Preliminary Results of CML1214, a Survey on Ponatinib Compassionate Use in Italy By the Gimema CML Working Party
Authors: Fava Carmen , Dragani Matteo Emidio , Boggione Paola , Paoloni Francesca , Luciano Luigiana , Gozzini Antonella , Pregno Patrizia , Abruzzese Elisabetta , Gambacorti-Passerini Carlo , Specchia Giorgina , Elena Chiara , Lunghi Monia , Pungolino Ester , Falzetti Franca , Galimberti Sara , Iurlo Alessandra , D'Arena Giovanni , Reddiconto Giovanni , Fozza Claudio , Bergamaschi Micaela , Crea Enrico , Saglio Giuseppe , Rege Cambrin Giovanna 
Published: November 2019

Background: Since its introduction ponatinib has proved great efficacy among patients (pts) with chronic myeloid leukemia (CML), representing in some settings like the T315I mutation the only therapeutical choice due to its unique conformation. Its use both in the cohort of heavily pretreated CML and frontline has led to promising results in terms of overall survival (OS) and progression free survival (PFS), as demonstrated in the PACE study (Cortes JE, Blood 2018) and in the single center experience of the MD Anderson (Jain P, Lancet Haematol 2015). The cardiovascular toxicity associated with treatment has been addressed both in protocols and real-life experiences: it is clear that the benefits of ponatinib in terms of molecular response have to be balanced with the possibility of adverse events such as arterial and venous thromboembolism, dyslipidemia and hypertension which have to be managed and, whenever possible, prevented (Dorer JD, Leuk Res 2016; Caocci G, Int J Cardiol 2019). Before the final registration of the drug by AIFA, ponatinib has been available in Italy since October 2011 to March 2015 in compassionate regimen: the results collected here represent a real-life experience on ponatinib use in a cohort of Italian patients mostly heavily pre-treated.
Methods: Italian chronic-phase (CP) CML pts treated with ponatinib in compassionate regimen since October 2011 were collected in the GIMEMA retrospective multicenter protocol CML1214 (clinicaltrials.gov NCT02448095). Primary objective of the study was the assessment of the tolerability and safety profile; secondary objectives were the assessment of the OS, PFS, best response, mutational status, rate of dose reductions. Data were collected following the rules of retrospective studies in Italy and all patients signed an informed consent.
Results: 34 pts with CP-CML were enrolled. Accelerated phase or blastic phase were considered as exclusion criteria. There were 17 males and 17 females, with a median age of 62 (25-84) years at ponatinib initiation. Sokal score was high in 7 (23.33%), intermediate in 17 (56.67%), low in 6 (20%) and unknown in 4 pts. Regarding previous TKIs, 22 (64.7%) pts had three previous lines of therapy, 10 (29.41%) two lines, 2 (5.8%) only one TKI before ponatinib. Two patients experienced a previous stem cell transplant (SCT) and other 10 (29.4%) harbored a T315I mutation before ponatinib initiation. At baseline none of the 34 patients were in major molecular remission (MMR). The median follow-up on ponatinib was 46.6 months (range 15.2-74.5). Cumulative incidence of MMR was 14.7% at three months, 20.6% at six months, 29.4% at nine months, and 55.5% at 36 months. Rate of OS at 36 months was 80% (Figure 1); the presence of T315I did not affect survival. At last follow-up 17 pts were still on treatment with ponatinib; eight pts died, 3 after SCT, 1 for cardiovascular toxicity, 3 for disease progression; one for unknown reason. The treatment-related vascular adverse events (AEs) represented 20.6% of total AEs reported: 6 of them were cardiovascular, 2 cerebrovascular, 2 peripheral, 3 new-onset hypertension, 2 cardiac failures. Non cardiovascular AEs were mostly due to hematological intolerance, with 43 events of neutropenia/thrombocytopenia out of 73 total collateral effects, followed by 9 reported skin problems (which varied from simple rash or desquamation to one episode of ichthyosis).
Conclusions: After a median follow up of 46.6 months, ponatinib provided substantial benefits in a cohort of pts in a timeframe where, after failing 2nd generation TKIs, no other chances were available except transplantation, and T315I positive patients were practically orphan of treatment before ponatinib. Aside from the large prospective PACE trial, results from GIMEMA CML1214 pair with other real-life experiences like the French PEARL (Heiblig M, Exp Hematol 2018) or the Spanish GELMC (Garcia-Gutierrez V, EHA 2016) reports, thus confirming the manageability and the effectiveness of this therapy in challenging clinical situations.

Disclosures
Fava: Incyte: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Pregno:Incyte: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Abruzzese:BMS: Consultancy; Incyte: Consultancy; Novartis: Consultancy; Pfizer: Consultancy. Gambacorti-Passerini:Pfizer: Honoraria, Research Funding; Bristol-Meyers Squibb: Consultancy. Elena:Pfizer: Consultancy; Novartis: Consultancy. Iurlo:Pfizer: Other: Speaker Honoraria; Novartis: Other: Speaker Honoraria; Incyte: Other: Speaker Honoraria. Saglio:Celgene: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; Incyte: Consultancy; BMS: Consultancy; Novartis: Consultancy; Ariad: Consultancy.