Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia

Leukemia (2008) 22, 1335–1342 & 2008 Macmillan Publishers Limited All rights reserved 0887-6924/08 $30.00 www.nature.com/leu SPOTLIGHT REVIEW Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia PD Emanuel In 1982, chronic myelomonocytic leukemia (CMML) was first classified in the category of myelodysplastic syndromes (MDSs), but it always seemed somewhat out of place compared with the rest of the MDS categories. In the 1990s, many argued that there were two different forms of CMML, a proliferative type and a myelodysplastic type. Then in 2001 the World Health Organization created a new category called the mixed myelodysplastic/myeloproliferative diseases, under which CMML was included. Although we still do not understand much about CMML pathogenesis nor do we have specific therapies for this disease, at least now most agree that it is in an appropriate category such that other areas of investigation can now proceed. On the other hand, we now understand a great deal of the pathogenesis underlying the disease now called juvenile myelomonocytic leukemia (JMML). JMML also fits in the new category of mixed myelodysplastic/myeloproliferative diseases. JMML is an excellent model malignancy for investigating and understanding dysregulated and aberrant signal transduction in the Ras pathway. It has also served as a teaching tool for exploring inherited predispositions to cancer. Leukemia (2008) 22, 1335–1342; doi:10.1038/leu.2008.162; published online 12 June 2008 Keywords: myeloproliferative; myelodysplastic; CMML; JMML; Ras; GM-CSF Review for this Series of Spotlight Reviews in Leukemia.3 As with MDS, the basis for the classification of these MPDs was largely based on morphological and clinical characteristics. Very little was known about the pathogenesis of these diseases except for evolving knowledge about the BCR–ABL fusion gene and CML. CMML did not entirely fit into the French–American– British MDS classification as well as the traditional four MPDs. During the 1990s, there were ongoing discussions at several different meetings and in some publications as to whether there should be a distinction between a proliferative type or version of CMML as opposed to a dysplastic type or version of CMML.4,5 These discussions, or the criteria to delineate between the two types, were based largely on the total white blood cell count. In 2001, the World Health Organization (WHO) reclassified most of the hematologic malignancies.6 As part of this reclassification, a new category of mixed myelodysplastic/ myeloproliferative diseases was created. Nearly all experts have been in agreement that CMML very appropriately fits into this mixed or ‘bridging’ category.7 There has been a 2008 revision of the WHO classification for myeloproliferative diseases (or myeloproliferative neoplasms).8 However, this revision does not substantively change the MDS/MPD mixed category.9 Introduction to chronic myelomonocytic leukemia Introduction to juvenile myelomonocytic leukemia For several decades, the classification of both myeloproliferative disorders (MPDs) and myelodysplastic syndromes (MDSs) was based largely, if not exclusively, on morphology. The French– American–British classification system for MDS was first devised in 19821 and included five entities: (1) refractory anemia, (2) refractory anemia with ringed sideroblasts, (3) refractory anemia with excess blasts, (4) refractory anemia with excess blasts in transformation and (5) chronic myelomonocytic leukemia (CMML). To many MDS experts, CMML always seemed out of place as compared with the other four entities. Although CMML patients clearly have some morphological characteristics compatible with MDS, CMML also has some characteristics of an MPD. Concordant with the French–American–British classification group, the Polycythemia Vera Study Group defined criteria for a diagnosis of polycythemia vera,2 which, as well as other reports, led to the evolution of the four major MPDs: (1) chronic myelogenous leukemia (CML), (2) polycythemia vera, (3) essential thromobocythemia and (4) primary myelofibrosis. A review of the chronological history and evolution of the MPDs, now becoming known as the myeloproliferative neoplasms, can be found in Dr Tefferi’s lead-off Spotlight During the comparable time period when the adult MDS and MPD categories were being defined, very little was understood about the disease we now know and call juvenile myelomonocytic leukemia (JMML). In the 1980s, it was most commonly known as juvenile chronic myelogenous leukemia, but other names ascribed to this disease in the past included juvenile chronic granulocytic leukemia, chronic and subacute myelomonocytic leukemia, CMML of childhood, infantile monosomy 7 and monosomy 7 syndrome.10–15 Some argued that it should be classified as a childhood form of MDS.16 But, similar to ‘adult-type’ CMML, this disease clearly had some characteristics of an MPD. Therefore, similar to CMML, it was quite fitting for the WHO reclassification schema to place JMML into the new category of mixed or ‘bridging’ myelodysplastic/myeloproliferative diseases. The name, JMML, was arrived upon in the mid1990s through the deliberations of the International JMML Working Group and through subsequent agreement by other groups, including the European Working Group on Myelodysplastic Syndromes in Childhood.17 Correspondence: Dr PD Emanuel, Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, 4301 West Markham Street, slot no. 623, Little Rock, AR 72205, USA. E-mail: Received 14 March 2008; revised 13 May 2008; accepted 19 May 2008; published online 12 June 2008 Similar to JMML (to be discussed below), CMML is a malepredominant disorder, with a male/female ratio of approximately 2:1. The reason for the male predilection in both CMML and JMML remains a mystery, with no solid clues to date. The median age of presentation of CMML is in the range of 65–75 CMMLFclinical presentation SPOTLIGHT Department of Medicine, Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA JMML and CMML PD Emanuel 1336 years. Common signs and symptoms largely relate to abnormalities in blood counts and include the following: (1) weakness and fatigue due to anemia, (2) petechiae, bruising and bleeding due to thrombocytopenia and (3) infections due to leukopenia. Splenomegaly and hepatomegaly can also variably be presenting signs, along with rare patients complaining of early satiety resultant from splenomegaly. CMMLFlaboratory findings The WHO diagnostic criteria for CMML include the following: (1) persistent peripheral blood monocytosis (greater than 1
109/l), (2) no Philadelphia chromosome or BCR–ABL fusion gene, (3) o20% myeloblasts or monoblasts in the peripheral blood or the bone marrow and (4) evidence of dysplasia in one or more myeloid lineages (Table 1).6 If evidence of dysplasia is absent or minimal, there are alternatives for diagno (...truncated)