Page 1497 - Williams Hematology ( PDFDrive )

1472 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1473

have been indicative of a clonal myeloid disorder. 981–983 Some cases Differential Diagnosis
may arise in the hematopoietic multipotential cell, others in a neu- Most leukemoid reactions are associated with an obvious underlying
trophil progenitor cell (Chap. 85). 981–985 Evidence points to defective cause, such as pancreatitis, carcinoma, connective tissue disease, smok-
apoptotic signals accounting, in part, for the striking accumulation er’s neutrophilia, and chronic bacterial or fungal infection. The leukocyte
of segmented neutrophils in the blood. The median age at onset is alkaline phosphatase level usually is markedly elevated in chronic neu-
986
987
approximately age 65 years. Younger patients may be affected. As in trophilic leukemia and markedly decreased in CML. More to the point,
most clonal myeloid diseases, men are affected more frequently than are molecular studies identifying BCR gene rearrangement or the presence
women. of BCR-ABL1 transcripts should distinguish chronic neutrophilic leu-
kemia (BCR-ABL1–negative) from neutrophilic CML (BCR-ABL1–pos-
Clinical Features itive; see “Special Clinical Features” above). In the latter case, more than
Symptoms and Signs Patients may complain of weakness, anorexia, half of the patients have thrombocytosis and megakaryocytic hyperpla-
weight loss, abdominal pain, and easy bruising. Symptoms and signs of sia, which are uncharacteristic of chronic neutrophilic leukemia. The
gouty arthritis occur in approximately one-third of cases. The spleen is presence of a CSF3R or JAK2 mutation with a classical clinical picture
enlarged in almost all cases, and the liver frequently is enlarged. Lymph- would be strong diagnostic evidence for the disease.
985
adenopathy is very infrequent. A hemorrhagic tendency is present in
some patients. Treatment
Laboratory Findings Although some patients have a normal No systematic studies of treatment have been reported. Although
hemoglobin concentration at the time of presentation, most have mild hydroxyurea, IFN-α, or cytarabine may decrease the white count and
to moderate anemia on presentation. The reticulocyte count usually spleen size, long-term benefit is unusual. 987–990 Intensive therapy has led
is between 0.5 and 3.0 percent. The platelet count rarely is less than to early posttreatment deaths. With identification of a specific genetic
9
125 × 10 /L and usually is normal. Coagulation times are normal. The mutation, either a JAK2 inhibitor (e.g., ruxolitinib) (for the CSF3R T618I
9
total leukocyte count usually is between 25 and 100 × 10 /L in most mutation) or dasatinib (for the CSF3R S783fs mutation) should be consid-
9
cases, and only rarely is less than 20 × 10 /L or exceeds 100 × 10 /L. ered. The disease is rare and clinical trials would be difficult. In vitro
9
Neutrophils compose 85 to 95 percent of the white cells. Although seg- studies of cell sensitivity and reports of individual responses may have
mented cells usually dominate, occasional cases have a high proportion to be relied upon. 991–993 Allogeneic stem cell transplantation in eligible
of band forms. Very infrequently, metamyelocytes, myelocytes, and patients may be curative. 994
nucleated red cells may be present in patients. Basophil and eosinophil
counts are not increased. Blasts nearly always are absent from the blood. Course and Prognosis
Neutrophil alkaline phosphatase activity is increased in almost all cases. The disease is fatal, with a median survival of approximately 2.5 years
The marrow invariably shows granulocytic hyperplasia with and a range of 0.5 to 6 years. 987–990 A case of spontaneous remission has
myeloid-to-erythroid ratios as high as 10:1. Myeloblasts are not overtly been reported. The prognosis is considerably worse than the prognosis
increased in number (0.5 to 3.0 percent). Megakaryocytes are either for CML despite the prevalence of mature neutrophils and the paucity
normal or slightly increased in number and have normal distribution of blasts. Newer approaches with dasatinib or ruxolitinib for the appro-
and morphology. Erythropoiesis usually is mildly decreased. Unlike priate genetic mutations (see “Treatment” above) may provide better
CML, reticulin fibrosis is unusual. A few cases with dysmorphic features outcomes. Causes of death have included (1) intracranial hemorrhage,
in the marrow (acquired Pelger-Hüet anomaly, erythroid, dysplasia, sometimes in the presence of adequate platelet counts and coagulation
micromegakaryocytes) have been reported. Serum vitamin B -binding times, suggesting a vascular infiltrative process; (2) severe infection; (3)
12
protein and vitamin B levels both are markedly increased above nor- transformation to AML; and (4) the toxic effects of intensive therapy.
12
mal. Serum uric acid concentration is increased, and serum LDH activ- The disease usually afflicts older persons, and cardiac, pulmonary, and
ity may be increased. vascular diseases contribute to a fatal outcome.
Almost every case examined postmortem had liver and splenic A remarkable frequency of concordant essential monoclonal gam-
enlargement. Portal hepatic and splenic red pulp infiltrates of neu- mopathy or myeloma has been described. 983,995–1003 In two cases, the
trophils or islands of extramedullary hematopoiesis with immature extreme neutrophilia proved to be a polyclonal response to a plasma
myeloid cells and megakaryocytes are characteristic. cell disorder. 983,1004 Chronic neutrophilic leukemia has evolved from
Cytogenetic and Genetic Findings By definition, the Ph chro- polycythemia vera or oligoblastic leukemia, 1005–1009 supporting its rela-
mosome, BCR gene rearrangements, and BCR-ABL1 transcripts are tionship to the clonal hemopathies. 983,1010,1011
absent. 987–990 Most patients have normal karyotypes, but approximately
25 percent of patients have nonrandom abnormalities of chromo- BCR REARRANGEMENT-NEGATIVE
somes. Deletions of chromosome 20q and trisomy 21 or 9 are the PHENOTYPICALLY TYPICAL CHRONIC
990
most common abnormalities. The disease has been shown to be asso-
ciated with a mutation in the colony-stimulating factor 3 receptor gene MYELOGENOUS LEUKEMIA
(CSF3R) alone (approximately 30 percent of cases), or a combination A very small proportion of patients (approximately 4 percent) with
of mutated CSF3R and a SET binding protein gene (SETBP1) mutation clinical manifestations within the limits usually applied to the diagnosis
(approximately 60 percent of cases) or the JAK2 V617F mutation alone of CML have neither a Ph chromosome (classic, variant, or masked)
(approximately 10 percent of cases). 991,992 Two principal mutations were nor evidence of rearrangement of BCR on chromosome 22. This cir-
observed in CSF3R: membrane proximal CSF3R S783fs mutation and trun- cumstance represents BCR-negative CML. The literature describing
cated CSF3R T618I mutation. The former results in deregulation of the JAK Ph chromosome–negative CML prior to 1987 is difficult to evaluate
family kinases and may respond to JAK inhibitors, whereas the later because many cases were not studied carefully for masked or vari-
deregulates SRC family-TNK2 kinases and confers sensitivity to dasa- ant translocations and for the BCR gene rearrangement. Ph chromo-
tinib. Four of five prior reports of JAK2 mutations in a single patient some–negative CML is a clonal disease that has the propensity for
991
903
with chronic neutrophilic leukemia were cited. In the fifth report, six lymphoid and myeloid transformation. 1012,1013 Although most cases
patients with the disease were studied and one had a JAK2 V617F mutation. of BCR rearrangement–negative CML are closer in manifestations to

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