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Philadelphia chromosome-negative chronic myelogenous leukemia without
breakpoint cluster region rearrangement: a chronic myeloid leukemia with a
distinct clinical course
R Kurzrock, HM Kantarjian, M Shtalrid, JU Gutterman and M Talpaz
Department of Clinical Immunology and Biological Therapy, UT M.D. Anderson
Cancer Center, Houston 77030.
The hallmarks of chronic myelogenous leukemia (CML) include the
Philadelphia chromosome (Ph) translocation [t (9;22)(q34;q11)] and
consistent molecular genetic aberrations: a break within a restricted 5.8
kb DNA segment, bcr, on chromosome 22q11; transposition of the c- abl
protooncogene from chromosome 9q34 to 22q11; and formation of a hybrid
bar-abl gene encoding an abnormal 210 Kd bcr-abl protein with augmented
tyrosine kinase enzymatic activity. These molecular phenomena may occur
even in the absence of cytogenetic evidence of the Ph translocation. They
are highly specific and sensitive markers for CML, and are presumed to play
a significant role in the pathogenesis of this malignancy. Surprisingly, we
have encountered 11 patients who lacked the Ph translocation, bcr
rearrangement, and (in the four patients with available mRNA) a bcr-abl
message, and yet had a disease phenotype at diagnosis that was a
morphologic facsimile of classic chronic phase CML. These patients
presented with high white blood cell counts, neutrophilia, occasional
basophilia, splenomegaly, and a hypercellular bone marrow with granulocytic
hyperplasia and a left shift in myeloid maturation. Despite the striking
resemblance between the early stages of bcr-negative and bcr-positive CML,
disease progression manifests distinctly in these two disorders. In
contrast to the blastic transformation that inevitably complicates
bcr-positive CML, the natural history of our 11 Ph-negative, bcr-negative
CML patients was characterized by increasing leukemia burden with
leukocytosis, pronounced organomegaly, extramedullary infiltrates, and
eventual bone marrow failure (anemia and thrombocytopenia) without marked
increases in blast cells. Our current observations suggest that a chronic
myeloid leukemia process can develop without associated changes in the bcr
or c- abl genes. Although the initial phase of this disease is
indistinguishable from CML, the presence or absence of molecular markers
may aid in the prediction of the clinical course of Ph-negative CML.
Volume 75,
Issue 2,
pp. 445-452,
01/15/1990
Copyright © 1990 by The American Society of Hematology
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