乌鸦传媒

In the first randomized comparison of targeted agents for acute lymphoblastic leukemia (ALL), ponatinib (Iclusig) prevailed over imatinib for untreated Philadelphia chromosome-positive (Ph+) cases.

More than twice as many patients treated with ponatinib achieved investigator-assessed complete response (CR) for at least 4 weeks and minimal residual disease (MRD) negativity by central review (MR4) versus imatinib (34.4% vs 16.7%, P=0.0021).

A similar advantage emerged for MRD negativity at the end of induction (41.6% vs 20.5%, P=0.0017) in the phase III trial. Duration of MRD negativity and time to treatment failure both favored ponatinib.

Substantially more patients discontinued imatinib because of disease progression, but rates of discontinuation for adverse events (AEs) were similar between groups, reported Elias Jabbour, MD, of the University of Texas MD Anderson Cancer Center in Houston, during the American Society of Clinical Oncology Virtual Plenary.

"When we looked at MRD negativity over time, the rate with ponatinib was substantially higher at any time compared with imatinib," said Jabbour. "Additionally, substantially deeper molecular responses, for example MR4.5, were observed for ponatinib compared with imatinib at the end of induction and over time."

Investigators defined progression-free survival (PFS) as the composite of 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 induction, or loss of MRD negativity. By that definition, median duration of PFS had yet to be reached in the ponatinib arm but was estimated at 20.0 months as compared with 7.9 months with imatinib.

"Among patients who discontinued therapy, fewer patients in the ponatinib arm received subsequent anticancer therapy (35% vs 57%)," said Jabbour. "It should be noted that this switching of therapy may have an impact on long-term outcomes.

Data for overall survival (OS) remain immature, but a trend favoring ponatinib had emerged after a median follow-up of 18-20 months.

"The efficacy and safety results demonstrate a favorable risk/benefit for ponatinib and should be considered as a standard of care for newly diagnosed Philadelphia chromosome-positive ALL," Jabbour concluded.

Questions About Applicability

The favorable outcome notwithstanding, the trial might have raised as many questions as it answered, according to invited discussant Anjali Advani, MD, of the Cleveland Clinic in Ohio. The median age of patients with ALL is 65, whereas the trial had a median age of 54. The patient population had a low prevalence of cardiovascular risk factors, which is relevant as ponatinib carries a risk of thromboembolic events.

"The question is whether we can generalize these results to the larger population who may be older or have comorbidities," said Advani. "There was a trend toward improved event-free survival [EFS] with ponatinib. However, with the new treatments we have -- such as antibody-based therapies or CAR T cells -- we are now able to salvage these patients. There was no overall survival benefit between the two arms in this trial."

Although the trial was the first randomized comparison of targeted agents for ALL, a fairer comparison would have been third-generation ponatinib versus second-generation dasatinib (Sprycel). Imatinib changed the treatment landscape for chronic myelogenous leukemia but has been less successful in ALL, she noted.

Also, treatment for newly diagnosed Ph+ ALL continues to evolve with regimens such as blinatumomab (Blincyto) plus a tyrosine kinase inhibitor (TKI).

Future studies of Ph+ ALL should include evaluations of genomic alterations and BCR/ABL mutation status, Advani continued. Longer follow-up is needed for both event-free survival (EFS) and OS. Age and comorbidities should be taken into account, and site-specific patterns of relapse, as well as the genomics of relapse, should be investigated.

Inhibitors of BCR/ABL plus chemotherapy or steroids represent standard-of-care for newly diagnosed Ph+ ALL. First- and second-generation BCR/ABL TKIs have demonstrated activity, but resistance develops in many cases, often driven by the T315I mutation, Jabbour noted in his introduction to the trial. Ponatinib is the only TKI that has demonstrated activity against BCR/ABL wild type and all single-mutant variants, including T315I.

Key Results

Jabbour presented the primary results from , an international randomized trial. Investigators randomized adults with newly diagnosed Ph+ ALL 2:1 to ponatinib or imatinib, each given along with reduced-intensity chemotherapy. The primary endpoint was MRD-negative CR.

The data showed that ponatinib plus chemotherapy doubled the likelihood that patients would achieve the primary endpoint (RR 2.06, 95% CI 1.19-3.56). A separate analysis showed a similar likelihood of achieving MRD negativity at the end of induction therapy (RR 1.94, 95% CI 1.19-3.17).

Median duration of MRD negativity and time to treatment failure were 20.9 and 21.9 months, respectively, for the imatinib arm, whereas neither endpoint had been reached for the ponatinib group.

Jabbour reported that 37% of patients who discontinued imatinib received a second- or third-generation TKI (ponatinib in 16% of cases), immunotherapy, or both. That compared with 19% in the ponatinib arm.

Ponatinib plus chemotherapy led to a 35% reduction in the hazard for EFS versus imatinib (95% CI 0.39-1.10). Investigators defined EFS as death from any cause, failure to achieve CR by the end of induction, or relapse from CR. Though median OS had yet to be reached in either treatment group, ponatinib was associated with a 24% reduction in the hazard versus imatinib (95% CI 0.38-1.52).

Treatment-emergent adverse events (all grades) that occurred more often with ponatinib were elevated liver function tests (alanine aminotransferase), pyrexia, constipation, peripheral neuropathy, hypertension, and fatigue.

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