Dr Short on the Role of Molecular and Genetic Testing in Ph+ Acute Lymphoblastic Leukemia

“Even if a patient relapses on imatinib or dasatinib, and you [then] test the [BCR-ABL1] kinase domain mutation and it's negative, that doesn't mean that you [necessarily have to] select another second-generation inhibitor. Once a patient relapses, we really need to be very aggressive with our [next selection of therapy].”

Nicholas James Short, MD, an associate professor in the Department of Leukemia of the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center, discussed how molecular and genetic testing plays a role in the management of Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL), particularly in the context of relapse and TKI selection.

Short explained that although BCR-ABL1 kinase domain mutation testing provides valuable biologic insight, its impact on therapeutic decision-making depends heavily on the clinical scenario. In patients who relapse after frontline therapy with first- or second-generation TKIs, such as imatinib (Gleevec) or dasatinib (Sprycel), the likelihood of identifying a resistance mutation—particularly the BCR-ABL1 T315Isubstitution—is high, Short said. Although confirming the presence of such mutations is informative and helps document disease biology, he underscored that mutation status often may not alter the immediate treatment strategy at relapse. In most cases, if a patient has not previously received the third-generation TKI ponatinib (Iclusig), this agent would be selected at relapse, regardless of the mutation profile.

He further explained that while there are data from chronic myeloid leukemia (CML) space suggesting that higher doses of ponatinib may be effective in patients harboring BCR-ABL1 T315I mutations, the more aggressive clinical behavior of Ph-positive ALL necessitates a different approach. Unlike CML, where sequential TKI selection based on mutation sensitivity is common, relapsed Ph-positive ALL requires prompt escalation to the most potent available therapy. As such, even in the absence of detectable BCR-ABL1 T315I kinase domain mutations, Short would favor ponatinib at relapse rather than cycling through alternative second-generation TKIs. Outside of selecting ponatinib, Short highlighted clinical trials looking at agents such as asciminib (Scemblix) or olverembatinib (HQP1351) as potential routes of therapy.

Short also highlighted that molecular testing has greater relevance earlier in the disease course. Awareness of mutation patterns and resistance mechanisms provides a biologic rationale for incorporating a more potent TKI such as ponatinib earlier in treatment, rather than reserving this type of agent solely for salvage. Additionally, Short highlighted a scenario where a patient received imatinib before developing a resistance mutation; if this patient is still sensitive to another second-generation agent such as dasatinib, switching therapies is a reasonable course. However, in the context of relapse, utilizing the most potent available therapy is key in order to address an aggressive disease biology, he concluded.