 27 out of 43 pts (63%; 95%CI 49-77) in A1 as compared to 16 out 43 pts (37%; 95%CI 23-51) in A2 ( p=0,031 ). The rates of MMR were not statistically different between A1 and A3 ( p=0.12 ). Conclusions Only 1/3 of pts on IM400 were correctly dosed and may not require systematic high dose IM. Two-thirds of the pts were not exposed enough to IM at standard dose and may benefit from individualized strategies. A tailored dose adjustment based on pharmacology resulted in higher MMR rate at 12 months (63% vs 37%), a magnitude in line with the results previously reported with second generation tyrosine kinase inhibitors or high dose IM front line. Our results may provide a strong rational to early personalize the use of IM and IM generic formulations in order to optimize the outcome for each patient. This study was supported by a grant from the French Department of Health (Programme Hospitalier de Recherche Clinique). | Median [C]min (ng/ml; (95% CI)) | Initial Assessment | M3 | M6 | M9 | M12 | | --------------------------------------------------- | ------------------ | ---------------- | ---------------- | ---------------- | ---------------- | | A1 | 591; (508-654) | 838; (746-922) | 1001; (748-1261) | 1062; (918-1221) | 1013; (830-1277) | | A2 | 651; (558-797) | 605; (487-786) | 591; (517-722) | 605; (460-720) | 646; (576-894) | | A3 | 1314; (1199-1514) | 1032; (899-1143) | 1002; (784-1205) | 935; (737-1073) | 1000; (846-1098) | | Mean IM daily dose (mg/d; (95% CI)) | Inclusion | M3 | M6 | M9 | M12 | | A1 | 400 | 538; (508-568) | 611; (563-658) | 607; (545-668) | 600; (535-665) | | A2 | 400 | 395; (387-402) | 392; (383-401) | 391; (381-401) | 391; (381-401) | | A3 | 400 | 400; (400-400) | 398; (385-410) | 389; (376-402) | 382; (370-395) | Table 1. Disclosures Rousselot: BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau; Pfizer: Consultancy. Johnson-Ansah: BMS: Speakers Bureau; Hybrigenics SA: Consultancy, Research Funding; Novartis: Consultancy, Speakers Bureau. Huguet: PFIZER: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Research Funding. Legros: Novartis: Research Funding, Speakers Bureau; ARIAD: Speakers Bureau; BMS: Speakers Bureau. Gardembas: Novartis: Speakers Bureau. Coiteux: ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau. Deau: BMS: Honoraria. Mahon: ARIAD: Consultancy; Pfizer: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. [1]: /embed/inline-graphic-2.gif

Synergistic cooperation between ABT-263 and MEK1/2 inhibitor: effect on apoptosis and proliferation of acute myeloid leukemia cells.

Abstract: // Kelly Airiau 1, 2 , Valerie Prouzet-Mauleon 1 , Benoit Rousseau 3 , Arnaud Pigneux 1, 2 , Marie Jeanneteau 2 , Manon Giraudon 2 , Kaoutar Allou 1, 2 , Pierre Dubus 4 , Francis Belloc 1, 2, * , Francois-Xavier Mahon 1, 2, * 1 Laboratoire d’Hematopoiese Leucemique et Cibles Therapeutiques, INSERM 1035, Universite Bordeaux, Bordeaux, France 2 CHU Bordeaux, Hopital Haut-Leveque, Laboratoire d’Hematologie, Pessac, France 3 Animalerie A2, Universite Bordeaux Segalen, Bordeaux, France 4 EA 2406 Histologie et Pathologie, Universite Bordeaux, Bordeaux, France * These authors have contributed equally to this work Correspondence to: Francois-Xavier Mahon, e-mail: francois-xavier.mahon@u-bordeaux.fr Keywords: acute myeloid leukemia, MEK inhibitors, BH3 mimetic drugs Received: June 28, 2015 Accepted: November 16, 2015 Published: November 27, 2015 ABSTRACT In spite of intensive research to improve treatment of acute myeloid leukemia (AML) more than half of all patients continue to develop a refractory disease. Therefore there is need to improve AML treatment. The overexpression of the BCL-2 family anti-apoptotic members, like BCL-2 or BCL-xL has been largely reported in lymphoid tumors but also in AML and other tumors. To counteract the anti-apoptotic effect of BCL-2, BH3 mimetics have been developed to target cancer cells. An increase in activity of ERK1/2 mitogen activated protein (MAP) kinase has also been reported in AML and might be targeted by MEK1/2 inhibitors. Hence, in the current work, we investigated whether the association of a BH3 mimetic such ABT-263 and the MEK1/2 inhibitor pimasertib (MEKI), was efficient to target AML cells. A synergistic increasing of apoptosis was observed in AML cell lines and in primary cells without affecting normal bone marrow cells. Such cooperation was confirmed on tumor growth in a mouse xenograft model of AML. In addition we demonstrated that MEKI sensitized the cells to apoptosis through its ability to promote a G1 cell cycle arrest. So, this combination of a MAP Kinase pathway inhibitor and a BH3 mimetic could be a promising strategy to improve the treatment of AML.

Treatment-free remission (TFR) in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) treated with second-line nilotinib (NIL): First results from the ENESTop study.

Abstract: 7054Background: The ENESTop (NCT01698905) study explores the discontinuation of NIL therapy in pts who achieved sustained MR4.5 (BCR-ABL1IS≤ 0.0032%) after switching from imatinib (IM) to NIL. Methods: The single-arm phase 2 study enrolled pts with CML-CP treated with tyrosine kinase inhibitor (TKI) for ≥ 3 y (including IM for > 4 wk followed by NIL for ≥ 2 y) and achieved MR4.5 on NIL. On study, pts continued NIL for 1 y (consolidation phase [CONS]). After 1 y, pts without confirmed loss of MR4.5 (consecutive BCR-ABL1IS > 0.0032%), were eligible to stop NIL (TFR). RQ-PCR was monitored every 12 wk in CONS and every 4 wk during first 48 wk of TFR. Upon confirmed loss of MR4 (consecutive BCR-ABL1IS > 0.01%) or loss of MMR (BCR-ABL1IS> 0.1%), NIL was re-initiated (ReRx). Primary endpoint was the proportion of pts with successful TFR (neither loss of MMR nor confirmed loss of MR4 by 48 wk of TFR) after a ≥ 48 wk follow up (data cutoff, 26 Nov 2015). Results: Of the 163 pts in CONS, 126 entered TFR (median dur...

Recommandations 2015 du France Intergroupe des Leucémies Myéloïdes Chroniques pour la gestion du risque d’événements cardiovasculaires sous nilotinib au cours de la leucémie myéloïde chronique

Abstract: Tyrosine kinase inhibitors targeting the BCR-ABL oncoprotein represent an outstanding progress in chronic myeloid leukemia and long-term progression-free survival has become a reality for a majority of patients. However, tyrosine kinase inhibitors may at best chronicize rather than cure the disease thus current recommendation is to pursue treatment indefinitely. As a consequence, high quality treatment and care must integrate optimal disease control and treatment tolerability. Tyrosine kinase inhibitors have an overall favorable safety profile in clinical practice since most adverse events are mild to moderate in intensity. However, recent evidence has emerged that new generation tyrosine kinase inhibitors may sometimes damage vital organs and if not adequately managed, morbidity and mortality may increase. The 2nd generation tyrosine kinase inhibitor nilotinib is licensed for the treatment of chronic myeloid leukemia with resistance or intolerance to imatinib and newly diagnosed chronic phase-chronic myeloid leukemia. Nilotinib represents an important therapeutic option but it is associated with an increased risk of cardiovascular events. The purpose of this article by the France Intergroupe des Leucemies Myeloides Chroniques is to provide an overview of nilotinib efficacy and cardiovascular safety profile and to propose practical recommendations with the goal to minimize the risk and severity of cardiovascular events in nilotinib-treated patients.

Hyperhomocysteinemia and high doses of nilotinib favor cardiovascular events in chronic phase Chronic Myelogenous Leukemia patients

Abstract: In chronic phase chronic myeloid leukemia (CP-CML), nilotinib (Tasigna®, Novartis, second-generation tyrosine kinase inhibitor, TKI2) as second-line therapy[1][1] results in successful responses and tolerance in ~50% of patients in the long-term.[2][2] As a consequence, some patients have been on

Loss of mutL homolog-1 (MLH1) expression promotes acquisition of oncogenic and inhibitor-resistant point mutations in tyrosine kinases

Abstract: Genomic instability drives cancer progression by promoting genetic abnormalities that allow for the multi-step clonal selection of cells with growth advantages. We previously reported that the IL-9-dependent TS1 cell line sequentially acquired activating substitutions in JAK1 and JAK3 upon successive selections for growth factor independent and JAK inhibitor-resistant cells, suggestive of a defect in mutation avoidance mechanisms. In the first part of this paper, we discovered that the gene encoding mutL homolog-1 (MLH1), a key component of the DNA mismatch repair system, is silenced by promoter methylation in TS1 cells. By means of stable ectopic expression and RNA interference methods, we showed that the high frequencies of growth factor-independent and inhibitor-resistant cells with activating JAK mutations can be attributed to the absence of MLH1 expression. In the second part of this paper, we confirm the clinical relevance of our findings by showing that chronic myeloid leukemia relapses upon ABL-targeted therapy correlated with a lower expression of MLH1 messenger RNA. Interestingly, the mutational profile observed in our TS1 model, characterized by a strong predominance of T:A>C:G transitions, was identical to the one described in the literature for primitive cells derived from chronic myeloid leukemia patients. Taken together, our observations demonstrate for the first time a causal relationship between MLH1-deficiency and incidence of oncogenic point mutations in tyrosine kinases driving cell transformation and acquired resistance to kinase-targeted cancer therapies.

Discontinuation or Cessation of Tyrosine Kinase Inhibitor Treatment in Chronic Myeloid Leukemia Patients with Deep Molecular Response

Abstract: Chronic myeloid leukemia (CML) is an example of successful targeted therapy with tyrosine kinase inhibitors (TKI). The overall survival of CML patients who respond to TKI is now considered very close to that of the healthy population control. Several clinical trials have demonstrated that some patients with CML in chronic phase who achieve sustained deep molecular remission (DMR) on TKI therapy can safely discontinue therapy and attempt treatment-free remission (TFR). It should be considered a future criterion for evaluating a successful clinical trial that will account for quality of life and economic factors, important aspects to consider.