Ponatinib, chemotherapy, and transplant in adults with Ph+ ALL: results from the phase II PONALFIL trial

Introduction

Philadelphia positive (Ph+) acute lymphoblastic leukemia (ALL) is a subtype of ALL characterized by the presence of the BCR-ABL1 rearrangement. It is the most common genetic subtype of ALL in adult patients, occurring in 25–30% of young adult patients and 40–50% of older adult and elderly patients. Outcomes for this patient subgroup have historically been poor; however, the introduction of tyrosine kinase inhibitors (TKI) in combination with traditional chemotherapy approaches followed by allogeneic hematopoietic stem cell transplant (alloHSCT) has improved outcomes. The addition of third-generation TKIs, such as ponatinib, has been shown to further improve outcomes. Below, we provide a summary of the key safety and efficacy data from a phase II, open-label, PONALFIL clinical trial (NCT02776605) of ponatinib, standard induction and consolidation chemotherapy followed by alloHSCT in adult patients with newly diagnosed Ph+ ALL, published by Ribera, et al., in Blood Advances in 2022.¹

Study design

Eligible patients were aged 18–60 years with newly diagnosed Ph+ ALL

• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤2;
• normal cardiac function as defined by an ejection fraction of ≥50%; and
• adequate organ function as defined by serum bilirubin ≤3 mg/dL and serum creatinine ≤3 mg/dL.

Patients underwent a 7-day steroid pretreatment cycle during which the presence of the BCR-ABL1 transcript was confirmed. This was followed by induction chemotherapy for 4 weeks and consolidation chemotherapy for 2 months (Figure 1).

Figure 1. Treatment schedule* 

ALL, acute lymphoblastic leukemia; HSCT, hematopoietic stem cell transplantation; IT, intrathecal; IV, intravenous; PO, per oral administration.
*Adapted from Ribera, et al.^1
†Prephase with prednisone 60 mg/m² and triple IT was given for a maximum of 1 week, while ALL was fully characterized.
^‡Triple IT with methotrexate (15 mg), cytarabine (30 mg), and hydrocortisone (20 mg).
^§After alloHSCT, only if molecular disease persisted or reappeared.

Objectives

• Coprimary endpoints were achievement of response (complete hematologic response [CHR], major molecular response [MMR], and complete molecular response [CMR]) post-induction and prior to HSCT, and event-free survival (EFS).
• Secondary endpoints included the rate of patients receiving HSCT in the first CMR, transplant-related mortality (TRM), overall survival (OS), type and frequency of adverse events (AE), and severe AE and the propensity-matched analysis comparing outcomes with those of the ALLPh08 trial (NCT01491763).

Results¹

Efficacy

• All patients completed the induction phase and were evaluable for patient response (Figure 2)
• CHR was achieved in 100% of patients
• CMR was achieved in 47% of patients at end of induction, MMR in 17% of patients, and no molecular response in 36% of patients
• Overall, 28 patients progressed to the consolidation portion of the trial, at the end of which 71% were in CMR, 25% were in MMR, and 4% did not achieve a molecular response
• Two patients withdrew from the trial at end-of-consolidation
• AlloHSCT was performed in 26 patients and no patient received autologous HSCT, with the median time from the start of treatment to the transplant was 5.7 months
• Five patients demonstrated molecular relapse, with a median time to onset of 8 months
• Overall, 20/26 patients in continuous CMR did not receive any TKI post-HSCT, with 18 patients remaining in the trial
• 3-year EFS probability was calculated at 70% (95% confidence interval [CI], 51–89%)
• At data cutoff, 29 patients were alive, with the 3-year OS probability being calculated at 96% (95% CI, 89–100%)

The following variables were selected for the propensity score analysis in patients from the PONALFIL and the ALLPh08 trials: age, ECOG Performance Status, white blood cell count, central nervous system involvement at diagnosis, cytogenetics, and BCR-ABL1 isoform. The 3-year OS rates for PONALFIL and ALLPh08 were 96% and 53%, respectively (p = 0.002).

Figure 2. Patient disposition* 

AlloHSCT, allogenic hematopoietic stem cell transplantation.
*Adapted from Ribera, et al.¹

Safety

AEs were reported in 20 patients (67%), with 16 patients (53%) experiencing a ≥Grade 3 AE. Three patients discontinued the study due to severe AEs (thrombosis of the central retina artery, severe bowel infection and perforation with peritonitis, and Grade 4 hepatic toxicity after alloHSCT). Transient Grade 2 liver toxicity was reported by 25% of patients who received ponatinib after HSCT.

The most common AEs of any grade were hematologic (28%), gastrointestinal (14%), hepatic (11%), and infection (8%). The most commonly reported ≥Grade 3 AEs were hematologic (42%), hepatic (22%), infection (17%) with only one vascular occlusive event. One patient died of graft-versus-host disease and two patients discontinued the trial each due to severe liver toxicity and protocol deviation.

Conclusion

The results demonstrate a favorable efficacy, alloHSCT performance, encouraging 3-year EFS and OS probabilities and an acceptable safety profile of the combination of ponatinib and standard chemotherapy followed by alloHSCT in adult patients with newly diagnosed Ph+ ALL. Furthermore, propensity score-matched analysis of the PONALFIL and ALLPh08 trials demonstrated a favorable OS rate (96% vs 53%) for ponatinib over imatinib. Taken together, these results showed that the combination of ponatinib with standard induction and consolidation chemotherapy followed by alloHSCT may provide a promising treatment option for adult patients with newly diagnosed Ph+ ALL.