MYELODYSPLASIA AND LEUKEMIAS

See also CHRONIC LYMPHOCYTIC LEUKEMIA

n.b. The initial step in differentiation of the hematopoietic stem cell is into the lymphoid vs. myeloid lines. The myeloid line gives rise to red cells, platelets, monocytes, and granulocytes (neutrophils, eosinophils, and basophils). Stem cells at the next level of differentiation can produce granulocytes and monocytes but not RBC or platelets.

I. Definitions and Pathophysiology

1. Myelodysplasia = dysplasia (pre-cancerous neoplastic change), in a clonal line of myeloid cells
   1. Ineffective hematopoiesis is typically present
      1. Rate of cell division in BM is actually higher than normal but cell maturation is impaired, leading to peripheral blood cytopenias-usually the presenting abnormality
      2. In some cases the rate of cell division in BM is lower than normal ("hypoplastic myelodysplasia")--difficult to distinguish BM findings from those of Aplastic Anemia.
   2. In addition, functional defects have been demonstrated in terminally differentiated cells in myelodysplasia

2. 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
   3. Presentation with infection, bleeding, hepatosplenomegaly, lymphadenopathy, and weakness
   4. Blast cells on peripheral smear
   5. Anemia is common

3. 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 megakaryocytic), 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. Usual onset is in adulthood
   4. Often presents with malaise, abdominal pain, splenomegaly, peripheral leukocytosis
   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.

4. Acute Lymphocytic Leukemia (ALL)
   1. Usual onset is in chilhood
   2. Presentation with infection, bleeding, hepatosplenomegaly, lymphadenopathy, and weakness
   3. Blast cells on peripheral smear
   4. Anemia is common
5. Diagnosis of myelodisplasias/leukemias-often requires bone marrow biopsy

1. 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

2. 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 bx of liver, spleen, LN, 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

3. 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. Categories are morphologic, based on findings on bone marrow bx but do correlate rougly with prognosis. In addition to those below, there are also M1-M7 for myeloid leukemias; L1-L3 for lymphoid leukemias?

1. Refractory anemia--rather a misnomer, as responsiveness to tx is not a criterion for diagnosis!
   1. Cytopenia of at least 1 lineage in peripheral blood (us. anemia)
   2. Normal or hypercellular BM w/dysplastic changes
   3. < 1% blasts in peripheral blood
   4. < 5% blasts in BM

2. Refractory anemia with ringed sideroblasts
   1. Cytopenia of at least 1 lineage in peripheral blood (almost always anemia)
   2. Dysplastic changes in BM
   3. Same % criteria of blasts in peripheral blood and BM as in refractory anemia
   4. Ringed sideroblasts account for > 15% of nucleated cells in BM

3. Refractory anemia with excess blasts
   1. Cytopenia of 2 or more lineages in peripheral blood
   2. Dysplastic changed in all 3 lineages in BM
   3. < 5% blasts in peripheral blood
   4. 5-20% blasts in BM

4. Chronic Myelomonocytic Leukemia--thought by some to be unrelated to other categories
   1. Peripheral blood monocytosis (?exact numerical threshold?)
   2. < 5% blasts in peripheral blood
   3. < 20% blasts in BM

5. Refractory anemia with excess blasts in transformation
   1. Hematologic features similar to refractory anemia w/excess blasts
   2. > 5% blasts in peripheral blood OR
   3. 21-30% blasts in BM OR
   4. Presence of Auer rods in the blasts

6. Acute myeloid leukemia (> 30% blasts in bone marrow)

III. Differential diagnosis of myelodysplasia--these conditions can cause dysplastic BM changes and myelosuppression, but unlike the case w/true myelodysplasia, the hematologic abnormalities resolve with tx of underlying cause:

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

IV. Risk factors for myelodysplasia and Acute Myeloid Leukemia

1. Radiation exposure
2. Chemotherapeutic agents e.g. alkylating agents, etoposide
3. Benzene and other organic compounds
4. Chloramphenicol
5. Phenylbutazone
6. Some viruses?

V. Natural history of myelodysplasia

1. 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)
2. Male: Female about 60:40
3. Dx usually made by detection of peripheral blood cytopenias, with or without corresponding sx (anemia, thrombocytopenia, and/or leukopenia)
4. 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.

VI. Natural History of AML

1. Death usually occurs from infection or hemorrhage as a consequence of functional aplasia secondary to marrow infiltration by tumor
2. Can also get organ infiltration, e.g. liver, spleen, LN, and meninges, and get organ dysfunction from that
3. Often get hyperuricemia from increased cell turnover; can get arthritis and nephropathy from this

VII. Natural History of CML

1. Median age at presentation is 53yo though can occur at any age
2. Presenting sx can include fatigue, anorexia, and weight loss, but 40% of pts are asymptomatic at diagnosis
3. Splenomegaly seen in about 50% at diagnosis
4. 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

VII. Prognostication in myelodysplasia

1. "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 BM
   3. # of hematopoietic lineages involved in the cytopenia
2. Older pts seem to have worse prognosis
3. Male pts have worse prognosis than females

VIII. 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

4. 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

IX. Treatment of AML

1. Chemotherapy: induction-consolidation pattern; can use higher doses in remission, because there is more functioning marrow
2. Bone marrow transplantation
   1. Either autologous or allogeniec
   2. Even with histocompatible donors, immune suppression is needed to avoid rejection
   3. Used for acute leukemias and CML.
   4. In AML, autologous BMT after intensive chemo increased 7y disease-free survival (Lancet 351:700, 1998--JW)
   5. 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)

X. 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)

2. Curative therapy with HLA-matched allogenic BM transplantation--ass'd 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

3. Other, investigational tx's as of 1999
   1. Bone marrow autografting with stem cells harvested from pt's own bone marrow and molecularly selected to exclude CML cells

(Source: Sci. Am. Medicine, 10/94; NEJM 340:1649, 1999; NEJM 340:1330, 1999; other sources as noted)