See also Chronic Lymphocytic Leukemia and Multiple Myeloma


I. Classification, epidemiology, and presentation

  1. Myelodysplasia
    1. Definition = dysplasia (pre-cancerous neoplastic change), in a clonal line of myeloid cells
    2. "Ineffective hematopoiesis" is typically present
      1. Usually involves higher-than-normal rate of cell division in bone with impaired cell maturation, leading to peripheral blood cytopenias-usually the presenting abnormality
      2. In some cases, lower-than-normal rate of cell division in bone marrow is present ("hypoplastic myelodysplasia")-difficult to distinguish bone marrow findings from those of Aplastic Anemia.
    3. In addition, functional defects have been demonstrated in terminally differentiated cells in myelodysplasia
    4. Diagnosis usually made by detection of peripheral blood cytopenias (anemia, thrombocytopenia, and/or leukopenia), with or without corresponding sx
    5. More common in the elderly (median age of onset in the 60's), though has been reported in children (many have Down's Syndrome; 40% progress to AML)
    6. Male: Female about 60:40
  1. Acute Myeloid Leukemia (AML)
    1. Note that there is no clear distinction between myelodysplasia and AML-The current "FAB" classification (see below) uses an arbitrary numerical cutoff re: % of blast cells in bone marrow.
    2. Usual onset is in adulthood (median age at diagnosis 65-72 in various studies represents 90% of acute leukemia in adults but < 10% of acute leukemia in children < 10yo)
    3. Male:female 1.7:1
    4. Presentation-Usually related to bone marrow replacement or infiltration of peripheral organs by malignant blast cells
      1. Peripheral blood cytopenias (anemia, thrombocytopenia, and/or leukopenia), with or without corresponding sx
      1. Hepatomegaly, splenomegaly, and/or lymphadenopathy
      2. Leukocytosis (if blast count is > 50k cells/microliter), which can cause leukostasis with CNS and pulmonary complications (infarction, bleeding)
      3. Bone pain (particularly in lower extremities) and/or pathologic fracture from marrow cavity expansion from proliferating blasts
      4. Cutaneous nodules ("myeloid sarcoma") without obvious bone marrow infiltration
      5. Can present with acute promyelocytic anemia (see below), an oncologic emergency
      6. Blast cells on peripheral smear
      7. Constitutional symtpoms (fever, weight loss)
  1. Chronic Myelogenous Leukemia (CML)
    1. Malignant clonal expansion of a pluripotent myeloid stem cell; malignant transformation occurs at the point where production of erythroid cells & platelets is still possible
    2. Typically see increased erythroid and platelet (or megakaryocyte), as well as myeloid, elements in the peripheral blood (WBC > 25k, high platelets in 30-50%, basophilia, immature granulocytes in peripheral blood), and myeloid hyperplasia in the bone marrow
    3. Presentation
      1. Can include fatigue, malaise, anorexia, weight loss, abdominal pain, and peripheral leukocytosis
      2. Splenomegaly seen in about 50% at diagnosis
      3. 40% of pts are asymptomatic at diagnosis
    4. Usual onset is in adulthood; median age at diagnosis 53yo
    5. The "Philadelphia" chromosome is responsible for the underlying pathophysiology
      1. Represents a t(9;22) translocation; seen in 95% of pts
      2. Results in fusion of the "Breakpoint Cluster" (BCR) gene on chromosome 22 to the "Ableson Leukemia Virus" (ABL) gene on chromosome 9, resulting in expression of BCR-ABL, a "fusion protein," a cytoplasmic tyrosine kinase which appears to be integral to oncogenesis in CML, though precise mechanisms not fully understood as of 1999
      3. The amount of the BCR sequence that is retained in the fusion gene determines the molecular weight of the fusion protein and is associated with clinical course
      4. Other genetic phenomenia, e.g. mutations or deletions of tumor-suppressor genes, may also play a role in pathophysiology.
  1. Acute Lymphocytic Leukemia (ALL)
    1. Accounts for 80% of pediatric leukemia
    2. Peak incidence is from 2-5yo
    3. Presentation similar to AML (see above) plus can have renal and CNS impairment from leukemic infiltration
    4. ALL survivors may experience the following sequelae:
      1. Cognitive impairment (especially if received cranial radiotherapy)
      2. CVA (especially if received cranial radiotherapy)
      3. short stature
      4. Cardiomyopathy (if receive anthracyclines
      5. Second malignancy (affects 2-3% of survivors, most commonly brain tumors and AML)
      6. Fertility problems
  2. Diagnosis of myelodisplasias/leukemias
  1. Bone marrow biopsy often required
  2. Specific (and pathognomonic) cytogenetic abnormalities (particularly in chromosomes 5,7,8, and 20) in myelodysplasia can be detected with fluorescent in situ hybridization and PCR, as adjuncts to traditional microscopic cytogenetic analysis
  3. Diagnosis of AML
    1. Clinical detection" = standard morphologic and cytogenetic methods
      1. Usually becomes clinically detectable only when tumor burden is at least 1,000,000,000 cells; 1-2 x 1,000,000,000,000 is enough to cause death; i.e. only 10 cell doublings in difference!
      2. Can use these methods on peripheral blood or marrow, or on biopsy of liver, spleen, lymph nodes or skin lesions
      3. "Auer rods"-pathognomonic for AML
      4. "Leukemic hiatus"-lack of intermediately mature cells in granulocyte line on peripheral smear; seen in AML or progression of CML
    2. PCR can detect residual abnormal cells with much greater sensitivity
    3. Also, monoclonal Ab's to detect cell surface antigens; cytogenetics to check for particular Ig gene rearrangements in B-cell lymphoid leukemias
  4. Diagnosis of CML
    1. Identification of "Philadelphia Chromosome" (see above) on cytogenetic analysis
    2. Molecular probes, e.g. PCR for BCR-ABL (also used to monitor response to therapy, though positive predictive value is unknown)
II. "FAB" (French, American, and British) classification of myelodysplasia and acute myeloid leukemia.  Click link for details.  LARGELY REPLACED BY WHO schema (see below)

III. World Health Organization classification of AML
  1. AML with cytogenetic abnormalities
    1. Good prognosis
      1. AML with t(8;21)
      2. AML with inv16 or t(16;16)
      3. Acute promyelocytic leukemia t(15,17)
    2. Poor prognosis
      1. AML with t(9;11)
      2. AML with t(6;9)
      3. AML with int(3) or t(3;3)
      4. AML (megakaryoblastic) with t(1;22)
  2. AML with multi-lineage dysplasia
    1. AML with myelodysplastic features or evolution from myelodysplastic syndrome (MDS)
  3. AML secondary to myelodysplastic syndrome therapy
    1. Radiation/alkylating agent-related AML and MDS
    2. Topoisomerase II inhibitor-related
  4. AML not otherwise specified-FAB classification

IV. Differential diagnosis of myelodysplasia-These conditions can cause dysplastic bone marrow changes and myelosuppression, but unlike the case w/true myelodysplasia, the hematologic abnormalities resolve with treatment of underlying cause:

  1. B12 deficiency
  2. Folate deficiency
  3. Viral infections including HIV
  4. Antibiotics
  5. Ethanol toxicity
  6. Lead toxicity

V. Risk factors

  1. Myelodysplasia and AML
  1. Radiation exposure
  2. Chemotherapeutic agents e.g. alkylating agents, etoposide, doxorubicin
  3. Benzene and other organic compounds
  4. Genetic abnormalities (Down syndrome, Fanconi anemia)
  5. History of aplastic anemia or myelodisplasia
  6. Chloramphenicol
  7. Phenylbutazone
  1. ALL
    1. Down syndrome
    2. Ataxia telangiectasia
    3. Fanconi anemia
    4. Bloom syndrome
    5. Klinefelter syndrome
    6. Neurofibromatosis
    7. Radiation exposure

VI. Natural history of myelodysplasia

  1. Wide variation in speed of progression to leukemia; in fact, not all cases of myelodysplasia end in leukemia.
    1. Those patients with the specific cytogenetic abnormality of an isolated deletion of long arm of chromosome 5 ("5q-") have a typically indolent course with only about 25% developing overt leukemia. Typically get anemia (often transfusion-dependent) w/o other serious peripheral blood cytopenias. 70% of these pts are female.
  2. "International Prognostic Scoring System," based on prospective study of 816 pts, divides pts into 4 prognostic groups based on the following factors:
    1. Specific cytogenetic abnormalities
    2. % of blasts in bone marrow
    3. # of hematopoietic lineages involved in the cytopenia
  3. Older pts seem to have worse prognosis
  4. Male pts have worse prognosis than females

VII. Natural History of AML

  1. Survival is inversely correlated with age at diagnosis (5y survival is 5% if > 65yo vs. 40-45% if < 45yo)
  2. Other predictors of poor outcome in patients with AML:
    1. Poor performance status
    2. High-risk cytogenetic and/or molecular findings
    3. Prior radiation exposure
    4. Prior cytotoxic therapy
    5. Prior history of myelodysplasia
  3. Death usually occurs from infection or hemorrhage as a consequence of functional aplasia secondary to marrow infiltration by tumor
  4. Can also get organ infiltration, e.g. of liver, spleen, lymph nodes, and meninges, and get organ dysfunction from that
  5. "Acute promyelocytic leukemia" (APL)
    1. An oncologic emergency
    2. Malignant promyelocytes contain granules with enzymes that activate clotting proteins-Can lead to life-threatening disseminated intravascular coagulation (DIC)
    3. Treated with high-dose all-trans retinoic acid (Vesanoid) which induces maturation of the promyelocytes with involution of the granules and reduces risk of DIC
  6. Spontaneous tumor lysis syndrome (TLS)
    1. Hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia from increased cell turnover
    2. Can cause renal failure and arthritis

VIII. Natural History of CML

  1. Typically progresses from clinically benign chronic phase to rapidly fatal blast crisis (increased production of hematopoietic precursors and presence of less mature precursors in peripheral blood) in 3-5y

IX. Treatment of Myelodysplasia

  1. Chemotherapy (anthracycline + cytarabine, usually)--responds less well (lower remission rates and higher relapse rates) than in pts with acute leukemia--us. 50-60% remission rate and 90% remission rate--probably b/c a higher % of pts with myelodysplasia have cytogenetic features ass'd with poor prognosis than pts presenting w/acute leukemia.
  2. Immunotherapeutics, e.g. cyclopsorine or monoclonal Ab's against proteins disproportionately expressed on blast cells--preliminary studies ongoing as of 1999
  3. Allogenic Bone-Marrow transplantation--results not as good as with AML; when successful, constitutes a definitive cure
    1. Autologous BM transplantation has also been used in pts who have had complete remission with chemo
  1. Tx of myelodysplasia-associated cytopenias
  1. Growth factors, e.g. Erythropoietin, G-CSF and GM-CSF, though G-CSF was ass'd with decreased survival c/w placebo in one trial of pts with Refractory Anemia w/Excess Blasts
  2. Other cytokines, e.g. interleukin-6 or interferon alfa--side f/x are troublesom

X. Treatment of AML

  1. Treat with ATRA if APL (see above) is suspected
  2. Treat leukostasis (see above) with leukapheresis (if available; if not, can trea with high-dose hydroxyurea, e.g. 4g Q6-8h)
  3. Treat tumor lysis syndrome (see above), if present, with hydration, rasburicas (Elitek) to reduce serum uric acid, and if indicated, dialysis
  4. Treat anemia and thrombocytopenia with appropriate blood products (irradiated, to avoid graft-vs-host disease)
    1. RBC transfusion generally indicated if Hb < 8g/dL
    2. Platelet transfusion generally indicated if platelets < 10k/microliter (or < 50k/microliter with active bleeding)
  5. Chemotherapy
    1. Generally given in an induction-consolidation pattern
    2. Induction is often anthracycline x 3d + cytosine arabinoside x 7d
    3. Can use higher doses in remission, because there is more functioning marrow
  6. Bone marrow transplantation
    1. Either autologous or allogenic
    2. Even with histocompatible donors, immune suppression is needed to avoid rejection
    3. In AML, autologous BMT after intensive chemo increased 7y disease-free survival (Lancet 351:700, 1998--JW)
    4. 346 pts with AML 16-55yo with complete remissions after induction chemo (cytarabine & idarubicin) were assigned to receive allogenic BMT (113; all who had suitable family donors); remaining pts randomized to autologous BMT vs. high-dose cytarabine. No diff. in 4y disease-free survival in the 3 groups, but overall survival slightly higher w/chemo (52% vs. 43% with autologous and 46 with allogenic BMT; just achieved stat. sig.) (NEJM 339:1649, 1998--JW)

XI. Treatment of CML

  1. Chronic phase treatment--Cytoreductive therapy prevents thrombotic complications and brings about "hematologic remission" in 90% of pts
    1. Busulfan
    2. Hydroxyurea (ass'd with better prolongation of chronic phase and better survival than Busulfan)
    3. Neither Busulfan nor Hydroxyurea reduces the % of pts who eventually develop blast crisis
    4. Interferon-Alfa + cytarabine (better response rates than Busulfan or Hydroxyurea)
    5. Imatinib mesylate (Gleevec)
      1. An inhibitor of tyrosine kinase, which is responsible for cell preliferation in CML
      2. May be associated with increased risk of heart failure
      3. In a trial of 1106 pts with newly-dx'd chronic-phase CML randomized to oral imatinib QD vs. IFN-alfa + cytarabine, 18mo incidence of disease progression was 8% in imatinib group vs. 26% in IFN-cytarabine group (sig.); imatinib was ass'd with sig. less drug toxicity (NEJM 348:994, 2003--JW)
      4. In a study in 1,106 pts with newly-diagnosed CML randomized to imatinib vs. (IFN + cytarabine), among imitanib recipients survival was 89% and disease-free survival was 83%.  There was no sig. diff. among pts randomized to the two groups though most pts crossed over to imitanib (NEJM 355:2408, 2006--JW)
  1. Curative therapy with HLA-matched allogenic BM transplantation--associated with 70% 10y survival in one series
    1. Preceded by high-dose chemotherapy, usually with busulfan + cyclophosphamide, or chemo + total-body irradiation
    2. Graft-versus-Leukemia effect (probably mediated by graft T cells) may play a role in achieving a cure; unfortunately, correlated with Graft-versus-Host disease
    3. Less successful in pts > 40yo b/c of higher treatment-related mortality
    4. Survival is greater when done during Chronic Phase than during accelerated phase or blast crisis.
    5. Survival is greater with related than with unrelated bone-marrow donors
  1. Bone marrow autografting (with stem cells harvested from pt's own bone marrow and molecularly selected to exclude CML cells)

XII. Treatment of ALL

  1. 3-phase chemotherapy is typical (induction, consolidation, maintenance) over 2-3y, with 5-year survival rates > 80%
  2. Risk of recurrence is higher in patients < 1yo of > 10yo, with WBC counts > 50k/mm3, and when Philadelphia chromosome is present

(Source: Sci. Am. Medicine, 10/94; NEJM 340:1649, 1999; NEJM 340:1330, 1999; Core Content Review of Family Medicine, 2012; other sources as noted)