Purpose of This PDQ Summary
General Information
Chronic Myelomonocytic Leukemia

Disease Overview Treatment Overview Current Clinical Trials

Juvenile Myelomonocytic Leukemia

Disease Overview Treatment Overview Current Clinical Trials

Atypical Chronic Myelogenous Leukemia

Disease Overview Treatment Overview Current Clinical Trials

Myelodysplastic/Myeloproliferative Disease, Unclassifiable

Disease Overview Treatment Overview Current Clinical Trials

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Changes to This Summary (11/06/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of myelodysplastic/myeloproliferative diseases. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board ¹.

Information about the following is included in this summary:

• Epidemiology and pathology.
• Cellular classification.
• Staging.
• Treatment options for different types of disease.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the 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 ² in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version ³, written in less technical language, and in Spanish ⁴.

General Information

The myelodysplastic/myeloproliferative diseases (MDS/MPD) 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/MPD entities is designated as myelodysplastic/myeloproliferative disease, unclassifiable (MDS/MPD-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/MPD 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/MPD category would allow for more focused clinical and laboratory investigations of myeloid proliferation, abnormal proliferation, and dysplasia.[1,4]

The etiology of MDS/MPD is not known. The incidence of MDS/MPD 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.[1] Reliable data concerning the incidence of aCML, a recently defined entity, are not available. The incidence of MDS/MPD-UC is unknown.

The pathophysiology of MDS/MPD involves abnormalities in the regulation of myeloid pathways for cellular proliferation, maturation, and survival. Clinical symptoms are caused by complications resulting from cytopenia(s), dysplastic cells that function abnormally, leukemic infiltration of various organ systems, and general constitutional symptoms, such as fever and malaise.[5] (For more information on fever, refer to the Fever, Sweats, and Hot Flashes ⁵ summary.) Patients with MDS/MPD do not have a Philadelphia chromosome or BCR/ABL fusion gene. No specific genetic defects have been identified for any of these entities, though abnormalities in regulation of the ras pathway of signaling proteins appears to be a common finding in CMML, aCML, and JMML and may have some role in the abnormal myeloid proliferation associated with these diseases.[4] In general, treatment of these diseases is tailored to the manifestations, myeloproliferative or myelodysplastic, that predominate in the individual patient.

References

1. Vardiman JW, Harris NL, Brunning RD: The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 100 (7): 2292-302, 2002.  [PUBMED Abstract]
   
   
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 Abstract]
   
   
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 Abstract]
   
   
4. Vardiman JW: Myelodysplastic/myeloproliferative diseases: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 47-8. 
   
   
5. Bain BJ: The relationship between the myelodysplastic syndromes and the myeloproliferative disorders. Leuk Lymphoma 34 (5-6): 443-9, 1999.  [PUBMED Abstract]
   
   

Chronic Myelomonocytic Leukemia

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

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

CMML is characterized pathologically by the following:[3]

• Persistent monocytosis is greater than 1 × 10⁹/L in the peripheral blood.
• No Philadelphia chromosome or BCR/ABL fusion gene.
• Fewer than 20% blasts in the blood or bone marrow.
• 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:[3]

• Fever, fatigue, night sweats, and weight loss. (Refer to the Fever, Sweats, and Hot Flashes ⁵, the Fatigue ⁶, and the Nutrition in Cancer Care ⁷ summaries 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.[3] 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.[4] 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.[4]

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.[3] Monocytes, though typically mature with an unremarkable morphology, can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin.[5] 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.[6] Mild normocytic anemia is common. (For more information on anemia, refer to the Fatigue ⁶ summary.) Moderate thrombocytopenia is often present. Bone marrow findings include the following:[3,7,8]

• 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.[3] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML.[9] 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.[4]

Although clonal cytogenetic abnormalities are found in 20% to 40% of patients with CMML, none is specific.[3,10,11] Point mutations of ras genes may occur in as many as 40% of patients with CMML.[3,11] The median survival time for CMML is 12 to 24 months.[11-13] Prognostic factors associated with shorter survival include the following:[11,13]

• 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.[11,13]

Various chemotherapy regimens for CMML have been used with only modest success.[12] 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.[14][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.[15][Level of evidence: 3iiiDiv]

Treatment with hydroxyurea is an option.[12] 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.[16][Level of evidence: 1iiA]

The nucleoside 5-azacitidine is an inhibitor of DNA methyltransferase that has been approved for the treatment of MDS, largely based on a Cancer and Leukemia Group B randomized trial.[17] This trial, in which patients were randomized to supportive care versus 5-azacitidine (75 mg/m²/day subcutaneously for 7 days every 28 days), included 10 patients with CMML.[17][Level of evidence: 1iiDii]

Bone marrow 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 bone marrow transplants 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.[18][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.[19][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.[20]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with chronic myelomonocytic leukemia ⁸. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁹.

References

1. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51 (2): 189-99, 1982.  [PUBMED Abstract]
   
   
2. Vardiman JW: Myelodysplastic/myeloproliferative diseases: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 47-8. 
   
   
3. Onida F, Beran M: Chronic myelomonocytic leukemia: myeloproliferative variant. Curr Hematol Rep 3 (3): 218-26, 2004.  [PUBMED Abstract]
   
   
4. Aul C, Bowen DT, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 83 (1): 71-86, 1998.  [PUBMED Abstract]
   
   
5. Kouides PA, Bennett JM: Morphology and classification of the myelodysplastic syndromes and their pathologic variants. Semin Hematol 33 (2): 95-110, 1996.  [PUBMED Abstract]
   
   
6. 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 Abstract]
   
   
7. Michaux JL, Martiat P: Chronic myelomonocytic leukaemia (CMML)--a myelodysplastic or myeloproliferative syndrome? Leuk Lymphoma 9 (1-2): 35-41, 1993.  [PUBMED Abstract]
   
   
8. 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 Abstract]
   
   
9. 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 Abstract]
   
   
10. Nösslinger T, Reisner R, Grüner H, et al.: Dysplastic versus proliferative CMML--a retrospective analysis of 91 patients from a single institution. Leuk Res 25 (9): 741-7, 2001.  [PUBMED Abstract]
    
    
11. 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 Abstract]
    
    
12. Bennett JM: Chronic myelomonocytic leukemia. Curr Treat Options Oncol 3 (3): 221-3, 2002.  [PUBMED Abstract]
    
    
13. Germing U, Kündgen A, Gattermann N: Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 45 (7): 1311-8, 2004.  [PUBMED Abstract]
    
    
14. 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 Abstract]
    
    
15. 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 Abstract]
    
    
16. 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 Abstract]
    
    
17. 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 Abstract]
    
    
18. 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 Abstract]
    
    
19. 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 Abstract]
    
    
20. 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 Abstract]
    
    

Juvenile Myelomonocytic Leukemia

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ² for more information.)

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 Diseases (MDS/MPD).[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:[5,6]

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:[5-8]

• 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 those caused by the Epstein-Barr virus, cytomegalovirus, human herpesvirus 6, histoplasma, mycobacteria, and toxoplasma. Laboratory testing can distinguish whether JMML or infectious diseases have affected the clinical and hematologic findings.[5,6,9-11]

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] 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.[8,12]

Morphologically, the peripheral blood picture in this disease shows leukocytosis, anemia, and frequently, thrombocytopenia.[6-8,13,14] 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.[6-8,13,14] Bone marrow findings include the following:[6,8,13,14]

• 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.[15,16] 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.[6,14,17] 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.[17] This genetic alteration results in a loss of neurofibromin, a protein that is involved in the regulation of the ras family of oncogenes.[17] Point mutations in ras have been reported to occur in the leukemic cells of 20% of patients with JMML.[6,18]

The median survival times for JMML vary from approximately 10 months to more than 4 years, depending partly on the type of therapy chosen.[7,8,19] 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.[6,7] A low platelet count and a high Hb F level have been associated with a worse prognosis.[8,13] Approximately 10% to 20% of cases may evolve to acute leukemia.[7,8]

No consistently effective therapy is available for JMML. Historically, more than 90% of patients have died despite the use of chemotherapy.[20] 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.[7][Level of evidence: 3iiiA]

BMT seems to offer the best chance of cure for JMML.[4,8,19-22] 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.[19][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.[23][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.[24]

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.[16,25]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with juvenile myelomonocytic leukemia ¹⁰. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁹.

References

1. Vardiman JW: Myelodysplastic/myeloproliferative diseases: introduction. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 47-8. 
   
   
2. Emanuel PD: Myelodysplasia and myeloproliferative disorders in childhood: an update. Br J Haematol 105 (4): 852-63, 1999.  [PUBMED Abstract]
   
   
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 Abstract]
   
   
4. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.  [PUBMED Abstract]
   
   
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. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 55-7. 
   
   
7. 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 Abstract]
   
   
8. 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 Abstract]
   
   
9. 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 Abstract]
   
   
10. Luna-Fineman S, Shannon KM, Lange BJ: Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Blood 85 (8): 1985-99, 1995.  [PUBMED Abstract]
    
    
11. Pinkel D: Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood 91 (1): 365-7, 1998.  [PUBMED Abstract]
    
    
12. Stiller CA, Chessells JM, Fitchett M: Neurofibromatosis and childhood leukaemia/lymphoma: a population-based UKCCSG study. Br J Cancer 70 (5): 969-72, 1994.  [PUBMED Abstract]
    
    
13. 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 Abstract]
    
    
14. Hess JL, Zutter MM, Castleberry RP, et al.: Juvenile chronic myelogenous leukemia. Am J Clin Pathol 105 (2): 238-48, 1996.  [PUBMED Abstract]
    
    
15. 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 Abstract]
    
    
16. 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 Abstract]
    
    
17. 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 Abstract]
    
    
18. 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 Abstract]
    
    
19. 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 Abstract]
    
    
20. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall.  [PUBMED Abstract]
    
    
21. 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 Abstract]
    
    
22. 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 Abstract]
    
    
23. 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 Abstract]
    
    
24. 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 Abstract]
    
    
25. 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 Abstract]
    
    

Atypical Chronic Myelogenous Leukemia

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. (For more information on anemia, refer to the Fatigue ⁶ summary.)
• 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]

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]

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with atypical chronic myeloid leukemia ¹¹. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁹.

References

1. Vardiman JW, Imbert M, Pierre R, et al.: Atypical chronic myeloid leukemia. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 53-4. 
   
   
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 Abstract]
   
   
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 Abstract]
   
   
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 Abstract]
   
   
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 Abstract]
   
   

Myelodysplastic/Myeloproliferative Disease, Unclassifiable

Disease Overview

Myelodysplastic/Myeloproliferative Disease, Unclassifiable (MDS/MPD-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/MPD entities.[1]

Diagnostic criteria for MDS/MPD-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. (For more information on anemia, refer to the Fatigue ⁶ summary.)
   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/MPD.

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

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

The incidence and etiology of MDS/MPD-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/MPD-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]

Adult patients with MDS/MPD 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/MPD-UC. Supportive care involves treating cytopenias and infection as necessary.

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with myelodysplastic/myeloproliferative disease, unclassifiable ¹². The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site ⁹.

References

1. Bain B, Vardiman JW, Imbert M, et al.: Myelodysplastic/myeloproliferative disease, unclassifiable. In: Jaffe ES, Harris NL, Stein H, et al., eds.: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Lyon, France: IARC Press, 2001. World Health Organization Classification of Tumours, 3, pp 58-9. 
   
   
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.  [PUBMED Abstract]
   
   
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 ¹³. Last accessed July 21, 2008. 
   
   

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Editorial changes were made to this summary.

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Glossary Terms

Randomized, controlled, nonblinded clinical trial with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Randomized, controlled, nonblinded clinical trial with disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total mortality as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with total disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.

Nonconsecutive case series with tumor response rate as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.