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CHAPTER 89 disease usually responds to a tyrosine kinase inhibitor, and median survival has

CHRONIC MYELOGENOUS been extended significantly. Allogeneic hematopoietic stem cell transplanta-
tion can cure the disease, especially if the transplantation is applied early in
LEUKEMIA AND RELATED the chronic phase, although this approach is now uncommon as a result of the
effect of tyrosine kinase inhibitor therapy. The effect of stem cell transplan-
DISORDERS tation is related in part to a robust graft-versus-leukemia effect, engendered
by donor T lymphocytes. The natural history of the chronic phase is to evolve
into an accelerated phase that often terminates in acute leukemia (blast
crisis), but the frequency of this progression has been markedly decreased by
Jane L. Liesveld and Marshall A. Lichtman the advent of tyrosine kinase inhibitors. Blast crisis results in a myelogenous
leukemic phenotype in 75 percent of cases and a lymphoblastic leukemic phe-
notype in approximately 25 percent of cases. Ph chromosome–positive acute
SUMMARY myeloblastic leukemia (AML) may appear de novo in approximately 1 percent
of cases of AML, and Ph chromosome–positive acute lymphocytic leukemia
The chronic myelogenous leukemias (CMLs) include BCR rearrangement- (ALL) may occur de novo in approximately 20 percent of cases of adult ALL
positive CML, chronic myelomonocytic leukemia, juvenile myelomonocytic and approximately 5 percent of childhood ALL cases. In Ph chromosome–
leukemia, chronic neutrophilic leukemia, chronic eosinophilic leukemia, and positive ALL, the translocation between chromosomes 9 and 22 results in
chronic basophilic leukemia. The term chronic, in contrast to acute, once had the fusion gene encoding a mutant tyrosine kinase oncoprotein that may be
prognostic implications. However, although the terms remain useful for nosol- identical in size to that in classic CML (210 kDa) in approximately one-third
ogy, they no longer reflect an invariable difference in prognosis. For example, of cases. A smaller mutant tyrosine kinase (190 kDa) is encoded in approxi-
acute myelogenous leukemia in children and young adults has higher remission mately two-thirds of cases. In children, the cells in approximately 90 percent
and cure rates than juvenile or chronic myelomonocytic leukemia in children or of cases contain a 190-kDa mutant tyrosine kinase. These acute leukemias may
adults, respectively. BCR rearrangement-positive CML presents with anemia, reflect (1) the presentation of CML in acute blastic transformation without a
exaggerated granulocytosis, a large proportion of myelocytes and mature preceding chronic phase or (2) de novo cases resulting from a BCR-ABL1 muta-
neutrophils, absolute basophilia, normal or elevated platelet counts, and, fre- tion occurring in a different early hematopoietic cell from the event in CML or
quently, splenomegaly. The marrow is intensely hypercellular, and marrow cells with as yet unidentified modifying gene alterations. Chronic myelomonocytic
contain the Philadelphia (Ph) chromosome in approximately 90 percent of cases leukemia has variable presenting features. Anemia may be accompanied by
by cytogenetic analysis. A rearrangement of the BCR gene on chromosome 22 is mildly or moderately elevated leukocyte counts; an elevated total monocyte
present by molecular diagnostic analysis in approximately 96 percent of cases count; a low, normal, or elevated platelet count; and sometimes splenomeg-
that have a classic morphologic appearance. The BCR-rearranged form of the aly. Although cytogenetic abnormalities may be present, there is no specific
genetic marker of the disease. In a very small proportion of cases, a translo-
cation involving the platelet-derived growth factor receptor (PDGFR)-β gene
is associated with eosinophilia and is responsive to a tyrosine kinase inhibitor.
Juvenile myelomonocytic leukemia occurs in infancy or very early childhood.
Acronyms and Abbreviations: ALL, acute lymphocytic leukemia; BCR, break- Anemia, thrombocytopenia, and leukocytosis with monocytosis are usual. The
point cluster region; CCyR, complete cytogenetic response; CFU-GM, colony-forming disease is refractory to treatment and, even with current maximal therapy and
unit–granulocyte-monocyte; CHR, complete hematologic response; CLL, chronic lym- stem cell rescue, cures are uncommon. Chronic neutrophilic leukemia presents
phocytic leukemia; CML, chronic myelogenous leukemia; CMML, chronic myelomono- with mild anemia and exaggerated neutrophilia, with very few immature
cytic leukemia; CMR, complete molecular response; DLI, donor lymphocyte infusion; cells in the blood. Splenomegaly is common. The disease usually occurs after
FISH, fluorescence in situ hybridization; G-CSF, granulocyte colony-stimulating factor; age 60 years. Chronic and juvenile myelomonocytic leukemia and chronic
GM-CSF, granulocyte-monocyte colony-stimulating factor; GRB2, growth factor neutrophilic leukemia have a propensity to evolve into acute myelogenous
receptor–bound protein-2; GTP, guanosine triphosphate; GTPase, guanosine triphos- leukemia. Prior to that evolution, morbidity and mortality are related to infec-
phatase; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; HPRT, tion, hemorrhage, and complicating medical conditions. Chronic eosinophilic
hypoxanthine phosphoribosyltransferase; hsp, heat shock protein; HUMARA, human leukemia represents the major subset of the hypereosinophilic syndrome. It is
androgen receptor assay; IFN, interferon; IL, interleukin; IRIS, International Random-
ized Study of Interferon; JAK, Janus-associated kinase; LTC-IC, long-term culture– a clonal disorder with a striking absolute eosinophilia, often neurologic and
initiating cell; MCP, monocyte chemotactic protein; MCyR, major cytogenetic cardiac manifestations secondary to toxic effects of eosinophil granules, and
response; MDS, myelodysplastic syndrome; MIP, macrophage inflammatory protein; sometimes a translocation involving the PDGFR-α gene that encodes a mutant
MMR, major molecular response; NF-κB, nuclear factor-κB; NF1, neurofibromatosis tyrosine kinase, imparting sensitivity to a tyrosine kinase inhibitor.
tumor-suppressor gene; NK, natural killer; NOD, nonobese diabetic; OCT-1, organic
cation transporter 1; PCR, polymerase chain reaction; PCyR, partial cytogenetic
response; PDGFR, platelet-derived growth factor receptor; Ph, Philadelphia chro- DEFINITION AND HISTORY
mosome; PI3K, phosphatidylinositol 3′-kinase; Rb, retinoblastoma; RT-PCR, reverse
transcriptase polymerase chain reaction; SCID, severe combined immunodeficiency; Chronic myelogenous leukemia (CML) is a multipotential hemato-
STAT, signal transducer and activator of transcription; TBI, total-body irradiation; TdT, poietic stem cell disease characterized by anemia, extreme blood
terminal deoxynucleotidyl transferase; TGF, transforming growth factor; TKI, tyrosine granulocytosis and granulocytic immaturity, basophilia, often throm-
kinase inhibitor; VEGF, vascular endothelial growth factor; WT, Wilms tumor. bocytosis, and splenomegaly. The hematopoietic cells contain a recip-
rocal translocation between chromosomes 9 and 22 in more than

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