Ponatinib, chemotherapy, and transplant in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia

Abstract

Promising results have been shown with the combination of ponatinib and chemotherapy in adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL). The PONALFIL (Ponatinib With Chemotherapy for Young Adults Ph Positive Acute Lymphoblastic Leukemia) trial combined ponatinib (30 mg/d) with standard induction and consolidation chemotherapy followed by allogeneic hematopoietic stem cell transplant (alloHSCT) in newly diagnosed Ph+ ALL patients aged 18 to 60 years. Ponatinib was only given pre-emptively after alloHSCT. Primary end points were hematologic and molecular response before 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 response, and alloHSCT was performed in 26 patients (20 in complete molecular response and 6 in major molecular response). Only 1 patient died (of graft-versus-host disease), and 5 patients exhibited molecular relapse after alloHSCT. No tyrosine kinase inhibitor was given 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 = .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 Ph+ ALL. Cross-trial comparison suggests improvement vs imatinib (clinicaltrials.gov identifier #NCT02776605).

Current Status of Novel Agents for the Treatment of B Cell Malignancies: What’s Coming Next?

“…Combination therapy with temsirolimus, an inhibitor of the oncogenic kinase mTOR, and lenalidomide demonstrates encouraging activity in patients with DLBCL and FL (NCT01076543) [ 459 ]. Ponatinib is a third-generation tyrosine kinase inhibitor with a wide spectrum of kinase inhibition [ 460 ]; it targets BCR-ABL1, an abnormal tyrosine kinase that is expressed in chronic myeloid leukemia and Philadelphia chromosome-positive (Ph + ) ALL; ponatinib shows clinical activity in R/R Ph + (BCR-ABL) ALL [ 461 ], and in the first-line setting in combination with standard chemotherapy (NCT01641107, [ 462 ]; NCT02776605, [ 463 ]) or blinatumomab (NCT03263572) [ 464 ]. A Phase III study is comparing the efficacy and the safety of the first in-class selective inhibitor of nuclear export, selinexor, in combination with bortezomib + dexamethasone vs. bortezomib + dexamethasone in patients with R/R MM (NCT03110562) [ 465 ].…”

Modern Management Options for Ph+ ALL

“…The Phase 2 PONALFIL trial from the Spanish PETHEMA (Programa Español de Tratamientos en HEMAtologia) Group combined ponatinib (30 mg/day) with standard induction and consolidation chemotherapy followed by allo-HSCT in newly diagnosed Ph+ ALL patients aged 18–60 years [ 32 ]. Ponatinib was only given after allo-HSCT if positive measurable residual disease (MRD) persisted or reappeared.…”

“…Ponatinib was only given after allo-HSCT if positive measurable residual disease (MRD) persisted or reappeared. Thirty patients (median age 49 [ 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ] years) entered the trial. All patients showed CHR, and allo-HSCT was performed on 26 patients (20 in CMR and 6 in MMR).…”

“…Table 1 summarizes the main results of trials using ponatinib for the treatment of newly diagnosed patients with Ph+ ALL. It is of note that the initial dose of ponatinib was not homogeneous among trials, ranging from 45 mg/day [ 28 , 31 ] to 30 mg/d [ 32 , 41 ].…”

The evolution of frontline therapy for adult Philadelphia‐positive acute lymphoblastic leukemia: Giant strides and ongoing challenges

“…CHR and CMR rates at 24 weeks were 86% and 41%, respectively 15 . In younger patients, the Spanish PETHEMA Group showed that the combination of ponatinib with multiagent induction and consolidation chemotherapy followed by SCT was associated with a 3‐year event‐free survival (EFS) of 70% and OS of 97% 16 . Importantly, ponatinib has a distinctly challenging side effect profile.…”