Ponatinib versus imatinib in combination with low-intensity chemotherapy in patients with newly-diagnosed Ph+ ALL: PhALLCON trial

BCR-ABL1 tyrosine kinase inhibitors (TKI) plus chemotherapy or steroids are the current standard-of-care first line treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).¹ Ponatinib is the only pan-inhibitory BCR-ABL1 TKI with activity against BCR-ABL1 wild-type and single mutation variants, and therefore, may improve long-term outcomes compared with other BCR-ABL1 TKIs. PhALLCON (NCT03589326) is an international trial comparing the efficacy and safety of ponatinib vs imatinib combined with low-intensity chemotherapy in adult patients with de novo Ph+ ALL.¹  

Study design

This phase III, multicenter trial enrolled patients with de novo Ph+ ALL or BCR-ABL1 positive ALL.¹ Eligibility patients were:  

• ≥18 years of age;
• Had an Eastern Cooperative Oncology Group performance status of 0 to 2;
• Absence of history or current diagnosis of chronic phase-chronic myeloid leukemia (CML), accelerated phase CML, or B-lymphoid blast phase CML; and
• Absence of clinically significant or uncontrolled cardiovascular disease.

Patients were randomized to either ponatinib + reduced intensity chemotherapy or imatinib + reduced intensity chemotherapy.¹ The treatment schema is shown in Figure 1.

The primary endpoint was measurable residual disease (MRD)-negative complete remission (CR) (defined as hematologic CR ≥4 weeks) in combination with MRD negativity (≤0.01% BCR-ABL1/ABL1 transcripts).¹ Key secondary endpoints were event-free survival, progression-free survival, and safety.

Figure 1. Treatment schema*         

CR, complete response; MRD, minimal residual disease; TKI, tyrosine kinase inhibitor.
*Adapted from Jabbour.^1
†Dose reduction to 15 mg once daily were implemented in patients who achieved MRD-negative CR after completion of the induction phase.

Results

At a median follow-up of 20.4 vs 18.1 months in the ponatinib and imatinib arm, more patients in the ponatinib arm continued to receive treatment at 41% and 12%, respectively.¹ The baseline characteristics are summarized in Table 1.

Table 1. Baseline characteristics*

Efficacy

Efficacy data was available for 154 and 78 patients in the ponatinib and imatinib arm, respectively.¹ The primary endpoint of MRD-negative CR at the end of induction was met, with ponatinib showing a two-fold increase in MRD-negative CR compared with imatinib (Figure 2). After each cycle of BCR::ABL1 ≤0.01%, the MRD-negativity response rate increased continuously and was higher in patients treated with ponatinib compared with imatinib (Figure 3). Patients receiving subsequent second- or third-generation TKI and/or immunotherapy were higher in the imatinib versus ponatinib arm (37% vs 19%). Median event-free survival was not met in the ponatinib arm compared to 29 months in the imatinib arm (hazard ratio, 0.65; 95% confidence interval [CI], 0.39–1.10) and median progression-free survival was 20 months in the ponatinib-treated arm (95% CI, 11.8–NE) compared with 7.9 months in the imatinib-treated arm (95% CI, 6.2–12).¹

Figure 2. Primary endpoint efficacy outcomes*

CR, complete remission; MRD, measurable residual disease.
*Adapted from Jabbour.¹

Figure 3. Efficacy outcomes BCR:ABL1 ≤0.01% during Cycles 3–9* 

C, cycle.
*Adapted from Jabbour.¹

Safety

Safety data was available for 163 and 81 patients in the ponatinib and imatinib arm, respectively.¹ A higher number of patients in the imatinib arm discontinued treatment compared with the ponatinib arm (86% vs 58%). Serious treatment-emergent adverse events (TEAE) were reported in 60% vs 56% of patients in the ponatinib and imatinib arms, respectively.¹

• In the ponatinib arm, Grade 3-4 and Grade 5 serious TEAEs were reported in 90% and 5% of patients, respectively.
• In the imatinib arm, Grade 3-4 TEAEs were reported in 93% of patients and Grade 5 were reported in 5% of patients.
• Grade 5 TEAEs reported in the ponatinib arm were septic shock (n = 4), abdominal sepsis, sepsis, pneumonitis, and respiratory failure (n = 1 each).
• Grade 5 TEAEs reported in the imatinib arm were septic shock, pseudomembranous colitis, pulmonary sepsis, and depressed level of consciousness (n = 1 each).

Conclusion

The PhALLCON trial reached its primary endpoint and demonstrated a higher MRC-negative CR rate at the end of induction compared with imatinib.¹ In addition, the safety profile of ponatinib was comparable to imatinib. These findings suggest that ponatinib combined with low-intensity chemotherapy appears to be a more effective therapy in patients with newly diagnosed Ph+ ALL and has the potential to be standard of care in this population.