Juvenile myelomonocytic leukemia in the molecular era: a clinician's guide to diagnosis, risk stratification, and treatment

Abstract

Juvenile myelomonocytic leukemia is an overlapping myeloproliferative and myelodysplastic disorder of early childhood . It is associated with a spectrum of diverse outcomes ranging from spontaneous resolution in rare patients to transformation to acute myeloid leukemia in others that is generally fatal. This unpredictable clinical course, along with initially descriptive diagnostic criteria, led to decades of productive international research. Next-generation sequencing now permits more accurate molecular diagnoses in nearly all patients. However, curative treatment is still reliant on allogeneic hematopoietic cell transplantation for most patients, and additional advances will be required to improve risk stratification algorithms that distinguish those that can be observed expectantly from others who require swift hematopoietic cell transplantation.

Figure 1.

Risk stratified treatment algorithm as proposed by the authors. *All the following: single mutation, <1 year of age, and normal hemoglobin F. (Low DNA methylation when testing becomes clinically available.) °Any of the following: multiple mutations, >1 year of age, or elevated hemoglobin F. (Intermediate or high DNA methylation when testing becomes clinically available.) 6-MP, 6-mercaptopurine; AZA, azacitidine.

Figure 2.

HCT and post-HCT strategy. Conditioning regiments include busulfan (BU; 16-20 mg/kg orally over 4 days) in combination with cyclophosphamide (CY; 120 mg/kg over 2 days) or fludarabine (FLU; 40 mg/m²/dose over 4 days) with or without melphalan (MEL; 140 mg/m² once). Assessment at day +30 after HCT is performed by NGS and evaluation of donor chimerism. Molecular response is defined by a reduction of mutant allele frequency of the driver mutation to <5%. Modulation of GVL includes rapid withdrawal of immunosuppression and administration of donor lymphocyte infusions (±azacitidine). If remission, including molecular remission and full donor chimerism, is achieved, patients are monitored with bone marrow aspirates every 90 days for the first 18 months to 2 years after transplant (routine follow-up). Patients with refractory disease, relapse, or transformation to AML may benefit from a second HCT.

Figure 3.

GVL kinetics in molecular responders vs nonresponders.