Evolving Role of TKIs and Antibody-Based Strategies Refines Ph-Positive ALL Management

As TKIs have continued to play an integral role in the management of Philadelphia chromosome–positive (Ph-positive) acute lymphoblastic leukemia (ALL), molecular markers and other prognostic factors have helped drive treatment decisions, according to Wendy Stock, MD.

“The appearance of the TKIs approximately 25 years ago revolutionized the way we treat Ph-positive ALL and has completely changed the paradigm and our survival rates, which have improved dramatically,” Stock said.

In an interview with OncLive®, Stock discussed the growing role of TKIs in Ph-positive ALL, the impact of molecular monitoring on treatment optimization, and ongoing efforts to refine dosing and treatment approaches to maximize efficacy and safety/quality of life.

Stock serves as co-chair of the Leukemia Committee for the National Cancer Institute-supported Alliance for Clinical Trials in Oncology and a co-leader of the Clinical and Experimental Therapeutics research program at the University of Chicago Medicine Comprehensive Cancer Center in Illinois.

OncLive: Within the Ph-positive ALL treatment paradigm, how have TKIs shaped current management strategies, and what unmet needs remain for these patients?

Stock: At the moment, the beauty of Ph-positive ALL is that we have many effective therapies in addition to the TKIs. The TKIs, of course, are an integral part of that treatment, but we are now exploring the possibility that we may get by with very minimal amounts of traditional chemotherapy by incorporating the antibody therapies that we’ve also developed against B-ALL [targeting] CD19- and CD22-positive [disease].

The combination of the TKI with antibody therapies, particularly studies that have shown benefit of third-generation TKIs—ponatinib [Iclusig]1 in particular—with blinatumomab [Blincyto]2 and intensive intrathecal therapy, have revolutionized the way we treat [Ph-positive ALL] and are allowing us to move away from the need for an allogeneic transplant to ensure long-term disease-free survival. There are still some challenges in the area, for sure, including isolated [CNS] nervous system relapses and certain potentially high-risk subsets who may need specific attention.

What factors influence treatment selection and sequencing considerations with these agents in Ph-positive ALL?

There are a number of studies [underway] worldwide that are looking at sequencing. [In the United States], we tend to incorporate the TKIs first, but very quickly—and sometimes simultaneously—start targeting with monoclonal antibodies. There are [ongoing] randomized studies evaluating the benefit of adding chemotherapy vs using TKI plus antibody therapy alone.

In Europe, the Italians have [led] the way in Ph-positive ALL with studies that have incorporated steroids, TKI, and blinatumomab, but they use a longer introductory phase of TKI plus steroids. Both [approaches] have merit and are being investigated.

What is the current role of molecular testing in Ph-positive ALL, and how often should clinicians assess for these alterations during treatment?

In Ph-positive ALL, unlike chronic myeloid leukemia, many patients experience an early emergence of resistance mutations, particularly the BCR-ABL1 T315I mutation. 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 [BCR-ABL1 T315I] mutation at baseline, but of course, if there’s any sign or hint of treatment resistance, one might look for that clone—particularly if incorporating a second-generation TKI, like dasatinib [Sprycel], as frontline treatment.

In terms of other molecular features of concern for higher risk, there’s the Ikaros-plus signature, which involves mutation or deletion of the Ikaros gene, which is very common in Ph-positive ALL. Approximately 80% of patients have a loss or mutation of Ikaros, such as the p15 and p16 genes, which are part of the Ikaros-plus signature, along with other potential gene mutations. Some people will test for the Ikaros-plus signature up-front, and it’s something we’re considering in terms of how to move forward with therapeutics, in terms of whether risk stratification is necessary or additional chemotherapy is needed for those patients.

Another important prognostic factor is an initially high white blood cell count, which is an old but true prognosticator. A count over 70,000 is considered adverse.

For response monitoring, in addition to morphologic evaluation via serial bone marrow exams, we now have much more sensitive molecular techniques, including RT-PCR for BCR-ABL1 and, importantly, next-generation sequencing to track immunoglobulin gene rearrangement that is part of the leukemic clone. That seems to be the most important prognosticator: eradication of this trackable clone is an excellent prognostic markers for DFS.

What key factors guide your approach to dosing and treatment sequencing with TKIs in patients with Ph-positive ALL, particularly regarding dose modifications or treatment holds to support adherence and minimize adverse effects?

A concern with ponatinib when used up-front was that at its originally prescribed doses, this drug can be quite toxic cardiovascularly.] Even now, we usually start at a lower dose than was originally recommended. However, it is possible, once patients achieve complete or significant molecular remission, to reduce the TKI to a lower dose. Typically, for patients receiving ponatinib up-front, once they’re in remission, we reduce the dose from 30 mg to 15 mg.

In general, blinatumomab is quite well tolerated. Initially, [some patients may experience] cytokine-mediated effects with first exposure, but these are [well understood and manageable.] Overall, treatment is quite straightforward these days.

Another important point is to always incorporate intrathecal therapy early and frequently, due to the risk of isolated CNS relapse. Ponatinib, blinatumomab, nor inotuzumab ozogamicin [Besponsa]—if that is the antibody is being incorporated in frontline treatment—penetrate the CNS. That raises the question of whether [using] some traditional chemotherapy agents that do penetrate the CNS, such as prophylactic doses of methotrexate or high-dose cytarabine, are useful and needed, particularly for high-risk patients. These are among the questions being explored by cooperative groups worldwide regarding next steps in treatment.

Finally, who needs an allogeneic transplant? Does such a transplant remain appropriate as frontline therapy? This is being investigated in several studies, particularly in Europe, and [we want to determine if we can] identify high-risk patients who should definitely be directed toward transplant if they are eligible candidates.

What are your thoughts on the emerging research suggesting that some patients with Ph-positive ALL who achieve deep, minimal residual disease (MRD)–negative remission following chemotherapy-free regimens and intensive intrathecal therapy may eventually discontinue TKI treatment and maintain durable, treatment-free remissions?

Another exciting and early emerging area of research is whether, with these novel approaches that are largely chemotherapy free, patients who are complete responders—[those who are MRD-negative by ClonoSEQ or NGS sequencing—and have completed rigorous intrathecal therapy courses can eventually discontinue TKI therapy. There are now case reports in the literature suggesting that this might actually be possible. We may be able to completely eradicate the disease and achieve treatment-free intervals following these intensive regimens without transplant.

This question will be examined carefully in prospective studies over the next number of years. It’s a truly exciting area where we can potentially think about curing the disease and [achieving] treatment-free remissions that are durable, similar to what has been observed in CML with the successful discontinuation of TKIs in a large percentage of patients.

References

1. Iclusig. Prescribing information. October 2025. Accessed November 3, 2025. https://www.iclusig.com/hcp/sites/default/files/2022-10/ICLUSIG-Prescribing-Information.pdf
2. Blincyto. Prescribing information. October 2025. Accessed November 3, 2025. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/blincyto/blincyto_pi_hcp_english.pdf