The Changing Landscape of Ph-Positive ALL

Josep Maria Ribera, MD, PhD

Treatment protocols for Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) are moving away from routine transplantation for patients in their first relapse toward avoiding it in most cases. According to Josep Maria Ribera, MD, PhD, this evolution is largely driven by advances in third-generation tyrosine kinase inhibitors (TKIs) and immunotherapy which have transformed patient outcomes.

“It is an evolving matter, from transplantation [for] everybody in the first days in ALL to now, avoid[ing] transplantation in almost all patients with ALL. There is a big change in the therapy of ALL, and it impacts the indication of transplantation in this disease,” explained Ribera, Catalan Institute of Oncology, in an interview with Targeted Oncology^TM.

Current standard treatments for this patient population involve combining first and second-generation TKIs with low-intensity chemotherapy, while clinical trials increasingly favor third-generation TKIs and immunotherapy. These modern approaches have led to high molecular response rates and significantly reduced the need for transplantation.

Looking ahead, Ribera anticipates a continued shift toward chemotherapy-free therapies, noting that with the availability of potent TKIs and standard immunotherapy options, the traditional treatment paradigm involving chemotherapy and transplantation is being reconsidered.

In the interview, Ribera, MD, PhD, further discussed the evolving treatment protocols for Ph-positive ALL.

Microscopic examination revealing red blood cells, white blood cells, neutrophils, eosinophils: ©AkuAku - stock.adobe.com

Targeted Oncology: Can you discuss the debate that you were a part of at the 2024 Society of Hematologic Oncology Annual Meeting?

Ribera: This was an interesting debate because we were debating the role of transplantation. It is an evolving matter, from transplant [for] everybody in first days in ALL to now, avoid[ing] transplantation in almost all patients with ALL. There is a big change in the therapy of ALL, and it impacts the indication of transplantation in this disease.

Can you explain the current standard treatment protocols for Ph-positive ALL and the rationale behind them?

We have to distinguish between assistential protocols and clinical trials. For assistential protocols in the real world, we are still using first- and second-generation TKI combined with low-intensity chemotherapy, and we follow these patients by [measurable residual disease (MRD)]. Then, the MRD level at 3 months after the initiation of therapy is the perfect moment to indicate the need for allogeneic stem cell transplantation.

Now, clinical trials use third-generation TKIs [and] use immunotherapy, and the panorama has completely changed. Outstanding responses, potent MRD negativity, deep MRD negativity—and then the indication for transplantation in these clinical trials remains marginal. It is important to distinguish what we are dealing with: clinical trials or assistential trials.

What are the primary benefits of combining chemotherapy with transplant in this space?

The benefit of TKIs and chemotherapy is to provide a high grade of response. The complete cytologic response is over 100%, and the molecular response is about 50% so this is an improvement. This limits the indication of transplantation to the patients who are MRD positive, but we can spare transplantation in those who are MRD negative. This is what occurs in real life.

Now, the advent of chemo[therapy]-free trials, immunotherapy-based trials, third–generation-based trials, improve the response and improve the quality of the response, and all of it is achieved with low-grade toxicity, so that they are feasible at all age groups. This is important for [older patients] in whom Ph-positive ALL is observed in half of ALL patients. It is important that now, the progress has been not only in efficacy, but also in tolerability and availability.

What evidence or research supports the use of chemotherapy and transplant as an optimal treatment?

In current evidence, especially through the evidence gained from clinical trials, once we achieve a deep response, the indication for transplantation diminishes. And now, in the most recent clinical trials, the indication is marginal, just for patients who are not achieving a complete molecular response. Even when treated with modern TKIs and immunotherapy, there is still a fraction of patients who are resistant to these therapies and still need transplantation, but this is a minority of them.

How does the efficacy of chemotherapy and transplant compare with chemotherapy-free regimens?

If we use a first- or second-generation TKI, at maximum, there is 60% overall survival. When we use chemotherapy-free approaches and immunotherapy, we achieve 90% overall survival. So, the differences are clear, but the experiences are not fully comparable, as they are not all comparable populations, because the 60% achieved with TKI, chemo[therapy], and transplantation comes from real life, and 90% overall survival with modern TKI and immunotherapy came from phase 2 clinical trials.

How do you address concerns regarding the long-term effects or quality of life for patients undergoing chemotherapy and transplant?

When we use attenuated chemotherapy and TKIs, patients have a better quality of life and can reach the transplantation in a good quality status. But transplantation is transplantation. There is transplant-related mortality in 10% to 15% of patients and substantial morbidity. When we compare this approach with modern approaches that are no chemotherapy, such as third-generation TKIs or immunotherapy, the quality of life is good. The tolerability is also good, and transplantation is spared, and the quality of life is gained. Importantly, they can be given to all their patients. We cannot transplant an 80-year-old patient, but we can treat [them] with chemo[therapy]-free approaches, and the difference in quality and quantity of life is evident.

What are some of the key factors in determining whether a patient is suited for chemotherapy-free regimens or the traditional chemotherapy transplant?

Chemotherapy regimens can theoretically be given to any patient. It depends on the patient’s status and prior conditions, as some may preclude the use of certain TKIs or immunotherapy. For example, patients with cardiovascular disease cannot receive ponatinib [Iclusig], so we would choose another TKI. Patients with previous neurological symptoms might not be able to receive brexucabtagene autoleucel [brexu-cel; Tecartus]. But if you can avoid these contraindications, and your patient does not have these specific antecedents, then any patient can be given these chemo[therapy]-free approaches.

How do you anticipate the debate around chemotherapy and transplant vs chemotherapy regimens evolving in the future?

I think the world is evolving to chemo[therapy]-free therapies. We have potent TKIs and standard immunotherapy, namely ponatinib and blinatumomab [Blincyto]. This is the way, and we are progressively abandoning the classical approach that is chemo[therapy], TKIs, and transplantation. There is a big change in treatment of Ph-positive [ALL] that is supported by more exciting improvements in overall survival and a good quality of life.

We are fortunate because we are now a step ahead in the treatment of Ph-positive ALL, and I believe that, ultimately, Ph-positive ALL could be a curable disease in 90% of patients. This is the level of achievement seen in children with ALL, so Ph-positive ALL could become the first adult ALL subtype with a cure rate similar to that in children. For physicians, this is remarkable news.