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

> **NIH NIH R37** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2022 · $711,288

## Abstract

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 t...

## Key facts

- **NIH application ID:** 10522937
- **Project number:** 1R37CA266550-01A1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Elliot Stieglitz
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $711,288
- **Award type:** 1
- **Project period:** 2022-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10522937

## Citation

> US National Institutes of Health, RePORTER application 10522937, Implementation of an interventional, risk-adapted clinical trial for children with newly diagnosed juvenile myelomonocytic leukemia. (1R37CA266550-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10522937. Licensed CC0.

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