Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)
Atypical chronic myeloid leukemia, Philadelphia chromosome-negative (Ph1-); Chronic myelodysplastic/myeloproliferative disease; Juvenile chronic myelomonocytic leukemia; Mixed myeloproliferative/myelodysplastic syndrome; Overlap syndrome; Refractory anemia with ring sideroblasts associated with marked thrombocytosis (RARS-T)
The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid neoplasms characterized at the time of their initial presentation by the simultaneous presence of myelodysplastic and myeloproliferative features, which prevent them from being classified as either myelodysplastic syndrome (MDS) or myeloproliferative neoplasm (MPN). The most common entities within the MDS/MPN group include chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia, BCR-ABL1 negative (aCML), and juvenile myelomonocytic leukemia (JMML). A less well-defined group of MDS/MPN-like diseases include MDS/MPN unclassifiable (MDS/MPN-U) and a recently recognized entity of MDS/MPN with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T), previously known as refractory anemia with ring sideroblasts and thrombocytosis. It was considered a provisional entity within the group of MDS/MPN-U in the 2008 edition of the WHO classification of hematopoietic tumors but has now been promoted to a full distinct entry in the updated 2016 WHO edition (Orazi et al. 2017).
The incidence of MDS/MPN is estimated at 0.1–3/100,000 individuals. However these figures likely underestimate the true incidence of these entities, since they have been historically grouped with myelodysplastic syndromes. Many of them have a nonspecific clinical presentation and have only recently been recognized as distinct diseases.
The most common MDS/MPN entity is CMML. Approximately 1000 cases are diagnosed annually in the United States, with a crude annual incidence rate of 0.3 per 100,000. aCML, JMML, MDS/MPN-RS-T, and MDS/MPN-U are all very rare.
All MDS/MPN with the exception of JMML occur in older adults, with a median age at diagnosis of 65–75 years. In comparison, JMML is seen exclusively in pediatric patients. The age range for JMML has been reported from <1 to 14 years, with 75% of cases diagnosed in children younger than 3 years old.
CMML and JMML have a moderate male predominance. In aCML, the male-to-female ratio is approximately 1:1. In MDS/MPN-RS-T, there is a slight female predominance.
WHO diagnostic criteria for chronic myelomonocytic leukemia
Persistent monocytosis ≥1 × 109/L and ≥ 10% of the leukocytes
Not meeting WHO criteria for BCR-ABL1 CML, PMF, PV, or ET
No PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 gene rearrangements
<20% blasts in blood or bone marrow
Dysplasia in one or more of the lineages. If myelodysplasia is absent or minimal, the diagnosis of CMML can still be made if the other requirements are met
An acquired clonal cytogenetic or molecular abnormality is present
The monocytosis has been present for at least 3 months, and all causes of reactive monocytosis have been excluded
CMML-0: blastsa <2% in blood, <5% in bone marrow
CMML- 1: blastsa2–4% in blood, 5–9% in bone marrow
CMML-2: blastsa 5–19% in blood, 10–19% in bone marrow, and/or when any Auer rods are present
WHO diagnostic criteria for atypical chronic myeloid leukemia, BCR-ABL1 negative
Leukocytosis (WBC ≥ 13 × 109 L) due to increased numbers of neutrophils and their precursors which comprise ≥10% of leukocytes
Dysgranulopoiesis, which may include abnormal chromatin clumping
Minimal absolute basophilia (usually <2% of leukocytes)
No or minimal absolute monocytosis (always ≤10% of leukocytes)
Hypercellular bone marrow with granulocytic proliferation and dysplasia, with or without dysplasia in the erythroid and megakaryocytic lineages
Less than 20% blasts in the blood and in the bone marrow
No BCR-ABL1, PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2 gene rearrangements
Not meeting WHO criteria for BCR-ABL1-positive CML, PMF, PV, or ET
WHO diagnostic criteria for JMML
I. Clinical and hematologic features (all four features mandatory)
PB monocyte count ≥1 × 109/L
Blast percentage in PB and BM <20%
Absence of Philadelphia chromosome (BCR/ABL1 rearrangement)
II. Genetic studies (1 finding sufficient)
Somatic mutation in PTPN11a or KRASa or NRASa
Clinical diagnosis of NF1 or NF1 mutation
Germline CBL mutation and loss of heterozygosity of CBLb
III. For patients without genetic features, besides the clinical and hematologic features listed under I, the following criteria must be fulfilled:
Monosomy 7 or any other chromosomal abnormality or at least two of the following criteria:
Hemoglobin F increased for age
Myeloid or erythroid precursors on PB smear
GM-CSF hypersensitivity in colony assay
Hyperphosphorylation of STAT5
WHO diagnostic criteria for myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis
Anemia associated with erythroid lineage dysplasia with or without multilineage dysplasia
≥15% ring sideroblasts, <1% blasts in PB and, <5% blasts in the BM
Persistent thrombocytosis with platelet count ≥450 × 109/L
Presence of a SF3B1 mutation or, in the absence of SF3B1 mutation, no history of recent cytotoxic or growth factor therapy
No BCR-ABL1 fusion gene, no rearrangement of PDGFRA, PDGFRB, FGFR1, or PCM1-JAK2, and no isolated del(5q), t(3;3)(q21;q26), or inv(3)(q21q26)
No preceding history of MPN, MDS (except MDS-RS), or other type of MDS/MPN
With the exception of JMML, MDS/MPN is frequently diagnosed in the elderly, and its management is mainly represented by supportive care with the goal of improving and preserving quality of life. Red blood cell and platelet transfusions based on individualized requirements represent the foundation of the supportive plan. CMML patients with the dysplastic variant of the disease and increased blasts are treated with hypomethylating agents azacitidine (approved in Europe) or decitabine (approved in the United States). Patients with the proliferative variant of CMML who show progressive increase in WBC or symptomatic extramedullary involvement usually require administration of chronic cytoreductive therapy, with hydroxyurea used as the gold standard. Indications for allogeneic hematopoietic stem cell transplantation (HCT) remain a matter of debate in CMML mainly because of the associated high risk of morbidity and mortality in the elderly patient population.
Allogeneic HCT is the only curative therapy of JMML and is pursued immediately in most children. It is recommended for all children with JMML associated with NF1 mutation, somatic PTPN11, and KRAS mutations and for most children with somatic NRAS mutations. On the other side, close observation without immediate allogeneic HCT is recommended for most children with JMML who have germline CBL mutation, Noonan syndrome, and acquired RAS mutations with normal hemoglobin F and platelet counts.
Unlike CMML and JMML, there is no standard of treatment for aCML, MDS/MPN-RS-T, or MDS/MPN-U. Allogeneic HCT represents the only currently known curative therapy, and it may be considered in selected patients with higher risk of disease and younger age.
The general prognosis of CMML patients is poor, with an expected median overall survival of approximately 30 months. Progression to AML occurs in 15–30% of the cases. The most important prognostic factor appears to be the blast count in peripheral blood and bone marrow (Orazi et al. 2017).
Patients with aCML typically have a very poor prognosis with a median survival time of 14–29 months (Wang et al. 2014). Thirty to 40% of the patients develop acute myeloid leukemia. The remaining patients appear to develop progressive organomegaly, leukocytosis, anemia, and thrombocytosis.
The clinical course of JMML is variable. One-third of patients have rapidly progressive disease, whereas two-thirds of patients have a relatively indolent course. The median survival time of patients who do not receive allogeneic HCT can be as short as 10–12 months. Ten to 18% of patients develop acute leukemia. At the same time, a subset of children with germline CBL mutations have experienced spontaneous remission of JMML or have grown to adulthood with persistent hematologic abnormalities but minimal clinical symptoms.
SF3B1 and JAK2-mutated MDS/MPN-RS-T cases have a better prognosis than the rest of the MDS/MPN group and a better prognosis than patients with MDS with ring sideroblasts without thrombocytosis. Of note, the outcome is significantly worse compared to patients with essential thrombocythemia.
In JMML, the morphologic evaluation of peripheral blood smear is crucial in suspecting this diagnosis. Peripheral blood examination shows immature monocytes, along with myelocytes, metamyelocytes, and nucleated red blood cells. Bone marrow morphology is relatively nonspecific. Bone marrow is hypercellular for age and typically shows myeloid predominance, although occasional cases are erythroid-rich. Monocytes typically account for 5–10% of the cellularity. Blasts (including promonocytes) represent <20% of all cells. Significant dysplasia is not a feature of JMML. Some cases have marrow fibrosis.
Presence of a monocytic proliferation is confirmed by cytochemical staining of the bone marrow aspirate smears with nonspecific esterase such as α-naphthyl butyrate esterase.
With flow cytometry, normal monocytes express CD13, CD33, and CD14. In CMML and JMML, the peripheral blood and bone marrow monocytes usually have an aberrant phenotype with two or more abnormalities such as aberrant expression of CD56, CD2, and CD23 or decreased expression of HLA-DR, CD13, CD15, CD64, or CD36. Granulocytes in MDS/MPN may also show abnormal scatter properties and aberrant phenotypic features.
In cases of CMML and JMML, immunohistochemistry can be performed on the bone marrow core to identify and quantify the monocytic cells. CD14 is the most sensitive and specific marker, followed by CD68 (PGM-1) and CD163 (Fig. 1d). The most useful marker for plasmacytoid dendritic cells is CD123. Plasmacytoid dendritic cells may also express CD14, CD43, CD68, CD45RA, CD33 (weak staining), CD4, and Granzyme B. An increased number of CD34-positive blasts is associated with disease progression in all MDS/MPN.
Clonal cytogenetic abnormalities are found in 20–40% of patients with CMML, but none is specific. The most frequent recurring abnormalities include +8, −7/del (7q) and structural abnormalities of 12p. As many as 40% of patients exhibit point mutations of RAS genes at diagnosis or during the course of disease. An acquired RAS mutation has been documented in cases of CMML evolving from the myelodysplastic to the myeloproliferative variant. The presence of mutations in both TET2 and SRSF2 has been found to be strongly associated with the diagnosis of CMML (Kohlmann et al. 2010; Kosmider et al. 2009; Bacher et al. 2011). In fact, either TET2, SRSF2, or ASXL1 gene mutation is present in the vast majority of patients with CMML (Bacher et al. 2011). The presence of TET2, RAS, and ASXL1 mutations seems to impart a more aggressive course independently of the cytogenetic abnormalities (Bacher et al. 2011; Itzykson et al. 2013; Ricci et al. 2010).
Recent studies of aCML have shown that 15–32% of patients have evidence of SETBP1 mutation and up to 10% have ETNK1 mutation. RAS gene mutations have been detected in 35% of the cases. CSF3R mutation seems to be absent or only very rarely present in carefully defined cases of aCML.
Recent advances in molecular profiling of JMML patients have allowed the simplification and streamlining of the diagnosis of JMML (see Table 3). Monosomy 7 is present in ~25% of patients, and ~10% of patients have evidence of other cytogenetic abnormalities. Approximately 90% of patients carry either somatic or germline mutations of RAS pathway genes, including PTPN11, KRAS, NRAS, CBL, or NF1 genes; these genetic aberrations are largely mutually exclusive and activate the RAS/RAF/MAPK pathway.
Cases of MDS/MPN-RS-T are usually positive for SF3B1 mutation (80–90%) with frequent JAK2 mutations (50–60%), the latter possibly acquired as a secondary genetic event. The other MPN-related mutations such as MPL W515 and CALR mutations have been described in rare patients with MDS/MPN-RS-T. Other commonly encountered mutations include ASXL1, DNMT3A, SETBP1, and TET2. Cytogenetic abnormalities have been reported in approximately 10% of the patients.
Molecular characteristics of the main MDS/MPN subtypes
When a patient presents with overlapping features of MDS and MPN, the differential diagnosis is usually very broad. The integration of detailed clinical, histologic, and molecular genetic information is critical to narrow down to the correct diagnosis. Molecular evaluation of difficult to classify myeloid neoplasms has become an indispensable diagnostic tool. Mutations found in MPN and MDS cases frequently overlap, but the overall frequency in conjunction with the relevant clinical and morphologic data is sufficiently distinct to classify the vast majority of the cases (see Table 5).
For instance, MPN-like megakaryocytes are commonly seen in association with marrow fibrosis and increased CD34+ myeloblasts in cases of MDS with fibrosis. However, these patients present with severe cytopenias with no past history of “proliferative” hematological features (leukocytosis or thrombocytosis) and thus do not fulfil the diagnostic criteria for MDS/MPN-U. The morphologic features seen in chronic eosinophilic leukemia, chronic neutrophilic leukemia, primary myelofibrosis, essential thrombocythemia, and MPN-U may share some features with MDS/MPN, but significant dysplasia or significant cytopenia(s) are absent. An iron stain is required in all cases to exclude MDS/MPN-RS-T. MDS with isolated del(5q) with concurrent JAK2 V617F mutations often show overlapping features of MDS and MPN, but the disease phenotype, efficacy of lenalidomide, and patient prognosis are not different from other 5q deletion syndromes, and thus reclassification is not warranted.
The most clinically relevant differential diagnoses for CMML include MDS, AML, and reactive monocytosis. The cases of reactive monocytosis typically do not have cytogenetic or molecular abnormalities. Of note, a subset of older patients may display clonal hematopoiesis with myeloid-type mutations in the absence of defining features of CMML or other myeloid neoplasm (so-called clonal hematopoiesis of indeterminate potential or CHIP). Thus, the presence of a myeloid-type mutation alone may be an incidental finding and does not necessarily exclude a reactive process. Morphologically, promonocytes and monoblasts are not conspicuous in normal or reactive bone marrow samples but may be increased in cases of CMML or AML. By flow cytometry, abnormal antigen expression may be present in reactive monocytes, including expression of CD2 and CD56 or underexpression of HLA-DR or CD13. However, aberrant expression is usually limited to one marker. The presence of two or more abnormally expressed antigens is significantly more frequent in myeloid neoplasms compared to reactive monocytosis.
The distinction between CMML and AML with monocytic differentiation can be challenging. Monoblasts are large cells with abundant, moderately to intensely basophilic cytoplasm, which may demonstrate pseudopod formation, scattered fine azurophilic granules, and vacuoles. Nuclei are round with delicate lacy chromatin and one or more prominent nucleoli. Promonocytes are large cells with intermediate features between monoblasts and immature monocytes. They have less basophilic and sometimes more obviously granulated cytoplasm with occasional large azurophilic granules and vacuoles. The nucleus is irregular with a delicately convoluted configuration. A nucleolus may be present. The distinction between promonocytes and other abnormal marrow elements such as dysplastic myeloid precursors or immature monocytes may be controversial. There appears to be a significant association between AML with monocytic differentiation and NPM1, DNMT3A, TET2, and KRAS mutations. NPM1 mutation has also been described in a small percentage (3–5%) of cases of CMML. In these cases careful review of the blast count is indicated to exclude the alternative diagnosis of AML associated with NPM1 mutation. Close follow-up of these patients is recommended, since presence of NPM1 mutation or 11q23 rearrangement may herald rapid progression to acute leukemia.
Finally, cases of PMF may show monocytosis at the time of diagnosis or may develop monocytosis during the course of the disease. These cases should not be called CMML but rather considered within the spectrum of PMF particularly if the bone marrow morphology is diagnostic of the latter. Monocytosis in PMF has been associated with disease progression.
For aCML, the main differential diagnosis is with chronic myeloid leukemia (CML), BCR-ABL1-positive, and other MPNs. Myeloid dysplasia is not a feature of CML, while basophilia and eosinophilia are consistently present in CML but only occasionally seen in aCML. BCR-ABL1 gene rearrangement should be interrogated in all cases of suspected aCML. Its presence is diagnostic of CML. Other MPNs, in particular advanced stage polycythemia vera and post-essential thrombocythemia myelofibrosis, can develop marked neutrophilia that resembles aCML. Bone marrow biopsy shows characteristic features of MPN with increased enlarged and atypical megakaryocytes. Dysgranulopoiesis is only rarely present in cases of advanced neutrophilic MPNs and is usually due to hydroxyurea treatment. Molecular profile of MPNs is usually very different from aCML with presence of JAK2/MPL/CALR mutations and absent SETBP1/ETNK1 mutations.
Chronic neutrophilic leukemia (CNL) is a very rare subtype of MPN, characterized by sustained neutrophilia, bone marrow hypercellularity due to granulocytic proliferation, and hepatosplenomegaly in the absence of identifiable cause of physiologic neutrophilia. The updated WHO classification guidelines require presence of >25 × 109/L WBC with >80% segmented neutrophils/bands and <10% immature granulocytes in peripheral blood. As opposed to aCML, cases of CNL are not characterized by dysplasia. Somatic activating CSF3R gene mutation is present in 90–100% of the cases of CNL and is currently considered a disease-defining mutation.
Cases of MDS may have prominent dysgranulopoiesis but are characterized by cytopenias. Presence of leukocytosis with circulating immature myeloid precursors is distinctly unusual. Bone marrow examination of MDS cases demonstrates increased erythropoiesis. Presence of a very high myeloid-to-erythroid ratio should raise the question of an overlap MDS/MPN entity. Molecular and cytogenetic profile of MDS and aCML cases may be similar and does not help in the differential diagnosis, although the frequency of SETBP1 mutation in MDS is much lower than in aCML.
JMML must be distinguished from reactive monocytosis. Since the clinical, morphologic, and immunophenotypic features of JMML are nonspecific and may be seen in infections or inflammatory conditions, molecular genetic and cytogenetic studies are crucial in this differential diagnosis. CMML also presents with persistent absolute monocytosis but is usually not in the differential diagnosis since it is a condition of older adults. Cases described as “CMML in childhood” in the older literature would likely be reclassified as JMML based on the current diagnostic criteria.
The differential diagnosis for MDS/MPN-RS-T is broad. It includes cases of MDS which display thrombocytosis, such as 5q− syndrome, MDS with abnormality of chromosome 3q21q26, as well as classical MPNs which may rarely have coincidental ring sideroblasts. The importance of performing an iron stain on a bone marrow aspirate smear while working up a patient suspected to have a chronic myeloid neoplasm cannot therefore be overemphasized.
References and Further Reading
- Kohlmann, A., Grossmann, V., Klein, H. U., et al. (2010). Next-generation sequencing technology reveals a characteristic pattern of molecular mutations in 72.8% of chronic myelomonocytic leukemia by detecting frequent alterations in TET2, CBL, RAS, and RUNX1. Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology, 28, 3858–3865.CrossRefGoogle Scholar
- Orazi, A., Bennett, J. M., Germing, U., Brunning, R. D., Bain, B. J., Cazzola, M., Foucar, K., Thiele, J., Baumann, I., Niemeyer, C. M., Hasserhian, R. P., & Malcovati, L. (2017). Myelodysplastic/myeloproliferative neoplasms. Lyon: IARC.Google Scholar