More Research Required to Advance Pediatric Ph-Like ALL Paradigm

Sarah K. Tasian, MD

Though there is no frontline standard for patients with pediatric Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL), Sarah K. Tasian, MD, explained that timely diagnostic interventions and subsequent enrollment on clinical trials will drive the treatment paradigm forward.

“What has really struck me over the years, having worked in this field for over a decade, is how heterogeneous Ph-like ALL is,” said Tasian. “We're constantly discovering new fusions. Despite that number of lesions, we really end up [subtyping] patients into 2 pathways—–either the ABL-class or CRLF2/JAK pathway [Ph-like ALL]. We hope that they can be targeted similarly, but it remains an active area of clinical investigation. I'm hopeful that we'll be able to answer that through our trials.”

One such agent that is being investigated in clinical trials is dasatinib (Sprycel), which was granted a supplemental biologics license application in August 2018 for use in combination with chemotherapy in newly diagnosed patients with Ph—positive ALL.

OncLive: Is there a difference between Ph-like ALL and Ph-positive ALL?

At the 2018 SOHO Annual Meeting, you presented on the diagnostic and therapeutic approach to taking care of patients with Ph-like ALL. Could you give an overview of that?

How are patients screened for this disease?

In an interview with OncLive, Tasian, an attending physician and assistant professor of pediatrics in the Division of Oncology at Children’s Hospital of Philadelphia, discussed the diagnostic and therapeutic approaches to treating patients with pediatric Ph-like ALL.Tasian: Yes. The 2 types of leukemia have a similar kinase activated gene expression profile, but they have totally different underlying genetic lesions.I reviewed the biology of the leukemias, the different genetic alterations that comprise those biologies, and how we diagnose patients using current clinical and previously researched testing algorithms. I covered practical tips about what you can do with routine clinical testing to identify some of these patients. Additionally, I gave a review of the preclinical data that informed some current clinical trials that are testing tyrosine kinase inhibitors (TKIs) and specific genetic subsets of patients with Ph-like ALL.We do things a little bit differently in pediatric patients than in adults. We have a pretty complicated, tiered genetic testing algorithm for children. We test all of our patients with high-risk B-cell ALL who were treated on our frontline Children's Oncology Group phase III clinical trial. We test all of our newly diagnosed patients with high-risk B-cell ALL, first by a gene expression screening tool called a low-density microarray (LDA). That helps us identify patients who don't need the testing because they don't have Ph-like ALL. For patients who have Ph-like ALL, it helps us tier the downstream molecular testing based on what we see on that LDA.

Is there an established frontline therapy?

What are the data on TKIs in pediatric patients?

Is there any crossover between adult and pediatric Ph-like ALL in terms of treatment?

What are the challenges in treating pediatric patients?

For patients who have more of what we call CRLF2 or JAK1/2 alterations, we have a separate phase II clinical trial for which patients can enter onto for the second phase of therapy. That trial is exploring the JAK inhibitor ruxolitinib (Jakafi). We don't yet know whether that will be effective. In the adult arena, there are also other clinical trials and FDA-approved medications. Most adult patients with Ph-like ALL are hopefully going onto the adult counterpart trials for what we have. People can also access these drugs commercially.These are 2 areas of active clinical trial research, so we don't have long-term efficacy data. A lot of [what we have] is preclinical data, where we've taken patient-derived xenographed models and treated them with these TKIs. That’s been very effective. There certainly are anecdotal clinical reports that have been published demonstrating activity with dasatinib or imatinib (Gleevec) in patients who have these ABL-class lesions. However, we're not quite there yet in terms of clinical efficacy.We think this is a major problem disease across the age spectrum. A lot of the initial work in Ph-like ALL was first characterized in children both in North America and in Europe. Then, there were 4 major studies, which were just published last year by 4 different groups, showing that this is just as much of a problem in adults as it is in children. We think the biology is a little bit different, but overall very similar. There are trials testing exactly the same medications in children as in adults. The difference is that we're doing it in newly diagnosed children and relapsed adults.The first hurdle is genetic diagnostics. We have to be able to figure out who these patients are in relatively real time. We never alter induction therapy, which is the first month of chemotherapy. However, we need to identify these patients before the end of induction therapy to add these TKIs. Access to good drugs in pediatrics has always been a challenge. Recently, we've been very fortunate to have pharmaceutical companies who are willing to partner with us to allow us access to novel TKIs for our patients.

U.S. Food and Drug Administration accepts Bristol-Myers Squibb’s application for Sprycel (dasatinib) in pediatric patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Published August 30, 2018. https://bit.ly/2LLh1Ko. Accessed August 30, 2018.

Now, we are most commonly using fusion-based platforms. We use the ARCHER FusionPlex Oncology Research Kit that helps us identify which kinase fusions patients have. It also helps us identify which TKI and which trial might be appropriate for that patient. It takes us a couple of weeks to figure all of this out, which is usually during their first month of therapy. Then, they can go on to receive the TKI starting in the second month of therapy.In pediatric oncology, we're very biased because we enroll most of our patients on trials. Patients who have Ph-like ALL with what we call ABL-class lesions are assigned to dasatinib on a separate arm of our frontline phase III trial, because we have tons of historic data that these patients have a very high risk of relapse and poor survival with regular chemotherapy.