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1390 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1391

new chimeric or fusion genes: RAR-α–PML, which is actively tran- Hepatomegaly, splenomegaly, and lymphadenopathy are more frequent
scribed in APL, and PML–RAR-α, which also is transcribed and may in monocytic leukemia. 207,505–507
account for the aberrancy in hematopoiesis. The PML–RAR-α gene has The proportion of monocytic cells is usually greater than
two isoforms that produce a short- and a long-type fusion messenger 75 percent. The total leukocyte count is higher in a larger proportion
RNA, respectively. Patients with the short isoform may have a worse of patients, and hyperleukocytosis occurs more frequently (approxi-
487
outcome than those with the longer form. Polymerase chain reaction mately 35 percent) than in other variants. 508–510 The marrow and blood
(PCR) for the mRNA of the fusion gene can be used to identify resid- cells may be largely monoblasts (acute monoblastic leukemia) or more
ual cells during remission and may predict relapse. The PML–RAR-α mature-appearing promonocytes and monocytes (acute monocytic
488
transgene can reproduce the disease in mice, although in some mod- leukemia) (see Fig. 88–2H). When the blood contains more mature-
els a superimposed FLT3 mutation is required to express the disease. appearing monocytic cells, the marrow contains a lower proportion of
FLT3 mutations are frequently found in human disease, especially in the blast cells, approximately 15 to 50 percent. When the blood monocytes
hypogranular variant. 157 are largely blast cells, the marrow contains approximately 50 to 90 per-
A propensity to hemorrhage is a striking feature of this subtype. cent blasts. In nearly all cases, 10 to 90 percent of monocytic cells react
The prothrombin and partial thromboplastin times are prolonged, and for nonspecific esterase stains, α-naphthyl acetate esterase, and naphthol
the plasma fibrinogen level is decreased in most cases. The disturbance AS-D-chloroacetate esterase; in a cytochemical or chemoluminescence
in coagulation first was thought to principally result from intravascu- assay; or with monoclonal antibodies against monocyte surface anti-
lar coagulation initiated by procoagulant released from the granules of gens, especially CD14. Immunoreactivity of cells for lysozyme is charac-
the leukemic promyelocytes. Elevated thrombin–antithrombin com- teristic. Serum and urine lysozyme levels are elevated in most patients.
plexes, prothrombin fragment 1+2, and fibrinopeptide A plasma levels Serum lactic dehydrogenase and β -microglobulin concentrations are
2
support that supposition. Increased levels of fibrinogen–fibrin degrada- increased in greater than 80 percent of patients. Plasminogen activa-
511
tion products, D-dimer, and evidence of plasminogen activation indi- tor inhibitor-2 is present in the plasma and the cells of a high proportion
512
cate fibrinolysis. 489–491 Furthermore, decreased levels of plasminogen, of patients. Auer rods are absent when monoblasts dominate but may
increased expression of annexin II on the leukemic cells, and reports of be present in cases where promonocytes and monocytes are prevalent
492
responses to tranexamic acid support a role for fibrinolysis in the bleed- in blood and marrow. Leukemic monocytes have Fc receptors and can
493
ing in APL. Release of nonspecific proteases may further contribute to ingest and kill microorganisms in some cases. 513,514
fibrinogenolysis. Thus, the coagulopathy is now considered tripartite. 494 There is an association between translocations involving chro-
Although APL responded to chemotherapy regimens for AML, mosome 11, especially region 11q23, and monocytic leukemia. 292–294
495
especially those containing an anthracycline antibiotic, the cyto- In particular, t(9;11) is found in leukemic monocytes. 295,296,507,508 In
logic pattern of response in the marrow often was paradoxical. 496–499 t(9;11) the β -interferon gene is translocated to chromosome 11, and
1
Persistence of leukemic promyelocytes preceded remission in the the protooncogene ETS-1 is translocated to chromosome 9 adjacent to
absence of further therapy, whereas induction of marrow cell hypopla- the α-interferon gene. The latter juxtaposition may be important in the
sia was classically considered a requirement for remission in patients pathogenesis of monocytic leukemia. 515
with AML. Generally, if leukemic blast cells persist after therapy for The expression of FOS is closely correlated with monocytic matu-
AML, relapse ensues unless hypoplasia is induced by more cytotoxic ration of cells in myelomonocytic and monocytic leukemia and in nor-
therapy. The unusual pattern of response in APL was put into context by mal monocytopoiesis. 516,517 Absence or markedly decreased expression
reports of successful treatment with isomers of retinoic acid, an agent of the retinoblastoma gene growth-suppressor product (p105) is pres-
499
that leads to maturation of leukemic promyelocytes in vitro. In 1988, ent in approximately half of patients with monocytic leukemia. Patients
518
the success of ATRA in remission induction was reported 500,501 and express a more dramatic phenotype. A variant of acute monocytic
confirmed. 290,291 Relapse occurs invariably, however, so chemotherapy leukemia in which the leukemic cells have monocytoid features and
regimens or addition of arsenic trioxide also were required. Use of are positive for early and late monocytic lineage antigens and for TdT
ATRA has decreased the risk of early hemorrhagic complications and activity often occurs after prior radiotherapy or chemotherapy and is
death and has enhanced the long-term response to chemotherapy. relatively resistant to treatment. A syndrome of acute monoblastic
519
Despite the improvement in therapy, approximately 5 to 10 percent of leukemia with t(8;16), resulting in MOZ-CBP fusion gene, is charac-
patients die during remission induction, most of hemorrhage, often into terized by mildly granular promonocytes (simulating hypogranular
the brain. The prolonged remissions of patients with promyelocytic leu- promyelocytes), intense phagocytosis of red cells, erythroblasts, and
kemia has been interrupted in approximately 3 percent of cases by the sometimes neutrophils and platelets in blood and marrow, simulating
later appearance of oligoblastic myelogenous leukemia with deletions macrophagic hemophagocytic syndrome, intravascular coagulation or
of all or part of chromosome 5 or 7 and no evidence of involvement of primary fibrinolysis, and a high frequency of extramedullary disease. 520
chromosome 17, compatible with a myelogenous leukemia secondary The management of monocytic leukemia is complicated by a
to cytotoxic chemotherapy. 501–503 The responsiveness to arsenic trioxide greater incidence of CNS or meningeal disease either at the time of
has provided additional treatment approaches that are discussed in the diagnosis or as a form of relapse during remission. Thus, examina-
“Therapy” section below. tion of cerebrospinal fluid is often recommended, even in the absence
of symptoms, when remission has been achieved. 208,507,508 Some thera-
ACUTE MONOCYTIC LEUKEMIA pists recommend prophylactic intrathecal therapy with methotrexate
or cytosine arabinoside for patients who enter remission after having
Monocytic leukemia was first reported by Reschad and Schilling- presented with hyperleukocytic acute monocytic leukemia because of
Torgau in 1913. Approximately 8 percent of patients with AML the risk of subclinical meningeal involvement. Others posit that high-
504
present with monocytic leukemia, which is referred to as M5 in the dose cytarabine with CNS penetration potential used in consolidation
FAB classification. Patients with monocytic leukemia have a higher chemotherapy suffices for this purpose. There are few data for guidance
prevalence (50 percent) of extramedullary tumors in the skin, gin- in this matter.
giva, eyes, larynx, lung, rectum and anal canal, bladder, lymph nodes, Rare cases of dendritic cell or Langerhans cell phenotype have been
meninges, CNS, and other sites than do other phenotypes (<5 percent). described (Chap. 71). 521,522 Uncommon cases of histiocytic sarcoma are

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