Implementation of an interventional, risk-adapted clinical trial for children with newly diagnosed juvenile myelomonocytic leukemia.

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Project Summary/Abstract Juvenile myelomonocytic leukemia (JMML) is a hematopoietic disorder of childhood that is associated with a poor prognosis. The current standard of care involves hematopoietic stem cell transplantation (HCT), resulting in many short and long-terms side effects. However, despite the intensity of HCT, outcomes are still poor with event free survival (EFS) at three years of only 50%. Enigmatically, there are rare patients who are known to experience spontaneous resolution of their disease with little to no treatment. While robust biomarkers of favorable and unfavorable prognosis have historically been lacking in this disease, we have demonstrated that a hypomethylated DNA signature identifies patients most likely to experience spontaneous resolution without HCT. In contrast, the presence of a hypermethylated DNA signature portended a poor outcome even after HCT. Our earlier work also showed that the presence of more than one somatically mutated gene was predictive of exceedingly poor outcomes. Both these biomarkers have since been validated in additional studies. Therapeutically, azacitidine and trametinib have each shown promise in early phase clinical trials in this disease although neither is curative as a monotherapy. Our preclinical data demonstrates that the combination of azacitidine and trametinib is more effective than either agent alone.Our overall hypothesis is that risk stratified therapy will be feasible in patients with newly diagnosed JMML and will ultimately result in improved outcomes. We expect that combinatorial therapy with azacitidine and trametinib (“Aza-MEK”) will provide excellent disease control for those with lower-risk JMML, while Aza-MEK + chemotherapy will yield molecular responses prior to HCT for those with high-risk JMML, therefore leading to better outcomes post- HCT. We further hypothesize that dual inhibition of JAK/STAT and MAPK signaling will confer synergy and, as such, we will test these agents in pre-clinical models to inform future clinical trials. In Aim 1 we will implement the first risk-stratified trial in JMML. In Aim 1a we will determine the feasibility of avoiding HCT in lower-risk patients (defined as those with a low DNA methylation signature and only one mutated gene) by treating with azacitidine in combination with trametinib (Aza-MEK) for up to 12 cycles. Lower-risk patients will only proceed to HCT in the setting of disease progression. In Aim 1b we will determine if adding Aza-MEK to cytarabine and fludarabine for high-risk patients (those with multiple mutations or an intermediate/high methylation signature) will increase the number of patients achieving a molecular remission pre-HCT. Finally, in Aim 2 we will interrogate the JAK/STAT pathway as a therapeutic target in JMML. Our data from in-vitro and in-vivo testing revealed single-agent activity of JAK2 inhibitors. In Aim 2a we will harness genetically engineered mice and in Aim 2b, patient derived xenograft models to test the hypothesis that ruxolitinib will be synergistic in combination with trametinib. Collectively, these studies will improve outcomes for patients with JMML by expanding treatment options beyond just HCT.