Dr Stock on the Multifaceted Role of Molecular Testing in Ph+ ALL

“In Ph-positive ALL, unlike in CML, many patients experience an early emergence of resistance mutations, particularly the [BCR-ABL1] T315Imutation. This is why, in the current [treatment] era, we’ve started to incorporate the third-generation TKI ponatinib up front to try to prevent the emergence of resistant clones, especially the T315I clone. We do not traditionally test for the presence of that mutation at baseline, but if there’s any hint of treatment resistance, one might look for that clone—particularly if incorporating a second-generation TKI, like dasatinib [Sprycel], as frontline treatment.”

Wendy Stock, MD, the Anjuli Seth Nayak Professor of Medicine at UChicago Medicine and co-leader of the Clinical and Experimental Therapeutics research program at the University of Chicago Medicine Comprehensive Cancer Center, discussed best practices for molecular testing in patients with Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL).

One factor that distinguishes Ph-positive ALL from chronic myeloid leukemia is the frequent and early emergence of resistance mutations, particularly the BCR-ABL1 T315I clone, Stock began. To counteract this rapid resistance development, hematologists have begun integrating the third-generation TKI ponatinib (Iclusig) in the up-front setting to try to avoid the development of those resistant clones, she said.

In practice, the presence of the BCR-ABL1 T315I mutation is not traditionally tested for at initial diagnosis, Stock explained. However, if there is any indication of emerging treatment resistance during therapy, testing for this clone becomes necessary, she emphasized. This is particularly crucial if a second-generation TKI, such as dasatinib (Sprycel), is incorporated as initial frontline treatment, she noted.

Furthermore, high-risk stratification in Ph-positive ALL requires identifying other molecular features, collectively known as the Ikaros-plus signature, according to Stock. The mutation or deletion of the Ikaros gene is common in this disease, affecting approximately 80% of patients, she reported. The Ikaros-plus signature constitutes the loss or mutation of Ikaros in combination with deletions or mutations in other genes, including the P15 and P16 genes, she added. Although testing for the Ikaros-plus signature is not universally performed up-front, it is considered a reasonable approach to take, she continued. Determining the presence of this signature is instrumental in guiding therapeutic decisions regarding necessary risk stratification and assessing whether the patient requires additional chemotherapy, she stated.

Beyond molecular genetics, a nonmolecular feature serving as an important prognosticator is initial white blood cell count, which is considered one of the more adverse prognosticators for outcome, she explained. Monitoring treatment response relies on serial bone marrows for morphologic monitoring of the disease, supplemented by much more sensitive molecular techniques, she summarized. Next-generation sequencing is now being employed in Ph-positive ALL to track the immunoglobulin gene rearrangement, she noted. Since this rearrangement is an intrinsic component of the leukemic clone, the eradication of this trackable clone might be the most important prognostic marker for achieving excellent disease-free survival, she concluded.