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1448 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1449

occurred during the chronic phase of the disease, but such complica- with BCR rearrangement-positive ALL. In patients with m-bcr CML,
tions are very rare until the disorder transforms to acute leukemia. Ele- monocytes are more prominent, the white cell count is lower on aver-
vated serum and urinary lysozyme levels are features of leukemia with age, and basophilia and splenomegaly are less prominent than in dis-
greater monocytic components and are not features of CML. Serum ease with classic BCR breakpoint (M-bcr). The few reported cases had
371
cholesterol is decreased in patients with CML. 372,373 a short interval before either myeloid or lymphoid blast transformation
Serum Angiogenic Factors Angiogenin, endoglin (CD105), vas- developed. 386,387
cular endothelial growth factor (VEGF), β-fibroblast growth factor, and
hepatocyte growth factor are increased strikingly in the serum of CML
patients. 307,308,374,375 HYPERLEUKOCYTOSIS
Approximately 15 percent of patients present with symptoms or signs
referable to leukostasis as a result of the intravascular flow-impeding
SPECIAL CLINICAL FEATURES effects of white cell counts greater than 300 × 10 /L. Hyperleuko-
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cytosis is more prevalent in children with Ph chromosome–positive
BCR-ABL1–POSITIVE THROMBOCYTHEMIA CML. The effects of total leukocyte counts from 300 to 800 × 10 /L
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Either of two syndromes—thrombocythemia with the Ph chromo- include impaired circulation of the lung, central nervous system, spe-
some and BCR-ABL1 rearrangement or thrombocythemia without a cial sensory organs, and penis, resulting in some combination of tac-
Ph chromosome but with the BCR-ABL1 rearrangement—may pre- hypnea, dyspnea, cyanosis, dizziness, slurred speech, delirium, stupor,
cede the overt signs of CML or its accelerated phase. 376–379 In general, visual blurring, diplopia, retinal vein distention, retinal hemorrhages,
the disease closely mimics classic essential thrombocythemia ini- papilledema, tinnitus, impaired hearing, and priapism. In asymptom-
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tially: marked platelet elevation, extreme megakaryocytic hyperplasia, atic patients with hyperleukocytosis, initial treatment with hydration
normal or mildly elevated white cell count, no or very slight myeloid and hydroxyurea usually can be used to decrease the white cell count.
immaturity in the blood, and minimal anemia. Minor bleeding, such Hydroxyurea treatment should be designed to accomplish a gradual
as epistaxis, erythromelalgia, or signs of thrombosis, such as cerebral decrease in white cell count over a few days so as to avoid the tumor
or limb ischemia, are occasionally present. In some cases, the absolute lysis syndrome. If signs of hyperleukocytosis are present, hydration, leu-
basophil count is mildly elevated. Approximately 5 percent of patients kapheresis, and hydroxyurea can be used simultaneously; hydroxyurea
with apparent essential thrombocythemia have a Ph chromosome. dose should be selected to avoid exaggerated tumor lysis.
376
In another study, two of 121 patients with essential thrombocythemia
had BCR-ABL1 transcripts, and one of these patients also had a Ph CONCURRENCE OF LYMPHOID MALIGNANCIES
chromosome in the marrow cells, whereas in a different study, four of
32 patients with thrombocythemia had low levels of BCR-ABL1 tran- CML may emerge in patients with established chronic lymphocytic
scripts in blood cells. Approximately one in 20 patients with CML pres- leukemia (CLL). 388–390 A few patients have presented with simultaneous
ent with the features of essential thrombocythemia. 377,378 Evolution to occurrence of the two diseases. 391,392 A single case of lymphocytic leuke-
blast crisis may occur. 380,381 moid reaction simulating CLL that regressed as CML emerged has been
reported. In some cases, the CLL lymphocytes did not contain the Ph
393
chromosome, whereas the CML cells did, suggesting the presence of
NEUTROPHILIC CHRONIC MYELOGENOUS two independent clonal disorders. 388,389,393,394 In other cases, the Ph chro-
LEUKEMIA mosome was present in the myeloid and lymphoid cells, indicating a
392
A rare variant of BCR-ABL1–positive CML has been described in common origin. Patients may present with Ph chromosome–positive
which the elevated white cell count is composed principally of mature acute lymphoblastic leukemia and, following chemotherapy-induced
neutrophils. 382,383 The white cell count is lower (on average: 30 to 50 × remission, develop the features of typical CML. 395
10 /L) at the time of diagnosis than is the case with classic CML (median:
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100 to 150 × 10 /L). Moreover, patients with neutrophilic CML usually
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do not have basophilia, notable myeloid immaturity in the blood, prom- DIFFERENTIAL DIAGNOSIS
inent splenomegaly, or low leukocyte alkaline phosphatase scores. The DISEASES MIMICKING CHRONIC
cells of these patients have the Ph chromosome but have an unusual
BCR-ABL1 fusion gene in that the breakpoint in the BCR gene is between MYELOGENOUS LEUKEMIA
exons 19 and 20. This breakpoint location results in fusion of most of the The diagnosis of CML is made based on the characteristic granulocyto-
BCR gene with ABL1 (e19a2 type BCR-ABL1), which leads to a larger sis, white cell differential count, increased absolute basophil count, and
fusion protein (230 kDa) compared to the fusion protein in classic CML splenomegaly coupled with the presence of the Ph chromosome or its
(210 kDa; see Fig. 89–3). This correlation between genotype and phe- variants (90 percent of patients) or a BCR rearrangement on chromo-
notype has not been observed in all cases. This variant usually has an some 22 (>95 percent of patients).
384
indolent course, which may be the result of very low levels of mRNA for Patients with other chronic hematopoietic stem cell diseases, such
p230 and the undetectable or barely detectable p230 protein in cells. 385 as polycythemia vera, essential thrombocythemia, or primary myelofi-
brosis, only occasionally have closely overlapping features. For exam-
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MINOR-BCR BREAKPOINT–POSITIVE CHRONIC ple, the total white cell count is greater than 30 × 10 /L in more than
MYELOGENOUS LEUKEMIA 90 percent of patients with CML and increases inexorably over weeks
or months of observation, whereas the total white cell count is less than
A small portion of patients with BCR-ABL1–positive CML have the 30 × 10 /L in more than 90 percent of patients with the three other clas-
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breakpoint on the BCR gene in the first intron (m-bcr), resulting in a sic chronic clonal myeloid diseases and usually does not change sig-
190-kDa fusion protein instead of the classic 210-kDa protein observed nificantly over months to years. Polycythemia vera is associated with
in most patients with CML (see Fig. 89–3). The m-bcr molecular lesion increased red cell mass and hemoglobin concentration and displays
is similar to that observed in approximately 60 percent of patients clinical signs of plethora; CML does not have these features. Patients

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