Page 931 - Hematology_ Basic Principles and Practice ( PDFDrive )

814 Part VII Hematologic Malignancies

Cytogenetic studies are valuable in assessing the effectiveness of copy-neutral loss of heterozygosity with duplication of gene muta-
therapy (see box on Genetic Testing for Acute Myeloid Leukemia and tions that have been already implicated in AML pathogenesis and a
Fig. 56.26). In most patients with AML, a clonal cell population loss of the corresponding normal allele.
cannot be detected during remission. However, some mutations, as Numerous studies using cytogenomics have uncovered a broad
mentioned earlier, such as DNMT3A, have been found during clini- range of cryptic CNAs in patients with AML and a normal karyotype,
cal remissions—hence the fourth aspect of AML heterogeneity. When as well as in patients exhibiting balanced translocations or chromo-
disease relapses, cells with the original chromosome anomalies are somal imbalances. Not only do these studies reveal a tremendous
observed. If an appropriate FISH or RT-PCR test is available, these degree of genetic diversity of AML; they also have shown that the
are the genetic tests of choice for predicting relapse because these estimated average number of CNAs per genome is 2–2.5. This
methods are less expensive and more sensitive than chromosomal finding implies either that most AML genomes are relatively stable
studies. or that more sensitive methods are required (e.g., complete genome
sequences) to capture the whole spectrum of genetic alterations.
Genomic imbalances (and their associated target genes) include gains
Acute Myeloid Leukemia with Complex Karyotype of regions 4q25–26 (PRDM5), 8p11.21 (ZMAT4), 8q24.21
(CCDC26), 13q32 (ABCC4), 14q23.1 (PRKCH), 16q24.1 (USP10,
Any karyotype with at least three chromosomal aberrations, regardless CRISPLD2), and 21q22.3 (PRMT2), as well as losses of regions 6q27
of their type and the individual chromosomes involved, is designated (RPS6KA2), 7p22.3 (FAM20C), 8q24.12 (TRPS1), 9p21.2 (TISCI),
as “complex.” Several studies have shown that patients with t(8;21), 10q11,21 (HNRNPF), 15q21.3 (RFX7), Xp11.4 (BCOR), and Xp25
t(16;16)/inv(16) and t(15;17) constitute a separate biologic and (STAG2) (Fig. 56.40). The biologic consequences of these small
clinical entity even if they contain additional abnormalities, because genomic imbalances are not fully understood. In some cases,
these additional cytogenetic abnormalities do not adversely affect the submegabase-sized CNAs may uncover cryptic rearrangements, as has
clinical outcome. Therefore the category of AML patients with a been shown for NSD1-NUP98 and MALT4-MLL fusion genes. The
complex karyotype exclude patients with t(8;21),inv(16)/t(16;16) systemic analysis of CNAs and regions of UPD in AML in the future
and t (15;17). Approximately, 10% to 12% of AML patients have may fully uncover genomic changes that contribute to AML
three or more chromosome abnormalities whereas 8% to 9% have pathogenesis.
five or more abnormalities. The incidence of a complex karyotype
increases with age. In patients with AML, age 18–60, 6% to 8% have
three or more chromosomal abnormalities whereas 17% to 19% of Acute Myeloid Leukemia in the Elderly
patients older than 60 have a complex karyotype. In three large series
of AML patients with a complex karyotype analyzed using multicolor The biology of AML changes with age. The spectrum of cytogenetic
FISH, more than 90% of patients had at least five abnormalities, with abnormalities in older adults includes a higher percentage of patients
a median number of chromosomal aberrations being between 6 and with abnormalities involving −5/del(5q), −7/del(7q), and 17p and a
10. Approximately 80% of all patients with a complex karyotype have lower incidence of translocations associated with a favorable prognosis
deletion 5q, followed by deletions 17p and 7q, occurring in approxi- and treatment outcome. Older patients with a complex karyotype
mately 50% of cases. At least 85% of all patients with AML with a have an extremely poor prognosis, with only 26% achieving CR
complex karyotype showed one of the three deletions. The prognosis owing to high rates of resistant disease. Multidrug resistance is present
of patients with a complex karyotype is generally very poor. Among in 57% of patients over 75 years of age and in 33% of patients with
patients with AML above the age of 60, which constitute the majority AML younger than 56 years of age. The OS rate in older adult
of patients with complex karyotype, only 10% to 44% of those who patients with AML is only 2% at 5 years. The biology of AML in the
harbor three or more chromosomal abnormalities achieve a CR, elderly patients may be a consequence of the age of hematopoietic
usually after a very short duration (median 6–8 months). CR rates stem cells, shortened telomere length (associated with older cells),
of karyotypically complex patients are slightly higher in younger presence of fewer normal stem cells to compete with the malignant
patients. clones and repopulate marrow following chemotherapy and as men-
The impact of cytogenetics on outcome in a pediatric group of tioned earlier, the increased frequency of age-related somatic muta-
patients with AML (excluding APL) demonstrated about 80% OS tions present in over 10% of healthy individuals over 70 years of age.
for 10 years in patients with CBF AML. In contrast, patients with
MLL abnormalities had an intermediate prognosis (61% OS at 10
years) with no evidence of heterogeneity according to the transloca- Therapy-Related Acute Myeloid Leukemia and
tion partner of MLL. Additional abnormalities among the 11q23 Therapy-Related Myelodysplastic Syndrome
leukemia have diverse prognoses; trisomy 8 is an independent favor-
able, whereas trisomy 19 is considered an adverse prognostic factor Therapy-related AML and MDS are distinct clinical syndromes
in MLL rearranged group of pediatric patients. occurring as late complications following high-dose chemotherapy,
The striking clinical, cytogenetic, and biologic heterogeneity of radiation therapy, or autologous stem cell transplantation. A normal
AML is only partly explained by the known chromosomal or molecu- karyotype is observed in 8%, and an abnormal karyotype is detected
18
lar rearrangements. DNA microarray technology provides a higher in 92% of the patient population. From the cytogenetic point of
resolution and has been demonstrated to detect cryptic copy number view, two different categories of therapy-related AML and MDS can
alterations (CNA) and UPD. The current clinical implications of be identified. The first group includes patients who develop AML/
aCGH + SNP microarray analyses in AML remains limited. However, MDS following exposure to alkylating agents approximately 5 years
in cases with UPD, gene mutations precede mitotic recombination, after therapy. These leukemias are associated with the presence of
resulting in loss of the remaining wild-type allele, which can act as a monosomy 5/del(5q) or monosomy 7/del(7q) (see Fig. 56.26, third
“second hit” mutation. UPD has been shown to be predictive of poor row). Many of these patients initially develop myelodysplastic features
event-free and OS. For example, SNP microarray analysis of patients before transforming into frank AML. Recurrent abnormalities of
with AML with a normal karyotype demonstrated UPD of chromo- chromosomes 5, 7, or both account for 70% of all abnormalities
some 13q, leading to duplication of a mutant FLT3 allele at band observed in therapy-related leukemia. These patients respond poorly
13q12, which was associated with significantly inferior OS. Approxi- to therapy and have a poor OS. A second group of patients develop
mately 20% of patients with AML and a normal karyotype have therapy-related AML without prior MDS. Leukemia cells in these
UPD. The most common chromosomal regions of UPD are 1p, 2p, patients often exhibit 11q23 (3%) and 21q22 (3%) balanced rear-
2q, 4q (TET2), 6p, 7q (EZH2), 11p (WT1), 11q, 13q (FLT3), 14q, rangements, attributed to the late effects of topoisomerase II inhibi-
16p, 17p (TP53), 19q (CEBPA), 21q (RUNX1), and Xq. The analysis tors combined with alkylating agents and radiation (see Figs. 56.32
of genes located within a UPD chromosomal region has shown a and 56.33). AML may develop within a few months to 3 years after