Treatment-Free Remission in Ponatinib-Treated CML Patients: The Italy-Tfr Experience
Authors: Fava Carmen , Santoro Marco , Caramella Marianna , Abruzzese Elisabetta , Giai Valentina , Cattaneo Daniele , Elena Chiara , Tiribelli Mario , D'Adda Mariella , Loglisci Giuseppina , Bonuomo Valentina , Grano Selene , Ferrari Jacqueline , Catania Federica Maria , Pungolino Ester Maria , Iurlo Alessandra 
Published: December 2023

Background: In recent years, treatment-free remission (TFR) has become a new therapeutic goal and is considered feasible even by international expert guidelines, at least in patients (pts) with a stable deep molecular response (DMR). From the EPIC study, we learned that many pts achieve a DMR very early, regardless of Sokal risk (Lipton, Lancet Oncol 2016). The Optic study showed that early dose reduction is associated with a containment of cardiovascular (CV) risk while maintaining therapeutic efficacy. In the cohort of pts initially treated with 45 mg QD, the number of events remained around 10% (Cortes, Blood 2021). Recommendations for treatment discontinuation suggest that it should be considered only after one line of treatment or after a second line if first-line TKI was switched for intolerance. Since 2016, there are case reports in the literature of imatinib-resistant pts, treated with ponatinib in second or following lines due to intolerance or resistance to previous TKIs, with or without ABL1 mutations, who reduced the daily dosage from 45 to 15 mg, still achieving a DMR and then discontinued ponatinib due to toxicity, obtaining a persistent TFR (Wisniowski, Blood 2016; Engel, J Oncol Pract 2016; Cohen, Leuk Lymphoma 2020).

Methods: Within the context of the Italy-TFR retrospective and prospective study (NCT04769947) which is ongoing and actually includes 467 pts, we collected the data of 19 pts who attempted TFR after ponatinib treatment.

Results: Median age was 44 years at diagnosis, 60 years at ponatinib discontinuation. 8 pts were male (42%); Sokal score was available for 14 pts: 5, 3 and 6 pts were low, intermediate and high risk, respectively. ELTS score was available for 11 pts: 6 pts, 4 and 1 were low, intermediate and high risk, respectively. 6 pts were treated with ponatinib in second line, 9 in third line, 3 in forth line. First-line therapy was available for 16 pts and was imatinib for 11 pts, nilotinib for 2 pts, dasatinib for 3 pts. Median duration of front-line treatment was 16 months (mos, IQR 11-34). Data on second line therapy was available for 11/12 pts: 5 pts were treated with nilotinib, 6 with dasatinib. Median duration of second-line treatment was 47 mos (IQR 19-58). Third line therapy was dasatinib for all 3 pts, with a duration of 1, 18 and 139 mos. Reason for starting ponatinib was intolerance for 8 pts, resistance for the others. For 7/11 resistant pts response at ponatinib start was CHR for one pt, MR1 for 3 pts, MR2 for 3 pts. 3 pts carried 1 ABL1 mutation at ponatinib start: 1 F359V, 1 M244V and 1 T315I; 1 pt carried 2 mutations: 1 Y253H and 1 E499E. Patients received ponatinib for a median of 47 mos (IQR 34-54). Starting dose was 45 mg for 6 pts, 30 mg for 8 pts and 15 mg for 5 pts. Response at 3 mos was available for 17 pts and was MR2 for 2 pts, MR3 for 9 pts and DMR for 6 pts. Median time to DMR was 18 mos (IQR 6-36). Ponatinib dose before treatment discontinuation was 15 mg for all but 4 pts: 1 was dose reduced from 45 mg to 30 mg, 1 stayed on 45 mg; 2 pts who had started with 15 mg dose reduced to 15 mg every other day. 11 pts discontinued in MR4, 7 pts in MR4.5 and 1 pt in MR5. Median duration of DMR before discontinuation was 25 mos (IQR 14-37). Reasons for discontinuation were: physician-patient shared choice for 9 pts, intolerance for 6 pts (among whom 1 had pancreatitis, 1 worsening of cardiac heart failure, 1 tachycardia, and 3 low-grade GI symptoms), need to start chemotherapy for a second neoplasia for 2 pts, pregnancy for 1 pt and auto-suspension for 1 pt. Only one pt had a CV adverse event (stroke) during treatment with ponatinib. 16/19 pts maintained TFR for a median time of 19 mos (IQR 8-32) and were still off treatment at the last follow-up. 3 pts had to resume treatment after 3, 4 and 9 mos. All 3 restarted treatment with ponatinib and reobtained DMR. All pts were alive at last follow-up, except for 2 pts who died for a gastric and a lung cancer.

Conclusions: Our data confirmed the efficacy of ponatinib in second or later lines of treatment. All pts, including those treated for resistance, achieved optimal responses at 3 mos. We also showed that TFR may be feasible for some pts treated in second or subsequent lines, not only for intolerance. Follow-up time extension and collection of data from additional pts are desired to confirm our observations, and seem to be of utmost importance to better define the characteristics of pts who might benefit from ponatinib with the purpose of TFR attempt.