<em>18-Months Follow-up of the Trial of Imatinib after Ponatinib Induction (TIPI) in the Front-Line Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Setting</Em>

Nicolini, Franck

Oral and Poster Abstracts
Oral
632. Chronic Myeloid Leukemia: Novel Molecules in Clinical Practice

Research, Clinical trials, Clinical Research, CML, Chronic Myeloid Malignancies, Diseases, Adverse Events, Myeloid Malignancies, Measurable Residual Disease

Franck E. Nicolini, MD, PhD^1,2, Aude Charbonnier, MD, PhD^1,3^*, Martine Escoffre-Barbe, MD^1,4^*, Eric Jourdan, MD, PhD^1,5^*, Gabrielle Roth-Guepin, MD^1,6^*, Marc G. Berger, MD, PhD^1,7^*, Shanti Ame, MD, PhD^1,8^*, Marion Simonet, MD^1,9^*, Hyacinthe A Johnson-Ansah, MD^1,10^*, Viviane Dubruille, MD^1,11^*, Amandine Charbonnier, MD^1,12^*, Philippe Rousselot, MD PhD^1,13^*, Corentin Orvain^1,14^*, Bertrand Joly, MD^1,15^*, Jean-Christophe Ianotto, MD, PhD, HDR^1,16^*, Emilie Cayssials, MD, PhD^1,17^*, Mathieu Meunier^1,18^*, Anne Parry, MD^1,19^*, Valerie Coiteux, MD^1,20^*, Laurence Legros, MD, PhD^1,21,22^*, Hacene Zerazhi, MD^1,23^*, Gabriel Etienne, MD, PhD^1,24^*, Philippe Quittet, MD^1,25^*, Ollivier Legrand, MD²⁶^*, Amelie Penot, MD^1,27^*, Lydia Roy, MD^1,28^*, Charlotte Doublet, MD^1,29^*, Stéphane Morisset^1,30^*, Romaine Mayet, PhD³¹^*, Gwenaëlle Garin, PhD³²^*, Stéphanie Dulucq, PharmD, PhD^1,33^*, Françoise Huguet, MD^1,34^* and Delphine Rea³⁵

¹Centre Léon Bérard, Fi-LMC, Lyon, France
²Hematology department & CRCL INSERM U1052, Centre Léon Bérard, Lyon, France
³Department of Hematology, Institut Paoli-Calmettes, Marseilles, France
⁴Hematology department, Hôpital de Pontchaillou, Rennes, France
⁵Hematology department, Institut de Cancérologie du Gard, CHU de Nîmes, Nimes, France
⁶Department of Clinical Hematology, CHRU Nancy, Vandoeuvre Les Nancy, France
⁷Laboratoire d'Hématologie Biologique, CHU Estaing, Clermont-Ferrand, France
⁸Department of hematology, Institut de Cancérologie de Strasbourg, Strasbourg, France
⁹Hematology department, Centre Hospitalier Universitaire, Besançon, France
¹⁰Caen University Hospital, Normandy, Hematology Institute, Caen, France
¹¹Hematology department, Hôtel Dieu, CHU de Nantes, Nantes, France
¹²Clinical Hematology Department, Amiens-Picardie University Hospital, Amiens, France
¹³Hematology department, Centre Hospitalier de Versailles, UMR1184, University Versailles Paris-Saclay, Le Chesnay, France
¹⁴Hematology Clinic, Angers University Hospital, Angers, France
¹⁵Hematology department, Centre Hospitalier Francilien Sud, Corbeil-Essonne, France
¹⁶Hematology department, Centre Hospitalier Universitaire de Brest, Brest, France
¹⁷Hematology department & CIC, CHU Poitiers & INSERM CIC 1402, Poitiers, France
¹⁸Department of Hematology CHU Grenoble Alpes, Grenoble, France
¹⁹Department of Hematology, Annecy Genevois Hospital Center, Pringy, France
²⁰Hôpital Huriez, Hematology department, Centre Hospitalier Universitaire, Lille, France
²¹Service d’Hématologie-Clinique Ambulatoire (SHCA), APHP, Hôpital Bicêtre, Le Kremlin-Bicêtre, France
²²INSERM UMRS-MD1197, Hôpital Paul Brousse, Villejuif, France
²³Oncologie Médicale et Hématologie clinique, CH d'Avignon - Hôpital Henri Duffaut, Avignon, France
²⁴Hematology, Institut Bergonié, Bordeaux, France
²⁵Hematology department, CHU Montpellier, Hôpital Saint Eloi, Montpellier, France
²⁶Clinical Hematology and Cellular Therapy Department, Sorbonne University, Saint Antoine Hospital, INSERM UMRs U938, Paris, France
²⁷Department of hematology, Centre Hospitalier Universitaire Dupuytren, Limoges, France
²⁸Hematology Department, Henri Mondor University Hospital, UPEC, IMRB, Assistance Publique Hopitaux de Paris, Créteil, France
²⁹Hematology department, Centre Hospitalo-Universitaire, Saint-Etienne, Saint Priest en Jarez, France
³⁰Hematology department, Centre Léon Bérard, Lyon, France
³¹DRC, Centre Léon Bérard, Lyon, France
³²DRC, Centre Léon Bérard, Lyon, FRA
³³Laboratory of Hematology, Hôpital Haut Lévêque, Centre Hospitalier Universitaire de Bordeaux, Pessac, France
³⁴Hematology Department, Institut Universitaire du Cancer-Oncopole & CHU de Toulouse, Toulouse, France
³⁵Department of Hématologie, Hôpital Saint-Louis, Paris, France

Introduction: Prevention of disease transformation and long-term achievement of sustained deep molecular response (DMR) followed by successful treatment-free remission (TFR) are the current main goals of treatment of CP-CML. This trial addressed the safety and efficacy of a 6-month debulking strategy using ponatinib as front-line therapy in newly diagnosed CP-CML, followed by maintenance with imatinib. This was intended to induce a high proportion of TFR, with minimal toxicity. This is an update after an 18-month follow-up.

Methods: TIPI is an open-label phase II national academic trial (Clinical Trial: NCT04070443) that enrolled newly diagnosed adult CP-CML patients (pts) ≤65 years, harbouring major BCR::ABL1 transcripts with no significant underlying cardio-vascular disease, uncontrolled hypertension or diabetes with end-organ damage. Pts were stratified according to ELTS scores. Primary endpoint is the rate at which pts reached TFR criteria at M36 (Rea et al. Cancer, 2018). Two of the secondary endpoints are the kinetics of molecular response and its safety during this 2-TKI strategy. Pts were treated with ponatinib 30 mg QD for 6 months, followed by imatinib 400 mg QD until TFR criteria (MR4.5 ≥2 years) were reached, before M60. Molecular assessments were centralised and BCR::ABL1 transcripts were expressed in % on the international scale (IS). BCR::ABL1 mutation screens were performed by NGS. Results were analysed on an intention-to-treat basis.

Results: One hundred and sixty nine pts were enrolled between November 2019 and October 2022. Median age was 48 (18-65) years, 113 pts were males (67%). Fifteen (9%) pts harboured additional chromosomal abnormalities (ACA). Eighty-four (51.5%) pts had b2a2 and 99 (61%) b3a2 transcripts and could eventually harbour both. ELTS were low for 67 (40%) pts, intermediate for 73 (44%) and high for 27 (16%), data unavailable for 2. European Society of Cardiology (ESC) score was <2% in 158/167 (93%) evaluable pts, 3-9% in 8 (5%) pts and >10% in 1 (2%) pt. The median follow-up at database lock was 18 (2.8-46.1) months. Induction data (M1→M6) have already been presented (FE. Nicolini et al, ASH 2023). After M6, median number of days on imatinib is 365 (19-365) and median dose of imatinib delivered between M6 → M18 is 400 (295-480) mg daily.

Whereas a total of 39 grade 3-5 AEs had been recorded at M18, only a minority (n=13, 33%) were observed on imatinib: 2 hematologic (grade 4 neutropenia at M6) and 11 non-hematologic SAEs (2 urinary tract perturbations and 1 of each of the following: grade 4 transaminitis, seizure, diplopia, deep vein thrombosis, breast cancer, baso-cellular carcinoma, Covid-19 infection, appendicitis, gonarthrosis). Interestingly, no cardio-vascular event occurred on imatinib. The event-free survival [(EFS), event = death from any cause, progression, permanent discontinuation of study treatment related to AEs, study withdraw] is 92 (87.5-95.95)% at M6, 88.7 (84-94)% at M9, 87.5 (83-93)% at M12, 86 (82-92)% at M18.

Regarding efficacy, 158 pts/163 (97%) were in EMR on ponatinib. At M6 following the end of ponatinib induction the cumulative incidence (CI) of MMR was 44 (37-52)% , and then on imatinib, 59 (52-67)% at M9, 65 (58-72.5)% at M12 and 68 (60.5-75)% at M18 . The CI of MR4 and MR4.5 were respectively 23 (16-29)% and 7 (3-10)% at M6, 32 (25-39)% and 8 (4-13)% at M9, 33 (26-40)% and 10 (5-14)% at M12; 40 (33-48)% and 13 (8-18)% at M18 These data indicate that consolidation by imatinib did not significantly impair the molecular levels previously obtained on ponatinib. A few (n=7, 8%) patients lost their MMR previously obtained at M6 on ponatinib, and this occurred more often in younger patients [28 (23-45.5) years vs 48 (39-56), p=0.048]. A total of 3 pts died, one from sudden death at M2.5, and 2 in blast crisis at M3 and M8, from allogeneic SCT-related complications. BCR::ABL1 mutations were identified in 3 patients one with E255K at M6 (MBC pt) and 2 with a M244V at M18.

Conclusions: We observed a significant decrease in SAEs while on imatinib as compared to during the ponatinib induction phase. Ponatinib induction followed by imatinib consolidation induces high rates of MMR and DMR at M18, higher than that with TKI2 as front-line therapy as reported in the literature in CP-CML pts. Whether or not this translates into substantial TFR rates is yet to be determined.

Disclosures: Nicolini: Kumquat Biosciences: Consultancy; Sun Pharma Inc: Consultancy; GSK: Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Charbonnier: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees. Escoffre-Barbe: Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Jourdan: GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Berger: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte Biosciences: Research Funding. Ame: Novartis: Consultancy, Speakers Bureau. Simonet: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees; Chugai Pharma: Membership on an entity's Board of Directors or advisory committees. Johnson-Ansah: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rousselot: Incyte: Consultancy; Pfizer: Consultancy. Ianotto: GSK: Membership on an entity's Board of Directors or advisory committees. Cayssials: Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Meunier: Alexion: Consultancy; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Speakers Bureau; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy. Coiteux: Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees. Legros: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte Biosciences: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees. Quittet: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Roy: Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Dulucq: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Huguet: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Biosciences: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Rea: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees.

OffLabel Disclosure: Ponatinib, as induction therapy in this trial is not licensed in this setting

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^*signifies non-member of ASH

478 18-Months Follow-up of the Trial of Imatinib after Ponatinib Induction (TIPI) in the Front-Line Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Setting