Summary

The therapeutic aim in juvenile myelomonocytic leukemia (JMML) is disease eradication rather than mitigation or palliation. Allogeneic hematopoietic stem cell transplant (HSCT) is a curative treatment option, achieving 5-year event-free survival (EFS) in the order of 55%. The response to chemotherapy, if any, is transient, and the duration of survival is not influenced.

Targeting the epigenome may be a useful alternative strategy. We previously reported recurrent DNA hypermethylation at specific genetic regions as a characteristic attribute of JMML cases with poor prognosis and high probability of relapse after HSCT. We followed this up with a comprehensive study investigating genome-wide DNA methylation profiles in 167 children with JMML, defining three JMML subgroups with unique molecular and clinical features and validated and harmonized these results in an intercontinental meta-analysis involving study groups in Europe, USA, and Japan.

Given the strong association between hypermethylation and treatment failure in JMML, the therapeutic potential of inhibiting DNA methylation appears particularly attractive. We were the first to report a pilot case where treatment with the DNA methyltransferase inhibitor azacitidine led to a complete hematologic and molecular remission before HSCT. We later documented 3 complete remissions and 2 partial remissions in 9 children receiving azacitidine prior to HSCT. These favorable results distinguished azacitidine as the most active pharmaceutical in JMML known so far and led to the industry-sponsored, multicenter, international phase 2 study AZA-JMML-001 (EudraCT 2014-002388-13), which recruited from 2015 to 2017 and documented a 61% response rate. Our institution provided central medical coordination, reference diagnostics, and pharmacodynamic studies for this trial.

To meet clinical needs particularly for JMML patients with high-risk profile, it is important to quickly transfer innovative therapy concepts for myeloid neoplasms to JMML. The availability of ex vivo models for preclinical testing is crucial for this process. We have therefore started the generation of JMML-derived induced pluripotent stem cell lines as important tools for drug development and future clinical study design.

We will also take the previous results to the clinic by implementing prospective DNA methylation classification for all children with JMML diagnosed in the European Working Group of Myelodysplastic Syndromes (EWOG-MDS) network, which is coordinated out of our institution. These investigations will pave the way for diversified prospective therapy studies for children with JMML. It is meanwhile accepted in the community that previous recommendations will have to be differentiated. When allocating therapy arms (including rapid HSCT, azacitidine with subsequent HSCT, azacitidine alone, or watch-and-wait) in a future study, the methylation classes will take a primary position.

https://www.research-for-children.de/groups/flotho/