Ponatinib Plus Reduced-intensity Chemo Could Be New SOC in Newly Diagnosed Ph+ ALL

Elias Jabbour, MD

Treatment with ponatinib (Iclusig) plus reduced-intensity chemotherapy led to an improvement in minimal residual disease (MRD)–negative complete remission (CR) rate compared with imatinib (Gleevec) plus reduced-intensity chemotherapy in newly diagnosed patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), according to data from the phase 3 PhALLCON trial (NCT03589326).

Findings presented at the 2023 EHA Congress showed that patients treated with the ponatinib regimen (n = 154) experienced a MRD-negative CR rate of 34.4% at the end of induction compared with 16.7% for those given the imatinib regimen (n = 78), meeting the trial’s primary end point (relative risk, 2.06; 95% CI, 1.19-3.56; P = .0021). A MRD-negative CR was defined as hematologic CR for at least 4 weeks and MRD negativity of no more than 0.01% of BCR::ABL1 transcripts (MR4).

Notably, irrespective of CR status, the MRD-negativity rate at the end of induction was 41.6% and 20.5% for the ponatinib and imatinib arms, respectively (relative risk, 1.94; 95% CI, 1.19-3.17; P = .0017).

"Based on the efficacy and safety [data from PhALLCON], ponatinib should be considered standard of care in frontline Ph-positive ALL,” presenting study author Elias Jabbour, MD, said in an interview with OncLive®. Jabbour is a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston.

The current frontline standard of care for patients with Ph-positive ALL is the combination of BCR::ABL1 TKIs and chemotherapy or steroids. Ponatinib is a BCR::ABL1 pan-inhibitor that has demonstrated activity against BCR::ABL1 wild-type and all single-mutant variants, including T315I mutations.

PhALLCON enrolled adult patients with newly diagnosed Ph-positive ALL or BCR::ABL1-positive ALL who did not have a history or current diagnosis of chronic myeloid leukemia. Patients were also required to have an ECOG performance status between 0 and 2, and an absence of clinically significant or uncontrolled cardiovascular disease.

Patients were randomly assigned 2:1 to receive reduced-intensity chemotherapy in combination with ponatinib at 30 mg once daily, with dose reduction to 15 mg once daily, or imatinib at 600 mg once daily. Induction therapy consisted of a TKI plus vincristine and dexamethasone for 3 cycles. Consolidation therapy included a TKI in combination with methotrexate and cytarabine for 6 cycles, and maintenance therapy featured a TKI in combination with vincristine and prednisone for 11 cycles. All cycles lasted 28 days. After maintenance, ponatinib or imatinib were continued until the end of the study. Notably, intrathecal therapy was given twice per month during the first 6 cycles for central nervous system disease prophylaxis.

"The primary end point of the study was something very original and very specific: MRD-negative CR at the end of induction, which was never done in ALL [prior to PhALLCON],” Jabbour said.

Event-free survival (EFS) served as a key secondary end point. Other secondary end points included molecular response rates, duration of MRD-negative CR, overall survival (OS), and safety.

As of the August 12, 2022, data cutoff, the median follow-up was 20.4 months (range, 18.4-23.9) in the ponatinib arm and 18.1 months (range, 13.9-24.3) in the imatinib arm. Forty-one percent of patients in the ponatinib arm remained on study treatment compared with 12% in the imatinib arm.

In the ponatinib group, reasons for discontinuing study treatment included hematopoietic stem cell transplant (HSCT; 30%), lack of efficacy (7%), adverse effects (AEs; 12%), progressive disease (4%), or other (4%). Eighteen percent of patients discontinued the study due to death (13%), patient withdrawal (4%), or other (1%).

In the imatinib arm, patients discontinued treatment due to HSCT (37%), lack of efficacy (26%), AEs (12%), progressive disease (6%), or other (5%). Twenty-two percent of patients discontinued the study due to death (16%), patient withdrawal (5%), and lost follow-up (1%). Rates of patients who underwent HSCT at any time were 34% and 48% in the ponatinib and imatinib arms, respectively.

The median age of patients in the ponatinib and imatinib groups were 54 years (range, 19-82) and 52 (range, 19-75), respectively. Thirty-seven percent of patients in both arms were at least 60 years of age. The majority of patients in both arms were female (55% for ponatinib and 53% for imatinib), had an ECOG performance status of 0 or 1 (96% and 94%), had at least 1 cardiovascular comorbidity (56% and 64%), and had a BCR::ABL1 dominant variant of p190 (70% and 65%). Twenty-eight percent and 33% of patients had at least 2 cardiovascular comorbidities for the ponatinib and imatinib arms, respectively.

The median leukocyte count was 4.4 x 109/L (range, 0.4-198) for the experimental group vs 3.2 x 109/L (range, 0.2-81) for the control group. The median leukocyte blasts rate was 80% (range, 0%-100%) and 75% (range, 0%-100%), respectively.

Additional data showed that MRD-negativity rates of BCR::ABL1 of 0.01% or less for ponatinib were 43% (n = 61/142), 63% (n = 57/90), 70% (n = 41/59), and 92% (n = 44/48) during cycles 3, 5, 7, and 9, respectively. Those rates were 22% (n = 15/68), 52% (n = 17/33), 40% (n = 8/20), and 47% (n = 7/15) for imatinib, respectively.

MRD-negativity rates of BCR::ABL1 of 0.0032% or less for the ponatinib arm were 27% (n = 38/142) in cycle 3, 40% (n = 36/90) in cycle 5, 48% (n = 28/59) in cycle 7, and 63% (n = 30/48) in cycle 9. Those rates were 15% (n = 10/68), 30% (n = 10/33), 25% (n = 5/20), and 27% (n = 4/15) for imatinib, respectively.

The median duration of MRD negativity for the ponatinib arm (n = 62) was not evaluable (NE; 95% CI, 17.0 months-NE) vs 20.9 months (95% CI, 10.9-NE) for the imatinib arm (n = 15).

Time to treatment failure was NE in the ponatinib arm (n = 164) compared with 21.9 months (95% CI, 12.3-NE) in the imatinib arm (n = 81). Thirty-five percent and 57% of patients underwent subsequent anticancer therapy in the experimental and control arms, respectively. Subsequent therapy included any BCR::ABL1 TKI or immunotherapy (29% for ponatinib and 46% for imatinib), a first-generation BCR::ABL1 TKI (10% and 9%), a second- or third-generation BCR::ABL1 TKI and/or immunotherapy (19% and 37%), and ponatinib-based therapy (8% and 16%).

“Responders to ponatinib had more sustained remission compared with imatinib, and time to treatment failure, whether from resistance or intolerance, were in favor of ponatinib,” Jabbour expanded.

Additional results demonstrated that the median EFS was NE in the ponatinib arm vs 29.0 months (95% CI, 22.9-NE) in the imatinib arm (HR, 0.65; 95% CI, 0.39-1.10). An EFS event was defined as death due to any cause, failure to achieve CR by the end of induction, or relapse from CR.

A progression-free survival (PFS) event was defined as death due to any cause, failure to achieve CR by the end of induction, relapse from CR, failure to achieve MRD negativity by the end of treatment, or loss of MRD negativity. The median PFS was 20.0 months (95% CI, 11.8-NE) and 7.9 months (95% CI, 6.2-12.4) for the ponatinib and imatinib arms, respectively (HR, 0.58; 95% CI, 0.41-0.83).

The median OS was NE in both arms (HR, 0.76; 95% CI, 0.38-1.52). “Due to short follow-up, we don't have mature data for OS,” Jabbour said.

Regarding safety, 99% of patients in both arms experienced at least 1 any grade treatment-emergent AE (TEAE). Rates of serious TEAEs, grade 3/4 TEAEs, and grade 5 TEAEs were 60%, 90%, and 5% in the ponatinib arm, respectively. Those rates were 56%, 93%, and 5% for imatinib, respectively. Treatment-emergent arterial occlusive events occurred in 2% of patients in the experimental arm and 1% of patients in the control arm. Rates of treatment-emergent venous thromboembolic events were 12% in each arm.

TEAEs led to dose discontinuation, reduction, and interruption in 10%, 20%, and 68% of patients who received the ponatinib regimen, respectively. Those rates were 9%, 22%, and 40% for the imatinib regimen, respectively.

The most common grade 3/4 hematologic TEAEs included anemia (31% for ponatinib and 36% for imatinib), decreased platelet count (63% and 58%), decreased white blood cell count (53% and 49%), decreased neutrophil count (49% and 46%), decreased lymphocyte count (38% and 47%), and febrile neutropenia (23% and 19%).

The most common grade 3/4 non-hematologic TEAEs consisted of headache (2% and 1%), nausea (3% and 7%), increased alanine transaminase (19% and 9%), pyrexia (2% and 2%), constipation (1% and 1%), increased lipase (13% and 19%), peripheral neuropathy (1% and 1%), hypokalemia (6% and 19%), vomiting (1% and 2%), hypertension (12% and 6%), and fatigue (2% and 1%).

Editor’s note: Dr Jabbour reported affiliations with AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Genentech, Pfizer, and Takeda.

Reference

Jabbour E, Kantarjian H, Aldoss I, et al. First report of PhALLCON: a phase 3 study comparing ponatinib vs imatinib in newly diagnosed Ph+ ALL. Presented at: 2023 EHA Congress; June 8-15, 2023; Frankfurt, Germany. Abstract S110.