TKI Landscape for Ph⁺ ALL Expanding

Preliminary findings from the phase III PhALLCON trial support the use of ponatinib (Iclusig; Takeda), a third-generation tyrosine kinase inhibitor (TKI) targeting the fusion oncoprotein BCR–ABL, as part of standard care for adults newly diagnosed with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph⁺ ALL).

Elias Jabbour, MD, of The University of Texas MD Anderson Cancer Center in Houston, reported the results during the February session of the American Society of Clinical Oncology's Plenary Series.

When imatinib (Gleevec; Novartis) debuted in 2001, it transformed Ph⁺ ALL's once dismal prognosis, observed Marlise Luskin, MD, of Dana-Farber Cancer Institute in Boston, MA. “As imatinib's potency and tolerability were increasingly recognized, we were able to de-escalate” induction chemotherapy, she said. However, “imatinib hasn't been a magic bullet—overall survival rates are below 50% in most studies.” Complete responses (CR) are often “insufficiently deep,” with minimal residual disease (MRD) being a persistent problem.

Other BCR–ABL TKIs have followed: Ponatinib targets the kinase domain resistance mutation behind roughly 75% of relapses, T315I, which still eluded second-generation drugs such as dasatinib (Sprycel; Bristol Myers Squibb) and nilotinib (Tasigna; Novartis). Until now, though, the only data suggesting that patients fare better with newer TKIs “have been from retrospective comparisons of separate trials,” Luskin said.

In PhALLCON, 245 patients were randomly assigned 2:1 to receive ponatinib or imatinib alongside low-dose chemotherapy. Among 232 evaluable patients, the MRD-negative (defined as BCR–ABL transcript levels of 0.01% or less) CR rate was significantly higher with ponatinib than imatinib—34.4% versus 16.7%, respectively.

Ponatinib induced deeper, more durable responses, Jabbour said, and its safety profile, with common side effects including anemia and decreased platelet counts, was “remarkably similar” to that of imatinib. Notably, arterial occlusion and venous thromboembolism—for which ponatinib, currently indicated for certain patients with chronic myeloid leukemia, carries a black box warning—“were infrequent.”

To Anjali Advani, MD, of the Cleveland Clinic in Ohio, the rarity of cardiovascular toxicities in PhALLCON was probably due to participants “being relatively young [median age 54 years], with a low incidence of risk factors.” Ph⁺ ALL is “typically a disease of the elderly, though, so the question is whether we can generalize these results to the larger population of older patients with more comorbidities.” She pointed out, too, that “in the U.S., most physicians use dasatinib, so it would have been nice to have data comparing this agent” with ponatinib.

As well, “I don't think 0.01% is a low enough cutoff to be considered MRD-negative; there's still potential for residual leukemia” that could provoke relapse, remarked Charles Schiffer, MD, of Wayne State University in Detroit, MI. The field is gradually recognizing that BCR–ABL transcript levels, detected by PCR, may not be the best marker, he added, and more sensitive next-generation sequencing assays are increasingly being used to monitor MRD.

Meanwhile, chemotherapy-free regimens for Ph⁺ ALL have been gaining ground, Advani observed. “We've seen excellent results so far” with, for instance, ponatinib plus the bispecific T-cell engager blinatumomab (Blincyto; Amgen). “The landscape is changing quickly, and a key issue now is when to use which approach.”

Some patients can likely avoid chemotherapy, agreed Nicolas Boissel, MD, PhD, of Hôpital Saint-Louis in Paris, France, albeit “we don't yet know how to identify them.” He wouldn't “get rid of these drugs altogether,” although “they remain useful, particularly for CNS [central nervous system] prophylaxis,” in which chemotherapy is directly injected into the CNS, a common relapse site.

Overall, questions still abound with Ph⁺ ALL management, Schiffer concluded. “But what we're really debating is how to achieve great, not just good, outcomes. That's remarkable progress.” –Alissa Poh

For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.