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1578 Pegylated Interferon-Alpha 2a in Combination with Nilotinib As First-Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (Nilopeg trial). Four-Year Follow-up ResultsClinically Relevant Abstract

Chronic Myeloid Leukemia: Therapy
Program: Oral and Poster Abstracts
Session: 632. Chronic Myeloid Leukemia: Therapy: Poster I
Saturday, December 5, 2015, 5:30 PM-7:30 PM
Hall A, Level 2 (Orange County Convention Center)

Franck E. Nicolini, MD, PhD1,2, Gabriel Etienne, MD, PhD2,3*, Viviane Dubruille, MD2,4*, Lydia Roy, MD2,5*, Françoise Huguet, MD2,6*, Laurence Legros, MD2,7*, Stéphane Giraudier, MD, PhD2,8*, Valérie Coiteux, MD2,9*, Agnes Guerci-Bresler, MD2,10*, Pascal Lenain, MD2,11*, Delphine Rea2,12*, Shanti Amé, MD2,13*, Pascale Cony-Makhoul, M.D.2,14*, Martine Gardembas, MD2,15*, Eric Hermet, MD2,16*, Philippe Rousselot, MD, PhD2,17*, Marie-Claude Gagnieu, PharmD, PhD18*, Stéphane Morisset, Stat1*, Christine Pivot, PharmD19*, Madeleine Etienne, CRA1,2*, Francois Guilhot, MD2,20, Stéphanie Dulucq, PharmD, PhD21* and Francois-Xavier Mahon, MD, PhD, Professor2,3*

1Hematology department 1G, Centre Hospitalier Lyon Sud, Pierre Bénite, France
2Fi-LMC group, Pessac, France
3Hematology department, Institut Bergonié, Bordeaux, France
4Department of Hematology, Nantes University Hospital, Nantes, France
5Hematology department, CHU de Poitiers, Poitiers, France
6Hematology department, Institut universitaire du cancer de Toulouse, Toulouse, France
7Hematology department, Hopital Archet 1, CHU Nice, Nice, France
8Hematology department, Hôpital Henri Mondor, Créteil, France
9Hematology department, Hôpital Claude Huriez, Lille, France
10Hematology department, Hôpital d'Adultes du Brabois, CHU Nancy, Nancy, France
11Hematology department, Centre Henri Becquerel, Rouen, France
12Hematology department, Hôpital Saint-Louis, Paris, France
13Hematology department, Hôpital Civil , CHU Strasbourg, Strasbourg, France
14Hematology department, Centre Hospitalier Annecy-Genevois, Site Annecy, Metz-Tessy, France
15Hematology Department, University Hospital, Angers, France
16Hematology department, CHU d’Estaing, Clermont-Ferrand, France
17Hematology Department, Hôpital André Mignot, Versailles, France
18Pharmacology laboratory, Hôpital Edouard Herriot, Lyon, France
19Central Pharmacy, Hôpital Edouard Herriot, Lyon, France
20Hematology department, Inserm CIC 1402, CHU de Poitiers, Poitiers, France
21Laboratory of Hematology, Hôpital Haut Lévêque, Pessac, France

Background & aims

In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy.

Methods

In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center [all expressed in % on the international scale (IS)]. All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR).

Results

Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8–52.8) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had “major” BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at “6”, and “12” months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI).

The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1.

Figure 1: Cumulative incidence of MR4.5

                    

The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 [1.03-1.16]), 24 months (p=0.005, OR = 1.08 [1.02-1.14]) and 48 months (p=0.024, OR = 1.09 [1.01-1.17], but not with the mean doses of nilotinib [p=0.84, OR = 0.99 [0.99-1.01], p=0.087, OR = 1 [0.99-1.01], and p=0.88, OR = 1 [0.99-1.01] respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke).

Conclusion

Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred.  However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress.

Disclosures: Nicolini: Novartis: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Research Funding , Speakers Bureau ; Bristol-Myers Squibb: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau ; Ariad Pharmaceuticals: Honoraria , Membership on an entity’s Board of Directors or advisory committees , Speakers Bureau . Etienne: ARIAD: Consultancy , Honoraria , Speakers Bureau ; Novartis: Consultancy , Honoraria , Other: Congress Travel/Accomodations , Research Funding , Speakers Bureau ; BMS: Consultancy , Honoraria , Speakers Bureau . Roy: BMS: Consultancy , Research Funding ; Novartis: Consultancy , Research Funding . Huguet: Novartis: Consultancy , Research Funding ; BMS: Consultancy , Speakers Bureau ; ARIAD: Consultancy , Speakers Bureau ; PFIZER: Consultancy , Speakers Bureau . Legros: ARIAD: Speakers Bureau ; BMS: Speakers Bureau ; Novartis: Research Funding , Speakers Bureau . Giraudier: Novartis: Speakers Bureau . Coiteux: BMS: Speakers Bureau ; ARIAD: Speakers Bureau ; Novartis: Speakers Bureau . Guerci-Bresler: ARIAD: Speakers Bureau ; BMS: Speakers Bureau ; Novartis: Speakers Bureau ; PFIZER: Speakers Bureau . Rea: Pfizer: Honoraria ; Ariad: Honoraria ; Novartis: Honoraria ; Bristol-Myers Squibb: Honoraria . Amé: BMS: Speakers Bureau ; Novartis: Speakers Bureau . Cony-Makhoul: Novartis: Consultancy , Honoraria , Speakers Bureau ; BMS: Consultancy , Honoraria , Speakers Bureau . Gardembas: Novartis: Speakers Bureau . Hermet: Novartis: Speakers Bureau ; BMS: Speakers Bureau . Rousselot: Pfizer: Consultancy ; BMS: Consultancy , Speakers Bureau ; Novartis: Speakers Bureau . Mahon: ARIAD: Consultancy ; Bristol-Myers Squibb: Consultancy , Honoraria ; Pfizer: Consultancy ; Novartis: Consultancy , Honoraria .

*signifies non-member of ASH