Iclusig plus reduced-intensity chemotherapy led to improved outcomes for patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia, and should be the new standard of care, one expert said.
Iclusig (ponatinib) plus reduced-intensity chemotherapy led to better outcomes than Gleevec (imatinib ) plus reduced-intensity chemotherapy in patients with newly diagnosed Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), according to data from the phase 3 PhALLCON trial that was presented at the 2023 European Hematology Association Congress.
Findings howed that patients treated with the Iclusig regimen (154 patients) experienced a minimal residual disease (MRD)–negative complete remission (CR) rate of 34.4% at the end of induction compared with 16.7% for those given the Gleevec regimen (78 patients). A MRD-negative CR was defined as hematologic CR (no signs of cancer) for at least four weeks and MRD negativity, meaning that minimal disease was not detected in blood tests.
Notably, irrespective of CR status, the MRD-negativity rate at the end of induction was 41.6% and 20.5% for the Iclusig and Gleevec groups, respectively.
"Based on the efficacy and safety (data from PhALLCON), (Iclusig) should be considered standard of care in frontline Ph-positive ALL,” presenting study author Dr. Elias Jabbour, said in an interview with CURE®’s sister publication, 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, which are drugs that target the BCR-ALB1 gene, and chemotherapy or steroids. Iclusig 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 be able to perform their daily activities with little to no help and have an absence of clinically significant or uncontrolled cardiovascular disease.
Patients were randomly assigned to receive reduced-intensity chemotherapy in combination with Iclusig at 30 mg once daily, with dose reduction to 15 mg once daily, or Gleevec at 600 mg once daily. Induction therapy — which is used to initially reduce the amount of cancer cells — consisted of a TKI plus vincristine and dexamethasone for three cycles.
Consolidation therapy included a TKI in combination with methotrexate and cytarabine for six cycles, and maintenance therapy featured a TKI in combination with vincristine and prednisone for 11 cycles. All cycles lasted 28 days. After maintenance, Iclusig or Gleevec were continued until the end of the study. Notably, intrathecal therapy was given twice per month during the first six 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.
While MRD-negative CR was the main goal of the study, event-free survival, which is the length of time patients live before experiencing complications or progression of their disease, served as a key secondary end point. Other secondary end points included molecular response rates, duration of MRD-negative CR, overall survival (time from treatment until death of any cause) and safety.
As of the Aug. 12, 2022, data cutoff, the median follow-up was 20.4 months (range, 18.4-23.9) in the Iclusig arm and 18.1 months (range, 13.9-24.3) in the Gleevec arm. Forty-one percent of patients in the Iclusig arm remained on study treatment compared with 12% in the Gleevec arm.
In the Iclusig group, reasons for discontinuing study treatment included hematopoietic stem cell transplant (HSCT; 30%), lack of efficacy (7%), side effects (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 Gleevec arm, patients discontinued treatment due to HSCT (37%), lack of efficacy (26%), side effect (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 Iclusig and Gleevec groups, respectively.
Additional data showed that MRD-negativity rates of BCR::ABL1 of 0.01% or less for Iclusig were 43% (61 of 142 patients), 63% (57 of 90 patients), 70% (41 of 59 patients), and 92% (44 of 48 patients) during cycles three, five, seven and nine, respectively. Those rates were 22% (15 of 68 patients), 52% (17 of 33 patients), 40% (eight of 20 patients) and 47% (seven of 15 patients) for Gleevec , respectively.
MRD-negativity rates of BCR::ABL1 of 0.0032% or less for the Iclusig arm were 27% (38 of 142 patients) in cycle three, 40% (36 of 90) in cycle five, 48% (28 of 59) in cycle seven and 63% (30 of 48) in cycle nine. Those rates were 15% (10 of 68), 30% (10 of 33), 25% (five of 20) and 27% (four of 15) for Gleevec , respectively.
The median duration of MRD negativity for the Iclusig arm (62 patients) was not evaluable, compared with 20.9 months for the Gleevec arm (15 patients).
Time to treatment failure was not evaluable in the Iclusig arm (164 patients) compared with 21.9 months in the Gleevec arm (81 patients). 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 Iclusig and 46% for Gleevec ), a first-generation BCR-ABL1 TKI (10% and 9%), a second- or third-generation BCR-ABL1 TKI and/or immunotherapy (19% and 37%) and Iclusig-based therapy (8% and 16%).
“Responders to Iclusig had more sustained remission compared with Gleevec , and time to treatment failure, whether from resistance or intolerance, were in favor of Iclusig,” Jabbour expanded.
Additional results demonstrated that the median event-free survival was not evaluable in the Iclusig arm and 29 months in the Gleevec arm. An event-free survival 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 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 progression-free survival was 20 and 7.9 months for the Iclusig and Gleevec arms, respectively.
The median overall survival was not evaluable in both arms.
“Due to short follow-up, we don't have mature data for (overall survival),” Jabbour said.
Regarding safety, 99% of patients in both arms experienced at least 1 any-grade treatment-emergent side effects. Rates of serious side effects, grade 3/4 side effects and deaths were 60%, 90%, and 5% in the Iclusig arm, respectively. Those rates were 56%, 93%, and 5% for Gleevec , 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.
Treatment-emergent side effects led to dose discontinuation, reduction, and interruption in 10%, 20%, and 68% of patients who received the Iclusig regimen, respectively. Those rates were 9%, 22%, and 40% for the Gleevec regimen, respectively.
The most common grade 3/4 hematologic side effects included anemia (31% for Iclusig and 36% for Gleevec ), 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 side effects 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%).
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