Page 1495 - Williams Hematology ( PDFDrive )

1470 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1471

Cytogenetic Findings A wide array of cytogenetic findings have In patients with eosinophilic leukemia without an imatinib-sen-
been reported in cases of chronic eosinophilic leukemia. Notable sitive mutation or in patients who become resistant to imatinib and
935
translocations include a high frequency of translocations involving chro- unresponsive to a second-generation TKI (e.g., dasatinib or nilotinib)
mosome 5, t(1;5), t(2;5), t(5;12), t(6;11), 8p11, trisomy 8, and numerous and who are progressing, ablative or nonablative allogeneic stem cell
others, infrequently. Chromosome 5 often is translocated at the site of transplantation can be considered if they are in an acceptable age range
the PDGFR-β gene, and the phenotype usually is more compatible with and have access to a matched-related or matched-unrelated donor. 942,943
CMML with eosinophilia. Chromosome 5 from band q31–35 contains In TKI-insensitive patients without the option of transplantation,
several genes relevant to eosinophilopoiesis, including those encoding empirical treatment with glucocorticoids, hydroxyurea, or anti–IL-5 944,945
IL-5, IL-3, GM-CSF, and PDGFR-β. A cryptic interstitial CHIC2 dele- to decrease eosinophil counts and mute the progress of eosinophil-
tion on chromosome 4 (q12;q12) results in the fusion gene FIL1L1– mediated cutaneous, cardiac, pulmonary, and neurologic tissue damage
PDGFR-α, normally separated by the CHIC2 gene, and in a phenotype should be considered. These approaches may relieve symptoms for a
that can be considered a form of chronic eosinophilic leukemia, virtu- time, but are temporizing if therapy with drugs that might be effective in
ally always associated with marrow mastocytosis, which is of particular inhibiting clonal expansion or evolution is not effective (e.g., cytarabine,
note because, like the PDGFR-β mutations in CMML with eosinophilia, anthracycline antibiotic, etoposide).
of a near-universal response to treatment with imatinib. 935–937
Course and Prognosis
Serum Tryptase Level Elevation Versus Normal Levels If chronic eosinophilic leukemia is not TKI-sensitive, the long-term
The elevation of serum tryptase level (>11.5 ng/mL) has been used to outlook is one of probable progressive cardiac and neurologic disabil-
distinguish a subset of patients who (1) are male, (2) have marrows that ity. Transformation to acute eosinophilic or myelogenous leukemia can
are intensely hypercellular with a higher proportion of immature eos- occur. Allogeneic stem cell transplantation is potentially curative. In
inophils and with dysmorphic mast cells with a CD117−CD25+CD2− tyrosine kinase sensitive cases, hematologic normalization, reversal of
genotype and phenotype (distinguishing these cells from classic marrow fibrosis and mastocytosis, resolution of skin lesions, normal-
mastocytosis, which are CD117+CD25+CD2+), (3) have dramatically ization of spleen size, and restoration of well-being occurs in the great
higher serum vitamin B and IgE levels, (4) are more prone to restric- preponderance of cases. Cardiac, neurologic, and pulmonary changes
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tive pulmonary disease and endomyocardial fibrosis, (5) have the usually cannot be reversed but should be stabilized. The long-term out-
FIP1L1–PDGFR-α fusion gene, and (6) are responsive to imatinib. look with tyrosine kinase therapy is uncertain. However, it likely will
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Patients with normal serum tryptase levels are more prone to obstruc- decisively and dramatically improve survival compared to other prior
tive pulmonary restrictive disease, eosinophilic dermatitis, and gastro- therapy and should greatly improve the prognosis of patients with a
intestinal complaints. molecular target for the drug.

Differential Diagnosis CHRONIC BASOPHILIC LEUKEMIA
Eosinophilia can occur for many reasons (Chap. 62). The first step is to This type of clinical disorder, in which the patient has marrow and
identify signs that may point to a clonal myeloid disease. These signs blood basophilia and other findings compatible with a clonal myeloid
include anemia, thrombocytopenia, splenomegaly, immature eosino- disease without evidence of the BCR-ABL1 translocation, is rare. Two
phils in the marrow examination, evidence of dysmorphic cells in blood reports of such a syndrome occurring in five patients have been pub-
or marrow, for example, atypical megakaryocytes or dysmorphic mast lished. 946,947 The marrow was intensely hypercellular in the three major
cells, cardiac or pulmonary manifestations, which may occur secondary lineages. Dysmorphic megakaryocytes were evident. Basophilia in mar-
to chronic eosinophilic leukemia, and markedly elevated serum trypt- row and blood was striking, although eosinophilia also was evident
ase or vitamin B level. The former signs, especially in the aggregate, in two patients and increased mast cells in three patients. The clinical
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are highly suggestive, but the presence of a cytogenetic abnormality in effects of basophilic mediator release were evident in two patients. One
myeloid cells is diagnostic of a clonal myeloid disease (leukemia). If the patient evolved to AML; another recovered after allogeneic transplan-
latter is not evident, PCR and/or flow cytometry to search for a clonal tation. The cases had similar findings, leading to the suggestion they
T lymphocyte abnormality should be performed. Whether the eosino- represented Ph chromosome–negative chronic basophilic leukemia. In
philic leukemia is typical or represents an eosinophilia with idiopathic one case, a PRKG2–PDGFR-β fusion gene was evident and the patient
myelofibrosis, CMML, or MDS is less important than if it has a muta- responded to imatinib.
tion that is imatinib sensitive (e.g., PDGFR mutation).

Therapy JUVENILE MYELOMONOCYTIC LEUKEMIA
Patients (nearly always men) whose cells display a FIP1L1–PDGFR-α Epidemiology
have a very high probability of responding to imatinib at a dose of 100 Ph chromosome–positive, adult-type CML occurring in children
to 400 mg/day. 936–940 The tyrosine kinase activity of this fusion protein is younger than age 15 years makes up approximately 3 percent of child-
948
two orders of magnitude more sensitive to imatinib than that of BCR- hood leukemias and approximately 10 percent of all cases of CML.
ABL1. However, because not all patients taking 400 mg/day achieve a Although CML occurs in children of all ages, it is rare in children
molecular remission, and that goal may be more likely to result in long- younger than age 5 years. With the exception of a propensity to present
term remission, initial therapy remains at 400 mg/day or an equivalent with higher total leukocyte counts and with leukostatic signs or symp-
dose of another TKI, such as dasatinib or nilotinib, and PCR monitor- toms, CML in children has the typical manifestations and course of the
ing is appropriate. Dose adjustment upward if molecular remission is disorder seen in adults.
not achieved can be considered. Unlike the case in CML, patients with A disorder different from adult-type CML, designated juvenile
chronic eosinophilic leukemia with significant side effects when taking myelomonocytic leukemia, represents approximately 1.5 percent of child-
imatinib, 400 mg/day, have a reasonable probability of having a good hood leukemias. It occurs most often in infants and children younger
response at lower doses. Dasatinib and nilotinib are also active. 941 than age 4 years and is similar in some respects to adult subacute or
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