Early results from a phase II clinical trial show that the third-generation tyrosine kinase inhibitor ponatinib plus the bispecific T-cell engager blinatumomab can produce complete molecular remissions in most patients with Philadelphia chromosome–positive acute lymphoblastic leukemia.
Over the past several years, the prognosis for Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) has improved due to the introduction of inhibitors of the oncogenic fusion kinase BCR–ABL, a major driver of ALL. The bispecific T-cell engager (BiTE) blinatumomab (Blincyto; Amgen), which exerts its effects by directing CD3+ T cells to CD19+ ALL cells via dual affinity for CD3 and CD19, has further transformed treatment. The question now is whether a tyrosine kinase inhibitor (TKI) plus blinatumomab is could be superior to other regimens.
Early results of one such trial were presented at the American Society of Clinical Oncology 2021 Annual Meeting, held June 4–8, by lead trial investigator Nicholas Short, MD, of The University of Texas MD Anderson Cancer Center in Houston. This phase II trial, which included 35 patients (28 of whom ultimately received study treatment) with newly diagnosed or relapsed or refractory Ph-positive ALL, was designed to investigate the use of the BCR–ABL inhibitor ponatinib (Iclusig; Takeda), a third-generation TKI, plus blinatumomab. Part of the rationale for using ponatinib is that resistance to first- and second-generation TKIs frequently arises due to the T315I gatekeeper mutation, and ponatinib has demonstrated activity against T315I-mutant BCR–ABL.
The complete response rate was 100% among the 19 newly diagnosed patients and 88% among the nine patients with relapsed or refractory disease. Of the patients with treatment-responsive disease, the rate of complete molecular remission (CMR)—considered a marker of superior prognosis and durable response—was 87% for newly diagnosed patients and 86% for those with relapsed or refractory disease, respectively. Although longer-term results remain to be obtained, “We're very encouraged by the data, particularly in the front-line setting,” Short commented.
Although the early data are promising, longer follow-up and larger patient cohorts are needed, said Anjali Advani, MD, of the Cleveland Clinic in Ohio, who was not involved in the research. “This is no criticism of this [trial],” she added. “This is just because this is new. What will really be exciting will be to see what happens in 5 years with this and how durable these remissions are, and … what the pattern of relapses is in those patients that relapse.” Indeed, compared with first- and second- generation TKIs, ponatinib's resistance mechanisms have not been well established.
Further, investigators don't know whether ponatinib plus blinatumomab will outshine the second-generation TKI dasatinib (Sprycel; Bristol Myers Squibb) plus blinatumomab, a combination investigated in a trial reported late last year (N Engl J Med 2020;383:1613–23). Although the CMR rates seen in the ponatinib trial appear greater than those in the dasatinib trial, the study populations were different, and cross-trial comparisons are inherently fraught with pitfalls. “I think we need more comprehensive data,” said Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York, NY, who was not involved in the research either.
Additionally, although the safety and toxicity profile of ponatinib plus blinatumomab was largely as expected based on those of either treatment alone, ponatinib can cause notable cardiotoxicity. “If you extend [the trial] up in age group and patients have more comorbidities, would you see more toxicity in those patients, and would it still be safe?” Advani asked.
Still, Short, Advani, and Park each independently called the results “encouraging.” If the remissions seen in this trial prove durable, some patients may be spared chemotherapy and stem cell transplantation.
Ponatinib plus blinatumomab has “surpassed our expectations,” Short said. “I think that it really is changing our paradigm.” –Nicole Haloupek