Ponatinib and Chemotherapy in Young Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblstic Leukemia. Preliminary Results of Ponalfil Clinical Trial
Authors: Ribera Josep-Maria , García Olga , Martinez Pilar , Fernandez Pau Montesinos , Boluda Blanca , Esteve Jordi , Esteban Daniel , Moreno María José , Alonso Natalia , González-Campos José , Bermúdez Arancha , Vives Susana , Tormo Mar , Hernández-Rivas Jesús María , Martinez-Lopez Joaquin , García-Sanz Ramón 
Published: November 2019

Background and objective. The combination of tyrosine kinase inhibitors (TKI) and chemotherapy (intensive, attenuated or minimal) has improved the prognosis of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL). The combination of HyperCVAD and ponatinib has improved the molecular response and survival compared with other combinations of chemotherapy and first or second generation tyrosine kinase inhibitors (TKI) (Jabbour, et al, Lancet Haematol. 2018; 5:e618-e627). The Spanish PETHEMA group conducts the phase 2 PONALFIL trial, that incorporates ponatinib to the same induction and consolidation schedule of the ALL Ph08 trial (Ribera JM et al. Cancer 2019. doi:10.1002/cncr.32156). The preliminary results of this trial are herein reported.
Patients and method. The PONALFIL trial (NCT02776605) combines ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin and prednisone) followed by consolidation (high-dose methotrexate, ARA-C, mercaptopurine, etoposide) and allogeneic HSCT in de novo Ph+ ALL patients aged 18-60 years. Regular molecular follow-up was performed after alloHSCT. No TKI after HSCT was planned unless persistence or reappearance of molecular disease. On July 2019, 21 out of the 30 patients had been recruited. Molecular studies were centrally carried out according to the Euro-MRD consortium on standardization (Pfeifer et al, Leukemia, 2019; PMID: 30858550). The response to therapy (complete morphological [CR], molecular [complete, CMR or major, MMR] after induction and before allogeneic HSCT), CR duration, overall survival [OS]) and toxicity in the first 21 cases is herein analyzed.
Results. Median age was 49 (19-59) years and 12 patients were female. One patient showed CNS involvement at diagnosis. Median WBC count was 12.4 (0.6-79.5) x109/L, Hb 87 (71-140) g/L, platelets 39 (15-180) x109/L. The immunologic phenotype was common in 13 cases, with molecular isoform p190 in 14 patients (67%), p210(b2a2) in 6 (21%) and p210(b3a2) in the remaining patient. CR was attained in 19/19 patients (2 are still on induction therapy), with CMR in 9/18 cases (50%), MMR in 4/18 (22%) and no molecular response in 5/18 (28%) (molecular response analysis pending in 1 patient). Six patients are receiving consolidation, 5 are waiting for allogeneic HSCT and 6 patients have been transplanted (4 in CMR, 1 in MMR, 1 with no data). At the time of the study one patient showed molecular relapse after allogeneic HSCT and is receiving ponatinib, whereas the remaining patients are alive and in CR1 (median follow-up of 3.7 months, range 0.3-18.2)
Sixty-nine adverse events (AE) have been registered in 9 patients, 8 of whom were severe (SAE) and occurred in 6 patients, prompting to withdrawn of the trial in 2 (thrombosis of the retinal central artery and severe bowel infection, one case each). The most frequent AE were hematologic (25%), gastrointestinal (14%), infections (7%), and cutaneous (7%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina, one case each).
Conclusions. The preliminary results of the PONALFIL trial show a high short-term antileukemic efficacy with acceptable toxicity profile.

Disclosures
Fernandez: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Teva: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Esteve:Pfizer: Consultancy; Novartis: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Amgen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Roche: Consultancy; Astellas: Consultancy, Speakers Bureau. Bermúdez:Fresenius: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees.