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
Authors: Nicolini Franck E. , Charbonnier Aude , Escoffre-Barbe Martine , Jourdan Eric , Roth-Guepin Gabrielle , Berger Marc G. , Ame Shanti , Simonet Marion , Johnson-Ansah Hyacinthe A , Dubruille Viviane , Charbonnier Amandine , Rousselot Philippe , Orvain Corentin , Joly Bertrand , Ianotto Jean-Christophe , Cayssials Emilie , Meunier Mathieu , Parry Anne , Coiteux Valerie , Legros Laurence , Zerazhi Hacene , Etienne Gabriel , Quittet Philippe , Legrand Ollivier , Penot Amelie , Roy Lydia , Doublet Charlotte , Morisset Stéphane , Mayet Romaine , Garin Gwenaëlle , Dulucq Stéphanie , Huguet Françoise 
Published: December 2024

Introduction: Prevention ofdisease 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 &lt;2% in 158/167 (93%) evaluable pts, 3-9% in 8 (5%) pts and &gt;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.