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1386 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1387

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the myeloproliferation. Candidate oncogenes on chromosome 21 In bilineal (interlineal) acute leukemias, a proportion of cells
responsible for the phenomenon include FPDMM, RUNX1 (CBF-β), (>10 percent) have lymphoid and myeloid markers; interlineal here
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and IFNAR, among others. GATA-1 mutations have been found in refers to lymphopoietic and myeloid gene expression. Bilineal (biphe-
nearly all patients with TMD and in acute megakaryocytic leukemia in notypic) leukemias are heterogeneous. Some patients have cells with
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Down patients. The TMD syndrome may disappear, only to be fol- both lymphoid and myeloid markers (chimeric), whereas other patients
lowed shortly thereafter by acute leukemia, predominantly AML, but have cells with either lymphoid or myeloid markers but evidence that
occasionally acute lymphocytic leukemia (ALL). all the cells are part of the same malignant clone (mosaic). The bilin-
One hypothesis for TMD is that the disorder originates in a primi- eal leukemias may be synchronous (lymphoid and myeloid cells are
tive cell of fetal hepatic hematopoiesis. The cell involutes and is replaced present simultaneously) or asynchronous (in which lymphoid cells are
with marrow stem cells. Approximately 25 percent of newborns with succeeded by myeloid cells or vice versa), but evidence exists for their
Down syndrome and transient leukemia develop acute megakaryocytic origin from the same clone.
leukemia in the first 4 years of life. 387–389 Cases of biphenotypic leukemia that are morphologically or cyto-
Very-low-dose cytarabine has been suggested for those patients chemically indicative of myelogenous leukemia have been referred to as
with severe hepatic fibrosis, very high white cell counts, or hydrops LY+AML; the cases that are more indicative of lymphocytic leukemia
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fetalis. TMD cells in these infants are very sensitive to cytarabine. 390,391 are referred to as MY+ALL. As a group, interlineal hybrid leukemias
Children with Down syndrome have a 150-fold risk of AML treated with current regimens respond to therapy at approximately the
and about a 40-fold risk of ALL by age 5 years. A slightly increased same rate as AML cases without lymphoid markers. Some observers
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risk of acute leukemia persists into older age. Myelogenous leukemia suggest altering drug regimens, depending on the balance between lym-
in patients with Down syndrome often has a megakaryoblastic or phoid and myeloid biochemical (drug-response) patterns. 412
erythroid phenotype and may have an interstitial deletion of Acute leukemias may be intralineal hybrids in that the blast cells
chromosome 21. 380,381,392–395 This requires mutation in the GATA1 gene in have markers for two or more myeloid lineages (e.g., erythroid, granu-
addition to trisomy 21, and sequential epigenetic changes occur as well locytic, and megakaryocytic) or, in the case of lymphocytic leukemias,
in the evolution of acute megakaryoblastic leukemia. 395,396 The response both immunoglobulin gene rearrangement (B-lymphocyte type) and
rate of infants with Down syndrome and AML to chemotherapy is very T-cell receptor gene rearrangement (T-lymphocyte type).
high over prolonged followup and better than the response of patients
without Down syndrome. 387,391,397,398 The response to adjusted-dose Myeloid–Natural Killer Cell Hybrids and t(8;13) Myeloid–
anthracycline antibiotic and cytarabine in Down syndrome children Lymphoid Leukemias
with AML is approximately 90 percent and the event-free 5-year sur- Although most hybrid leukemias share myeloid and either B- or T-
394
vival is approximately 80 percent. In those cases with relapsed or lymphocyte markers, two notable syndromes are associated with hybrid
refractory disease, outcomes are poor even with allogeneic HSC trans- leukemias: (1) the myeloid leukemia and natural killer cell hybrid
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plantation. ALL may occur, and the response to therapy is similar to (CD56+, CD7+, CD13+, CD33+) 413–419 and (2) the lymphoma, eosin-
the response of patients without Down syndrome of the same age. Most ophilia, and t(8;13) myeloid leukemia hybrid. 420,421 Signs of lymphoma,
solid tumors occur less frequently in Down syndrome patients. 390 such as mediastinal or other lymphadenopathy and extranodal lym-
Congenital or neonatal leukemia, a rare syndrome, occurs 10 times phoid tumor, are mixed with findings compatible with AML in both
more frequently in newborns with Down syndrome than in newborns syndromes. The morphology of the myeloid–natural killer cell leukemia
without trisomy 21. 392,393 Leukocytosis, blood and marrow blast cells, often simulates APL, with hypergranular cytoplasm present but abnor-
hepatosplenomegaly, thrombocytopenia, purpura, anemia, and skin mality of chromosome 17 absent. The hybrids can appear de novo or
infiltrates are usual. The disease has been diagnosed prenatally. Cyto- after relapse of a lymphoma, T-cell leukemia, or blast crisis of CML. The
genetic abnormalities can occur and mark the leukemic clone. 393,400,401 hybrid leukemias usually have a poor prognosis. Myeloid antigens may
Monocytic leukemia and t(4;11) are the most common phenotype and not be evident at diagnosis in the natural killer cell hybrid but appear
karyotype. 401–403 A case of vertical (transplacental) transmission of acute later in the course. Hematopoietic stem cell transplantation should be
422
monocytic leukemia from mother to son has been reported. 404 considered in an eligible patient. 423
Infants who are normal at birth but develop AML in the first few Hybrid leukemias may result from either lineage infidelity caused
weeks of life (neonatal leukemia) often display pallor, inadequate food by genetic misprogramming or promiscuous gene expression, which
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intake, insufficient weight gain, diarrhea, and lethargy. The presence of occurs transiently in the differentiation of normal pluripotential
a cytogenetic abnormality on band q23 of chromosome 11 is a very poor HSCs. In the case of promiscuity, persistence of the transient normal
prognostic sign. Most infants with congenital or neonatal leukemia do event is thought to be present because of the block in differentiation
not survive for more than a few weeks or months. Because treatment that occurs. Genetic misprogramming (infidelity) could result from
408
has been largely ineffective, observation to ascertain if TMD or a tran- rearrangements of the DNA sequences that control the transcription of
sient leukemia is present has been recommended if the clinical picture genes designating differentiation antigens. 424
is unclear. 405
Mixed Leukemias
In these cases, lymphoid and myeloid cells are present simultaneously
HYBRID AND MIXED LEUKEMIAS but are derived from separate clones, or sequential myeloid and lym-
Hybrid Leukemias phoid leukemia are present but the two lineages are derived from sep-
Although coincidental myeloid and lymphoid clonal diseases have been arate clones.
reported for more than 60 years, the availability of techniques to iden-
tify surface antigens with monoclonal antibodies, immunoglobulin MEDIASTINAL GERM CELL TUMORS AND
gene, and T-lymphocyte receptor gene rearrangements with molecular
methods, and chromosome translocations by chromosome banding ACUTE MYELOGENOUS LEUKEMIA
cytogenetic techniques has led to the appreciation of several types of An unusual but significant concordance has been reported between
hybrid acute leukemia. 406–411 nonseminomatous mediastinal germ cell tumors and AML, especially

Kaushansky_chapter 88_p1373-1436.indd 1386 9/21/15 11:01 AM