|LETTER TO THE EDITOR
|Ahead of print
Juvenile myelomonocytic leukemia: A case series of a rare hematological disease
Kalaivani S Subramanian, Sree Rekha Jinkala, Rakhee Kar, Debdatta Basu, Biswajit Dubashi
Department of Pathology, Jawaharlal Institute of Postgraduate, Medical Education and Research (JIPMER), Puducherry, India
Sree Rekha Jinkala,
Department of Pathology, Jawaharlal Institute of Postgraduate, Medical Education and Research (JIPMER), Puducherry
Source of Support: None, Conflict of Interest: None
Juvenile myelomonocytic leukemia (JMML) is a rare but frequently lethal clonal myeloproliferative neoplasm (MPN) of childhood. JMML accounts for less than 1% of childhood leukemias. It predominately affects young children under the age of 4 years and is characterised by the overproduction of mature and immature myelomonocytic cells that infiltrate the spleen, lungs and intestines. Over the years, several different classification systems have been used to define JMML. The name JMML now encompasses all diagnoses formerly referred to as Juvenile Chronic Myeloid Leukemia (JCML), Chronic Myelomonocytic Leukemia of Infancy, and Infantile Monosomy 7 Syndrome. World Health Organization (WHO) 2016 classifies JMML as an overlap of myelodysplastic syndrome/myeloproliferative disorder because JMML shares characteristics with both of these groups of disorders. This is one disorder where the molecular pathogenesis has been clearly elucidated. Children with neurofibromatosis type 1 (NF1) and Noonan syndrome are at increased risk for developing JMML., About 14% of children with JMML are also clinically diagnosed with NF1, and up to 30% carry the NF1 gene mutation.
Three cases of JMML were diagnosed over a period of 4 years at our institute. All the three patients presented with fever and hepatospenomegaly; one patient had café au lait spots. Complete hemogram showed anemia, thrombocytopenia, leucocytosis, absolute monocytosis and circulating myeloid precursors [Figure 1]a [Figure 1]b [Figure 1]c. Bone marrow examination showed myelomonocytic hyperplasia with blasts ranging from 2% to 12% [Figure 1]d [Figure 1]e [Figure 1]f [Figure 1]g. Two cases had normal cytogenetics and one showed gain of marker chromosome not specific for any leukemia, but negative for monosomy 7. All three cases were negative for BCR-ABL translocation. One patient showed elevated fetal hemoglobin (HbF) levels (42%), café au lait spots and normal Leucocyte alkaline phosphatase (LAP) score. The detailed case details are tabulated in [Table 1]. These patients were diagnosed according to WHO 2008 guidelines, criteria proposed at the JMML Symposium at Atlanta, in 2007, and also satisfy the recent additions made in the WHO 2016 classification of myeloid neoplasms [Table 2]. All the patients were started on Acute Myeloid Leukemia (AML) chemotherapy protocol. Two patients defaulted after six cycles and two cycles of chemotherapy. The third patient, did not get HLA compatible donor, could not be transplanted and subsequently underwent splenectomy. Spleen showed expansion and congestion of red pulp with extramedullary hematopoiesis. IHC with CD14 highlighted the monocytoid cells proving the splenic infiltration. This patient is still on follow-up with no circulating blasts at 40 months.
|Figure 1: Peripheral smear showing (a) monocytoid cells and a nRBC (Leishman × 400); (b) a blast (Leishman × 400), inset shows a cabot ring in RBC (Leishman × 1000); (c) neutrophils and circulating myelocyte (Leishman × 400); (d) bone marrow aspirate showing monocytoid cells and an occasional blast (Geimsa × 400); (e) imprint smear with few immature myeloid cells, occasional blast and mature lymphocytes (Leishman × 400); (f) CD14 highlighting monocytoid cells (DAB × 400); (g) CD34 highlighting occasional blast (DAB × 400)|
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Unlike acute leukemia, JMML is not a disease induced by a complete block in differentiation, but instead results from shunting of hematopoietic differentiation toward the monocytic pathway. It is characterised by the overproduction of mature and immature myelomonocytic cells that infiltrate the spleen, lungs and intestines. All organs can be infiltrated by this monocytic proliferation leading to multisystemic failure. Blast crisis with transformation into acute myeloid leukemia occurs in one third of patients.
The 2008 WHO diagnostic criteria for JMML include absolute monocyte count >1000/μL, <20% blasts in the bone marrow, and absence of the BCR- ABL fusion gene plus two of the four following criteria: (1) circulating myeloid precursors; (2) WBC >10,000/μL; (3) increased HbF for age; or (4) hematopoietic progenitor hypersensitivity to GM-CSF. However, based on the identification of multiple gene mutations in JMML, alternative diagnostic criteria were devised at the JMML Symposium in Atlanta, in 2007. These proposed criteria have incorporated NF1, RAS, and PTPN11 mutational status or the identification of monosomy 7 into the diagnostic assessment [Table 2]. These have now been adopted and included in the 2016 WHO classifications of myeloid neoplasms.
The close differential diagnoses of this disorder are myeloproliferative neoplasms such as chronic myeloid leukemia (CML), atypical CML and CMML because of the similarities in their clinical and bone marrow findings. However, the age of presentation, absolute monocyte count, LAP score, HbF, cytogenetics and absence of Philadelphia chromosome can help in differentiating from other mimics. In general, a pediatric patient presenting with hepatospenomegaly with leucocytosis, monocytosis and thrombocytopenia (unlike CML) with bone marrow showing myelomonocytic hyperplasia and blasts less than 20% should be suspected as a case of JMML and subjected to cytogenetics, BCR-ABL translocation studies and HbF estimation. Elevated HbF level is not necessary for a diagnosis of JMML, as at least one-third of confirmed JMML patients have normal HbF levels.
JMML is a disease with a variable course; in a significant proportion of patients the disease progresses rapidly, while others show indolent course. Treatment modalities include non- intensive chemotherapy, intensive induction therapy, allogeneic stem-cell transplantation. Allogenic stem cell transplantation is the only curative therapy which cures approximately 50% of patients. Patients of JMML can also progress to blast crisis (AML M4/M5); but more frequently succumb to disease due to tissue infiltration of myeloid cells. Hence, these patients should be kept on close monitoring.
JMML is a rare pediatric leukaemia which poses diagnostic and therapeutic challenges. Awareness of this rare entity helps in early diagnosis and curative BM transplant.
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Conflicts of interest
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[Table 1], [Table 2]