Ph+ ALL Management Updates: Expert Insights

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EP: 1.Ph+ ALL Management Updates: Expert Insights

EP: 2.Advancing the Treatment Landscape in Philadelphia-Positive ALL

EP: 3.Ponatinib Advances as Frontline Therapy in Ph+ ALL: PhALLCON Study Highlights

EP: 4.PhALLCON Trial: Safety and Efficacy of Ponatinib in Philadelphia-positive ALL

EP: 5.Optimizing Real-World Ponatinib Use in Ph+ ALL: Treatment Considerations

EP: 6.Advances in Ph+ ALL: Evolving Therapies and Future Strategies

Transcript:

Bijal D. Shah, MD, MS: Hi. My name’s Dr Bijal Shah, from the Moffitt Cancer Center. It’s my great delight and privilege to introduce Dr Hagop M. Kantarjian from the MD Anderson Group. Dr Kantarjian, you’ve developed this field quite a lot over the past few decades, really bringing hyper-CVAD [cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, methotrexate, cytarabine, and dexamethasone] and the hyper-CVAD–TKI [tyrosine kinase inhibitor] combinations to the forefront for the treatment of ALL, specifically Philadelphia chromosome [Ph+]–positive ALL [acute lymphoblastic leukemia]. What has been your perspective over these years?

Hagop M. Kantarjian, MD: So Philadelphia-positive ALL has been a very interesting subset of ALL, the most common form. And before 2000, it was a death sentence because the patients could be induced into remission in 90% of the cases with intensive chemotherapy, but unless they had an allogeneic stem cell transplantation available, they were not curable. And the cure with transplant was only about 40%. Since 2000, things are changing very rapidly, and the potential long-term survival in Philadelphia-positive ALL is changing significantly. So I think this will be a nice session to review some of the aspects of the disease and how things have changed. Bijal, in your view, can you give us an idea about how we diagnose Philadelphia-positive ALL and what are the common signs and symptoms, and how do you … these patients.

Bijal D. Shah, MD, MS: Absolutely. I think one of the first things to really recognize about Philadelphia-positive ALL is it does tend to impact an older patient population. We tend to see the frequency of this entity increase for every decade of age. We also tend to see these Philadelphia-positive ALLs present with a more proliferative signature. So higher white blood cell counts and presentation, higher LDH [lactate dehydrogenase]. And so, when I see this combination, an older patient with proliferative leukemia, instantly my alarm bells are going off, saying, OK, perhaps this is a Philadelphia-positive case. We try to dig a little bit deeper then…regardless of whether patients present with these features to make sure we rule it out at the same time.

And so, we’ll classically conduct FISH testing, fluorescence in situ hybridization, looking for the BCR-ABL translocation. And our center will commonly also perform P190 breakpoint and P210 breakpoint for the Philadelphia chromosome just like as just as we would in CML [chronic myeloid leukemia] to get a nice baseline as we go forward. These are the tools that I use to unmask the Philadelphia chromosome­–positive cases. We have tried to move further with the recognition that there are other mutations that can influence the outcome of our ALL patients. Ikaros, particularly in combination with CDKN2A or CDKN2B loss or PAX5 mutations, these can inform the likelihood of success with novel approaches for the management of Philadelphia chromosome­–positive ALL. So these are some of the things now, the next-generation sequencing piece, that I try to build into the diagnostic workup for my patients. The last thing I’ll say is CSF [cerebrospinal fluid] evaluation and treatment is a mandate for patients with Ph-positive ALL. Again, these tend to be more proliferative and by that virtue tend to have a higher risk of central nervous system [CNS] involvement. Hagop, what do you see when you’re seeing these patients, when you’re treating the patients? What are some of the challenges in particular as you’ve embarked on developing some of these newer approaches to the treatment of this disease?

Hagop M. Kantarjian, MD: So let me approach a few points that you mentioned, which I think are relevant. The first one is, is there a difference between a Philadelphia-positive ALL that presents with P190 or P210? And historically, different studies have shown some differences, particularly the fact that P210 may be associated with the worse prognosis with some regimens. But it is important to state that with the newer regimens that combined ponatinib with blinatumomab that we’ll discuss, perhaps then we don’t see much of the difference anymore. So the effectiveness of this therapy has overcome some of the prognostic factors. And at least the ponatinib and blinatumomab [combination] has also overcome the prognostic impact of these additional mutations. Another thing you pointed out is the CNS prophylaxis. And, historically, when we use intensive chemotherapy, we use only …

But as we progress from hyper-CVAD [with] imatinib to hyper-CVAD [with] ponatinib and the patients are living longer, we started seeing CNS relapses. So we are increasing the CNS prophylaxis. We increased that to 12 from 8 and more recently, because we removed the intensive chemotherapy, which was high-dose Ara-C [cytarabine], we have increased the CNS prophylaxis to 15. So these are 2 management issues, which are important, that relate to P190, to P210, and the CNS prophylaxis in these patients.

So what are the challenges in diagnosing these patients? I would add one short point, which is people recognize now an entity called Philadelphia-like ALL, and people think that it should be treated the same as Ph-positive ALL. But that’s not the case because for, let’s say, 100 cases of ALL, 25 will have Philadelphia-like disease, but 20 of those 25 will have CRLF2 overexpression with or without JAK mutations. And these have to be treated differently, without the TKIs. But there are 5 of those 100 who will have ABL translocation. So the translocation is from chromosome 9q34, but they translocate to a gene other than the BCR, and these patients respond in identical manner to Philadelphia-positive ALL, and we should treat them the same way as Philadelphia-positive ALL. And so it’s very important to communicate with your pathologists about the need to look at the Philadelphia-like ALL, which have ABL translocations rather than just the CRLF2 overexpression.

Transcript is AI-generated and edited for clarity and readability.