Essai clinique - Combinaison Glivec + Interféron

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"Nous avons lancé une seconde étude pour évaluer l’efficacité non plus du glivec seul, mais de l’association Glivec et Interféron, une molécule autrefois utilisée dans le traitement de la LMC." Et là, bonne surprise : la combinaison de ces traitements a permis chez des dizaines de malades d’obtenir la disparition du marqueur de la maladie. "A partir de ces observations, je crois que l’on peut raisonnablement envisager d’arrêter un jour le traitement chez ces patients, à condition bien sûr de les maintenir sous surveillance médicale stricte, avec des examens biologiques réguliers."
Article signé : Nancy Cattan - 15 Novembre 2009
http://cancer-familles.medicalistes.org ... ?article96

Que reste-t-il de l’interféron en hématologie ?
T. Cluzeau et N. Mounier, 22 juin 2008
http://www.springerlink.com/content/k7665241303x8635/
http://cat.inist.fr/?aModele=afficheN&cpsidt=20354649

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Imatinib-Interferon combination - ASH 2009 Recollections – and why I went there again…
Written by Jan Geissler - Tuesday, 15 December 2009

''Dr. Guilhot presented the French SPIRIT Trial on 12 month follow-up with 695 newly diagnosed patients. Treatment arms were Imatinib-400mg, Imatinib-600, Imatinib-400+AraC, and Imatinib+PegIFN. 636 patients were now analyzed. Now at 24 months, there was a clear advantage of the Imatinib+IFN group, with 46% of patients in optimal molecular response (PCR smaller 0.1%), while only 26% of the Imatinib-400mg patients achieved the same response. 22% of Imatinib-PegIFN-patients became PCR-negative, compared to 10% on Imatinib only. Overall, 5-10% of patients discontinued Imatinib during the first year, and 45% of patients discontinued PegIFN. Average doses of Peg-IFN were 54µg/week. He concluded that the superiority of Imatinib+PegIFN combination in term of molecular responses was confirmed at 24 months. Weekly dose of PegIFN has now been decreased to 45µg for the first 3 months of treatment. There is a relationship between duration of PegIFN exposure and the depth of molecular reponses (which seemed to say, my personal interpretation: better a constant low dose, rather than a high dose of IFN with the risk of interruptions).

In a Nordic CML Study Group (Denmark, Finland, Norway and Sweden) and Israel multicenter study a total of 130 newly diagnosed patients were randomized. CML patients had to be in complete hematological remission following 3 months of Imatinib-400mg induction therapy. The study arms were Imatinib-400mg, and the combination of Imatinib-400mg and Peg-IFNa2b (PegIntron, Schering-Plough). Imatinib dose was fixed at 400mg. Peg-IFN was started at 30 µg/week but could be escalated to 50 µg/week or reduced down to 15 µg/week depending on tolerability. Major molecaluar response rate at 52 weeks was significantly higher in the Imatinib+PegIFN arm (82%) compared to the Imatinib-only arm (54%). No unpredictable complications or adverse events were reported.

Interestingly, the presented observation in the German CML-IV Study (comparing Imatinib-400, Imatinib-400+AraC, Imatinib-400+IFN, Imatinib-800, and Imatinib-after-IFN-failure) did not come to the same conclusions. In the trial, so far 954 patients were evaluated. In this study, incidence of major molecular response was higher in Imatinib-800 (61%) as compared to 42% (Imatinib-400) and 45% (Imatinib-400+IFN). Overall survival by therapy did not show any significant difference between the arms. When I asked off the record, some were assuming that the difference might be due to "normal" Interferon being used in the CML-IV study, while the above studies used pegylated Interferon, leading to better tolerability and hence better exposure of the CML cells to Peg-IFN.

Lastly, the Italian GIMEMA trial comparing Imatinib-400mg with Imatinib-400+IFN: While there had been initial advantages of the combination arm, at 24 months these differences were lost. No surprise: the proportion of patients in this trial continuing IFN dropped from 41% at 12 months to 18% at 18 months, 13% at 24 months, 3% at 36 months, and by the end of the fourth year, all patients were off IFN. No information about IFN dosage was given (but some might suspect dosage was the problem). ''

Extrait de http://www.cmladvocates.net/index.php?I ... &task=view

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Laboratoire d’Hématologie du CHRU de Lille. Pr Claude Preudhomme - Avril 2009
Titre du projet
« Quantification de la maladie résiduelle chez les patients porteurs de LMC inclus dans le protocole SPIRIT. »
''Les premiers résultats de l’étude sur plus de 630 patients et 12 mois
de traitement, publiés en novembre 2008 dans la revue américaine
‘Blood’2, montrent que l’association entre l’Imatinib et l’interféron
offre la meilleure réponse au niveau moléculaire. L’étude doit se
poursuivre pour comparer les résultats sur 18 mois, mais ceux-ci
donnent à penser que cette association fera partie des traitements de
base dans les futurs protocoles.''
Extrait de http://www.fondationdefrance.org/conten ... 3%AFde.pdf

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Randomized Comparison of Imatinib Versus Imatinib Combination Therapies in Newly Diagnosed Chronic Myeloid Leukaemia (CML) Patients in Chronic Phase (CP): First Results of the Phase III (SPIRIT) Trial from the French CML Group (FI LMC)
Blood (ASH Annual Meeting Abstracts) 2008 112: Abstract 183
http://abstracts.hematologylibrary.org/ ... type=HWCIT

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CML: Adding Pegylated Interferon to Imatinib Increases Response - mai 2009
http://journals.lww.com/oncology-times/ ... ib.14.aspx

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Voir L'interferon alpha réveille les cellules souches cancéreuses
http://www.alte-smp.org/forumalte3/view ... ?f=9&t=621

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Sustained Molecular Response With Interferon Alfa Maintenance After Induction Therapy With Imatinib Plus Interferon Alfa in Patients With Chronic Myeloid Leukemia. - 2010 Feb 8
Burchert A, Müller MC, Kostrewa P, Erben P, Bostel T, Liebler S, Hehlmann R, Neubauer A, Hochhaus A.
Klinik für Hämatologie, Onkologie und Immunologie, Philipps Universität Marburg und Universitätsklinikum Giessen und Marburg, Standort Marburg, Marburg; III. Medizinische Klinik, Universitätsmedizin Mannheim, Universität Heidelberg, Mannheim; and Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany.
''Imatinib induces sustained remissions in patients with chronic myelogenous leukemia (CML), but fails to eradicate CML stem cells. This is of major concern regarding the issues of cure, long-term imatinib tolerability, and imatinib resistance. We therefore asked whether interferon alfa-2a (IFN) alone could maintain molecular remissions achieved by a prior combination therapy with imatinib and IFN. PATIENTS AND METHODS: Imatinib therapy was stopped in 20 patients who had concomitantly been pretreated with imatinib and IFN for a median of 2.4 years (range, 0.2 to 4.8 years) and 2.5 years (range, 0.2 to 4.9 years), respectively. After imatinib discontinuation, remission status was monitored monthly by quantitative analysis of the peripheral-blood BCR-ABL mRNA levels using real-time polymerase chain reaction. Proteinase-3 expression and proteinase-3-specific cytotoxic T cells (CTLs) were longitudinally measured to assess putative markers of IFN response. RESULTS: With a median time of 2.4 years after imatinib withdrawal (range, 0.5 to 4.0 years), 15 (75%) of 20 patients remained in remission. The number of patients in complete molecular remission increased under IFN from two patients at baseline to five patients after 2 years. Relapses occurred in five patients within 0.4 years (range, 0.2 to 0.8 years), but patients underwent rescue treatment with imatinib, re-establishing molecular remission. IFN therapy was associated with an increase in the expression of leukemia-associated antigen proteinase 3 and induction of proteinase-3-specific CTLs. CONCLUSION: Treatment with IFN enables discontinuation of imatinib in most patients after prior imatinib/IFN combination therapy and may result in improved molecular response. Induction of a proteinase-3-specific CTL response by IFN may contribute to this effect.''
http://www.ncbi.nlm.nih.gov/pubmed/2014 ... dinalpos=1

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Interferon Alpha 2a (IFN) Maintenance Therapy After Imatinib Plus IFN Induction Therapy in Chronic Myeloid Leukemia (CML) Induces Stable Long-Term Molecular Remissions and Is Associated with Increased Proteinase 3 (PR3) Expression and the Presence of PR1-Specific T-Cells
ASH2009 – décembre 2009
Andreas Burchert, MD, Martin C Müller, MD, Philippe Kostrewa, cand., med., Philipp Erben, MD, Tilman Bostel, MD, Simone Liebler, MD, Rüdiger Hehlmann, MD, Andreas Neubauer, MD and Andreas Hochhaus, MD
Department of Hematology, Oncology and Immunology, Universitätsklinikum Giessen und Marburg, Marburg, Germany Medical Faculty of Mannheim, University of Heidelberg, Mannheim, Germany
Dept. Hematology, Oncology, Immunology, Philipps University Marburg, Marburg, German Department of Hematology/Oncology, Universitätsklinikum Jena, Jena, Germany
‘Together, IFN maintenance after a prior imatinib/IFN induction therapy may be an effective alternative to permanent imatinib therapy, because it enables to safely discontinue imatinib even in those patients that have not achieved a CMR at the time of pausing imatinib. Induction of a PR1-specific CTL response by IFN may contribute to the particular efficacy of IFN after CML-debulking by imatinib`.
Extrait de http://ash.confex.com/ash/2009/webprogr ... 23533.html

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The role of interferon-alpha in the treatment of chronic myeloid leukemia
Cytokine & Growth Factor Reviews, Volume 18, Issue 5, Pages 459-471
L. Kujawski, M. Talpaz
‘Biological agents have long been used in the treatment of cancer, and interferon-alpha was the first human cytokine to be widely studied in this setting. Chronic myeloid leukemia (CML) is a hematopoietic stem cell disorder for which interferon-alpha has demonstrated substantial activity. In the 1980s interferon-alpha became first-line therapy for patients with chronic-phase CML, not eligible for allogeneic stem cell transplantation. Following the discovery of the leukemic oncogene BCR/ABL and its causal association with CML, the potent BCR/ABL tyrosine kinase inhibitor imatinib mesylate was developed. Imatinib proved to be superior to interferon-alpha in all outcome measures, making imatinib the new standard of care for patients with CML. There is both clinical and laboratory evidence suggesting imatinib therapy alone is not curative in CML, whereas IFN has induced a low but reproducible curative effect in some patients. This unique activity may be the basis for the reincorporation of IFN into the management of CML. These observations may be best explained by imatinib's negligible activity against the leukemic stem cell (LSC) population. This review discusses the history of interferon-alpha in the treatment of CML, the evolution of molecularly targeted therapies, and some of the lessons we have learned from years of informative research in CML. It also explores the new challenge of managing minimal residual disease in the imatinib era, and addresses the promising role for LSC-directed therapies in the future treatment of CML.’
Extrait de http://linkinghub.elsevier.com/retrieve ... 0107000846

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The response to imatinib and interferon-{alpha} is more rapid than the response to imatinib alone: a retrospective analysis of 495 Philadelphia-positive Chronic Myeloid Leukemia patients in early chronic phase.
Haematologica. 2010 Mar 19
Palandri F, Castagnetti F, Iacobucci I, Martinelli G, Amabile M, Gugliotta G, Poerio A, Testoni N, Breccia M, Bocchia M, Crugnola M, Rege-Cambrin G, Martino B, Pierri I, Radaelli F, Specchia G, Pane F, Saglio G, Rosti G, Baccarani M.
University of Bologna, S. Orsola-Malpighi Hospital, Bologna.
''Background Before the introduction of imatinib (IM), Interferon alpha (IFN-alpha)-based regimens were the golden standard for treatment of early chronic phase chronic myeloid leukemia (ECP-CML) patients. The combination IFN-alpha with IM is currently being investigated in at least two large clinical trials, the German CML Study IV and the French SPIRIT trial. DESIGN AND METHODS: We reviewed the cytogenetic and molecular responses of 76 ECP-CML patients who were treated with imatinib (IM) and Interferon-alpha (IFN-alpha) and of 419 ECP-CML patients treated with imatinib alone front-line. RESULTS: The complete cytogenetic response rate (CCgR) was higher in the IM+IFN-alpha group than in the imatinib group at 6 months (60% vs. 42%, p=0.003), but not at 48 months (88% vs 88%). The durability of the CCgR was similar in the two groups, with 94% and 91% of complete cytogenetic responders in continuous CCgR at 48 months (p=0.56). The major molecular response (MMolR) rate was higher in the IM+IFN-alpha group at 6 months (58% vs. 34%, p=0.0001) and 12 months (67% vs. 47%, p=0.001) but not later on (65% vs. 57%, at 48 months, p=0.25). OS and PFS were comparable in the two groups; a significant trend to better EFS was observed in patients treated with PegIFNalpha (91% vs. 78%, p=0.02). Conclusions These data suggest that the response to the combination treatment is more rapid. It is not yet known how much a rapid reduction will influence the longer-term overall and progression-free survival, and the cure rate.''
Extrait de http://www.ncbi.nlm.nih.gov/pubmed/20305139

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Voir aussi Interferon Alpha
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Voir Successful treatment of a chronic-phase T-315I-mutated chronic myelogenous leukemia patient with a combination of imatinib and interferon-alfa.
January 20, 2012
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