tretinoin and Leukemia--Myelomonocytic--Juvenile

Juvenile myelomonocytic leukemia (JMML) is an aggressive pediatric malignancy with myelodysplastic and myeloproliferative features. Curative treatment is restricted to hematopoietic stem-cell transplantation. Fludarabine combined with cytarabine (FLA) and 5-azacitidine (AZA) monotherapy are commonly used pre-transplant therapies. Here, we present a drug screening strategy using a flow cytometry-based precision medicine platform to identify potential additional therapeutic vulnerabilities.. We screened 120 dual- and 10 triple-drug combinations (DCs) on peripheral blood (n = 21) or bone marrow (n = 6) samples from 27 children with JMML to identify DCs more effectively reducing leukemic cells than the DCs' components on their own. If fewer leukemic cells survived a DC ex vivo treatment compared with that DC's most effective component alone, the drug effect was referred to as cooperative. The difference between the two resistant fractions is the effect size.. We identified 26 dual- and one triple-DC more effective than their components. The differentiation agent tretinoin (TRET; all-trans retinoic acid) reduced the resistant fraction of FLA in 19/21 (90%) samples (decrease from 15% [2%-61%] to 11% [2%-50%] with a mean effect size of 3.8% [0.5%-11%]), and of AZA in 19/25 (76%) samples (decrease from 69% [34%-100+%] to 47% [17%-83%] with a mean effect size of 16% [0.3%-40%]). Among the resistant fractions, the mean proportion of CD38. TRET enhanced the effects of FLA and AZA in ex vivo assays with primary JMML samples.

Topics: Azacitidine; Child; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myelomonocytic, Juvenile; Tretinoin

Topics: Antineoplastic Agents; Diagnosis, Differential; Failure to Thrive; Female; Genetic Testing; Hepatomegaly; Humans; Infant; Leukemia, Myelomonocytic, Juvenile; Splenomegaly; Stem Cell Transplantation; Tretinoin; Xanthogranuloma, Juvenile