Page 1496 - Williams Hematology ( PDFDrive )

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

CMML because the two diseases share a prominent monocytic compo- Although clonal chromosome abnormalities have been found in
968
nent in the leukemic cell population. 949–952 some cases, the cytogenetic abnormalities have no consistent pattern,
and more than half of the patients have normal karyotypes. The BCR-
Pathogenesis ABL1 fusion gene is not present. 968–970 The phenotype of monosomy
This disorder is a clonal myeloid disease that originates in an early 7 syndrome overlaps with juvenile myelomonocytic leukemia, and
hematopoietic multipotential cell. Evidence indicates this cell may an abnormality of chromosome 7 (del 7, del 7q, others) is present in
be pluripotential (myeloid-lymphoid) in some cases and myeloid in approximately one-fifth of patients. 949
others. 953–956 Patient-derived induced pluripotential stem cells recapit-
ulated the growth patterns in vitro of the human disease and drug Course, Prognosis, and Treatment
957
inhibition of MEK kinase reduced their GM-CSF growth potential. The median survival of patients with juvenile myelomonocytic leuke-
RAS mutations in hematopoietic cells are present in approximately 20 mia has been less than 2 years. 949,950 Children younger than 2 years are
882
percent of patients. Approximately one in 10 patients with juvenile more likely to have a protracted course. The disease has been refrac-
958
myelomonocytic leukemia have mutations of NF1 and manifest type tory to most chemotherapy. In a study of nine patients, four of whom
1 neurofibromatosis. This frequency is approximately 400 times the were treated with a five- or six-drug intensive regimen, remissions were
expected occurrence in a comparable pediatric population. 959–961 The 11 months to more than 27 months, compared with untreated or lightly
971
linkage between neurofibromin, the protein encoded by the NF1 gene, treated patients, four of whom died within 7 months. Even in the
GTPase activity proteins, and the activation state of RAS-encoded pro- treated patients, complete suppression of the disease did not occur, and
966
teins has led to a postulated sequence of events that may be triggered treatment protocols to induce and sustain remissions were lacking.
by the extraordinarily heightened sensitivity of the colony-forming cells A program of cytosine arabinoside, etoposide, vincristine, and isotre-
in the marrow and blood of infants with the disease to the proliferative tinoin resulted in a highly favorable response in five children treated.
effects of GM-CSF. The latter initiates signal transduction from the cell Three patients relapsed and were treated with cytarabine by infusion
membrane to the nucleus via RAS protein activation. 961,962 Mutations in and subcutaneously and with etoposide. All patients were alive, and the
the PTPN11 gene have been found in approximately one-third of chil- range of survival at the time of publication was 8 to 89 months, with a
dren with juvenile myelomonocytic leukemia, and the mutations in median survival of 27 months. The resistance of these cells to currently
NF1, RAS, and PTPN11 usually do not coincide. 1025,1026 However, they available therapy is distressingly highlighted by the sense of success in
each may act through a common pathway. PTPN11 encodes SHP-2, prolonging the life of infants and young children by a few years. Inten-
a phosphatase, which is an upstream regulator of RAS; thus, all three sive therapy can control disease, but curative chemotherapy has been
972
mutations can contribute to deregulation of RAS signaling. As an aside, elusive. The inclusion of isotretinoin was based on a prior report of
children with Noonan syndrome, which is characterized by short stat- responsiveness to the drug used alone; however, this observation has
973
ure, dysmorphic facies, skeletal abnormalities, and cardiac defects, have not been confirmed. The GM-CSF antagonist E21R, inhibitors of
a germ-cell mutation of PTPN1. These children may have a transient RAF-1 gene expression, blockers of RAS protein farnesylation, and
disorder that closely mimics juvenile myelomonocytic leukemia. 963 angiogenesis inhibitors are among other drug approaches to the disease
being studied. 952,974
Clinical Findings Allogeneic stem cell transplantation is an important approach
Symptoms and Signs Infants present with failure to thrive, and chil- to therapy and may provide the best chance of long-term survival in
dren present with malaise, fever, persistent infections, and exaggerated selected children. 975–977 Hence, a rapid search for a matched-unrelated
skin, oral, or nasal bleeding. Hepatomegaly can occur. Splenomegaly, donor, including cord blood sources, is important in patients without
sometimes massive, is present in almost all cases. Lymphadenopathy is matched sibling donors. Transplantation from a histocompatible sibling
frequent. 949–952 More than half of the patients have eczematoid or mac- or matched-unrelated donor resulted in an event-free survival at 5 years
ulopapular skin lesions and xanthomatous lesions, and multiple café- of approximately 50 percent, and from matched-cord blood stem cells
964
950
au-lait spots (neurofibromatosis type 1) may occur. The xanthomas of approximately 45 percent, unless monosomy 7 was present, which
977
may be the earliest signs of neurofibromatosis. 950,951 Noonan syndrome lowers 5-year survival to approximately 25 percent. Children trans-
(dysmorphic facies, short stature, heart disease, mental retardation, planted before age 1 year had better results (approximately 50 percent)
977
cryptorchidism, webbed neck, chest deformities, and bleeding diathesis) than did older children (approximately 30 percent). DLI has placed a
978
may coexist. 951 posttransplantation patient in relapse into remission, but, in general,
Laboratory Findings Anemia, thrombocytopenia, and mild to this procedure is ineffective in patients who relapse after transplantation.
moderate leukocytosis are common. The leukocyte count usually is A minority of patients have a smoldering course for 2 to 4 years.
9
greater than 10 × 10 /L with a median leukocyte count at diagnosis of Thereafter, the disease usually rapidly progresses, and patients die of
9
approximately 35 × 10 /L. The blood has an increased monocyte con- infection or hemorrhage. Occasional patients have a very long survival
centration of 1 to 100 × 10 /L, immature granulocytes including a small (>10 years) despite persistence of abnormal blood counts and sple-
9
percentage of blast cells, and nucleated red cells. Fetal hemoglobin con- nomegaly, independent of the type or intensity of therapy. Some chil-
centration is increased in approximately two-thirds of the patients. The dren convert to a full-blown AML with a rapidly fatal outcome. Cases of
marrow aspirate is hypercellular as a result of granulocytic hyperplasia; juvenile myelomonocytic leukemia may be associated with transforma-
the number of erythroblasts and megakaryocytes usually are decreased. tion to acute lymphoblastic leukemia. 979
Monocytic cells are increased but may not be as striking as in the blood.
Leukemic blast cells are present in modest proportions (<20 percent). CHRONIC NEUTROPHILIC LEUKEMIA
Cell culture of blood and marrow shows a striking preponderance
of monocytic progenitors, even in the absence of overt monocytosis in History, Pathogenesis, and Epidemiology
the marrow. 965,966 Granulocyte-monocyte colony-forming cells show a In 1920, Tuohey described the first recorded case of an unusual sustained
980
marked tendency to spontaneous growth if adherent (monocytic) cells neutrophilia with splenomegaly without fever, inflammation, cancer, or
966
are not depleted from culture. The effect is mediated by a release of other cause of a leukemoid reaction. Use of X-chromosome-linked poly-
large quantities of GM-CSF by monocytes in culture. 967 morphic genes in blood cells and FISH of chromosome abnormalities

Kaushansky_chapter 89_p1437-1490.indd 1471 9/18/15 3:42 PM