Evaluation of relationship between the genetic abnormalities and disease phenotype is required in juvenile myelomonocytic leukemia

Response:

In their letter, Flotho et al comment on our recently published paper on spontaneous improvement of hematologic abnormalities in patients having juvenile myelomonocytic leukemia (JMML) with NRAS or KRAS2 glycine to serine (Gly12Ser) mutation.¹ 

Our 3 patients with Gly12Ser mutation in the RAS gene continue hematologic and clinical improvement despite no chemotherapy 3 to 5 years after diagnosis. Based on no significant difference in proliferative response of granulocyte-macrophage (GM) progenitors to low doses of GM colony-stimulating factor between the patients with Gly12Ser mutation and the other RAS mutants, Flotho et al claim that our dose-response study does not support weaker oncogenic activity of RAS Gly12Ser compared with the activity of the other substitutions. However, more importantly there is marked reduction in numbers of circulating GM progenitors during the clinical course in patients with the RAS Gly12Ser substitution. Taken together with substantial decreases in leukocyte counts and spleen size during a 3- to 5-year follow up, their leukemic burden appears to become smaller.

The European Working Group of Myelodysplastic Syndromes in Childhood (EWOG-MDS) previously showed that platelet count 33 × 10⁹/L or more, hemoglobin F less than 15%, and age younger than 2 years at diagnosis identify a prognostically favorable subgroup in 72 JMML patients receiving no allogeneic hematopoietic stem cell transplantation (HSCT).²  However, their genetic background was unclear. Some of the subjects enrolled in the study might have inactivation of the NF1 gene or mutations in the NRAS, KRAS2, or PTPN11 genes. Flotho et al presented that 4 patients with NRAS mutation (codon 12 Gly > Val, codon 12 Gly > Ala, codon 12 Gly > Asp, codon 13 Gly > Asp) survive 4.5 to 21.5 years without HSCT. Coupled with our 3 patients with the RAS Gly12Ser mutation, JMML patients carrying RAS mutations may be heterogenous with respect to the hematologic progression.

Flotho et al recommend prompt HSCT for every patient with JMML, except children with Noonan syndrome, based on the superiority of HSCT over other treatment modalities. In recent reports,^3,4  approximately 50% of JMML patients who received such transplants were alive and leukemia-free after 4 to 5 years. The major cause of treatment failure is high incidence of leukemia recurrence after HSCT. In the results of the EWOG-MDS/European Blood and Marrow Transplantation (EBMT) Group trial,⁴  age younger than 2 years at diagnosis was associated with a better probability of event-free survival after HSCT. Nevertheless, it remains to be determined whether interval between diagnosis and HSCT influences the outcome. Therefore, we have chosen close follow-up rather than HSCT in JMML patients showing improvement of hematologic abnormalities despite no chemotherapy. Further studies are needed to elucidate whether the prognosis is similar or different among various genetic abnormalities in this disorder.