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Advancing the Treatment Landscape in Philadelphia-Positive ALL
Key opinion leaders review the evolution of Ph+ ALL treatment, from Hyper-CVAD to novel TKIs, blinatumomab, and deintensification, improving remission rates and survival.
Hagop M. Kantarjian, MD: So I wanted to ask you to review, briefly, the treatment landscape in newly diagnosed Philadelphia [chromosome]–positive ALL [acute lymphoblastic leukemia] starting from 2000 to the present day, and then maybe elaborate on some of the unmet needs in the diagnosis and the treatment of Philadelphia-positive ALL.
Bijal D. Shah, MD, MS: Absolutely. And just to dovetail on your last comment, I mean, perhaps we should be thinking about calling it ABL-rearranged leukemia and just move away from this nomenclature of Philadelphia chromosome–positive, and that might help us to move things forward. But along those same lines, it can be difficult in the community to get the kind of next-generation sequencing testing that we need to help uncover some of this.
And particularly with that discussion with the pathologists you mentioned, you do your FISH [fluorescence in situ hybridization] probe for the BCR-ABL and ... if you don’t pay attention, if you don’t notice that ABL is rearranged, perhaps not with the BCR partner or that there are other abnormalities, [it] can be easy to miss these cases. And hopefully folks aren’t shy about reaching out. And ... we can better, more readily identify such cases so that they don’t go untreated because even the Philadelphia-like ALL with the other ABL class rearrangements without the TKIs [tyrosine kinase inhibitors] do quite poorly. In terms of the approach to current therapy, around 2000, as I alluded to in the beginning of our conversation, the hyper-CVAD [regimen; cyclophosphamide, vincristine sulfate, doxorubicin hydrochloride, methotrexate, cytarabine, and dexamethasone] emerged, and we started to see for the first time the introduction of imatinib to that backbone. And we saw something that was new: high rates of response upwards of 90%, which was outstanding given where we were previously with high rates of failure, often with patients coming off therapy post induction due to persistent disease.
With the introduction of imatinib, we were now seeing complete remissions. But they were not durable, plain and simple. Even with transplant, the majority of patients were relapsing, particularly if they did not go on to a posttransplant TKI maintenance with the imatinib or another novel TKI. I think that really set the stage for trying to do better. And we saw ... this leapfrog event as we developed newer TKIs, the second-generation TKIs, with studies involving nilotinib and bosutinib and perhaps most relevant, dasatinib. Dasatinib has the added advantage of being a LYN-SRC inhibitor. So we get some B-cell receptor inhibition on top of the BCR-ABL inhibition. And when combined with hyper-CVAD, that seems to do much better in terms of the durability of response.
However, transplants still seem to be necessary for a large percentage of these patients. I’m elaborating from the ALLIANCE data where this trial was studied. So ... with the MD Anderson Group, there was the initial data that had suggested that maybe transplant is helpful, maybe it’s not, particularly as you get above 40 or so years of age. But moving to the ALLIANCE data, it really seemed like that was a needed component. But boy, [what] a marked improvement relative to imatinib and hyper-CVAD, from about 40% complete remission, durable remission rates, to around 70% remission rate. The great thing about what we do is then the third-generation TKIs came along. We learned from our treatment with dasatinib that we were enriching for what are called gatekeeper mutations, mutations involving this particular amino acid, T315I, being the substitution, blocking the ability for dasatinib and all of the other first- and second-generation TKIs. Ponatinib was able to overcome it. And it made sense then to ask the question of, this is what we’re enriching for in relapse. Perhaps we can do better, but building ponatinib onto that backbone and again, that’s exactly what the MD Anderson group did and demonstrated for really the first time that in a majority of patients we could avoid allogeneic stem cell transplant consolidation and still achieve that same 70% durable remission rate. And I think that that is incredible. And what’s been amazing to see, particularly when we recognize, well, who does this disease effect? Well, predominantly our older patients, [and this] attempts to now step away from some of that intensity. So…before I go any further, I want to actually ask you, what has been your approach to deintensification? Is it just reducing the chemotherapy intensity? I know there’s also been a lot of interest around bringing novel agents like blinatumomab or others into the forefront for ALL.
Hagop M. Kantarjian, MD: So I think that’s a very important question. So if you look today at the standard of care in the United States, it is based on the confirmatory trial from the intergroup that looked at the regimen of hyper-CVAD [with] dasatinib. And what they showed is 2 things. One, you could induce almost all patients into a complete remission. And then if you use allogeneic transplantation, you cure more patients than if you continue with the chemotherapy and dasatinib. So this is now the established standard of care. As you pointed out, the estimated 5-year survival is about 50% to 60%. Beyond this, the hyper-CVAD was combined with ponatinib because of the observation that 20% of the patients who are relapsing were relapsing with the T315I-type mutation. So that led to the hyper-CVAD [plus] ponatinib regimen, where in a large population, we published in the single-arm trial from a single institution that the estimated 8-year survival is about 75%.
Now, as we were trying to establish this as a new standard of care, new data emerged that in fact blinatumomab, which is a CD19-bispecific T-cell engager, in the setting of the relapsed/refractory Philadelphia-positive ALL, that drug was superior to intensive chemotherapy. So this led in 2017 to the notion of de-escalating from intensive chemotherapy and using blinatumomab instead. Now in Europe, they had done multiple studies with the first-, second-, and third-generation TKIs with less chemotherapy in older patients, and they always found that this was well tolerated. Most of the patients achieved the CR [complete response], but in fact the patients were relapsing. So then when blinatumomab emerged, we started doing the ponatinib-blinatumomab and the Italian group that did the dasatinib-blinatumomab. And we published in sequence on those 2 regimens, which are now gaining ground in the community practice, and look like they appear to be quite effective.
Transcript is AI-generated and edited for clarity and readability.
