Introduction to chronic 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 for this Series of s 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 juvenile myelomonocytic leukemia

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, 11, 12, 13, 14, 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 mid-1990s 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

CMML—clinical presentation

Similar to JMML (to be discussed below), CMML is a male-predominant 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 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.

CMML—laboratory 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) <20% 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 diagnostic criteria including (a) an acquired, clonal cytogenetic abnormality in marrow cells or (b) persistent monocytosis for more than 3 months or (c) all other causes of monocytosis have been excluded. The WHO also recommended further subcategorizing CMML into CMML-1 (<5% blasts in the blood, <10% in the marrow) and CMML-2 (5–19% blasts in the blood, 10–19% in the marrow).⁶ Contrary to the thrombocytosis often seen in BCR–ABL+CML patients, CMML patients will typically have moderate-to-severe thrombocytopenia as well as anemia, fitting with their partial myelodysplastic characteristics. In terms of other laboratory and ancillary tests, cytogenetic abnormalities are found in 20–40% of CMML patients, but there are no consistently recurring chromosomal translocations that can be depended on for diagnostic criteria. In this context, one specific and unique chromosomal translocation, t(5;12)(q31;p12), gained much attention in the past years because of elegant pathogenetic studies that demonstrated that this unique translocation results in an abnormal fusion gene, TEL/PDGFR.¹⁸ Unfortunately, although these studies were quite intellectually stimulating, the reality is that the incidence of this translocation in CMML patients is, at most, only 1–2% of cases.

Table 1 - Diagnostic criteria for CMML and JMML.

Full table

CMML—pathogenesis

A clear understanding of the pathogenesis has been, and continues to be, elusive. In addition to the t(5;12) translocation discussed above, activating point mutations in the RAS oncogene appear to occur more frequently in CMML than in other diseases in the MDS and MPD categories, but again, these RAS gene mutations are not specific for a diagnosis of CMML. The incidence of RAS oncogene mutations varies widely in studies, from 20% to as high as 60%. In addition to the t(5;12) translocation and RAS mutations, other pathogenetic studies in CMML patients have given a plethora of different findings without a cohesive message. JAK2 mutations, found frequently in polycythemia vera, essential thrombocythemia and primary myelofibrosis, are much more rare in CMML, reported in 3 and 13% of patients in two recent series.^{19, 20} Activating mutations in FLT3 are among the most common genetic events in acute myelogenous leukemia and harbor a poor prognosis. Interestingly, investigators have now created a 'knock-in' murine model of CMML with an Flt3-ITD (internal tandem duplication).²¹ Again, although this murine model may prove to teach us much regarding mouse models of myeloproliferative neoplasms with monocytic features, the reality is that, in this study, only 6 of 194 (3.1%) CMML patients were found to harbor an FLT3-ITD mutation, whereas 38 of 194 (19.6%) harbored either an N-RAS or K-RAS mutation.²¹

CMML—diagnosis, clinical course and treatment

In addition to applying the above-mentioned WHO criteria, there are no specific diagnostic criteria or tests that can be applied. Other forms of MPDs and MDS should be ruled out when considering a CMML diagnosis. It should be duly stressed that, as with all MPDs and MDS categories, a diagnosis of CMML should not be applied with the first abnormal peripheral blood count but rather be established only after the patient has been followed for weeks to months with repeated laboratory testing. An overall median survival for CMML patients is about 12–24 months, but the range is very wide with a great deal of clinical heterogeneity.²² Additionally, it has been noted in many CMML patients that a rapid escalation in leukocytosis can be noted in times of concurrent infection. Clinicians should be advised to observe whenever possible and not assume an escalation of disease, because often the rapid escalation of leukocytosis resolves as the infection is treated. Many different prognostic scoring systems for CMML have been proposed, both as an entity within the MDS group and as a unique disease (reviewed in ref. ²³). One recent scoring system utilized hemoglobin, absolute lymphocyte count, peripheral blood immature cells and lactate dehydrogenase and demonstrated that the presence of immature circulating myeloid cells is the strongest independent variable for shortened survival.^{23, 24}

There are no specific therapeutics for CMML patients. Agents such as 5-azacitidine and decitabine, both recently receiving regulatory approvals for use in MDS, are also generally approved for use in CMML. CMML patients, having been previously included in MDS categories, were included in some of the clinical trials of these agents. However, the absolute numbers of CMML patients in these trials appears to be too low to reach meaningful conclusions about their effectiveness in CMML as a unique disease. A recent report details a small number of CMML patients treated with decitabine. During the trial, induction of hypomethylation was tracked along with clearance of mutant alleles.²⁵ Allogeneic stem cell transplantation remains the only known curative regimen for CMML but is an option only to a minority of patients, as the median age is in the 65–75 age range. It may be, if proven by future clinical trials, that nonmyeloablative options may prove effective and available to more patients in the older age group.

JMML—clinical presentation

The vast majority of cases of JMML present between birth and 6 years of age, with a median age at presentation of 2 years. If a child is significantly older than 6 years, other potential diagnoses should be very strongly considered. 'Adult-type' CMML, as discussed above, has been noted in very young children, even to the point of overlapping with the JMML age group. There is a male predominance in JMML of at least 2.5:1. As with CMML, the reasons for this male predominance are completely unknown. JMML rarely presents as a congenital disease, that is, it is rarely diagnosed in the newborn period. On the other hand, many cases present between 3 months and 12 months of age. JMML has been documented in at least one set of monozygotic twins, wherein there was evidence for the embryonic origin of partial chromosome 7 deletion.²⁶ Interestingly, one of the twin boys presented at 7 months of age with JMML, whereas his brother did not develop disease until 25 months of age. The diagnosis of JMML was confirmed (see below) by our laboratory in each of these children.

Typical presenting features, as noted by the parents, can include pallor, failure to thrive, decreased appetite, irritability, enlarging or protuberant abdomen (secondary to hepatosplenomegaly), dry cough and tachypnea, skin rashes or lymphadenopathy.^{11, 27} Owing to infiltration by relatively normal-appearing monocytes and macrophages into nonhematopoietic organs, JMML patients can also present with secretory diarrhea or bloody diarrhea, as well as pulmonary abnormalities or pulmonary failure, from frequent infiltration into the lungs and gastrointestinal tract.²⁸ Central nervous system involvement is quite rare. These suggestive clinical features make up part of the minimal diagnostic criteria for JMML, as adopted by the International JMML Working Goup (Table 1):¹⁷
Hepatosplenomegaly
Lymphadenopathy
Pallor
Fever
Skin Rash.

JMML—laboratory findings

In addition to the suggestive clinical features as detailed above, the International JMML Working Group also proposed minimal laboratory criteria for a diagnosis of JMML to be made. It should be noted that all three of these laboratory criteria need to be met for a diagnosis of JMML:¹⁷
Peripheral blood monocyte count greater than 1000/l
Absence of Philadelphia chromosome and BCR–ABL gene rearrangement
Bone marrow blasts less than 20%. The peripheral blood white blood cell count is increased in the vast majority of cases (median=33 000/l), but rarely exceeds 100 000/l, differentiating it even further from BCR–ABL+CML.²⁷ Peripheral blood monocytosis, mild to marked, is required for the diagnosis, and dysplasia within monocytes can often be noted. Basophilia, commonly noted in CML, is rarely encountered in JMML. Generally, there is some degree of anemia and thrombocytopenia, usually moderate, but in some cases either can be severe. Causes for anemia and thrombocytopenia are likely multifactorial, including splenic sequestration, consumptive processes and lack of production secondary to overcrowding in the marrow and to cytokine inhibitory processes. In addition, one can usually note immature myeloid precursors and nucleated red cells on the peripheral smear. Myeloblasts and monoblasts may at times be present on the peripheral smear, but their percentage rarely exceeds 15%. Bone marrow findings in JMML are nonspecific and typical for an MPD. The bone marrow aspirate typically shows hypercellularity, with granulocytic and monocytic forms predominating; however, the monocytosis in the marrow is usually less pronounced than that seen in the peripheral blood. By definition, blasts must be <20%, and all stages of myeloid maturation are usually identifiable. Erythroid and megakaryocytic series can be decreased, either due to the granulocytic hypercellularity and subsequent 'crowding out' phenomenon or due to cytokine suppression.^{14, 29} If the clinician is able to obtain blood before the need for red blood cell transfusions, a hemoglobin electrophoresis can be useful in helping to establish the diagnosis, as greater than 50% of JMML patients will demonstrate a reversion to fetal red blood cell characteristics, including (1) increased levels of hemoglobin F, even when corrected for age, (2) low carbonic anhydrase levels and (3) expression of the i antigen.³⁰ It should be emphasized that elevated fetal hemoglobin levels are not necessary for a diagnosis of JMML, due to the fact that at least one-third of confirmed JMML diagnoses have normal fetal hemoglobin levels. Furthermore, the hemoglobin F level elevations can cover a broad range from as little as a few percent to as much as 70–80%. In other laboratory parameters, hypergammaglobulinemia can also be noted.¹¹

Karyotype analysis in JMML, by definition, must be negative for the Philadelphia chromosome t(9;22). There are no consistently recurring chromosomal translocations noted in JMML. Monosomy 7, deletion of 7q and other chromosome 7 abnormalities occur in approximately 25–30% of cases.²⁷ Infantile monosomy 7 syndrome was once thought to be a separate entity from JMML. But now, if an infant with chromosome 7 abnormalities fits the diagnostic criteria for JMML, the infant or child is considered to have JMML and not a separate disorder. At least for now, until the molecular aberrations are further delineated, chromosome 7 abnormalities are considered to be an added association in JMML and not necessarily causal. In addition to chromosome 7 abnormalities, other karyotype changes are noted only in approximately 5–10% of JMML patients, predominantly involving chromosomes 3 and 8, but several other chromosome aberrations have been sporadically reported.²⁸

JMML—pathogenesis

Contrary to the situation in CMML, much is now known about JMML pathogenesis. In fact, so many strides have been made in delineating JMML pathogenesis in the last two decades that it can rightfully be put forth that, of all the myeloid blood cell diseases, JMML is second only to CML in terms of pathogenetic understanding. And it can also rightfully be asserted that all of JMML pathogenesis revolves around aberrations of the Ras signaling pathway and that study of this rare disease has divulged significant information regarding the Ras signaling pathway, which is a vital component of most normal cells as well as several malignant phenotypes, including many solid tumors.

At the cellular or cell biology level, two important characteristics typify the dysregulated hematopoiesis evident in JMML. Although neither is absolutely specific for JMML, in vitro laboratory testing for these traits has greatly aided JMML diagnostics. Mononuclear cells isolated from either peripheral blood or bone marrow sources from JMML patients typically demonstrate evidence of spontaneous proliferation of granulocyte-macrophage colonies.^{10, 12, 31} But spontaneous proliferation of myeloid colonies can occasionally be noted in other myeloid leukemias and MPDs, and even with some concurrent infectious processes.³² Even more specific to JMML, myeloid colony proliferation is the result of an acquired hypersensitivity by leukemic progenitor cells to granulocyte-macrophage colony-stimulating factor (GM-CSF).³³ This hypersensitivity is selective to GM-CSF, with normal sensitivity in JMML precursors to interleukin-3 and to G-CSF, and therefore is unique in JMML, in that other myeloproliferative diseases can demonstrate cytokine hypersensitivity but usually this is to multiple cytokines.^{34, 35, 36, 37} Although much of JMML pathology revolves around the monocytic lineage, the pathogenesis of JMML has clearly been traced back to the stem cell level, and JMML is a clonal malignancy originating at the pluripotent stem cell level.^{38, 39}

At the molecular pathogenetic level a clinical association between JMML and the dominant familial cancer syndrome neurofibromatosis type 1 led astute investigators to the Ras signaling pathway.^{40, 41, 42, 43} Children with neurofibromatosis type 1 have a 500-fold increased predilection for developing JMML or other myeloid disorders. Interestingly, and for as yet unknown reasons, adults with neurofibromatosis type 1 outgrow this risk for myeloid diseases. Similarly, and also due to as yet unknown regulatory factors, children with Down's syndrome also have a predilection for myeloid disorders, a risk that they appear to outgrow at about the same age as in JMML patients. Children with inherited neurofibromatosis type 1 are deficient in one of their two alleles for the neurofibromatosis type 1 gene (NF1). Scientific investigations have elucidated that approximately 10–25% of JMML patients acquire a somatic second hit to their remaining normal wild-type NF1 gene in their hematopoietic cells.^{43, 44} This complete lack of NF1 leads to a lack of neurofibromin, encoded by the NF1 gene, and subsequently hematopoietic cells cannot 'turn-off' Ras signaling. In essence, lack of neurofibromin due to NF1 gene loss is effectively the same as an activating RAS gene point mutation. Point mutations at codons 12, 13 or 61 of NRAS, KRAS or HRAS genes are commonly encountered in many human cancers.^{45, 46} Point mutations of NRAS or KRAS (but not HRAS) are seen in approximately 20–25% of JMML patients and are usually mutually exclusive of patients with NF1 mutations.^{40, 47, 48, 49, 50, 51} There is a second inherited genetic disorder associated on a clinical basis with JMML, and that disorder is Noonan syndrome.^{52, 53, 54} The causative gene for Noonan syndrome is the PTPN11 gene, which encodes for the protein tyrosine phosphatase SHP2.^{55, 56} Somatic mutations in PTPN11 represent the most frequent molecular lesion identified to date in JMML, with up to 35% of JMML cases demonstrating PTPN11 mutations, often mutually exclusive with RAS or NF1 mutations.^{57, 58, 59, 60, 61} Mouse models of these genetic lesions have proven their causal role in myeloproliferative disease development as well as hyperactivation of the Ras pathway and GM-CSF hypersensitivity.^{62, 63, 64, 65, 66, 67} The interested reader can see one of several recent reviews for a more in-depth review of these biochemical and genetic aberrations.^{46, 68, 69, 70} Taken together, genetic lesions can be identified in the Ras signaling pathway in at least 70% of children with JMML, and that percentage may be as high as 85% (Figure 1). In recent studies in Noonan syndrome and related disorders, mutations have been found in PTPN11, KRAS and now in SOS1.^{68, 71, 72, 73, 74} However, investigations in JMML have not yielded any abnormalities to date in SOS1, nor in many other genes encoding for other components of the RAS pathway, including SHC1, GRB2, GAB1, BRAF, MEK1 and MEK2.^{75, 76} Additionally, mutations common in other myeloid diseases such as FLT3 and JAK2 are rarely, if ever, found in JMML.^{77, 78}

Figure 1.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) signal transduction via the ras signaling pathway. Figure depicts a GM-CSF molecule binding to its cell surface receptor composed of and subunits. Intracytoplasmic signaling components of the Ras pathway are as depicted. Signaling component molecules that are mutated in juvenile myelomonocytic leukemia (JMML) patients are marked with an asterisk, and the approximate abnormality rate found for these components in JMML patients is noted in the box accompanying the figure.

Full figure and legend (77K)

JMML—diagnosis, clinical course and treatment

In applying the international consensus criteria for a diagnosis of JMML, the clinician must first apply the suggestive clinical features and the three minimal laboratory criteria as noted above. In addition to these diagnostic criteria, other further diagnostic criteria must be met by meeting at least two (minimum) of the following:¹⁷
Increased hemoglobin F (corrected for age)
Immature myeloid precursors on the peripheral blood smear
White blood cell count >10 000/l
Clonal cytogenetic abnormalities (including monosomy 7)
GM-CSF hypersensitivity of myeloid progenitors (in vitro).

In appropriate clinical situations, testing for a variety of viral conditions may be warranted (on a rule-out basis), as the clinical presentation of JMML has been occasionally noted in cytomegalovirus, human herpesvirus 6 and persistent Epstein–Barr viral infections.^{79, 80, 81, 82} A search for clinical evidence of either neurofibromatosis type 1 and/or Noonan syndrome should be conducted in the patient and in family members. Both of these genetic conditions can occur in either heritable or sporadic forms. There are agreed-upon NIH diagnostic criteria for neurofibromatosis type 1, including (1) six or more café-au-lait spots of >5 mm in prepubertal individuals or >15 mm in postpubertal individuals, (2) two or more neurofibromas of any type or one plexiform neurofibroma, (3) freckling in the axillary or inguinal region, (4) optic glioma, (5) two or more Lisch nodules (iris hamartomas), (6) a distinct bony lesion such as sphenoid dysplasia or thinning of the long bone cortex with/without pseudoarthrosis or (7) a first-degree relative with neurofibromatosis type 1. An individual needs to fulfill at least two of these criteria for a diagnosis of neurofibromatosis type 1. Although making a diagnosis of Noonan syndrome can be less definitive, associated clinical features include dysmorphic facial features, proportionate short stature, heart disease (most commonly pulmonic stenosis and hypertrophic cardiomyopathy), webbed neck, chest deformity, cryptorchidism, mental retardation and bleeding diatheses.⁸³ Testing for GM-CSF hypersensitivity or for mutations in RAS or PTPN11 genes in hematopoietic cells is still considered nonstandard, but it is performed routinely by at least three research labs worldwide (Drs Mignon Loh, Peter Emanuel and Charlotte Niemeyer; respective email addresses are lohm@peds.ucsf.edu; pdemanuel@uams.edu; charlotte.niemeyer@uniklinik-freiburg.de). Whereas RAS and PTPN11 gene testing is not complicated, NF1 gene testing is quite cumbersome and problematic. Dr Ludwine Messiaen in Birmingham, Alabama, USA, performs clinical diagnostic testing for neurofibromatosis type 1, regardless of whether there is a hematopoietic abnormality or not.

The clinical course of JMML can be very heterogeneous. Poor prognostic factors include (1) age less than 2 years, (2) low platelet count and (3) elevated fetal hemoglobin levels.^{16, 84} However, the scientific reasons as to why these factors portend a poor prognosis remain a mystery. Left untreated (which rarely occurs anymore), the natural course of JMML is rapidly fatal with 80% of patients surviving <3 years. Children under the age of 1 year with Noonan syndrome and a PTPN11 mutation have been known to undergo spontaneous resolution in some cases.^{52, 53, 54} Spontaneous improvement of other JMML patients with RAS mutations has also been noted.⁸⁵ Unfortunately, the majority of JMML patients will show disease progression, although conversion to a blast-type crisis is noted in <20%.

Allogeneic hematopoietic stem cell transplantation is the only curative treatment regimen for JMML. Although allogeneic hematopoietic stem cell transplantation can achieve long-term event-free survival in about 50% of patients, it is still hampered by relapse rates that are still quite high in the 30–40% range.^{86, 87, 88} Second transplants are of proven benefit, especially if used in conjunction with reduced immunosuppression, presumably leading to a stronger graft-versus-leukemia effect. On the other hand, donor lymphocyte infusions have proven ineffective in post-transplant relapse situations.⁸⁹ Likewise, standard chemotherapy, regardless of the intensity (low to moderate to high), has proven ineffective beyond anecdotal cases.^{27, 90, 91} 13-Cis retinoic acid has shown some responses, but the responses are typically more akin to disease stabilization or partial remission induction, as opposed to the complete remissions induced by all-trans retinoic acid in acute promyelocytic leukemia.⁹² Part of the difficulty with the above progress has arisen in assessing response to nontransplant treatment regimens. The development of molecularly targeted, mechanism-based therapeutics has been slowed down due to the rarity of this disease and consequently the reluctance of involvement by the pharmaceutical industry. Several agents, targeting the GM-CSF pathway or other pathways, have been reported in either in vitro or anecdotal clinical settings.^{93, 94, 95, 96} Farnesyltransferase inhibitors have demonstrated significant clinical activity in a phase II trial conducted by the Children's Oncology Group.⁹⁷ But correlative studies showed that this clinical activity was not due to blocking Ras farnesylation, as these agents were designed to do, nor had any correlation with RAS mutational status. Thus, farnesyltransferase inhibitor therapy in JMML cannot be considered as a targeted agent, at least at this stage.

In summary, it seems that in 2008, JMML stands about where CML did in 1998. We now know much about the pathogenesis of this fascinating, yet rare, mixed myeloproliferative/myelodysplastic disease. The study of JMML has provided us great insights into aberrant signal transduction through the Ras pathway and the ultimate development of malignancy. It has also revealed to us much about the genetic predisposition to cancer. But thus far the best we can offer to JMML patients and their families is a more accurate diagnosis and potential prognosis, and advice that they need to seek allogeneic hematopoietic stem cell transplantation as their best chance for long-term survival. Maybe 10 years from now, JMML will have an imatinib-like drug, just like CML does now.

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