Myeloproliferative Disorder

  • Dana-Farber/Brigham and Women's Cancer Care

    Myeloproliferative disorder refers to a group of slow-growing blood cancers in which large numbers of abnormal red blood cells, white blood cells, or platelets grow in the bone marrow and blood. Learn about myeloproliferative disorders and find information on how we support and care for people with myeloproliferative disorders before, during, and after treatment.

Treatment 

The Hematologic Oncology Center provides specialized care for all types of cancers of the blood, including leukemia, lymphoma, multiple myeloma and Waldenström’s macroglobulinemia.

The center also includes the hematopoietic stem cell transplantation program, which is one of the largest and most experienced in the world.

To make sure your care is as seamless as possible, a dedicated team of clinicians, who are highly specialized experts in your type of blood cancer, will care for you throughout the treatment process, from diagnosis though long-term follow-up.

Your care team will include oncologists, surgeons, hematologists, physician assistants, nurses, and clinical social workers who are committed to delivering safe, high-quality patient care.  

We develop personalized, comprehensive treatment plans for all our patients, offering the latest therapies and supportive resources and taking your individual needs into account.

In addition to conventional treatment approaches, you may have the opportunity to participate in clinical trials that offer access to new, innovative treatments for your type of cancer.

A variety of services and programs also support your care, including nutrition services, emotional support and counseling, pain management, donor services for stem cell transplantation, and support for cancer survivors.

Learn more about treatment and care in the Hematologic Oncology Center 

Contact us 

New patients: See Center page for phone numbers by treatment program

All other inquiries: 617-632-6140 

Fax: 617-632-3730 

Information for: Patients | Healthcare Professionals

General Information About Myelodysplastic/Myeloproliferative Neoplasms

Myelodysplastic/myeloproliferative neoplasms are a group of diseases in which the bone marrow makes too many white blood cells.

Myelodysplastic/myeloproliferativeneoplasms are diseases of the blood and bone marrow. Normally, the bone marrow makes blood stem cells (immature cells) that become mature blood cells over time. A blood stem cell may become a myeloid stem cell or a lymphoid stem cell. A lymphoid stem cell becomes a white blood cell. A myeloid stem cell becomes one of three types of mature blood cells:

  • Red blood cells that carry oxygen and other substances to all tissues of the body.
  • White blood cells that fight infection and disease.
  • Platelets that form blood clots to stop bleeding.
Blood cell development; drawing shows the steps a blood stem cell goes through to become a red blood cell, platelet, or white blood cell.  Drawing shows a myeloid stem cell becoming a red blood cell, platelet, or myeloblast, which then becomes a white blood cell. Drawing also shows a lymphoid stem cell becoming a lymphoblast and then one of several different types of white blood cells. 
Blood cell development. A blood stem cell goes through several steps to become a red blood cell, platelet, or white blood cell.

Myelodysplastic/myeloproliferative neoplasms have features of both myelodysplastic syndromes and myeloproliferative disorders.

In myelodysplastic diseases, the blood stem cells do not mature into healthy red blood cells, white blood cells, or platelets. The immature blood cells, called blasts, do not work the way they should and die in the bone marrow or soon after they enter the blood. As a result, there are fewer healthy red blood cells, white blood cells, and platelets.

In myeloproliferative diseases, a greater than normal number of blood stem cells become one or more types of blood cells and the total number of blood cells slowly increases.

This summary is about neoplasms that have features of both myelodysplastic and myeloproliferative diseases. See the following PDQ summaries for more information about related diseases:

  • Myelodysplastic Syndromes Treatment
  • Chronic Myeloproliferative Disorders Treatment
  • Chronic Myelogenous Leukemia Treatment

There are different types of myelodysplastic/myeloproliferative neoplasms.

The 3 main types of myelodysplastic/myeloproliferative neoplasms include the following:

  • Chronic myelomonocytic leukemia (CMML).
  • Juvenile myelomonocytic leukemia (JMML).
  • Atypical chronic myelogenous leukemia (CML).

When a myelodysplastic/myeloproliferative neoplasm does not match any of these types, it is called myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-UC).

Myelodysplastic/myeloproliferative neoplasms may progress to acute leukemia.

Tests that examine the blood and bone marrow are used to detect (find) and diagnose myelodysplastic/myeloproliferative neoplasms.

The following tests and procedures may be used:

  • Physical exam and history: An exam of the body to check general signs of health, including checking for signs of disease such as an enlarged spleen and liver. A history of the patient’s health habits and past illnesses and treatments will also be taken.
  • Complete blood count (CBC) with differential: A procedure in which a sample of blood is drawn and checked for the following:
    • The number of red blood cells and platelets.
    • The number and type of white blood cells.
    • The amount of hemoglobin (the protein that carries oxygen) in the red blood cells.
    • The portion of the sample made up of red blood cells.
    Complete blood count (CBC); left panel shows blood being drawn from a vein on the inside of the elbow using a tube attached to a syringe; right panel shows a laboratory test tube with blood cells separated into layers: plasma, white blood cells, platelets, and red blood cells.  
    Complete blood count (CBC). Blood is collected by inserting a needle into a vein and allowing the blood to flow into a tube. The blood sample is sent to the laboratory and the red blood cells, white blood cells, and platelets are counted. The CBC is used to test for, diagnose, and monitor many different conditions.
  • Peripheral blood smear: A procedure in which a sample of blood is checked for blast cells, the number and kinds of white blood cells, the number of platelets, and changes in the shape of blood cells.
  • Blood chemistry studies: A procedure in which a blood sample is checked to measure the amounts of certain substances released into the blood by organs and tissues in the body. An unusual (higher or lower than normal) amount of a substance can be a sign of disease in the organ or tissue that produces it.
  • Bone marrow aspiration and biopsy: The removal of a small piece of bone and bone marrow by inserting a needle into the hipbone or breastbone. A pathologist views both the bone and bone marrow samples under a microscope to look for abnormal cells.
    Bone marrow aspiration and biopsy; drawing shows a patient lying face down on a table and a Jamshidi needle (a long, hollow needle) being inserted into the hip bone. Inset shows the Jamshidi needle being inserted through the skin into the bone marrow of the hip bone. 
    Bone marrow aspiration and biopsy. After a small area of skin is numbed, a Jamshidi needle (a long, hollow needle) is inserted into the patient’s hip bone. Samples of blood, bone, and bone marrow are removed for examination under a microscope.

    The following tests may be done on the sample of tissue that is removed:

    • Cytogenetic analysis: A test in which cells in a sample of blood or bone marrow are viewed under a microscope to look for certain changes in the chromosomes. The cancer cells in myelodysplastic/myeloproliferative neoplasms do not contain the Philadelphia chromosome that is present in chronic myelogenous leukemia.
    • Immunocytochemistry: A test in which a sample of bone marrow is treated with special antibodies and viewed under a microscope to check for certain color changes in the sample of bone marrow. This type of test is used to tell the difference between myelodysplastic/myeloproliferative neoplasms, leukemia, and other conditions.
     

Chronic Myelomonocytic Leukemia

Chronic myelomonocytic leukemia is a disease in which too many myelocytes and monocytes (immature white blood cells) are made in the bone marrow.

In chronic myelomonocytic leukemia (CMML), the body tells too many bloodstem cells to become two types of white blood cells called myelocytes and monocytes. Some of these blood stem cells never become mature white blood cells. These immature white blood cells are called blasts. Over time, the myelocytes, monocytes, and blasts crowd out the red blood cells and platelets in the bone marrow. When this happens, infection, anemia, or easy bleeding may occur.

Older age and being male increase the risk of chronic myelomonocytic leukemia.

Anything that increases your chance of getting a disease is called a risk factor. Possible risk factors for CMML include the following:

  • Older age.
  • Being male.
  • Being exposed to certain substances at work or in the environment.
  • Being exposed to radiation.
  • Past treatment with certain anticancer drugs.

Signs and symptoms of chronic myelomonocytic leukemia include fever, weight loss, and feeling very tired.

These and other signs and symptoms may be caused by CMML or by other conditions. Check with your doctor if you have any of the following:

  • Fever for no known reason.
  • Infection.
  • Feeling very tired.
  • Weight loss for no known reason.
  • Easy bruising or bleeding.
  • Pain or a feeling of fullness below the ribs.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options for CMML depend on the following:

  • The number of white blood cells or platelets in the blood or bone marrow.
  • Whether the patient is anemic.
  • The amount of blasts in the blood or bone marrow.
  • The amount of hemoglobin in red blood cells.
  • Whether there are certain changes in the chromosomes.

Juvenile Myelomonocytic Leukemia

Juvenile myelomonocytic leukemia is a childhood disease in which too many myelocytes and monocytes (immature white blood cells) are made in the bone marrow.

Juvenile myelomonocytic leukemia (JMML) is a rare childhood cancer that occurs more often in children younger than 2 years. Children who have neurofibromatosis type 1 and males have an increased risk of juvenile myelomonocytic leukemia.

In JMML, the body tells too many bloodstem cells to become two types of white blood cells called myelocytes and monocytes. Some of these blood stem cells never become mature white blood cells. These immature white blood cells are called blasts. Over time, the myelocytes, monocytes, and blasts crowd out the red blood cells and platelets in the bone marrow. When this happens, infection, anemia, or easy bleeding may occur.

Signs and symptoms of juvenile myelomonocytic leukemia include fever, weight loss, and feeling very tired.

These and other signs and symptoms may be caused by JMML or by other conditions. Check with your doctor if you have any of the following:

  • Fever for no known reason.
  • Having infections, such as bronchitis or tonsillitis.
  • Feeling very tired.
  • Easy bruising or bleeding.
  • Skin rash.
  • Painless swelling of the lymph nodes in the neck, underarm, stomach, or groin.
  • Pain or a feeling of fullness below the ribs.

Certain factors affect prognosis (chance of recovery) and treatment options.

The prognosis (chance of recovery) and treatment options for JMML depend on the following:

  • The age of the child at diagnosis.
  • The number of platelets in the blood.
  • The amount of a certain type of hemoglobin in red blood cells.

Atypical Chronic Myelogenous Leukemia

Atypical chronic myelogenous leukemia is a disease in which too many granulocytes (immature white blood cells) are made in the bone marrow.

In atypical chronic myelogenous leukemia (CML), the body tells too many bloodstem cells to become a type of white blood cell called granulocytes. Some of these blood stem cells never become mature white blood cells. These immature white blood cells are called blasts. Over time, the granulocytes and blasts crowd out the red blood cells and platelets in the bone marrow.

The leukemiacells in atypical CML and CML look alike under a microscope. However, in atypical CML a certain chromosome change, called the "Philadelphia chromosome" is not there.

Signs and symptoms of atypical chronic myelogenous leukemia include easy bruising or bleeding and feeling tired and weak.

These and other signs and symptoms may be caused by atypical CML or by other conditions. Check with your doctor if you have any of the following:

  • Shortness of breath.
  • Pale skin.
  • Feeling very tired and weak.
  • Easy bruising or bleeding.
  • Petechiae (flat, pinpoint spots under the skin caused by bleeding).
  • Pain or a feeling of fullness below the ribs on the left side.

Certain factors affect prognosis (chance of recovery).

The prognosis (chance of recovery) for atypical CML depends on the number of red blood cells and platelets in the blood.

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Myelodysplastic/myeloproliferative neoplasm, unclassifiable, is a disease that has features of both myelodysplastic and myeloproliferative diseases but is not chronic myelomonocytic leukemia, juvenile myelomonocytic leukemia, or atypical chronic myelogenous leukemia.

In myelodysplastic/myeloproliferativeneoplasm, unclassifiable (MDS/MPD-UC), the body tells too many bloodstem cells to become red blood cells, white blood cells, or platelets. Some of these blood stem cells never become mature blood cells. These immature blood cells are called blasts. Over time, the abnormal blood cells and blasts in the bone marrow crowd out the healthy red blood cells, white blood cells, and platelets.

MDS/MPN-UC is a very rare disease. Because it is so rare, the factors that affect risk and prognosis are not known.

Signs and symptoms of myelodysplastic/myeloproliferative neoplasm, unclassifiable, include fever, weight loss, and feeling very tired.

These and other signs and symptoms may be caused by MDS/MPN-UC or by other conditions. Check with your doctor if you have any of the following:

  • Fever or frequent infections.
  • Shortness of breath.
  • Feeling very tired and weak.
  • Pale skin.
  • Easy bruising or bleeding.
  • Petechiae (flat, pinpoint spots under the skin caused by bleeding).
  • Pain or a feeling of fullness below the ribs.

Stages of Myelodysplastic/Myeloproliferative Neoplasms

There is no standard staging system for myelodysplastic/myeloproliferative neoplasms.

Staging is the process used to find out how far the cancer has spread. There is no standard staging system for myelodysplastic/myeloproliferativeneoplasms. Treatment is based on the type of myelodysplastic/myeloproliferative neoplasm the patient has. It is important to know the type in order to plan treatment.

Treatment Option Overview

There are different types of treatment for patients with myelodysplastic/myeloproliferative neoplasms.

Different types of treatments are available for patients with myelodysplastic/myeloproliferativeneoplasms. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment. Patients may want to think about taking part in a clinical trial. Some clinical trials are open only to patients who have not started treatment.

Five types of standard treatment are used:

Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). The way the chemotherapy is given depends on the type and stage of the cancer being treated. Combination chemotherapy is treatment using more than one anticancer drug.

See Drugs Approved for Myeloproliferative Disorders for more information.

Other drug therapy

13-cis retinoic acid is a vitamin-like drug that slows the cancer's ability to make more cancer cells and changes the way these cells look and act.

Stem cell transplant

Stem cell transplant is a method of replacing blood-forming cells that are destroyed by chemotherapy. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

Stem Cell Transplant

Drawing of stem cells being removed from a patient or donor. Blood is collected from a vein in the arm and flows through a machine that removes the stem cells; the remaining blood is returned to a vein in the other arm.   Drawing of a health care provider giving a patient treatment to kill blood-forming cells. Chemotherapy is given to the patient through a catheter in the chest.   Drawing of stem cells being given to the patient through a catheter in the chest.  

Stem cell transplant (Step 1). Blood is taken from a vein in the arm of the donor. The patient or another person may be the donor. The blood flows through a machine that removes the stem cells. Then the blood is returned to the donor through a vein in the other arm.

Stem cell transplant (Step 2). The patient receives chemotherapy to kill blood-forming cells. The patient may receive radiation therapy (not shown).

Stem cell transplant (Step 3). The patient receives stem cells through a catheter placed into a blood vessel in the chest.

Supportive care

Supportive care is given to lessen the problems caused by the disease or its treatment. Supportive care may include transfusiontherapy or drug therapy, such as antibiotics to fight infection.

Targeted therapy

Targeted therapy is a cancer treatment that uses drugs or other substances to attack cancer cells without harming normal cells. Targeted therapy drugs called tyrosine kinase inhibitors (TKIs) are used to treat myelodysplastic/myeloproliferative neoplasm, unclassifiable. TKIs block the enzyme, tyrosine kinase, that causes stem cells to become more blood cells (blasts) than the body needs. Imatinib mesylate (Gleevec) is a TKI that may be used. Other targeted therapy drugs are being studied in the treatment of JMML.

See Drugs Approved for Myeloproliferative Disorders for more information.

New types of treatment are being tested in clinical trials.

Information about clinical trials is available from the NCI Web site.

Patients may want to think about taking part in a clinical trial.

For some patients, taking part in a clinical trial may be the best treatment choice. Clinical trials are part of the cancer research process. Clinical trials are done to find out if new cancer treatments are safe and effective or better than the standard treatment.

Many of today's standard treatments for cancer are based on earlier clinical trials. Patients who take part in a clinical trial may receive the standard treatment or be among the first to receive a new treatment.

Patients who take part in clinical trials also help improve the way cancer will be treated in the future. Even when clinical trials do not lead to effective new treatments, they often answer important questions and help move research forward.

Patients can enter clinical trials before, during, or after starting their cancer treatment.

Some clinical trials only include patients who have not yet received treatment. Other trials test treatments for patients whose cancer has not gotten better. There are also clinical trials that test new ways to stop cancer from recurring (coming back) or reduce the side effects of cancer treatment.

Clinical trials are taking place in many parts of the country. See the Treatment Options section that follows for links to current treatment clinical trials. These have been retrieved from NCI's listing of clinical trials.

Follow-up tests may be needed.

Some of the tests that were done to diagnose the cancer or to find out the stage of the cancer may be repeated. Some tests will be repeated in order to see how well the treatment is working. Decisions about whether to continue, change, or stop treatment may be based on the results of these tests. This is sometimes called re-staging.

Some of the tests will continue to be done from time to time after treatment has ended. The results of these tests can show if your condition has changed or if the cancer has recurred (come back). These tests are sometimes called follow-up tests or check-ups.

Treatment Options for Myelodysplastic/Myeloproliferative Neoplasms

Chronic Myelomonocytic Leukemia

Treatment of chronic myelomonocytic leukemia (CMML) may include the following:

  • Chemotherapy with one or more agents.
  • Stem cell transplant.
  • A clinical trial of a new treatment.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic myelomonocytic leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Juvenile Myelomonocytic Leukemia

Treatment of juvenile myelomonocytic leukemia (JMML) may include the following:

  • Combination chemotherapy.
  • Stem cell transplant.
  • 13-cis-retinoic acidtherapy.
  • A clinical trial of a new treatment, such as targeted therapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with juvenile myelomonocytic leukemia. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Atypical Chronic Myelogenous Leukemia

Treatment of atypical chronic myelogenous leukemia (CML) may include chemotherapy.

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with atypical chronic myeloid leukemia, BCR-ABL1 negative. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

Myelodysplastic/Myeloproliferative Neoplasm, Unclassifiable

Because myelodysplastic/myeloproliferativeneoplasm, unclassifiable (MDS/MPN-UC) is a rare disease, little is known about its treatment. Treatment may include the following:

  • Supportive care treatments to manage problems caused by the disease such as infection, bleeding, and anemia.
  • Targeted therapy (imatinib mesylate).

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with myelodysplastic/myeloproliferative neoplasm, unclassifiable. For more specific results, refine the search by using other search features, such as the location of the trial, the type of treatment, or the name of the drug. Talk with your doctor about clinical trials that may be right for you. General information about clinical trials is available from the NCI Web site.

To Learn More About Myelodysplastic/Myeloproliferative Neoplasms

For more information from the National Cancer Institute about myelodysplastic/myeloproliferativeneoplasms, see the following:

For general cancer information and other resources from the National Cancer Institute, see the following:


This information is provided by the National Cancer Institute.

This information was last updated on December 12, 2013.


General Information About Myelodysplastic/ Myeloproliferative Neoplasms

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][4]

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.[1] 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:[5]

  • Cytopenia(s).
  • Dysplastic cells that function abnormally.
  • Leukemic infiltration of various organ systems.
  • General constitutional symptoms, such as fever and malaise. (Refer to the PDQ summary on Sweats and Hot Flashes for more information on fever.)

Prognosis and Survival

Patients with MDS/MPN 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.

  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.

  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.

  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.

Chronic Myelomonocytic Leukemia

Disease Overview

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 Neoplasms (MDS/MPN).[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][4]

  • 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][4]

  • Fever, fatigue, night sweats, and weight loss. (Refer to the PDQ summaries on Sweats and Hot Flashes, Fatigue, 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.[3][4] 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.[5] 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.[5]

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][4] Monocytes, though typically mature with an unremarkable morphology, can exhibit abnormal granulation, unusual nuclear lobation, or finely dispersed nuclear chromatin.[6] 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.[7] 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:[3][4][8][9]

  • 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][4] Autoimmune phenomena, including pyoderma gangrenosum, vasculitis, and idiopathic thrombocytopenia have been observed in CMML.[10] 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.[5]

Although clonal cytogenetic abnormalities are found in 20% to 40% of patients with CMML, none is specific.[3][11][12] Point mutations of ras genes may occur in as many as 40% of patients with CMML.[3][12] The median survival time for CMML is 12 to 24 months.[12][13][14] Prognostic factors associated with shorter survival include the following:[12][14]

  • 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.[12][14]

Treatment Overview for Myelodysplastic/ Myeloproliferative Neoplasms

Various chemotherapy regimens for CMML have been used with only modest success.[13] 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.[15][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.[16][Level of evidence: 3iiiDiv]

Treatment with hydroxyurea is an option.[13] 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.[17][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.[18] 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.[18][Level of evidence: 1iiDii]

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.[19][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.[20][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.[21]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with chronic myelomonocytic leukemia. 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.

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.

  2. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008.

  3. Onida F, Beran M: Chronic myelomonocytic leukemia: myeloproliferative variant. Curr Hematol Rep 3 (3): 218-26, 2004.

  4. Emanuel PD: Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22 (7): 1335-42, 2008.

  5. Aul C, Bowen DT, Yoshida Y: Pathogenesis, etiology and epidemiology of myelodysplastic syndromes. Haematologica 83 (1): 71-86, 1998.

  6. Kouides PA, Bennett JM: Morphology and classification of the myelodysplastic syndromes and their pathologic variants. Semin Hematol 33 (2): 95-110, 1996.

  7. 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.

  8. Michaux JL, Martiat P: Chronic myelomonocytic leukaemia (CMML)--a myelodysplastic or myeloproliferative syndrome? Leuk Lymphoma 9 (1-2): 35-41, 1993.

  9. 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.

  10. Saif MW, Hopkins JL, Gore SD: Autoimmune phenomena in patients with myelodysplastic syndromes and chronic myelomonocytic leukemia. Leuk Lymphoma 43 (11): 2083-92, 2002.

  11. 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.

  12. 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.

  13. Bennett JM: Chronic myelomonocytic leukemia. Curr Treat Options Oncol 3 (3): 221-3, 2002.

  14. Germing U, Kündgen A, Gattermann N: Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 45 (7): 1311-8, 2004.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  21. 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.

Juvenile Myelomonocytic Leukemia

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][2][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][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][6][7][8][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][11][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][7][8][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][7][8][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][21][22][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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with juvenile myelomonocytic leukemia. 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.

References:

  1. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008.

  2. Emanuel PD: Myelodysplasia and myeloproliferative disorders in childhood: an update. Br J Haematol 105 (4): 852-63, 1999.

  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.

  4. Aricò M, Biondi A, Pui CH: Juvenile myelomonocytic leukemia. Blood 90 (2): 479-88, 1997.

  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. Emanuel PD: Juvenile myelomonocytic leukemia and chronic myelomonocytic leukemia. Leukemia 22 (7): 1335-42, 2008.

  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.

  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.

  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.

  11. Luna-Fineman S, Shannon KM, Lange BJ: Childhood monosomy 7: epidemiology, biology, and mechanistic implications. Blood 85 (8): 1985-99, 1995.

  12. Pinkel D: Differentiating juvenile myelomonocytic leukemia from infectious disease. Blood 91 (1): 365-7, 1998.

  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.

  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.

  15. Hess JL, Zutter MM, Castleberry RP, et al.: Juvenile chronic myelogenous leukemia. Am J Clin Pathol 105 (2): 238-48, 1996.

  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.

  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.

  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.

  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.

  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.

  21. Freedman MH, Estrov Z, Chan HS: Juvenile chronic myelogenous leukemia. Am J Pediatr Hematol Oncol 10 (3): 261-7, 1988 Fall.

  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.

  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.

  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.

  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.

  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.

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][2][3][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][2][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][2][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][2][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][2][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][2][3][4] Bone marrow findings include the following: [1][2][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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with atypical chronic myeloid leukemia, BCR-ABL1 negative. 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.

References:

  1. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008.

  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.

  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.

  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.

  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.

Myelodysplastic/ Myeloproliferative Neoplasm, Unclassifiable

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

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with myelodysplastic/myeloproliferative neoplasm, unclassifiable. 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.

References:

  1. Orazi A, Germing U: The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia 22 (7): 1308-19, 2008.

  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.

  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 February 07, 2012.


This information is provided by the National Cancer Institute.

This information was last updated on March 7, 2014.

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