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1450 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1451

with primary myelofibrosis invariably have marked teardrop poiki- blood white cell concentration, spleen size, and dose of cytolytic therapy
locytes and other severe red cell shape, size, and chromicity changes, planned. If these variables suggest a high risk for a significant amount
as well as prominent nucleated red cells in the blood; CML rarely has of cell lysis, allopurinol 300 mg/day orally and adequate hydration
these features. Patients with essential thrombocythemia have a plate- to maintain a good urine flow should be instituted prior to therapy.
let count greater than 450 × 10 /L and usually only mild neutrophilia Allopurinol is associated with a high frequency of allergic skin reac-
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(<20 × 10 /L); the slight neutrophilia distinguishes it from the propor- tions and should be discontinued after the blood leukocyte count and
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tion (approximately 25 percent) of CML patients with platelet counts spleen size have decreased and the risk of exaggerated cell lysis has
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greater than 450 × 10 /L, who at the time of diagnosis have white cell passed. If hyperuricemia is extreme, usually over 9 mg/dL, rasburicase
407
counts above 25 × 10 /L. In addition, patients with the clinical features can be administered. Rasburicase is a recombinant urate oxidase that
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of polycythemia vera or primary myelofibrosis do not have the Ph converts uric acid to allantoin. Rasburicase, unlike allopurinol, reduces
chromosome or BCR rearrangement in their blood and marrow cells, the uric acid pool very rapidly, does not result in the accumulation of
except in extremely rare cases. A very small proportion of patients with xanthine or hypoxanthine, and does not require alkalinization of urine
408
apparent essential thrombocythemia has BCR-ABL1 transcripts in their facilitating phosphate excretion. Although the manufacturer recom-
marrow and blood cells, and occasionally a Ph chromosome and may mends a dose every day for 5 days, several reports have indicated that
represent an atypical initial phase of CML (see “BCR-ABL1–Positive one injection will produce a rapid and sustained decrease in serum uric
Thrombocythemia” above). The presence of a mutation in the JAK2 gene acid, significantly decreasing the cost of therapy. Another alternative
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in more than 95 percent of patients with polycythemia vera is an impor- is to use allopurinol for a few days after one injection of rasburicase. A
tant distinguishing feature (Chap. 84). The blood cells of approximately dose of 0.2 mg/kg of ideal body weight of rasburicase intravenously has
50 percent of patients with primary myelofibrosis or essential throm- been used. 410
bocythemia carry the JAK2 gene mutation and in those with primary
myelofibrosis who do not, a significant proportion have a mutation in
the calreticulin or the c-MPL gene (Chap. 86). INITIAL CYTOREDUCTION THERAPY
Increased awareness of the features of related disorders, such as A TKI is now used as initial therapy in patients with CML. In cases
chronic myelomonocytic leukemia (CMML) and chronic neutrophilic where the white cell count is markedly elevated, hydroxyurea can be
leukemia, and an appreciation that older patients are prone to atypical used prior to or in conjunction with a TKI. If rapid cytoreduction is
clonal myeloid diseases, have minimized the inappropriate diagnosis of required because of signs of the hyperleukocytic syndrome, leukapher-
Ph chromosome–negative CML, which should be avoided unless the esis and hydroxyurea often are combined.
clinical features are characteristic of classic CML and a masked Ph chro-
mosome or BCR rearrangement is not found. Leukapheresis
Reactive leukocytosis can occur with absolute neutrophil counts Leukapheresis can control CML only temporarily. For this reason, it is
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of 30 to 100 × 10 /L. Usually these leukemoid reactions occur in the rarely used in chronic phase CML and is useful in only two types of
setting of an overt inflammatory disease (e.g., pancreatitis), cancer (e.g., patients: the hyperleukocytic patient in whom rapid cytoreduction can
lung), or infection (e.g., pneumococcal pneumonia). If the incitant is reverse symptoms and signs of leukostasis (e.g., stupor, hypoxia, tinni-
not apparent, the absence of granulocytic immaturity, basophilia, or tus, papilledema, priapism), 249–251 and in the pregnant patient with CML
splenomegaly, and the absence of BCR/ABL1 in blood cells virtually who can be controlled by leukapheresis treatment without other ther-
eliminates classic CML as a consideration. apy either during the early months of pregnancy when therapy poses a
The precise diagnosis of CML is helpful in estimating the patient’s higher risk to the fetus or, in some cases, throughout the pregnancy. 411,412
prognosis, identifying the utility of TKIs, and assessing the timing of spe- Because of the large body burden of leukocytes in marrow, blood, and
cial therapies, such as allogeneic hematopoietic stem cell transplantation. spleen, and the high proliferative rate in CML, leukocyte reduction by
apheresis is less efficient than in other types of leukemia. 249,251 Leuka-
pheresis reduces the burden of tumor cells subject to chemotherapeu-
Ph CHROMOSOME–POSITIVE CLONAL tically induced cytolysis and thus the production and the excretion of
MYELOID DISEASES AND APLASTIC ANEMIA uric acid. In hyperleukocytic nonpregnant patients, leukapheresis is
The Ph chromosome has been found rarely in patients with appar- best used in conjunction with hydroxyurea to ensure rapid and optimal
reduction in white cell count.
396
ent polycythemia vera, polycythemia vera that later evolves into Ph
chromosome–positive CML, 397–399 primary myelofibrosis, 400,401 and mye-
lodysplastic syndrome (MDS). 402,403 Molecular studies to determine Hydroxyurea
the presence of the BCR-ABL1 were not performed in cases reported Hydroxyurea 1 to 6 g/day orally, depending on the height of the white
413
before 1985. Essential thrombocythemia with a Ph chromosome and/ cell count, can be used to initiate elective therapy. Urgent treatment
or BCR-ABL1 rearrangement in blood cells was discussed earlier (see of extraordinary total white cell counts may require higher doses. The
“Special Clinical Features” above). Rare cases of aplastic anemia have dose of hydroxyurea should be decreased as the total white cell count
presented with BCR-ABL1–positive cells or have evolved into BCR- decreases and usually is given at 1 to 2 g/day when the total white cell
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ABL1 CML. 404,405 count reaches 20 × 10 /L. The drug should be temporarily discontinued
if the white cell count drops below 5 × 10 /L. If hydroxyurea is being
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used in combination with a TKI, it is usually tapered and discontinued
once a hematologic response to the TKI is observed.
THERAPY
Anagrelide
HYPERURICEMIA Anagrelide can be used for platelet reduction in patients who present with
Hyperuricemia and hyperuricosuria are frequent features of CML at elevated platelet counts. This agent acts directly to decrease megakary-
diagnosis or in relapse. The need for treatment of hyperuricemia is ocyte mass, and it can lead to a precipitous fall in platelet counts. In
406
a function of the elevated pretreatment serum uric acid concentration, occasional patients who still have significant thrombocythemia after a

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