Chronic Myelogenous Leukemia

Aka: Chronic Myelogenous Leukemia, Chronic Myeloid Leukemia, CML, Philadelphia Chromosome, BCR-ABL1 Fusion Gene

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II. Epidemiology

  1. Common in Atomic bomb survivors
  2. Peak Incidence at ages 30 to 50 years old

III. Pathophysiology

  1. Chronic phase (Mild, indolent course)
    1. Excessive Granulocyte (Neutrophils) proliferation
  2. Blastic phase (Malignant, leukemic course)
    1. Increased blasts and Promyelocytes

IV. Symptoms

  1. Asymptomatic in 20% of patients
  2. Weakness
  3. Hypermetabolism
    1. Weight loss
    2. Fever
  4. Arthralgias
  5. Bone pain
  6. Excessive bleeding (spontaneous or with surgery)

V. Signs

  1. Splenomegaly (90%)
  2. Hepatomegaly
  3. Lymphadenopathy

VI. Labs

  1. Philadelphia Chromosome (BCR-ABL1 Fusion Gene)
    1. Present in 90 to 95% of CML cases on peripheral blood or Bone Marrow testing
      1. Also present in ALL (2-4% of children, 20-40% of adults)
    2. Reciprocal Chromosome translocation
      1. Long arm of Chromosome 22 (c-sis oncogene)
      2. Long arm of Chromosome 9 (c-abl oncogene)
    3. Translocation of C-abl at bcr breakpoint
      1. Forms bcr/abl
  2. Complete Blood Count
    1. Chronic Phase
      1. White Blood Cell Count > 200,000/uL
      2. Granulocytes (especially Neutrophils) predominate
    2. Transitional Phase (50% of patients)
      1. Leukocytosis
      2. Thrombocytosis or Thrombocytopenia
    3. Blast Phase
      1. Increased Leukocytosis
      2. Thrombocytosis
  3. Bone Marrow Biopsy and Peripheral Smear
    1. Chronic Phase
      1. Myeloblasts represent <5% of cells
    2. Blast Phase
      1. Large proportion of immature cells
    3. Images
      1. HemeoncCmlBlood.jpg
      2. HemeoncCmlMarrow.jpg
      3. HemeoncCmlBlastCrisis.jpg
  4. Other Findings
    1. Vitamin B12 markedly elevated
    2. Leukocyte Alkaline Phosphatase reduced
    3. Uric Acid increased

VII. Management: CML Treatment

  1. Treatment for cure
    1. Allogeneic Stem Cell Transplant (SCT)
  2. Chronic Phase suppression
    1. First Line
      1. Tyrosine Kinase Inhibitor: Imatinib (Gleevac)
        1. Gleevac is generic in U.S. as of February 2016
        2. Monitor for complications (thrombotic events, CV and GI complications)
        3. Monitor CBC every 3 months
      2. Interferon-alfa with Cytarabine
        1. May be poorly tolerated
        2. Studies to date show unclear efficacy
          1. Baccarani (2002) Blood 99:1527 [PubMed]
          2. Guilhot (1997) N Engl J Med 337:223 [PubMed]
    2. Alternative (prior first line agents)
      1. Hydroxyurea (used to stabilize chronic phase)
      2. Busulfan
        1. Risk of myelosuppression
        2. Hydroxyurea is preferred
    3. Other Alkylating Agents (not in marrow transplant)
      1. Cytarabine
      2. Cyclophosphamide
      3. Melphalan
    4. Splenectomy rarely indicated
      1. Hypersplenism
      2. Repeated painful splenic infarctions
    5. Consider Bone Marrow Transplantation in first year
      1. Results in 70% long-term disease free survival
  3. Blast Crisis
    1. Often refractory to treatment
      1. Hydroxyurea
    2. Try protocols for Acute Lymphocytic Leukemia
      1. Vincristine
      2. Prednisone

VIII. Management: Surveillance of CML Survivors

  1. Complete Blood Count (CBC) every 3 months
    1. Hematology Consultation for Neutropenia (ANC <1000/mm3) or Thrombocytopenia (Platelet Count <50k/mm3)
  2. Symptom surveillance
    1. Diarrhea
    2. Fluid retention
    3. Nausea or Vomiting
    4. Headache
    5. Myalgias
    6. Rash
  3. Patients treated with Hematopoietic Stem Cell Transplantation
    1. See Hematopoietic Stem Cell Transplant for protocol

IX. Course

  1. Initially indolent
  2. Later progresses to leukemic phase (Blast Crisis)
    1. Blast phase onset after 6-12 months post diagnosis
    2. Annual progression to blast phase: 25% of patients

X. Prognosis

  1. Five year survival
    1. Age under 50 years old: 84% five year survival
    2. Age over 50 years old: 48% five year survival

XI. References

  1. (2001) Med Lett Drugs Ther 43(1106):49-50
  2. Druker in Abeloff (2004) Clinical Oncology p. 2899-915
  3. Enright in Hoffman (2000) Hematology 40:1155-67
  4. Davis (2014) Am Fam Physician 89(9): 731-8 [PubMed]
  5. Gbenjo (2023) Am Fam Physician 107(4): 397-405 [PubMed]

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Related Studies

Ontology: Myeloid Leukemia, Chronic (C0023473)

Definition (MEDLINEPLUS)

Leukemia is cancer of the white blood cells. White blood cells help your body fight infection. Your blood cells form in your bone marrow. In leukemia, the bone marrow produces abnormal white blood cells. These cells crowd out the healthy blood cells, making it hard for blood to do its work. In chronic myeloid leukemia (CML), there are too many granulocytes, a type of white blood cell.

Most people with CML have a gene mutation (change) called the Philadelphia chromosome.

Sometimes CML does not cause any symptoms. If you have symptoms, they may include:

  • Fatigue
  • Weight loss
  • Night sweats
  • Fever
  • Pain or a feeling of fullness below the ribs on the left side

Tests that examine the blood and bone marrow diagnose CML. Treatments include chemotherapy, stem cell transplants, infusion of donated white blood cells following stem cell transplants, surgery to remove the spleen, and biologic and targeted therapies. Biologic therapy boosts your body's own ability to fight cancer. Targeted therapy uses substances that attack cancer cells without harming normal cells.

NIH: National Cancer Institute
Definition (NCI_NCI-GLOSS) A slowly progressing disease in which too many white blood cells are made in the bone marrow.
Definition (NCI) A chronic myeloproliferative neoplasm characterized by the expression of the BCR-ABL1 fusion gene. It presents with neutrophilic leukocytosis. It can appear at any age, but it mostly affects middle aged and older individuals. Patients usually present with fatigue, weight loss, anemia, night sweats, and splenomegaly. If untreated, it follows a biphasic or triphasic natural course; an initial indolent chronic phase which is followed by an accelerated phase, a blast phase, or both. Allogeneic stem cell transplantation and tyrosine kinase inhibitors delay disease progression and prolong overall survival.
Definition (CSP) chronic leukemia in which myeloid progenitor cells predominate; the hallmark of CML, the Philadelphia chromosome, is a reciprocal translocation between chromosomes 9 and 22 which activates the proto- oncogene c-abl.
Definition (MSH) Clonal hematopoetic disorder caused by an acquired genetic defect in PLURIPOTENT STEM CELLS. It starts in MYELOID CELLS of the bone marrow, invades the blood and then other organs. The condition progresses from a stable, more indolent, chronic phase (LEUKEMIA, MYELOID, CHRONIC PHASE) lasting up to 7 years, to an advanced phase composed of an accelerated phase (LEUKEMIA, MYELOID, ACCELERATED PHASE) and BLAST CRISIS.
Concepts Neoplastic Process (T191)
MSH D015464
ICD9 205.1
ICD10 C92.1 , M9863/3
SnomedCT 92818009, 63364005, 188735005, 154592009
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Spanish leucemia mieloide crónica, enfermedad, Leucemia mielocítica crónica, Leucemia granulocítica crónica, Leucemia mieloide crónica, LMC, Leucemia mielógena cronica, Leucemia Mieloide Crónica, Leucemia Mielogenosa Crónica, Leucemia Mielogenosa Crónica BCR-ABL Positiva, Leucemia Crónica Mieloide, Leucemia Crónica Granulocítica, Leucemia Crónica Mielocítica, Leucemia Crónica Mielogenosa, LMC - Leucemia mieloide crónica, leucemia mieolocítica crónica, leucemia mieloide crónica, SAI, leucemia mieloide crónica, SAI (trastorno), Leucemia Crónica Mielógena BCR-ABL Positiva, Leucemia Mielógena Crónica, Leucemia Mielógena Crónica BCR-ABL Positiva, Leucemia Crónica Mielogenosa BCR-ABL Positiva, Leucemia Crónica Mielógena, Leucemia Mielogénica Crónica BCR-ABL Positiva, morfología: leucemia mielógena crónica, no clasificada como subtipo en CIE - O, leucemia mielógena crónica, no clasificada como subtipo en la Clasificación Internacional de Enfermedades para Oncología (anomalía morfológica), leucemia mielógena crónica, no clasificada como subtipo en la Clasificación Internacional de Enfermedades para Oncología, morfología: leucemia mielógena crónica, no clasificada como subtipo en CIE - O (anomalía morfológica), (M)leucemia mieloide crónica, leucemia granulocítica crónica, leucemia mielocítica crónica, leucemia mieloide crónica, enfermedad (trastorno), leucemia mieloide crónica, leucemia mielógena crónica, Leucemia crónica mielógena, Leucemia mielógena crónica, Leucemia Granulocítica Crónica, Leucemia Mielocítica Crónica
Italian Leucemie mieloidi croniche, Leucemia mieloide, cronica, Leucemia mielogenica cronica, Leucemia mielogena cronica BCR-ABL positiva, Leucemia mieloide Ph1 positiva, Leucemia mieloide cronica, Leucemia mielogena cronica, Leucemia mieloide Philadelphia-positiva, Leucemia mielocitica cronica, Leucemia granulocitica cronica
Dutch chronische granulocytaire leukemie, chronische myelogene leukemie, myelocytaire leukemie chronisch, CML, chronische myelocytaire leukemie, myeloïde leukemie, chronisch, leukemie myelocytair chronisch, chronisch; myelose, granulocytair; leukemie, chronisch, leukemie; granulocytair, chronisch, leukemie; myelocytair, chronisch, leukemie; myeloïd, chronisch, myelocytair; leukemie, chronisch, myelose; chronisch, myeloïd; leukemie, chronisch, chronische myeloïde leukemie, myeloïde leukemieën chronisch, Granulocytaire leukemie, chronische, Leukemie, chronische granulocytaire, Leukemie, myelogene chronische, Myelocytenleukemie, chronische, Myelogene leukemie, chronische, Chronische myeloïde leukemie, Leukemie, chronische myeloïde, Leukemie, myeloïde chronische, Myeloïde leukemie, chronische
French Leucémie granulocytaire chronique, Leucémie myélogène chronique, LMC, Leucémie chronique myélocytaire, Leucémie myéloïde chronique, Leucémie myéloïde chronique chromosome-philadelphie positive, LMC Ph+, LMC Philadelphie positive, Leucémie myéloïde chronique BCR-ABL positive, Leucémie myéloïde chronique à chromosome Philadelphie positif, LMC BCR-ABL +, Leucémies myéloïdes chroniques, Leucémie myélocytaire chronique, LMC (Leucémie Myéloïde Chronique)
German chronische myelozytische Leukaemie, chronische granulozytische Leukaemie, chronische myelogene Leukaemie, chronische myeloide Leukaemie, Leukaemie myelozytisch chronisch, CML, myeloide Leukaemie chronisch, myeloide Leukaemie, chronisch, Chronische myeloische Leukämie, Philadelphia-positiv, Chronische granulozytäre Leukämie, Philadelphia-positiv, Leukämie, myeloische, chronische, BCR/ABL-positiv, Chronische myeloische Leukaemie, Leukaemien chronisch myeloid, chronische myeloische Leukaemie, Granulozytäre Leukämie, chronische, Leukämie, granulozytäre, chronische, Leukämie, myelogene, chronische, Leukämie, myelozytäre, chronische, Myelogene Leukämie, chronische, Myeloische Leukämie, chronische, Myelozytäre Leukämie, chronische
Portuguese Leucemia granulocítica crónica, Leucemia mielocítica crónica, Leucemia mielogénica crónica, Leucemia Mielogênica Crônica, Leucemia Crônica Mielogênica, Leucemia Mielogênica Crônica BCR-ABL Positiva, Leucemia Crônica Granulocítica, Leucemia Crônica Mielocítica, Leucemia Crônica Mieloide, Leucemia Mieloide Crônica, Leucemia Crônica Mielógena BCR-ABL Positiva, Leucemia Mieloide Crônica BCR-ABL Positiva, Leucemia Mielógena Crônica, Leucemia Crônica Mielógena, Leucemia Mielógena Crônica BCR-ABL Positiva, Leucemia mielóide crónica, Leucemias meilóides crónicas, Leucemia Granulocítica Crônica, Leucemia Mielocítica Crônica
Japanese ﾏﾝｾｲｺﾂｽﾞｲｾｲﾊｯｹﾂﾋﾞｮｳ, ﾏﾝｾｲｶﾘｭｳｷｭｳｾｲﾊｯｹﾂﾋﾞｮｳ, 骨髄性Ph1陽性白血病, 白血病-Philadelphia陽性骨髄性, 白血病-骨髄性-フィラデルフィア陽性, 白血病-BCR-ABL陽性慢性骨髄性, Philadelphia陽性骨髄性白血病, 骨髄性白血病-Ph1, フィラデルフィア1陽性骨髄性白血病, BCR-ABL陽性慢性骨髄性白血病, 白血病-骨髄性-Philadelphia陽性, Ph1陽性骨髄性白血病, 骨髄性白血病-Ph1陽性, 白血病-フィラデルフィア陽性骨髄性, 骨髄性白血病-フィラデルフィア1陽性, 白血病-Ph1陽性骨髄性, 白血病-骨髄性-Ph1陽性, フィラデルフィア陽性骨髄性白血病, 骨髄性白血病-フィラデルフィア陽性, 白血病-慢性骨髄性, 骨髄性白血病-Philadelphia陽性, 慢性顆粒球性白血病, 慢性顆粒球白血病, 慢性骨髄性白血病, 慢性骨髄白血病, 白血病-慢性顆粒球性, 白血病-顆粒球性-慢性, 白血病-骨髄性-慢性, 顆粒球性白血病-慢性, 骨髄性白血病-慢性
Finnish BCR-ABL-positiivinen krooninen myelogeeninen leukemia
Russian MIELOIDNYI LEIKOZ PH1-POLOZHITEL'NYI, ЛЕЙКОЗ МИЕЛОГЕННЫЙ ХРОНИЧЕСКИЙ, BCR-ABL ПОЛОЖИТЕЛЬНЫЙ, ЛЕЙКОЗ МИЕЛОИДНЫЙ PH-ПОЛОЖИТЕЛЬНЫЙ, LEIKOZ GRANULOTSITARNYI KHRONICHESKII, ЛЕЙКОЗ МИЕЛОИДНЫЙ ХРОНИЧЕСКИЙ, LEIKOZ MIELOIDNYI PH-KHROMOSOMA POLOZHITEL'NYI, KHRONICHESKII MIELOIDNYI LEIKOZ, ЛЕЙКОЗ МИЕЛОИДНЫЙ PH-ХРОМОСОМА ПОЛОЖИТЕЛЬНЫЙ, LEIKOZ MIELOIDNYI PH-POLOZHITEL'NYI, МИЕЛОИДНЫЙ ЛЕЙКОЗ PH1-ПОЛОЖИТЕЛЬНЫЙ, MIELOIDNYI LEIKOZ KHRONICHESKII, MIELOLEIKOZ KHRONICHESKII, GRANULOTSITARNYI LEIKOZ KHRONICHESKII, LEIKOZ MIELOIDNYI KHRONICHESKII, LEIKOZ MIELOGENNYI KHRONICHESKII, BCR-ABL POLOZHITEL'NYI, МИЕЛОИДНЫЙ ЛЕЙКОЗ PH-ПОЛОЖИТЕЛЬНЫЙ, MIELOIDNYI LEIKOZ PH-POLOZHITEL'NYI, ГРАНУЛОЦИТАРНЫЙ ЛЕЙКОЗ ХРОНИЧЕСКИЙ, ЛЕЙКОЗ ГРАНУЛОЦИТАРНЫЙ ХРОНИЧЕСКИЙ, МИЕЛОИДНЫЙ ЛЕЙКОЗ ХРОНИЧЕСКИЙ, МИЕЛОЛЕЙКОЗ ХРОНИЧЕСКИЙ, ХРОНИЧЕСКИЙ МИЕЛОИДНЫЙ ЛЕЙКОЗ
Czech Chronická myelocytická leukemie, Chronické leukemie myeloidní, Chronická myeloidní leukemie, Chronická granulocytická leukemie, CML, Chronická myelogenní leukemie, Chronické myeloidní leukemie, chronická myeloidní leukémie - filadelfský chromozóm pozitivní, leukémie myelogenní chronická BCR-ABL pozitivní, leukemie myeloidní chronická, chronická myeloidní leukemie, chronická granulocytární leukemie BCR/ABL pozitivní, chronická myeloidní leukémie, leukemie myeloidní chronická BCR-ABL pozitivní
Korean 만성 골수성 백혈병
Croatian LEUKEMIJA, MIJELOIČNA, KRONIČNA
Swedish Leukemi, myeloid, kronisk, BCR-ABL positiv
Polish Białaczka szpikowa przewlekła, Białaczka granulocytowa przewlekła, Białaczka szpikowa Ph1 pozytywna, Białaczka szpikowa Filadelfia-dodatnia, Białaczka mielocytowa przewlekła, Białaczka szpikowa przewlekła BCR-ABL pozytywna, Białaczka szpikowopochodna przewlekła, Białaczka szpikowa Filadelfia pozytywna
Hungarian Chronicus granulocytás leukaemia, Idült myelocytás leukemia, Chronikus myeloid leukaemia, Chronikus myeloid leukemia, Idült myeloid fehérvérűség, Myeloid leukemia, chronikus, Chronikus myelogen leukaemia, Krónikus myelocytás fehérvérűség, Chronikus granulocytás leukemia, Chronikus myelogen leukemia, Chronikus myelocytás leukaemia, Chronicus leukaemia, myelocytás, Leukemiák, chronicus myeloid
Norwegian Kronisk myelogen leukemi, BCR-ABL-positiv, Kronisk myelogen leukemi
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: Philadelphia Chromosome (C0031526)

Definition (MSH) An aberrant form of human CHROMOSOME 22 characterized by translocation of the distal end of chromosome 9 from 9q34, to the long arm of chromosome 22 at 22q11. It is present in the bone marrow cells of 80 to 90 per cent of patients with chronic myelocytic leukemia (LEUKEMIA, MYELOGENOUS, CHRONIC, BCR-ABL POSITIVE).
Definition (NCI) A translocation between chromosomes 9 and 22. It is the hallmark for chronic myelogenous leukemia (CML).
Definition (NCI_NCI-GLOSS) An abnormality of chromosome 22 in which part of chromosome 9 is transferred to it. Bone marrow cells that contain the Philadelphia chromosome are often found in chronic myelogenous leukemia.
Concepts Pathologic Function (T046)
MSH D010677
English 1 Chromosome, Ph, 1 Chromosomes, Ph, Chromosome, Ph 1, Chromosome, Ph1, Chromosome, Philadelphia, Chromosomes, Ph 1, Chromosomes, Ph1, Ph 1 Chromosome, Ph 1 Chromosomes, Ph1 Chromosome, Ph1 Chromosomes, PHAA CHROMOSOME, Ph, Philadelphia Chromosome, Philadelphia Chromosome [Disease/Finding], ph 1 chromosome, philadelphia chromosome, chromosomes philadelphia, chromosome philadelphia, Philadelphia Translocation, Philadelphia chromosome
Swedish Philadelphiakromosom
Czech filadelfský chromozóm
Finnish Philadelphia-kromosomi
Russian PH1 KHROMOSOMA, KHROMOSOMA FILADEL'FIISKAIA, PH1 ХРОМОСОМА, ХРОМОСОМА ФИЛАДЕЛЬФИЙСКАЯ
German PHAA CHROMOSOM, Ph1-Chromosom, Philadelphia-Chromosom
Italian Cromosoma Ph1, Cromosomi di Filadelfia
French Chromosome Ph, Chromosome de Philadelphie, Chromosome Philadelphie, Chromosome Ph 1, Chromosome Ph1
Polish Chromosom Filadelfia
Japanese Ph1染色体, フィラデルフィア染色体, 染色体-フィラデルフィア, 染色体-Ph1
Norwegian Philadelphiakromosom, Ph1-kromosom
Spanish Cromosoma Philadelphia, Cromosoma Filadelfia, Cromosoma Ph1
Portuguese Cromossomo Philadelphia, Cromossomo Filadélfia, Cromossomo Ph1
Dutch Chromosoom, Philadelphia-, Ph1-chromosoom, Philadelphia-chromosoom
Derived from the NIH UMLS (Unified Medical Language System)

Ontology: BCR-ABL Fusion Gene (C1835417)

Definition (NCI) A fusion gene that results from a translocation t(9;22)(q34;q11) that fuses the 5' part of the BCR gene to the 5' side of exon 2 of the ABL1 gene. There are 3 potential products that are formed depending on which BCR exon has the breakpoint. All of the protein products have constitutively active tyrosine kinase activity. This fusion is associated with both chronic myeloid leukemia and acute lymphoblastic leukemia.
Definition (NCI_NCI-GLOSS) A gene formed when pieces of chromosomes 9 and 22 break off and trade places. The ABL gene from chromosome 9 joins to the BCR gene on chromosome 22, to form the BCR-ABL fusion gene. The changed chromosome 22 with the fusion gene on it is called the Philadelphia chromosome. The BCR-ABL fusion gene is found in most patients with chronic myelogenous leukemia (CML), and in some patients with acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML).
Concepts Gene or Genome (T028)
English BCR/ABL FUSION GENE, BCR-ABL Oncogene, BCR-ABL, BCR-ABL Fusion Gene, BCR/ABL1 Fusion Gene, BCR-ABL1 Fusion Gene, BCR-ABL fusion gene
Derived from the NIH UMLS (Unified Medical Language System)

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