REGULAR ARTICLE Ponatinib, chemotherapy, and transplant in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia Josep-Maria Ribera,1 Olga Garcıa-Calduch,1 Jordi Ribera,1 Pau Montesinos,2 Isabel Cano-Ferri,2 Pilar Martınez,3 Jordi Esteve,4 Daniel Esteban,4 Marıa Garcıa-Fortes,5 Natalia Alonso,6 Jos alez-Campos,7 Arancha Berm e Gonz udez,8 Anna Torrent,1 Eul alia Genesca, Santiago Mercadal, Joaquın Martınez-Lopez, and Ramo 1 9 3 n Garcıa-Sanz10 1 Department of Hematology, Institut Catala d'Oncologia (ICO)-Hospital Germans Trias i Pujol, Josep Carreras Leukemia Research Institute (IJC), Institut Germans Trias i Pujol Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/18/5395/1921879/advancesadv2022007764.pdf by guest on 20 January 2023 (IGTP), Universitat Autonoma de Barcelona, Badalona, Spain; 2Department of Hematology, Hospital Universitari i Polit encia, Spain; 3Department of Hematology, ecnic La Fe, Val 4  Hospital Doce De Octubre, Madrid, Spain; Department of Hematology, Hospital Clınic, Barcelona, Spain; Department of Hematology, Hospital Universitario Virgen De La 5 Victoria, Malaga, Spain; 6Department of Hematology Complejo Hospitalario Universitario Santiago de Compostela, Santiago de Compostela, Spain; 7Department of Hematology, Hospital Universitario Virgen del Rocıo, Instituto de Biomedicina de Sevilla (IBIS)/Consejo Superior de Investigaciones Cientıficas (CSIC)/Centro de Investigacion Biom edica en Red C ancer (CIBERONC), Universidad de Sevilla, Seville, Spain; 8Department of Hematology, Hospital Universitario Marqu es de Valdecilla, Santander, Spain; 9 Department of Hematology, ICO-Hospital Duran i Reynals, Hospitalet de Llobregat, Spain; and 10Department of Hematology, Hospital Universitario de Salamanca (HUS/ Instituto de Investigacion Biomedica de Salamanca), CIBERONC and Center for Cancer Research-Instituto de Biologıa Molecular y Celular del Cancer (Universidad de Salamanca-CSIC), Salamanca, Spain Promising results have been shown with the combination of ponatinib and chemotherapy in Key Points adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph1 ALL). The  Ponatinib and PONALFIL (Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic chemotherapy Leukemia) trial combined ponatinib (30 mg/d) with standard induction and consolidation followed by alloHSCT chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly for Ph1 ALL are diagnosed Ph1 ALL patients aged 18 to 60 years. Ponatinib was only given pre-emptively effective and safe in after alloHSCT. Primary end points were hematologic and molecular response before adults aged ,60 years. alloHSCT and event-free survival (EFS), including molecular relapse as event. Thirty patients (median age, 49 years; range, 19-59 years) entered the trial. All exhibited hematologic  Cross-trial response, and alloHSCT was performed in 26 patients (20 in complete molecular response comparison suggests and 6 in major molecular response). Only 1 patient died (of graft-versus-host disease), and 5 improvement vs patients exhibited molecular relapse after alloHSCT. No tyrosine kinase inhibitor was given imatinib. after HSCT in 18 of 26 patients. Twenty-nine patients are alive (median follow-up, 2.1 years; range, 0.2-4.0 years), with 3-year EFS and overall survival (OS) of 70% (95% confidence interval, 51-89) and 96% (95% confidence interval, 89-100), respectively. Comparison of the PONALFIL and the ALLPh08 (Chemotherapy and Imatinib in Young Adults With Acute Lymphoblastic Leukemia Ph [BCR-ABL] Positive; same schedule, using imatinib as the tyrosine kinase inhibitor) trials by propensity score showed significant improvement in OS for patients in PONALFIL (3-year OS, 96% vs 53%; P 5 .002). The most frequent grade 3 to 4 adverse events were hematologic (42%), infectious (17%), and hepatic (22%), with only one vascular occlusive event. The combination of chemotherapy with ponatinib followed by alloHSCT is well tolerated, with encouraging EFS in adults with newly diagnosed Ph1 ALL. Cross-trial comparison suggests improvement vs imatinib (clinicaltrials.gov identifier #NCT02776605). Submitted 4 April 2022; accepted 16 May 2022; prepublished online on Blood Requests for data sharing may be submitted to jribera@iconcologia.net or Advances First Edition 8 June 2022; final version published online 22 Septermber 2022. olga.garcia.calduch@fundacionpethema.es. The study protocol is also available at DOI 10.1182/bloodadvances.2022007764. https://www.fundacionpethema.es. Presented at the 64th American Society of Hematology Annual Meeting & Exposition, © 2022 by The American Society of Hematology. Licensed under Creative Atlanta, 11-14 December 2021 (Blood. 2021;138[supplement 1]:1230). Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC- ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. 27 SEPTEMBER 2022 • VOLUME 6, NUMBER 18 5395 Introduction were aged 18 to 60 years with newly diagnosed Ph1 ALL and an Eastern Cooperative Oncology Group (ECOG) score #2, normal car- diac function (defined by an ejection fraction above 50%), and ade- The Philadelphia (Ph) chromosome or BCR::ABL1 rearrangement is quate organ function (serum bilirubin #3.0 mg/dL and serum the most frequent genetic aberration in adults with acute lympho- creatinine #3.0 mg/dL, unless higher levels were believed to be due blastic leukemia (ALL), with an incidence of 25% to 30% in young to ALL). Key exclusion criteria included: active hepatitis infection; any adults and 40% to 50% in older adults and elderly patients.1 The active infection not controlled by antibiotics; history of acute pancreati- introduction of tyrosine kinase inhibitors (TKIs) initially combined tis within 1 year or history of chronic pancreatitis; history of alcohol with standard-dose chemotherapy and later with attenuated or mini- abuse; triglyceride levels .450 mg/dL; any clinically significant uncon- mal chemotherapy followed by allogeneic hematopoietic stem cell trolled or active cardiovascular condition, including clinical evidence of transplant (alloHSCT) in fit patients significantly improved outcomes grade 3 to 4 heart failure as defined by the New York Heart Associa- compared with historical controls.2-8 Imatinib was the first TKI used tion functional criteria, uncontrolled hypertension, arrhythmias, ischemic Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/18/5395/1921879/advancesadv2022007764.pdf by guest on 20 January 2023 in trials, but similar or slightly better results have been observed with cardiovascular or neurologic events, or deep venous or pulmonary the use of dasatinib.7-9 Although not approved for regular use, trials embolism; any impairment in gastrointestinal absorption of ponatinib; with nilotinib showed promising results.10 Two recent clinical trials active second malignancy; or history of treatment with ponatinib. have shown impressive short-term results with the combination of a The study protocol was reviewed and approved by the institutional second- or third-generation TKI (dasatinib or ponatinib, respectively) review board or an independent ethics committee at all participating with blinatumomab and without induction and consolidation chemo- centers. All patients provided written informed consent. therapy.11,12 These results question the need for intensive chemo- therapy and alloHSCT in all patients with Ph-positive (Ph1) ALL. Procedures Ponatinib is a third-generation TKI with a wide spectrum of kinase inhi- Patients received a 7-day steroid pretreatment during which the bition.13 It is active against most known ABL1 mutations and is the presence of the BCR-ABL1 transcript was centrally confirmed. only TKI with activity against Ph1 ALL subclones with the T315I muta- Table 1 presents the chemotherapy schedule. Induction chemo- tion.14 Ponatinib has shown clinical activity as a single drug in therapy included vincristine, daunorubicin, and prednisone along relapsed or refractory Ph1 ALL.15 A phase 2 clinical trial combining 4 weeks. Consolidation chemotherapy consisted of high-dose meth- ponatinib with hyperfractionated cyclophosphamide, vincristine, doxo- otrexate, high-dose cytarabine, mercaptopurine, and etoposide for rubicin, and dexamethasone (hyper-CVAD) in newly diagnosed Ph1 2 months. Patients received oral ponatinib 30 mg/d from diagnosis ALL patients showed promising results, with polymerase chain reac- to 1 week before alloHSCT. Intrathecal therapy (IT) with metho- tion (PCR)-based complete molecular response (CMR) of 73% after trexate, cytarabine, and hydrocortisone was given at pre-phase 3 months of therapy and a 3-year event-free survival (EFS) of 70%.16 (1 dose), during induction (2 doses), consolidation (3 doses), during In a propensity score–matched analysis, ponatinib in combination with the conditioning regimen of alloHSCT (1 dose), and after alloHSCT hyper-CVAD chemotherapy showed a significantly better prognosis (5 doses, every 2 months) for a total of 12 doses. For patients pre- compared with hyper-CVAD and dasatinib.17 Moreover, a phase 2 senting with active central nervous system (CNS) disease, the IT clinical trial with ponatinib plus prednisone in patients aged $60 years regimen was repeated twice weekly until the cerebrospinal fluid or unfit for intensive chemotherapy and alloHSCT reported CMR at became clear of leukemic cells, and the cell count normalized. Reg- 24 weeks in 40.9% of patients, a median duration of CMR of 11.6 ular cerebrospinal fluid prophylaxis was then administered. months, and a median EFS of 14.3 months.18 The results of these studies suggest a beneficial role for ponatinib in adults with newly alloHSCT was scheduled in all patients after consolidation regard- diagnosed Ph1 ALL. A phase 3 trial comparing imatinib vs ponatinib less of molecular response. Patients received a standard condition- combined with attenuated chemotherapy in adults with de novo Ph1 ing schedule of cyclophosphamide (60 mg/kg IV, on days 26 and ALL is ongoing (clinicaltrials.gov identifier #NCT03589326). 25) and fractioned total body irradiation of 13 Gy (days 24 to –1). For patients undergoing umbilical cord blood HSCT, the recom- In the phase 2 PONALFIL trial (Ponatinib With Chemotherapy for mended conditioning regimen included thiotepa (5 mg/kg per day Young Adults Ph Positive Acute Lymphoblastic Leukemia; Clinical- IV, on days –7 and –6; maximum dose of 10 mg/kg), fludarabine trials.gov identifier #NCT02776605), we investigated the efficacy (50 mg/m2 per day IV over 1 hour, on days –5, –4, and –3), busul- and safety of first-line ponatinib plus standard induction and consoli- fan (3.2 mg/kg per day IV over 3 hours, on days –5, –4, and –3), dation chemotherapy followed by alloHSCT in patients aged 18 and thymoglobulin (2 mg/kg per day over 8 hours, on days –4, –3, to 60 years with newly diagnosed Ph1 ALL. A propensity and 22). Non-myeloablative conditioning was only used in patients score–matched analysis was also performed comparing outcomes who were not candidates for a myeloablative regimen, and the regi- with those of the ALLPh08 Trial (Chemotherapy and Imatinib in men consisted of fludarabine (30 mg/m2 IV, days 28 to –4) and Young Adults With Acute Lymphoblastic Leukemia Ph [BCR-ABL] melphalan (70 mg/m2 IV, days –3 and –2). The first-choice donor Positive; clinicaltrials.gov identifier #NCT01491763)19 that had the was an HLA-identical sibling. If not available, a 10/10 same design and schedule and used imatinib as the TKI. HLA–matched unrelated donor was selected. If an unrelated donor with these characteristics was not found, the third option was a Patients and methods good umbilical cord blood donor (with 4/6 HLA compatibility and adequate cellularity) or a haploidentical donor. Autologous HSCT Study design and participants was only scheduled if there was absolute contraindication to any The PONALFIL trial was a phase 2, open-label, single-arm trial per- type of alloHSCT, with the conditioning regimen being the same as formed in 30 adult patients at 9 centers in Spain. Eligible patients that used in the myeloablative alloHSCT. Management of HSCT 5396 RIBERA et al 27 SEPTEMBER 2022 • VOLUME 6, NUMBER 18 Table 1. Chemotherapy schedule of the PONALFIL trial Molecular studies Phase Route Dose Days Bone marrow and peripheral blood samples from all patients at Induction* baseline were evaluated in a central facility. A fluorescence in situ Ponatinib By mouth 30 mg Until consolidation hybridization study on myeloid precursors was not performed at Vincristine IV 1.5 mg/m2 1, 8, 15, 22 diagnosis. Samples were processed according to the standardized (maximum 2 mg) consensus guidelines for MRD assessment in Ph1 ALL by real-time Daunorubicin IV 45 mg/m2 1, 8, 15, 22 quantitative reverse transcriptase of the EuroMRD group [https:// doi.org/10.1016/S2352-3026(18)30176-5]. MRD assessments by Prednisone IV 60 mg/m2 1-14 2 immunoglobulin heavy chain clonality studies or by multiparameter IV 30 mg/m 15-21 flow cytometry were not performed. IV 15 mg/m2 22-28 BCR::ABL1 kinase domain (KD) mutational testing was performed Triple IT† IT 1, 28 Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/18/5395/1921879/advancesadv2022007764.pdf by guest on 20 January 2023 by direct Sanger sequencing and allele-specific PCR for T315I Consolidation mutation at baseline and at molecular relapse in a centralized and Ponatinib By mouth 30 mg Until HSCT certified laboratory. An exploratory copy number abnormality (CNA) Methotrexate IV 1.5 g/m2 1, 28, 56 analysis was performed at diagnosis using a 750 000 single nucleo- Mercaptopurine By mouth 50 mg/m2 1-7, 28-35, 56-63 tide polymorphism array from Affymetrix (Thermo Fisher Scientific, Etoposide IV 100 mg/m2 14, 42 Santa Clara, CA). Hematologic and cytogenetic responses were 2 assessed in local laboratories. Cytarabine IV 1000 mg/m /12h 14, 15, 42, 43 Triple IT† IT 1, 28, 56 Outcomes Maintenance The coprimary end points were the achievement of response (CHR, Ponatinib‡ By mouth 30 mg (first year) Daily major molecular response [MMR], and CMR) after induction and 15 mg (second year) before HSCT and the EFS. The secondary end points included the *Pre-phase with prednisone 60 mg/m2 and triple IT was given for a maximum of rate of patients receiving HSCT in first CMR, the transplant-related 1 week, while ALL was fully characterized. †Triple IT with methotrexate (15 mg), cytarabine (30 mg), and hydrocortisone (20 mg). mortality (TRM), the overall survival (OS), the type and frequency of ‡After alloHSCT, only if molecular disease persisted or reappeared. AE and severe AE (SAE), and the matched analysis comparing out- comes with those of the ALLPh08 trial,19 which included the same approach except for the use of imatinib (600 mg/d) instead of ponatinib. was conducted according to the guidelines of each participating CHR was defined as bone marrow blasts ,5%, peripheral blood dif- center. ferential without blasts (neutrophils $1.5 3 109/L, platelets $100 3 109/L), and no evidence of extramedullary involvement by leukemia. After alloHSCT, frequent monitoring of molecular response was per- CMR and MMR were defined as the BCR::ABL1/ABL1 ratio formed (every month) using quantitative reverse polymerase chain ,0.01% and ,0.10%, respectively, assessed by reverse-transcription reaction (RQ-PCR) for BCR::ABL1. If the measurable residual dis- quantitative real-time PCR for BCR::ABL1 transcripts with a sensitivity ease (MRD) level was ,0.01%, no further treatment was pre- of at least 30 000 molecules of ABL. EFS was defined as the time scribed. If the MRD level was $0.01%, ponatinib at a dose of 30 from enrollment to failure of achieving CHR at week 6, lack of molecu- mg/d by mouth was given for the first year and 15 mg/d during the lar response before HSCT, molecular or hematologic relapse, or death second year. In case of autologous HSCT, ponatinib (30 mg/d, by by any cause, whichever occurred first; the OS was calculated for the mouth), mercaptopurine (40 mg/m2 per day, by mouth), and metho- entire study population as the time from enrollment to death by any trexate (15 mg/m2 per week, intramuscularly) were scheduled dur- cause or last follow-up. Patients who withdrew from the trial were con- ing the first year after HSCT, and the ponatinib dose was reduced sidered as censures at the time of withdrawal. to 15 mg/d in the second year in patients with sustained CMR. AEs and SAEs were recorded from the date informed consent was Ponatinib dose reduction (to 15 mg) or suspension was planned in obtained up to 30 days after the last administration of ponatinib, case of serious nonhematologic or hematologic toxicities. In the and at any time if they were suspected to be related to study medi- case of arterial or venous occlusive events, ponatinib treatment was cation. AEs and SAEs were graded by using Common Terminology not resumed unless the potential benefits outweighed the risk of Criteria for Adverse Events version 4.0. recurrent events, or the patient had no other treatment options. For serious nonhematologic adverse events (AEs) other than arterial or Statistical analysis venous occlusions, ponatinib treatment was resumed only after res- Sample size estimation was based on demonstrating noninferiority in olution of the AE or when the potential benefit of resuming therapy terms of CMR after consolidation with respect to the historical control was judged to outweigh the risks. In case of any hematologic AE, (50%).19 For a unilateral a error of 0.05 and estimating the absence dose reduction or therapy suspension was allowed only after con- of losses, because all patients who started treatment are valid for firmed complete hematologic response (CHR). Supportive care induction, N 5 30 was considered to be sufficient for detecting a dif- measures (ie, antimicrobial prophylaxis or treatment, tumor lysis pro- ference $25.5%16 from the historical control with 90% power. phylaxis or therapy, transfusion of blood products) were imple- mented according to the standard procedures of each participating The main clinical and hematologic variables are expressed as fre- center. quency and as percentages for categorical variables. For continuous 27 SEPTEMBER 2022 • VOLUME 6, NUMBER 18 PONATINIB for Ph1 ACUTE LYMPHOBLASTIC LEUKEMIA 5397 measurements, summary statistics included median, minimum, and Table 2. Baseline characteristics of the 30 patients included in the maximum. Differences in subgroups by different covariates were trial evaluated with the x2 test and Fisher’s exact tests, if necessary, for Characteristic Patients (N 5 30) categorical variables and the median test for continuous variables. Male/female 17 (57%)/13 (43%) OS and EFS curves were plotted by using the Kaplan-Meier method Median (range) age, y 49 (19-59) and compared by using the log-rank test. Propensity score analysis ECOG score ,2 27 (90%) with 1:1 matching was performed by using logistic regression to calculate the propensity score and the nearest neighbor matching CNS involvement 1 (3%) method without calipers, as the matching method for comparison of Median (range) WBC count, 3109/L 6.4 (0.6-359.3) outcomes of patients included in the PONALFIL trial vs the ALL Median (range) hemoglobin, g/L 9.0 (6.3-14.5) P08 trial.20,21 Median (range) platelets, 3109/L 38.5 (11.0-206.0) Data collection and statistical analyses were performed at the Median (range) LDH, U/L 358.5 (160.0-3278.0) Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/18/5395/1921879/advancesadv2022007764.pdf by guest on 20 January 2023 PETHEMA Data Center for ALL using SPSS version 24 (IBM SPSS Median (range) BCR-ABL1/ABL ratio, % 39.7 (0.073-2763.3) Statistics; IBM Corporation, Armonk, NY) and R version 3.5.2 Phenotype (R Foundation for Statistical Computing, Vienna, Austria) software. Early pre-B 2 (7%) Two-sided P values ,.05 were considered statistically significant. Common 27 (90%) Pre-B 1 (3%) Results Cytogenetics Patient characteristics t(9;22) isolated 18 (60%) From April 2017 to February 2020, thirty patients were consecu- t(9;22) with additional chromosomal abnormalities 12 (40%) tively enrolled and treated in this trial. The data cutoff was November BCR rearrangement (bone marrow) 2021, and the median duration of follow-up was 2.1 years (range, p190 20 (67%) 0.2-4.0 years). Patient characteristics are presented in Table 2. The p210 9 (30%) median age was 49 years (range, 19-59 years), and 13 of 30 patients were female. One patient exhibited CNS involvement at p230 1 (3%) diagnosis. The ECOG score was ,2 in 90% of patients. The Data are presented as no. (%) unless otherwise indicated. median white blood cell count was 6.4 3 109/L (range, 0.6-359.3 LDH, lactate dehydrogenase; WBC, white blood cell; WHO, World Health Organization. 3 109/L), hemoglobin was 90 g/L (range, 63-145 g/L), and platelet levels were 38 3 109/L (range, 11-206 3 109/L). The p190 iso- form was shown in 20 (67%) patients, p210 in 9 (30%) patients, and p230 in 1 (3%) patient. showed molecular relapse (median, 8 months; range, 3-21 months). One withdrew from the protocol and received alternative therapy Response to treatment and outcome (dasatinib) and presented hematologic relapse (being successfully Figure 1 presents the flowchart of the study. All patients completed rescued with fludarabine, high-dose cytarabine, idarubicin, and the induction phase and were evaluable for treatment response. granulocyte-colony stimulating factor chemotherapy and ponatinib); CHR was achieved in all patients. At end induction, CMR was the remaining 4 patients received ponatinib (30 mg/d until molecular attained in 14 (47%) of 30 patients and MMR in 5 (17%) of 30 remission, 15 mg/d afterward), with sustained CMR. One additional patients; no molecular response was observed in 11 (36%) of 30 patient in CMR received dasatinib because of refusal of posttrans- patients. Two patients withdrew from the trial after induction due to plant IT CNS prophylaxis. In all, 20 of 26 patients (including the thrombosis of the central artery of the retina and severe intestinal patient who died of graft-versus-host disease and the patient who infection with bowel perforation and peritonitis (one case each). withdrew from the trial because of liver toxicity) in continuous CMR Both patients received dasatinib together with the consolidation did not receive any TKI after HSCT, with 18 remaining in the trial. chemotherapy prescribed by the trial. The 3-year EFS probability was 70% (95% confidence interval [CI], Consolidation was given to 28 patients. At the end of consolidation, 51-89) (Figure 2A), the 7 events being molecular refractoriness 20 (71%) of 28 patients were in CMR, 7 (25%) of 28 were in before HSCT (n 5 1), TRM (n 5 1) and molecular relapse after MMR, and 1 patient (4%) did not achieve molecular response. Four HSCT (n 5 5). At the close of follow-up, 29 patients were alive, of 7 patients in MMR had the p210 isoform, whereas the patient with a 3-year OS probability of 96% (95% CI, 89-100) (Figure 2B). without molecular response exhibited the p190 isoform. Two Results of biologic studies patients withdrew from the trial at the end of consolidation by physi- cian decision (1 patient was in prison, and the other received blina- According to Sanger sequencing, no ABL1 KD mutations at diagno- tumomab because of lack of molecular response). No relapses sis were found in any patient. No T315I mutations were found by before alloHSCT were detected. alloHSCT was performed in 26 allele-specific PCR at diagnosis and in the 5 patients who experi- patients, and no patient underwent autologous HSCT. The median enced molecular relapse. The single nucleotide polymorphism array time from the start of treatment to transplant was 5.7 months (range, was performed in 19 patients with available DNA at diagnosis. All 4.2-9.6 months). One patient died of severe acute graft-versus-host patients exhibiting MMR or no molecular response (n 5 7), and disease, and another withdrew from the trial due to grade 4 hepatic those experiencing molecular relapse (n 5 5), were also analyzed. toxicity. Both patients were in CMR before withdrawal. Five patients Ikaros (IKZF1) deletion was detected in 11 (58%) of 19 patients, 5398 RIBERA et al 27 SEPTEMBER 2022 • VOLUME 6, NUMBER 18 30 patients enrolled A and treated 1.0 0.8 3-year EFS: 70% (95% CI, 51-89) 30 patients completed EFS probability 0.6 the induction Discontinuation (2 patients) • Thrombosis of the central artery of the retina 0.4 • Severe gastrointestinal infection Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/18/5395/1921879/advancesadv2022007764.pdf by guest on 20 January 2023 28 patients completed 0.2 the consolidation Discontinuation (2 patients) • Physician decision 0.0 (patient in prison) • Alternative therapy due to 0 1 2 3 4 5 26 patients submitted to lack of molecular response Years after diagnosis alloHSCT Discontinuation (3 patients) B 1.0 • Dead (GVHD) • Severe liver toxicity 3-year OS: 96% (95% CI, 89-100) • Protocol deviation 0.8 23 patients completed the trial OS probability 0.6 Figure 1. Patient disposition. GVHD, graft-versus-host disease. 0.4 whereas CDKN2A/B, PAX5, or RB1 losses were observed in 8 (42%) of 19 patients, 7 (37%) of 19, and 5 (26%) of 19, respec- 0.2 tively. The IKZF1plus profile (concomitant deletion of IKZF1 with CDKN2A, CDKN2B, PAX5, or P2RY8-CRLF2 in the absence of 0.0 ERG deletion) was observed in 6 (32%) of 19 participants. Of the 7 of 16 patients with MMR (n 5 6) or no molecular response (n 5 1) 0 1 2 3 4 5 before HSCT and with genetic material available at diagnosis, 4 Years after diagnosis showed IKZF1 deletion (IKZF1plus in 2), 1 showed CDKN2A/B and PAX5 deletion, 1 showed duplication from ABL1 to 9qter (derived Figure 2. EFS and OS. (A) EFS for patients included in the PONALFIL trial from from BCR::ABL1 rearrangement), and 1 only showed polymorphic enrollment to failure of achieving CHR at week 6, lack of molecular response CNAs. The patient not achieving molecular response showed a before HSCT, molecular or hematologic relapse or death by any cause. (B) OS for IKZF1 deletion together with 3p- (PTPRG), monosomy 9 patients form diagnosis to death or last follow-up. (CDKN2A/B, PAX5), 13q- (RB1), and monosomy 15 (SPRED1). Among the 5 patients with molecular relapse, 3 showed IKZF1 dele- gastrointestinal (14%), hepatic (11%), and infectious (8%). Overall, tion (1 of them being IKZF1plus), and 1 showed duplication from 16 (53%) of 30 patients experienced a grade $3 AE. The most ABL1 to 9qter (derived from BCR::ABL1 rearrangement); 1 patient common were hematologic (42%), hepatic (22%), and infectious did not show any CNAs. (17%). Cardiovascular events occurred in 1 patient (thrombosis of Propensity score analysis central artery of the retina). Three patients permanently discontinued the study due to SAEs (thrombosis of central retina artery, severe The following variables were selected for propensity score analysis bowel infection and perforation with peritonitis, and grade IV hepatic in patients from the PONALFIL and the ALLPh08 trials: age, ECOG toxicity after alloHSCT [1 case each]). Only 1 of 4 patients who score, white blood cell count, CNS involvement at diagnosis, cyto- received ponatinib after HSCT experienced transient grade 2 liver genetics [isolated t(9;22) and t(9;22) with additional chromosomal toxicity. abnormalities], and BCR::ABL1 isoform (p190, p210, and p230). Table 3 presents the characteristics of the 2 matched cohorts. The 3-year OS rates for the PONALFIL and ALLPh08 trials were 96% Discussion vs 53% (P 5 .002), respectively (Figure 3). This study confirms the safety and high antileukemic efficacy (100% hematologic CR, and 71% CMR at the end of consolidation), the Safety high rate of alloHSCT performance (26 of 30 patients [87%]), and A total of 106 AEs were registered in 20 patients (67%) (Table 4). the promising EFS (70% at 3 years) and OS (96% at 3 years) of The most frequent AEs of any grade were hematologic (28%), the combination of ponatinib (30 mg/d) and standard chemotherapy 27 SEPTEMBER 2022 • VOLUME 6, NUMBER 18 PONATINIB for Ph1 ACUTE LYMPHOBLASTIC LEUKEMIA 5399 Table 3. Characteristics of the 2 cohorts matched for propensity Table 4. AEs of any grade and of grade ‡3 in the patients score analysis included in the series ALLPh08 PONALFIL Any grade Grade ‡3 Characteristic (N 5 30) (N 5 30) P Total number 106 36 Male 16/30 (53%) 17/30 (57%) .795 No. of patients 20/30 (67%) 16/30 (53%) Age, median [minimum; maximum], y 46 (19, 56) 49 (19, 59) .439 Hematologic 30 (28%) 15/36 (42%) ECOG score ,2 27 (90%) 27 (90%) 1.0 Infectious 8 (8%) 6/36 (17%) White blood cell count, 3109/L 1.0 Gastrointestinal 15 (14%) 1/36 (3%) ,30 22 (73%) 22 (73%) Skin 5 (5%) 1/36 (3%) $30 8 (27%) 8 (27%) Respiratory 6 (6%) 2/36 (6%) CNS involvement 2 (7%) 1 (3%) 1.0 General 4 (4%) — Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/18/5395/1921879/advancesadv2022007764.pdf by guest on 20 January 2023 Cytogenetics .602 Neurologic 4 (4%) — t (9;22) 16 (53%) 18 (60%) Ocular 2 (2%) 2/36 (6%) t (9;22) with additional chromosomal abnormalities 14 (47%) 12 (40%) Hepatic 12 (11%) 8/36 (22%) Isoform .278 Hypertension 1 (1%) — p190 14 (47%) 20 (67%) Vascular occlusive event 1 (1%) 1/36 (3%) p210 15 (50%) 9 (30%) Other 17 (16%) — p230 1 (3%) 1 (3%) followed by alloHSCT in adults aged ,60 years with newly diag- alloHSCT in first CR according to physician decision. A post hoc nosed Ph1 ALL. Moreover, these results compared favorably with 6-month landmark analysis found no difference in OS in patients those of the ALLPh08 trial with the same design and schedule, undergoing transplant vs nontransplanted patients. A phase 2 trial using imatinib as a TKI. (LAL1811) from the Italian GIMEMA Group administered 45 mg of The efficacy of ponatinib as a single drug in relapsed or refractory ponatinib per day plus steroids in 44 patients newly diagnosed with Ph1 ALL15 prompted the inclusion of this drug in first-line therapy of Ph1 ALL aged $60 years, or unfit for intensive chemotherapy and adults with Ph1 ALL in combination with intensive chemotherapy,16 HSCT.18 The median age was 67 years. The CHR and CMR at 24 minimal chemotherapy,18 and recently with blinatumomab.12 A first weeks were reached in 38 (86.4%) of 44 patients and in 18 report of a phase 2 trial conducted at the MD Anderson Cancer (40.9%) of 44 patients, respectively. The median EFS was 14.31 Center (MDACC) combined hyper-CVAD with ponatinib in 37 adult months (95% CI, 9.30-22.31), whereas medians of OS and CR patients with de novo Ph1 ALL.22 An update of the trial found a duration were not reached; the median duration of CMR was 11.6 100% CHR for the 65 patients with active disease at enrollment, months. with CMR being achieved in 63 (83%) of 76 patients. The 3-year The current trial included only young and middle-aged adults continuous complete remission (CR) was 83% (95% CI, 69-91), (median age, 49 years) because it was aimed to perform alloHSCT the 3-year EFS was 70% (95% CI, 56-80), and the 3-year OS was in all patients at the best molecular response after consolidation. 76% (95% CI, 63-85).16 Fifteen patients (20%) underwent The dose of ponatinib was reduced to 30 mg to avoid or reduce vascular occlusive events. The chemotherapy schedule can be con- sidered as standard, although asparaginase was omitted to avoid an 1.0 increase in hepatic and vascular toxicity when combined with ponati- nib. As expected, all patients displayed CHR, and the rate of CMR PONALFIL; 3-year OS, 96% (95% CI, 89-100) at the end of consolidation was 71%, a rate similar to that achieved 0.8 with the trial of hyper-CVAD and ponatinib.16 Two patients withdrew from the trial after induction for an occlusive arterial event and a severe infection, respectively, whereas 2 additional patients aban- OS probability 0.6 PETHEMA ALLPh08; 3-year OS, 53% (95% CI, 33-73) doned the trial after consolidation due to a situation that precluded the performance of HSCT (patient in prison) and by physician deci- 0.4 sion to offer alternative therapy due to the lack of molecular response, respectively. The alloHSCT was performed in 87% of CR 0.2 patients and was well tolerated, with only TRM occurring in 1 patient and severe liver toxicity in another. All patients were in CMR p = .002 after HSCT. It is noteworthy that pre-emptive TKI administration after 0.0 HSCT was scheduled in the trial; however, 20 of 26 patients never 0 2 4 6 8 10 12 received ponatinib or another TKI as maintenance therapy. Molecu- Years after diagnosis lar relapse was observed in 5 patients and was managed with pona- tinib (n 5 4) or dasatinib (n 5 1, by physician decision), with Figure 3. OS of PONALFIL vs ALLPh08 trials by propensity score matching. hematologic relapse occurring in the patient who received dasatinib. 5400 RIBERA et al 27 SEPTEMBER 2022 • VOLUME 6, NUMBER 18 The 3-year EFS and OS of 70% (95% CI, 51-89) and 96% (95% In conclusion, our trial yielded good results in terms of the efficacy CI, 89-100) can be considered satisfactory. and tolerability of the combination of ponatinib and standard induc- tion and consolidation chemotherapy followed by alloHSCT in adults It is also worth noting that a restrictive definition of EFS (including up to age 60 years with newly diagnosed Ph1 ALL. It also showed molecular failure or relapse as event) was used in this trial. A pro- that a pre-emptive strategy for ponatinib after transplantation is feasi- pensity score–matched analysis with comparable patients from the ble and allows a reduction of ponatinib exposure in a significant ALLPh08 study,19 with the same design and interventions except number of patients. for the use of imatinib instead of ponatinib, showed a clear improve- ment in outcomes in favor of the PONALFIL trial. Identical results were observed in the propensity score–matched comparison of the Acknowledgments trial with hyper-CVAD and ponatinib vs hyper-CVAD and dasatinib The authors thank Incyte for providing ponatinib to all study conducted at the MDACC.16 patients free of cost, to CABYC for helping in the conduction of the trial, and to the following institutions for their contribution to Downloaded from http://ashpublications.org/bloodadvances/article-pdf/6/18/5395/1921879/advancesadv2022007764.pdf by guest on 20 January 2023 Overall safety and tolerability of the treatment were considered the study: ICO-Hospital Germans Trias i Pujol, Josep Carreras acceptable, and no unexpected AEs were observed. The rate of Leukemia Research Institute (IJC) (J.-M.R., O.G.-C., J.R., A.T., permanent discontinuation due to toxicity during the entire study and E.G.); Hospital Universitari i Politecnic La Fe (P. Montesinos, was 13% and was directly attributable to ponatinib in only 1 case. I.C.-F.); Hospital Doce De Octubre (P. Martınez, J.M.-L.); Hospi- The most frequent grade $3 AEs were hematologic, infectious, and tal Clınic (J.E. and D.E.); Hospital Universitario Virgen De La Vic- hepatic, as observed in other similar trials. toria (M.G.-F.); Complejo Hospitalario Universitario Santiago de Despite having a different postconsolidation approach, our study Compostela (N.A.); Hospital Universitario Virgen del Rocıo (J.G.- reported results similar to those of the trial with hyper-CVAD and C.); Hospital Universitario Marqu es de Valdecilla (A.B.); ICO- ponatinib conducted at MDACC, and showed better outcomes Hospital Duran i Reynals (S.M.); and Hospital Universitario de compared with the ALLPh08 trial.19 However, several limitations Salamanca (HUS/IBSAL), CIBERONC and Center for Cancer should be highlighted. First, this is a single-arm phase 2 study. Sec- Research-IBMCC (USAL-CSIC) (R.G.-S.). ond, the number of patients was limited, a fact that precludes analy- The PETHEMA Foundation, a nonprofit organization, was the sis of subsets of patients according to genetic and molecular sponsor of the trial, and the PETHEMA Data Center elaborated background. No ABL1 KD mutations were found at diagnosis by the database, and organized training meetings in which principal using Sanger sequencing, and the T315I mutation was not found in investigators and collaborative investigators participated. This any patient by using allele-specific PCR. IKZF1 gene mutations project was supported in part by the ISCIII (PI14/01971 and were found at diagnosis in 4 of 7 patients who did not achieve PI19/01828), cofunded by ERDF/ESF, “A way to make Europe”/ CMR (IKZF1 plus in 2 patients), but no conclusion can be drawn “Investing in your future,” CERCA/Generalitat de Catalunya SGR from this low number of cases.23 Third, the follow-up is still short, 2017 288 (GRC)/“La Caixa.” This project has received funding despite all patients having completed the trial. from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement no. 116026. This Joint Undertaking receives Recently published clinical trials include immunotherapy with mono- support from the European Union’s Horizon 2020 research and clonal antibodies (blinatumomab) combined with a TKI (dasatinib or innovation and the European Federation of Pharmaceutical ponatinib) without or with minimal chemotherapy as first-line therapy Industries and Associations. of Ph1 ALL in adults; they found a high rate of hematologic and molecular responses and promising short-term EFS and OS.11,12,24 Authorship In the D-ALBA (Frontline Sequential Dasatinib and Blinatumomab in Adult Philadelphia Positive Acute Lymphoblastic Leukemia) trial from Contribution: J.-M.R. designed the study and coordinated the trial; the GIMEMA Group, CHR was achieved in all patients (N 5 63) P. Montesinos, I.C.-F., P. Martınez, J.E., D.E., M.G.-F., N.A., J.G.-C., with the combination of ponatinib and a short course of steroids, A.B., A.T., E.G., S.M., and J.M.-L. were responsible for patient care; and CMR achieved after the second blinatumomab course was J.R. and R.G.-S. performed genetic analyses; O.G.-C. contributed to 60%.11 Transplantation was performed in 29 (50%) of 58 patients database set-up, reviewed and cleaned data, and contributed to who started blinatumomab. The 2-year OS probability was 95% in data analysis; and all authors were involved in drafting of the manu- the first analysis and 87.8% with a median follow-up of 27 months script and approved the final draft. (accessed 1 July 2021).25 In the last update of a phase 2 trial con- Conflict-of-interest disclosure: J.-M.R. has received honoraria and ducted at MDACC combining ponatinib and blinatumomab upfront travel grants from Incyte, Novartis, Takeda, AMGEN, and Pfizer. The during induction and consolidation, CHR was attained in all 24 remaining authors declare no competing financial interests. patients with newly diagnosed Ph1 ALL, with CMR of 91% at the end of consolidation, and 2-year EFS and OS of 95%.12 No ORCID profiles: J-.M.R., 0000-0003-1042-6024; P. Montesi- patients underwent alloHSCT in this trial. These impressive results nos, 0000-0002-3275-5593; D.E., 0000-0001-8897-3170; M.G.-F., 0000-0002-0959-9449; E.G., 0000-0002-5657-4842; have questioned the need for alloHSCT in all young adults with Ph1 S.M., 0000-0003-4741-7885; R.G.-S., 0000-0003-4120-2787. ALL, at least in those treated with ponatinib as TKI. Further studies should establish the optimal role of alloHSCT in Ph1 ALL in Correspondence: Josep-Maria Ribera, ICO-Hospital Germans Trias trials combining TKI, attenuated or minimal chemotherapy, and i Pujol, Josep Carreras Leukemia Research Institute (IJC), C/Canyet immunotherapy. s/n, o8916 Badalona, Spain; e-mail: jribera@iconcologia.net. 27 SEPTEMBER 2022 • VOLUME 6, NUMBER 18 PONATINIB for Ph1 ACUTE LYMPHOBLASTIC LEUKEMIA 5401 References 1. Chiaretti S, Vitale A, Cazzaniga G, et al. Clinico-biological features of 5202 patients with acute lymphoblastic leukemia enrolled in the Italian AIEOP and GIMEMA protocols and stratified in age cohorts. Haematologica. 2013;98(11):1702-1710. 2. Fielding AK, Rowe JM, Buck G, et al. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014;123(6):843-850. 3. 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