Disease Overview

The myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are clonal myeloid disorders that possess both dysplastic and proliferative features but are not properly classified as either myelodysplastic syndromes (MDS) or chronic myeloproliferative disorders (CMPD).[1] This category is composed of three major myeloid disorders: chronic myelomonocytic leukemia (CMML), juvenile myelomonocytic leukemia (JMML), and atypical chronic myeloid leukemia (aCML). Myeloid disease that shows features of both MDS and CMPD but does not meet the criteria for any of the three major MDS/MPN entities is designated as myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-UC).

The French-American-British classification scheme for myeloid disorders did not contain this overlap category, which made the classification of CMML particularly difficult.[2,3] Recognizing the special diagnostic challenge that these diseases represent, a group of pathologists and clinicians sponsored by the World Health Organization (WHO) created the MDS/MPN category to provide a less restrictive view of myeloid disorders, which in some instances clearly overlap.[4] The WHO group proposed that the new MDS/MPN category would allow for more focused clinical and laboratory investigations of myeloid proliferation, abnormal proliferation, and dysplasia.[1]

Incidence and Mortality

The etiology of MDS/ MPN is not known. The incidence of MDS/MPN varies widely, ranging from approximately 3 per 100,000 individuals older than 60 years annually for CMML to as few as 0.13 per 100,000 children from birth to 14 years annually for JMML.[5] Reliable data concerning the incidence of aCML, a recently defined entity, are not available. The incidence of MDS/MPN-UC is unknown.

Histopathology

The pathophysiology of MDS/MPN involves abnormalities in the regulation of myeloid pathways for cellular proliferation, maturation, and survival. Clinical symptoms are caused by complications resulting from the following:[6]

• Cytopenia(s).
• Dysplastic cells that function abnormally.
• Leukemic infiltration of various organ systems.
• General constitutional symptoms, such as fever and malaise.

Patients with MDS/MPN do not have a Philadelphia chromosome or BCR/ABL fusion gene.

An international consortium has proposed uniform response criteria to be used in clinical trials because of the spectrum of presentations ranging from the myelodysplastic to the myeloproliferative.[7]

References

1. Vardiman JW, Thiele J, Arber DA, et al.: The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 114 (5): 937-51, 2009. [PubMed: 19357394]
2. Germing U, Gattermann N, Minning H, et al.: Problems in the classification of CMML--dysplastic versus proliferative type. Leuk Res 22 (10): 871-8, 1998. [PubMed: 9766745]
3. Voglová J, Chrobák L, Neuwirtová R, et al.: Myelodysplastic and myeloproliferative type of chronic myelomonocytic leukemia--distinct subgroups or two stages of the same disease? Leuk Res 25 (6): 493-9, 2001. [PubMed: 11337023]
4. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PubMed: 27069254]
5. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100 (7): 2292-302, 2002. [PubMed: 12239137]
6. Bain BJ: The relationship between the myelodysplastic syndromes and the myeloproliferative disorders. Leuk Lymphoma 34 (5-6): 443-9, 1999. [PubMed: 10492067]
7. Savona MR, Malcovati L, Komrokji R, et al.: An international consortium proposal of uniform response criteria for myelodysplastic/myeloproliferative neoplasms (MDS/MPN) in adults. Blood 125 (12): 1857-65, 2015. [PMC free article: PMC4915792] [PubMed: 25624319]

Disease Overview

The World Health Organization (WHO) classifies chronic myelomonocytic leukemia (CMML) as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN).[1] The WHO recognizes a dysplastic subtype and a proliferative subtype, with prognostic groups differentiated by the percentage of blasts in the bone marrow (higher percentage with worse prognosis).[2]

CMML is a clonal disorder of a bone marrow stem cell. Monocytosis is a major defining feature. CMML exhibits heterogenous clinical, hematological, and morphologic features, varying from predominantly myelodysplastic to predominantly myeloproliferative. Evolution to acute myeloid leukemia (AML) portends a particularly poor prognosis.[3]

CMML is characterized pathologically by the following:[4,5]

• Persistent monocytosis is greater than 1 × 10⁹/L in the peripheral blood.
• No Philadelphia chromosome or BCR/ABL fusion gene.
• No platelet-derived growth factor receptor-alpha (PDGFRA) and platelet-derived growth factor receptor-beta (PDGFRB) rearrangement.
• Fewer than 20% blasts in the blood or bone marrow (including monoblasts/promonocytes).
• Dysplasia involving one or more myeloid lineages or, if myelodysplasia is absent or minimal, either an acquired clonal cytogenetic bone marrow abnormality or at least 3 months of persistent peripheral blood monocytosis, if all other causes are ruled out.

Clinical features of CMML include the following:[4,5]

• Fever, fatigue, night sweats, and weight loss. (Refer to the PDQ summaries on Fatigue, Hot Flashes and Night Sweats, and Nutrition in Cancer Care for more information.)
• Infection.
• Bleeding caused by thrombocytopenia.
• Hepatomegaly (in some patients).
• Splenomegaly (in some patients).
• In patients with normal or slightly decreased white blood cell count, clinical features may be identical to MDS.
• In patients with elevated white blood cell count, features are more like chronic myeloproliferative disorders (CMPD), including more frequent splenomegaly and hepatomegaly.

The median age at diagnosis of CMML is 65 to 75 years with a male predominance of 1.5 to 3.1.[4,5] Because CMML is grouped with chronic myeloid leukemia in some epidemiologic surveys and with MDS in others, no reliable incidence data are available for CMML.[6] Although the specific etiology of CMML is unknown, exposure to occupational and environmental carcinogens, ionizing radiation, and cytotoxic agents has been associated in some cases.[6]

Morphologically, the disease is characterized by a persistent peripheral blood monocytosis (always >1 × 10⁹/L) that may exceed 80 × 10⁹/L with monocytes typically accounting for more than 10% of the white blood cells.[4,5] Monocytes, though typically mature with an unremarkable morphology, can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin.[7] Fewer than 20% blasts are seen in the blood or bone marrow. Neutrophilia occurs in nearly 50% of patients with neutrophil precursors (e.g., promyelocytes and myelocytes) accounting for more than 10% of the white blood cells.[8] Mild normocytic anemia is common. (Refer to the PDQ summary on Fatigue for more information on anemia.) Moderate thrombocytopenia is often present. Bone marrow findings include the following:[4,5,9,10]

• Hypercellularity (75% of cases).
• Blast count less than 20%.
• Granulocytic proliferation (with dysgranulopoiesis).
• Monocytic proliferation, dyserythropoiesis (e.g., megaloblastic changes, abnormal nuclear contours, ringed sideroblasts, etc.).
• Micromegakaryocytes and/or megakaryocytes with abnormally lobated nuclei (as many as 80% of the cases).
• Fibrosis (30% of the cases).

Hepatosplenomegaly may be present.[4,5] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML.[11] Care should be taken to identify cases of CMML with eosinophilia, a subtype of CMML, because of its association with severe tissue damage secondary to eosinophil degranulation. In CMML with eosinophilia, all criteria for CMML are present, and the eosinophil count in the peripheral blood is more than 1.5 × 10⁹.[6]

Recurrent somatic mutations have been identified in most patients with CMML, including mutant signaling molecules (especially NRAS, KRAS, JAK2, and SETBP1), epigenetic regulators (especially TET2 and ASXL1), splicing factors (especially SRSF2), and transcription factors (especially RUNX1).[12-15] A CMML-specific prognostic scoring system can distinguish four risk groups based on the following factors:[16]

1. Red blood cell transfusion dependency.
2. White blood cell count at least 13 × 10 ⁹/L.
3. Bone marrow blasts at least 5%.
4. Genetic risk group based on cytogenetics (trisomy 8, ≥3 abnormalities on karyotype, or chromosome 7 abnormalities are high risk), and mutations of either ASXL1, NRAS, RUNX1, or SETBP1.

The best prognostic group has a median survival of more than 10 years with no leukemic evolution in the first decade of follow-up. The worst prognostic group has a median survival of 20 months with a 50% evolution to AML by 2 years.[16]

Prognostic factors associated with shorter survival include the following:[17,18]

• Low hemoglobin level.
• Low platelet count; high white blood cell, monocyte, and lymphocyte counts.
• Presence of circulating immature myeloid cells.
• High percentage of marrow blasts.
• Low percentage of marrow erythroid cells.
• Abnormal cytogenetics.
• High levels of serum LDH and beta-2-microglobulin.

Progression to acute leukemia occurs in approximately 15% to 20% of cases.[17,18]

Treatment Overview

Treatment with hydroxyurea is an option for patients with worsening leukocytosis, thrombocytosis, or splenomegaly.[19] In a randomized clinical trial, 105 patients with advanced CMML were enrolled to compare treatment with hydroxyurea versus treatment with etoposide. Doses were scheduled to escalate to hydroxyurea 4 g/d and etoposide 600 mg/week in the absence of response and finally to adjust to maintain white blood cells between 5 × 10⁹/L and 10 × 10⁹/L. Median actuarial survival was 20 months in the hydroxyurea arm versus 9 months in the etoposide arm (P < .001). Main factors associated with poor survival were allocation to the etoposide arm, unfavorable karyotype (i.e., monosomy 7 or complex abnormalities), and anemia.[20][Level of evidence: 1iiA]

The nucleoside azacitidine is an inhibitor of DNA methyltransferase that has been approved for the treatment of MDS and CMML, largely based on a Cancer and Leukemia Group B randomized trial and a randomized trial conducted in Europe.[21,22] Azacitidine may improve both the dysplastic and proliferative features of CMML. Erythropoietic growth factors may help to reduce transfusion requirements when anemia supervenes. This trial, in which patients were randomized to supportive care versus azacitidine (75 mg/m²/day subcutaneously for 7 days every 28 days), included 10 patients with CMML.[21][Level of evidence: 1iiDii] Lenalidomide with or without azacitidine has also been studied in CMML.[23] Inhibitors of JAK2, such as ruxolitinib, are also being evaluated.[24]

Bone marrow transplantation (BMT) or stem cell transplantation appears to be the only current treatment that alters the natural history of CMML. In a review of 118 young MDS patients (median age 24, age range 0.3–53 years) who received allogeneic BMT from matched unrelated donors, the actuarial probability of survival at 2 years for the 12 patients with CMML was 10%. Transplant-related mortality was influenced by the age of the patient (i.e., <18 years, 40%; 18–35 years, 61%; >35 years, 81%). This study included patients who received transplants as early as 1986, which may have influenced the patient survival data.[25][Level of evidence: 3iiiA] In a recent review of 50 allogeneic transplantations for CMML (i.e., median age 44, age range 19–61 years) from related (n = 43) or unrelated (n = 7) donors, the 5-year-estimated overall survival was 21%. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute graft versus host disease grade II through grade IV and for a higher relapse rate in patients with T cell-depleted grafts, suggesting a graft-versus-CMML effect. This latter series represents the largest cohort of patients with adult CMML and allogeneic stem cell transplantation to date.[26][Level of evidence: 3iiiA]

A case report suggests that targeted therapy with imatinib mesylate may be effective in a subset of patients with CMML related to PDGFβR fusion oncogenes.[27]

Various chemotherapy regimens for CMML have been used with only modest success.[19] In a study evaluating single-agent therapy with topotecan, a topoisomerase I inhibitor, 25 patients with CMML were treated with topotecan at doses that induce bone marrow aplasia (2.0 mg/m²/day by continuous infusion for 5 days). Complete hematologic remissions were induced in 28% of patients. Toxic effects were significant, and the median duration of remission was 8 months.[28][Level of evidence: 3iiiDiv] In a follow-up study, topotecan was used in combination with cytarabine, a pyrimidine-analog antimetabolite. This combination regimen induced complete remission in 44% of patients with CMML; median duration of complete response was 50 weeks, and patients required monthly maintenance therapy.[29][Level of evidence: 3iiiDiv]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PubMed: 18480833]
2. Arber DA, Orazi A, Hasserjian R, et al.: The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood 127 (20): 2391-405, 2016. [PubMed: 27069254]
3. Germing U, Strupp C, Knipp S, et al.: Chronic myelomonocytic leukemia in the light of the WHO proposals. Haematologica 92 (7): 974-7, 2007. [PubMed: 17606449]
4. Onida F, Beran M: Chronic myelomonocytic leukemia: myeloproliferative variant. Curr Hematol Rep 3 (3): 218-26, 2004. [PubMed: 15087071]
5. Emanuel PD: Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22 (7): 1335-42, 2008. [PubMed: 18548091]
6. Aul C, Bowen DT, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 83 (1): 71-86, 1998. [PubMed: 9542325]
7. Kouides PA, Bennett JM: Morphology and classification of the myelodysplastic syndromes and their pathologic variants. Semin Hematol 33 (2): 95-110, 1996. [PubMed: 8722681]
8. Bennett JM, Catovsky D, Daniel MT, et al.: The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87 (4): 746-54, 1994. [PubMed: 7986717]
9. Michaux JL, Martiat P: Chronic myelomonocytic leukaemia (CMML)--a myelodysplastic or myeloproliferative syndrome? Leuk Lymphoma 9 (1-2): 35-41, 1993. [PubMed: 8477199]
10. Maschek H, Georgii A, Kaloutsi V, et al.: Myelofibrosis in primary myelodysplastic syndromes: a retrospective study of 352 patients. Eur J Haematol 48 (4): 208-14, 1992. [PubMed: 1592101]
11. Saif MW, Hopkins JL, Gore SD: Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 43 (11): 2083-92, 2002. [PubMed: 12533032]
12. Meggendorfer M, Roller A, Haferlach T, et al.: SRSF2 mutations in 275 cases with chronic myelomonocytic leukemia (CMML). Blood 120 (15): 3080-8, 2012. [PMC free article: PMC3580040] [PubMed: 22919025]
13. Kosmider O, Gelsi-Boyer V, Ciudad M, et al.: TET2 gene mutation is a frequent and adverse event in chronic myelomonocytic leukemia. Haematologica 94 (12): 1676-81, 2009. [PMC free article: PMC2791942] [PubMed: 19797729]
14. Malcovati L, Papaemmanuil E, Ambaglio I, et al.: Driver somatic mutations identify distinct disease entities within myeloid neoplasms with myelodysplasia. Blood 124 (9): 1513-21, 2014. [PMC free article: PMC4148773] [PubMed: 24970933]
15. Patnaik MM, Itzykson R, Lasho TL, et al.: ASXL1 and SETBP1 mutations and their prognostic contribution in chronic myelomonocytic leukemia: a two-center study of 466 patients. Leukemia 28 (11): 2206-12, 2014. [PubMed: 24695057]
16. Elena C, Gallì A, Such E, et al.: Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia. Blood 128 (10): 1408-17, 2016. [PMC free article: PMC5036538] [PubMed: 27385790]
17. Onida F, Kantarjian HM, Smith TL, et al.: Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood 99 (3): 840-9, 2002. [PubMed: 11806985]
18. Germing U, Kündgen A, Gattermann N: Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 45 (7): 1311-8, 2004. [PubMed: 15359628]
19. Bennett JM: Chronic myelomonocytic leukemia. Curr Treat Options Oncol 3 (3): 221-3, 2002. [PubMed: 12057067]
20. Wattel E, Guerci A, Hecquet B, et al.: A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Français des Myélodysplasies and European CMML Group. Blood 88 (7): 2480-7, 1996. [PubMed: 8839839]
21. Kaminskas E, Farrell A, Abraham S, et al.: Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 11 (10): 3604-8, 2005. [PubMed: 15897554]
22. Fenaux P, Mufti GJ, Hellstrom-Lindberg E, et al.: Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 10 (3): 223-32, 2009. [PMC free article: PMC4086808] [PubMed: 19230772]
23. Sekeres MA, Tiu RV, Komrokji R, et al.: Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes. Blood 120 (25): 4945-51, 2012. [PMC free article: PMC3525020] [PubMed: 22915641]
24. Padron E, Painter JS, Kunigal S, et al.: GM-CSF-dependent pSTAT5 sensitivity is a feature with therapeutic potential in chronic myelomonocytic leukemia. Blood 121 (25): 5068-77, 2013. [PMC free article: PMC4347259] [PubMed: 23632888]
25. Arnold R, de Witte T, van Biezen A, et al.: Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: an EBMT survey. European Blood and Marrow Transplantation Group. Bone Marrow Transplant 21 (12): 1213-6, 1998. [PubMed: 9674854]
26. Kröger N, Zabelina T, Guardiola P, et al.: Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 118 (1): 67-73, 2002. [PubMed: 12100129]
27. Magnusson MK, Meade KE, Nakamura R, et al.: Activity of STI571 in chronic myelomonocytic leukemia with a platelet-derived growth factor beta receptor fusion oncogene. Blood 100 (3): 1088-91, 2002. [PubMed: 12130532]
28. Beran M, Kantarjian H, O'Brien S, et al.: Topotecan, a topoisomerase I inhibitor, is active in the treatment of myelodysplastic syndrome and chronic myelomonocytic leukemia. Blood 88 (7): 2473-9, 1996. [PubMed: 8839838]
29. Beran M, Estey E, O'Brien S, et al.: Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia. J Clin Oncol 17 (9): 2819-30, 1999. [PubMed: 10561358]

Disease Overview

Note: Juvenile myelomonocytic leukemia (JMML) was classified as a myelodysplastic syndrome (MDS) under the French-American-British scheme.[1] The World Health Organization classification removed JMML from MDS, placing it in the new category Myelodysplastic/ Myeloproliferative Neoplasms (MDS/MPN).[1-3]

JMML (also known as juvenile chronic myelomonocytic leukemia) is a rare hematopoietic malignancy of childhood accounting for 2% of all childhood leukemias.[4] A number of clinical and laboratory features distinguish JMML from adult-type chronic myeloid leukemia, a disease noted only occasionally in children. In children presenting with clinical features suggestive of JMML, a definitive diagnosis requires the following:[5-7]

Major criteria (all three required)

• No Philadelphia chromosome or BCR/ABL fusion gene.
• Peripheral blood monocytosis is greater than 1 × 10⁹/L.
• Fewer than 20% blasts (including promonocytes) in the blood and bone marrow.

Minor criteria (two or more required)

• Fetal hemoglobin (Hb F) increased for age.
• Immature granulocytes in the peripheral blood.
• White blood cell count is greater than 1 × 10⁹/L.
• Clonal chromosomal abnormality (e.g., monosomy 7).
• Granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors in vitro.

The clinical features of JMML at the time of initial presentation may include the following:[5-9]

• Constitutional symptoms (e.g., malaise, pallor, and fever) or evidence of an infection.
• Symptoms of bronchitis or tonsillitis (in approximately 50% of cases).
• Bleeding diathesis.
• Maculopapular skin rashes (in 40%–50% of cases).
• Lymphadenopathy (in approximately 75% of cases).
• Hepatosplenomegaly (in most cases).

The clinical and laboratory features of JMML can closely mimic a variety of infectious diseases, including the following:

• Those caused by the Epstein-Barr virus.
• Cytomegalovirus.
• Human herpesvirus 6.
• Histoplasma.
• Mycobacteria.
• Toxoplasma.

Laboratory testing can distinguish whether JMML or infectious diseases have affected the clinical and hematologic findings.[5,6,10-12]

JMML typically presents in young children (median age approximately 1 year) and occurs more commonly in boys (male to female ratio approximately 2.5:1). The cause for JMML is not known.[6,7] Children with neurofibromatosis type 1 (NF1) are at increased risk for developing JMML, and up to 14% of cases of JMML occur in children with NF1.[9,13]

Morphologically, the peripheral blood picture in this disease shows leukocytosis, anemia, and frequently, thrombocytopenia.[6-9,14,15] The median reported white blood cell count varies from 25 × 10⁹/L to 35 × 10⁹/L. In 5% to 10% of children with JMML, however, it is greater than 100 × 10⁹/L. The leukocytosis is comprised of neutrophils, promyelocytes, myelocytes, and monocytes. Blasts, including promonocytes, usually account for less than 5% of the white blood cells and always for less than 20%. Nucleated red blood cells are seen frequently. Thrombocytopenia is typical and may be severe.[6-9,14,15] Bone marrow findings include the following:[6,7,9,14,15]

• Hypercellularity with granulocytic proliferation.
• Hypercellularity with erythroid precursors (in some patients).
• Monocytes comprising 5% to 10% of marrow cells (30% or more in some patients).
• Minimal dysplasia.
• Reduced numbers of megakaryocytes.

A distinctive characteristic of JMML leukemia cells is their spontaneous proliferation in vitro without the addition of exogenous stimuli, an ability that results from the leukemia cells being hypersensitive to GM-CSF.[16,17] No Philadelphia chromosome or BCR/ABL fusion gene exists. Although cytogenetic abnormalities, including monosomy 7, occur in 30% to 40% of patients, none is specific for JMML.[6,15,18] In JMML associated with NF1, loss of the normal NF1 allele is common, and loss of heterozygosity for NF1 has been observed in some patients with JMML who lack the NF1 phenotype.[18] This genetic alteration results in a loss of neurofibromin, a protein that is involved in the regulation of the ras family of oncogenes.[18] Point mutations in ras have been reported to occur in the leukemic cells of 20% of patients with JMML.[6,19]

The median survival times for JMML vary from approximately 10 months to more than 4 years, depending partly on the type of therapy chosen.[8,9,20] Prognosis is related to age at the time of diagnosis. The prognosis is better in children younger than 1 year at the time of diagnosis. Children older than 2 years at the time of diagnosis have a much worse prognosis.[6,8] A low platelet count and a high Hb F level have been associated with a worse prognosis.[9,14] Approximately 10% to 20% of cases may evolve to acute leukemia.[8,9]

Treatment Overview

No consistently effective therapy is available for JMML. Historically, more than 90% of patients have died despite the use of chemotherapy.[21] Patients appeared to follow three distinct clinical courses:

1. Rapidly progressive disease and early demise.
2. Transiently stable disease followed by progression and death.
3. Clinical improvement that lasted for as long as 9 years before progression or, rarely, long-term survival.

A recent retrospective review described 60 children with JMML treated with chemotherapy (nonintensive and intensive) and/or bone marrow transplantation (BMT) using sibling or unrelated human leukocyte antigen (HLA)-matched donor marrow or autologous marrow. The median survival was 4.4 years.[8][Level of evidence: 3iiiA]

BMT seems to offer the best chance of cure for JMML.[4,9,20-23] A summary of the outcome of 91 patients with JMML treated with BMT in 16 different reports is as follows: 38 patients (41%) were still alive at the time of reporting, including 30 of the 60 (50%) patients who received grafts from HLA-matched or 1-antigen mismatched familial donors, 2 of 12 (17%) with mismatched donors, and 6 of 19 (32%) with matched unrelated donors.[4]

In a retrospective study investigating the role of BMT for chronic myelomonocytic leukemia (CMML), 43 children with CMML and given BMT were evaluated. In 25 cases, the donor was a HLA-identical or a one-antigen-disparate relative, in four cases a mismatched family donor, and in 14 cases a matched unrelated donor. Conditioning regimens consisted of total-body radiation therapy and chemotherapy in 22 patients, whereas busulfan with other cytotoxic drugs were used in the remaining patients. Six of 43 patients (14%), five of whom received transplants from alternative donors, failed to engraft. Probabilities of transplant-related mortality for children transplanted from HLA-identical/one-antigen-disparate relatives or from matched unrelated donors/mismatched relatives were 9% and 46%, respectively. The probability of relapse for the entire group was 58%; the 5-year event-free survival (EFS) rate was 31%. The authors of this study concluded that children with CMML and an HLA-compatible relative should be transplanted as early as possible.[20][Level of evidence: 3iiiDii]

In a more recent retrospective review from Japan, the records of 27 children with JMML who underwent allogeneic hematopoietic stem cell transplantation (SCT) were examined to determine the role of different variables that potentially influence outcome. The source of grafts was HLA-identical siblings in 12 cases, HLA-matched unrelated individuals in 10 cases, and HLA-mismatched donors in five cases. Total-body radiation therapy was used in 18 cases. At 4 years after SCT, EFS and overall survival (OS) were 54.2% (+/- 11.2% standard error [SE]) and 57.9% (+/- 11.0% [SE]), respectively. Six patients died of relapse and three died of complications. Patients with abnormal karyotypes showed a significantly lower OS than those with normal karyotypes (P < .001). Patients younger than 1 year showed a significantly higher OS than those older than 1 year. Other variables studied were not associated with OS. A multivariate analysis of these factors indicated that the abnormal karyotype was the only significant risk factor for lower OS.[24][Level of evidence: 3iiiA] Five of 10 patients with JMML responded to the oral administration of 13-cis retinoic acid (i.e., two complete responses, three partial responses); median duration of response was 37 months. Treatment with retinoic acid was associated with a decrease in spontaneous colony formation and in GM-CSF hypersensitivity.[25]

Molecular-targeting therapies currently under evaluation include the use of farnesyltransferase inhibitors that prevent ras protein maturation, which may result in increased tumor cell apoptosis and inhibition of tumor cell growth.[17,26]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PubMed: 18480833]
2. Emanuel PD: Myelodysplasia and myeloproliferative disorders in childhood: an update. Br J Haematol 105 (4): 852-63, 1999. [PubMed: 10554793]
3. Hasle H, Niemeyer CM, Chessells JM, et al.: A pediatric approach to the WHO classification of myelodysplastic and myeloproliferative diseases. Leukemia 17 (2): 277-82, 2003. [PubMed: 12592323]
4. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997. [PubMed: 9226148]
5. Niemeyer CM, Fenu S, Hasle H, et al.: Response: differentiating myelomonocytic leukemia from infectious disease. Blood 91(1): 365-367.
6. Vardiman JW, Pierre R, Imbert M, et al.: Juvenile myelomonocytic leukaemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 55-7.
7. Emanuel PD: Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22 (7): 1335-42, 2008. [PubMed: 18548091]
8. Luna-Fineman S, Shannon KM, Atwater SK, et al.: Myelodysplastic and myeloproliferative disorders of childhood: a study of 167 patients. Blood 93 (2): 459-66, 1999. [PubMed: 9885207]
9. Niemeyer CM, Arico M, Basso G, et al.: Chronic myelomonocytic leukemia in childhood: a retrospective analysis of 110 cases. European Working Group on Myelodysplastic Syndromes in Childhood (EWOG-MDS) Blood 89 (10): 3534-43, 1997. [PubMed: 9160658]
10. Lorenzana A, Lyons H, Sawaf H, et al.: Human herpesvirus 6 infection mimicking juvenile myelomonocytic leukemia in an infant. J Pediatr Hematol Oncol 24 (2): 136-41, 2002. [PubMed: 11990701]
11. Luna-Fineman S, Shannon KM, Lange BJ: Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Blood 85 (8): 1985-99, 1995. [PubMed: 7718870]
12. Pinkel D: Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood 91 (1): 365-7, 1998. [PubMed: 9414312]
13. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994. [PMC free article: PMC2033537] [PubMed: 7947106]
14. Passmore SJ, Hann IM, Stiller CA, et al.: Pediatric myelodysplasia: a study of 68 children and a new prognostic scoring system. Blood 85 (7): 1742-50, 1995. [PubMed: 7703482]
15. Hess JL, Zutter MM, Castleberry RP, et al.: Juvenile chronic myelogenous leukemia. Am J Clin Pathol 105 (2): 238-48, 1996. [PubMed: 8607451]
16. Emanuel PD, Bates LJ, Castleberry RP, et al.: Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77 (5): 925-9, 1991. [PubMed: 1704804]
17. Emanuel PD, Snyder RC, Wiley T, et al.: Inhibition of juvenile myelomonocytic leukemia cell growth in vitro by farnesyltransferase inhibitors. Blood 95 (2): 639-45, 2000. [PubMed: 10627474]
18. Side LE, Emanuel PD, Taylor B, et al.: Mutations of the NF1 gene in children with juvenile myelomonocytic leukemia without clinical evidence of neurofibromatosis, type 1. Blood 92 (1): 267-72, 1998. [PubMed: 9639526]
19. Flotho C, Valcamonica S, Mach-Pascual S, et al.: RAS mutations and clonality analysis in children with juvenile myelomonocytic leukemia (JMML). Leukemia 13 (1): 32-7, 1999. [PubMed: 10049057]
20. Locatelli F, Niemeyer C, Angelucci E, et al.: Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood. J Clin Oncol 15 (2): 566-73, 1997. [PubMed: 9053478]
21. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall. [PubMed: 3052147]
22. Sanders JE, Buckner CD, Thomas ED, et al.: Allogeneic marrow transplantation for children with juvenile chronic myelogenous leukemia. Blood 71 (4): 1144-6, 1988. [PubMed: 3281722]
23. Smith FO, King R, Nelson G, et al.: Unrelated donor bone marrow transplantation for children with juvenile myelomonocytic leukaemia. Br J Haematol 116 (3): 716-24, 2002. [PubMed: 11849238]
24. Manabe A, Okamura J, Yumura-Yagi K, et al.: Allogeneic hematopoietic stem cell transplantation for 27 children with juvenile myelomonocytic leukemia diagnosed based on the criteria of the International JMML Working Group. Leukemia 16 (4): 645-9, 2002. [PubMed: 11960345]
25. Castleberry RP, Emanuel PD, Zuckerman KS, et al.: A pilot study of isotretinoin in the treatment of juvenile chronic myelogenous leukemia. N Engl J Med 331 (25): 1680-4, 1994. [PubMed: 7605422]
26. Rowinsky EK, Windle JJ, Von Hoff DD: Ras protein farnesyltransferase: A strategic target for anticancer therapeutic development. J Clin Oncol 17 (11): 3631-52, 1999. [PubMed: 10550163]

Disease Overview

Atypical chronic myelogenous leukemia (aCML) is a leukemic disorder that exhibits both myelodysplastic and myeloproliferative features at the time of diagnosis.

Atypical CML is characterized pathologically by the following:[1]

• Peripheral blood leukocytosis with increased numbers of mature and immature neutrophils.
• Prominent dysgranulopoiesis.
• No Philadelphia chromosome or BCR/ABL fusion gene.
• Neutrophil precursors (e.g., promyelocytes, myelocytes, and metamyelocytes) accounting for more than 10% of white blood cells.
• Minimal absolute basophilia with basophils accounting for less than 2% of white blood cells.
• Absolute monocytosis with monocytes typically account for less than 10% of white blood cells.
• Hypercellular bone marrow with granulocytic proliferation and granulocytic dysplasia.
• Fewer than 20% blasts in the blood or bone marrow.
• Thrombocytopenia.

Clinical features of aCML include the following:[1-4]

• Anemia. (Refer to the PDQ summary on Fatigue for more information on anemia.)
• Thrombocytopenia.
• Splenomegaly (in 75% of cases).

Although cytogenetic abnormalities are found in as many as 80% of the patients with aCML, none is specific.[1-3,5] No Philadelphia chromosome or BCR/ABL fusion gene exists.

The exact incidence of aCML is unknown. The median age at the time of diagnosis of this rare leukemic disorder has been reported to be in the seventh or eighth decade of life.[1-3]

Morphologically, aCML is characterized by myelodysplasia associated with bone marrow and peripheral blood patterns similar to chronic myelogenous leukemia, but cytogenetically it lacks a Philadelphia chromosome or BCR/ABL fusion gene.[1] The white blood cell count in the peripheral blood is variable. Median values range from 35 × 10⁹/L to 96 × 10⁹/L, and some patients may have white blood cell counts greater than 300 × 10⁹/L.[1-3,5] Blasts in the peripheral blood typically account for less than 5% of the white blood cells. Immature neutrophils usually total 10% to 20% or more.[1] The percentage of monocytes is rarely more than 10%. Minimal basophilia may be present.[1-3,5] Nuclear abnormalities, such as acquired Pelger-Huët anomaly, may be seen in the neutrophils. Moderate anemia (often showing changes indicative of dyserythropoiesis) and thrombocytopenia are common.[1-4] Bone marrow findings include the following: [1-3,5]

• Granulocytic hypercellularity.
• Blast count less than 20%.
• Dysgranulopoiesis
• Megakaryocytic dysplasia.
• Erythroid precursors accounting for more than 30% of marrow cells with dyserythropoiesis present (in some cases).

The median survival times for aCML are reported to be less than 20 months, and thrombocytopenia and marked anemia are poor prognostic factors.[1,2] Atypical CML evolves to acute leukemia in approximately 25% to 40% of patients.[1,3] In the remainder, fatal complications include resistant leukocytosis, anemia, thrombocytopenia, hepatosplenomegaly, cerebral bleeding associated with thrombocytopenia, and infection.[3,4]

Treatment Overview

The optimal treatment of aCML is uncertain because of the rare incidence of this chronic leukemic disorder. Treatment with hydroxyurea may lead to short-lived partial remissions of 2- to 4-months' duration.[4] Atypical CML, appears to respond poorly to treatment with interferon-alpha.[4]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PubMed: 18480833]
2. Hernández JM, del Cañizo MC, Cuneo A, et al.: Clinical, hematological and cytogenetic characteristics of atypical chronic myeloid leukemia. Ann Oncol 11 (4): 441-4, 2000. [PubMed: 10847463]
3. Costello R, Sainty D, Lafage-Pochitaloff M, et al.: Clinical and biological aspects of Philadelphia-negative/BCR-negative chronic myeloid leukemia. Leuk Lymphoma 25 (3-4): 225-32, 1997. [PubMed: 9168433]
4. Kurzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR rearrangement-negative chronic myelogenous leukemia revisited. J Clin Oncol 19 (11): 2915-26, 2001. [PubMed: 11387365]
5. Bennett JM, Catovsky D, Daniel MT, et al.: The chronic myeloid leukaemias: guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87 (4): 746-54, 1994. [PubMed: 7986717]

Disease Overview

Myelodysplastic/ Myeloproliferative Neoplasm, Unclassifiable (MDS/ MPN-UC) (also known as mixed myeloproliferative/myelodysplastic syndrome, unclassifiable and overlap syndrome, unclassifiable) shows features of both myeloproliferative disease and myelodysplastic disease but does not meet the criteria for any of the other MDS/MPN entities.[1]

Diagnostic criteria for MDS/MPN-UC can be either:[1]

1. The combination of four sets of criteria (a–d):

   1. Clinical, laboratory, and morphologic features of myelodysplastic syndrome (MDS) (e.g., refractory anemia, refractory anemia with ringed sideroblasts, refractory cytopenia with multilineage dysplasia, and refractory anemia with excess of blasts) with fewer than 20% blasts in the blood and bone marrow. (Refer to the PDQ summary on Fatigue for more information on anemia.)
   2. Prominent myeloproliferative features, e.g. platelet count greater than 600 × 10⁹/L associated with megakaryocytic proliferation, or white blood cell count greater than 13.0 × 10⁹/L with or without splenomegaly.
   3. No history of an underlying chronic myeloproliferative disorder (CMPD), MDS, or recent cytotoxic or growth factor therapy that could cause the myelodysplastic or myeloproliferative features.
   4. No Philadelphia chromosome or BCR/ABL fusion gene, del(5q), t(3;3)(q21;q26), or inv(3)(q21q26).
2. Mixed myeloproliferative and myelodysplastic features that cannot be assigned to any other category of MDS, CMPD, or MDS/MPN.

Clinical characteristics of MDS/MPN-UC include the following:

• Features of both MDS and CMPD.
• Hepatomegaly.
• Splenomegaly.

The incidence and etiology of MDS/MPN-UC are unknown.

Laboratory features typically include anemia and dimorphic erythrocytes on the peripheral blood smear.[1] Thrombocytosis (platelet count >600 × 10⁹/L) or leukocytosis (white blood cell count >13 × 10⁹/L) are present. Neutrophils may exhibit dysplastic features, and giant or hypogranular platelets may be present. Blasts make up less than 20% of the white blood cells and of the nucleated cells of the bone marrow. The bone marrow is hypercellular and may exhibit proliferation in any or all of the myeloid lineages. Dysplastic features are present in at least one cell line.[1]

No cytogenetic or molecular findings are available that are specific for MDS/MPN-UC. In one small series, six of nine patients (those with ringed sideroblasts associated with marked thrombocytosis [RARS-T]) showed a JAK2 V617F mutation causing constitutive activation of the JAK2 tyrosine kinase (a mutation also commonly observed in patients with polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis).[2] Because of its rare occurrence, the prognosis and predictive factors are unknown.[1]

Treatment Overview

Adult patients with MDS/MPN associated with platelet-derived growth factor receptor gene rearrangements are candidates for imatinib mesylate at standard dosages.[3] Because of its rare occurrence, the literature only minimally addresses other treatment options for MDS/MPN-UC. Supportive care involves treating cytopenias and infection as necessary.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

1. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008. [PubMed: 18480833]
2. Szpurka H, Tiu R, Murugesan G, et al.: Refractory anemia with ringed sideroblasts associated with marked thrombocytosis (RARS-T), another myeloproliferative condition characterized by JAK2 V617F mutation. Blood 108 (7): 2173-81, 2006. [PMC free article: PMC1895556] [PubMed: 16741247]
3. U.S. Food and Drug Administration: FDA approves imatinib mesylate (Gleevec) as a single agent for the treatment of multiple indications. Rockville, Md: Food and Drug Administration, Center for Drug Evaluation and Research, Office of Oncology Drug Products (OODP), 2006. Available online. Last accessed December 8, 2016.

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of myelodysplastic/ myeloproliferative neoplasms. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Myelodysplastic/ Myeloproliferative Neoplasms Treatment are:

• Aaron Gerds, MD
• Mikkael A. Sekeres, MD, MS (Cleveland Clinic Taussig Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as “NCI’s PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary].”

The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Myelodysplastic/ Myeloproliferative Neoplasms Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/myeloproliferative/hp/mds-mpd-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389321]

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