One size doesn’t fit all in Ph-like ALL

Sean M. Post

In this issue of Blood, Tasian et al provide compelling evidence that tailored therapies are an effective strategy in treating genetically defined Philadelphia chromosome–like (Ph-like) acute lymphoblastic leukemia (ALL).1

Through their use of patient-derived xenograft (PDX) models of childhood Ph-like ALL, the authors demonstrate the therapeutic efficacy and pharmacodynamic signaling inhibition of phosphoinositide 3-kinase (PI3K) pathway inhibitors, dual PI3K/mammalian target of rapamycin (mTOR) inhibitors, and combinational therapies. By designing therapies based on specific genetic alterations commonly observed in Ph-like ALL (eg, cytokine receptor-like factor 2 [CRLF2]/Janus kinase 2 [JAK2] –mutant Ph-like ALL and Abelson murine leukemia viral oncogene homolog 1 [ABL1]/platelet-derived growth factor receptor [PDGFR] –mutant Ph-like ALL), the authors developed robust strategies that eradicated disease in the majority of transplanted animals and thereby provide a persuasive rationale for using PI3K/mTOR inhibitors with JAK inhibitors and ABL inhibitors in the clinical setting.

ALL is the most common cancer in children and remains the most frequent cause of cancer-related deaths in the United States among children younger than age 20 years.2 Although survival rates have improved dramatically over the past decades for pediatric patients with ALL, cure rates in adults remain low despite intensive chemotherapy.3 Meanwhile, patients who do achieve complete remission often suffer significant adverse effects as a consequence of current chemotherapy regimens, and many patients ultimately relapse. Thus, there is a tremendous need to develop targeted treatment protocols based on specific genetic alterations that will improve survival rates and reduce unwarranted toxicity.

To this end, subsets of ALL patients who harbor specific and recurrent alterations, such as the chromosomal translocation t(9;22) (Philadelphia chromosome), have been identified. This translocation results in the generation of an oncogenic chimeric protein (BCR-ABL1) that drives proliferation through aberrant tyrosine kinase signaling. However, the majority of ALL patients do not harbor this translocation, which implicates other genomic or molecular events in the pathogenesis of many ALLs. A high-risk pediatric ALL subgroup has recently been identified that has a gene expression profile similar to Ph+ patients but lacks the characteristic BCR-ABL1 fusion that defines Ph+ ALL.4,5 These patients were subsequently denoted as having Ph-like ALL. Further investigation revealed that many of these individuals overexpress CRLF2 because of rearrangements of the CRLF2 locus, and they also often carry mutations in JAK2 or have activation of the JAK/STAT pathway.6 In patients with Ph-like ALL who do not harbor CRLF2 rearrangements, chimeric fusion proteins that deregulate the normal function of other tyrosine kinases (ABL1 and PDGFRB) are frequently observed.5

These alterations (CRLF2/ABL/PDGFRB) ultimately result in downstream activation of the PI3K/AKT/mTOR signaling cascade. Given the importance of the PI3K/AKT/mTOR pathway on cell growth and survival, these molecules represent critical therapeutic nexuses.7 Thus, numerous agents have been tested in both preclinical models and in clinical trials. For example, the PI3Kδ inhibitor (idelalisib) and the mTORC1 inhibitors (everolimus and temsirolimus), have obtained approval from the US Food and Drug Administration for some hematologic malignancies and solid tumors, respectively. However, these agents have not proved to be magic bullets, because idelalisib specifically targets PI3Kδ, and mTORC1 inhibition can allow a PI3K-dependent feedback loop to form, resulting in AKT and MAPK activation.8 Therefore, there is a pressing need to identify the most effective inhibitors that simultaneously inhibit both upstream and downstream components of these pathways and also suppress activation of escape mechanisms that induce therapeutic resistance.

In their article, Tasian et al developed a preclinical strategy to tackle this daunting issue by using pediatric PDX models of Ph-like ALL treated with various PI3K, mTOR, and dual-PI3K/mTOR inhibitors that directly targeted PI3Kα (BYL719), PI3Kδ (idelalisib), TORC1/TORC2 (AZD2014), and PI3K/mTOR (gedatolisib). They hypothesized that ablating the signaling cascades emanating from these molecules would inhibit the proliferative potential of these cells. Indeed, treatment with each of these inhibitors substantially reduced leukemic burden in transplanted mice. Importantly, the most robust activity was noted in the gedatolisib-treated cohort. Furthermore, pharmacodynamic analyses revealed that gedatolisib treatment provided the most significant inhibition of mTORC1 (pS6 and p4EBP1) and mTORC2 (pAKTSer473) targets. Next, the authors hypothesized that combined PI3K/mTOR pathway inhibition, along with JAK inhibition or ABL inhibition in genetically defined Ph-like ALL models (CLRF2 and ABL/PDGFR alterations, respectively), would have superior efficacy compared with monotherapy. These multipronged treatment strategies significantly prolonged survival and resulted in near-eradication of Ph-like ALL in CRLF2/JAK2-mutant models compared with monotherapy with gedatolisib or ruxolitinib (a JAK inhibitor). Likewise, the combination of gedatolisib plus dasatinib (an ABL inhibitor) in Ph-like ALL ABL1-mutant models effectively eliminated leukemic proliferation and extended survival when compared with either inhibitor alone. Taken as a whole, the investigation revealed the superior efficacy of gedatolisib compared with isoform-specific PI3Ks and mTOR inhibitors, and most strikingly, it demonstrated the combinatorial impact of including JAK2 or ABL inhibitors in genetically defined contexts.

Going forward, these studies offer 2 seminal points. First and most obvious is that clinical trials that combine multiple kinase inhibitors are warranted for patients with Ph-like ALL. Second, these studies highlight the fact that the painstaking approach to developing preclinical models based on specific genetic alterations for which there are relevant targeted therapies offers a robust platform for testing novel genetically tailored therapeutic concepts. This is a salient point, because clinicians are often presented with a critical dilemma when biological paradigms are incompletely understood: How does one simultaneously target a multifaceted pathway when it is not overtly clear whether a specific agent(s) will apply the necessary therapeutic pressure? This is often the case in Ph-like ALL, because there are many redundant and complementary signaling events activating the same targets. Thus, the most logical (yet difficult) choices are to select agent(s) that can directly ablate an entire pathway (such as dual-PI3K/mTOR inhibitors in combination with JAK or ABL inhibitors). Given the multitude of novel agents currently being tested in clinical trials, only time will tell if the combinations presented here will be as efficacious in human patients, but these empirical studies based on rational combinatorial approaches defined by clinical and genomic contexts provide an excellent starting point for offering patients a chance for long-term disease eradication.


  • Conflict-of-interest disclosure: The author declares no competing financial interests.


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