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1034 Part VII Hematologic Malignancies

TABLE Significant Features of B-Acute Lymphoblastic Leukemia With Recurrent Cytogenetic Abnormalities in the 2008 World Health
66.4 Organization Classification
Cytogenetic Abnormality Phenotype Clinical Correlates Incidence #
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t(9;22)(q33;q11.2) CD19 , CD10 , CD25 ; Seen more frequently in adults; traditionally 19% of all adult ALL
frequent expression of associated with extremely poor outcome; patients; incidence
myeloid antigens improved early event-free survival with increases with age
targeted therapy
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−
t(v;11q23) CD19 , CD10 ; aberrant Frequent presentation with high WBC count, 9% of Ph adult ALL
–
Common fusion partners include AF4 expression of myeloid CNS involvement
(4q21) and ENL (19p13) antigen CD15
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t(12;21)(p13;q22) CD19 , CD10 ; aberrant Sensitive disease with favorable outcome on 2% to 3% of Ph adult ALL
–
Cryptic translocation; requires FISH expression of myeloid standard therapy
antigen CD13
–
Hyperdiploidy CD19 , CD10 ; no Sensitive disease with favorable outcome on 10% of Ph adult ALL
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+
Chromosome number >50, <66 distinctive phenotype standard therapy
Extra copies of nonrandom chromosomes,
most frequently 21,X,14, and 4
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–
Hypodiploidy CD19 , CD10 ; no Poor prognosis 4% of Ph adult ALL
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Chromosome number <46 distinctive phenotype
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t(5;14)(q31;q32) CD19 , CD10 ; no Reactive eosinophilia driven by IL-3 Rare in adults
distinctive phenotype overexpression driven by the
translocation; blasts may be <20% in the
BM and undetectable in peripheral blood
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t(1;19)(q23;p13.3) CD19 , CD10 ; No significant association with response to 3% of Ph adult ALL
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–
cytoplasmic µ + therapy on current protocols
ALL, Acute lymphoblastic leukemia; BM, bone marrow; CNS, central nervous system; FISH, fluorescent in situ hybridization; IL-3, interleukin-3; Ph, philadelphia
chromosome; WBC, white blood cell.
Data from Moorman AV, Harrison CJ, Buck GA, et al, Adult Leukaemia Working Party, Medical Research Council/National Cancer Research Institute: Karyotype is an
independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC)
UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood 109:3189, 2007; and Pui CH, Relling MV, Downing JR: Acute lymphoblastic leukemia. N Engl J
Med 350:1535, 2004.
in situ hybridization (FISH) analysis, hyperdiploid DNA content can in 25% of adults diagnosed with ALL. The translocation results in
be determined by flow cytometry using DNA-binding fluorescent BCR-ABL1 fusion and the resulting leukemia has a poor outcome
dyes and corresponds to a DNA content between 1.16 and 1.6. without the inclusion of TKIs into frontline treatment. Intrachromo-
However, some studies have demonstrated that hyperdiploidy result- somal amplification of chromosome 21 (iAMP21) is defined as a gain
ing from duplication of specific chromosomes (4, 10, and 17) is a of at least three copies of regions of chromosome 21 that include
better indicator of a favorable prognosis than the actual ploidy or the RUNX1. The abnormality seen in 2% of B-ALL patients is associated
DNA content. Careful analysis of the specific pattern of chromosomal with an older age at diagnosis and poor outcome with standard-risk
gains and losses or flow cytometry peaks for DNA content is required therapy. iAMP21 is usually the sole cytogenetic abnormality but can
to distinguish true hyperdiploid cases from near-haploid cases that be seen in patients with Ph-like ALL (see later). In addition, use of
have undergone endoreplication (vide infra). In contrast to hyperdip- technology to assess copy number variation has identified submicro-
loidy, a hypodiploid karyotype is associated with an adverse prognosis. scopic genomic alterations that have significant impact on the biology
Hypodiploid ALL with near-diploid chromosome numbers (44–45) of B-ALL. These involve transcription factors such as IKZF1 (Ikaros),
is associated with somewhat distinct biology (loss of sex chromosome, EBF, and PAX5. The role of these transcription factors in B-cell
dicentric chromosomes, presence of recurrent cytogenetic abnormali- development and the biology of B-ALL are discussed in greater detail
ties such as ETV6-RUNX1) and is associated with a better outcome. in Chapter 64.
In contrast, presence of hypodiploidy with chromosome numbers less One of the most critical and clinically relevant discoveries with
than 44 is invariably associated with poor outcome. The most respect to ALL has been the description of high-risk ALL with a gene
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common chromosome complements within the hypodiploid group expression profile similar to that of Ph ALL but without the BCR-
are near haploid (24–31 chromosomes) and low hypodiploid (32–39 ABL1 fusion gene. This subtype of leukemia is referred to as Ph-like
chromosomes), and are both associated with a poor outcome. Of ALL and the kinase-activating alterations are a result of a diverse
note, low-hypodiploid ALL is frequently associated with germline group of genetic lesions that result in dysregulated cytokine receptor
TP53 mutations and at least in a subset of cases appears to be a and tyrosine kinase signaling. The lesions can be grouped into a
manifestation of Li–Fraumeni syndrome. Both near-haploid and surprisingly small number of broad categories. The most frequent
low-hypodiploid ALL have activation of phosphatidylinositol 3-kinase category involves CRLF2 rearrangements that account for almost
(PI3K)/mammalian target of rapamycin (mTOR) and MEK-ERK 50% of Ph-like ALLs. The rearrangements involve either transloca-
signaling that can potentially be targeted by PI3K inhibitors. tion of IGH2 at locus on chromosome 14q32 to CRLF2 on Xp22.3/
A structural abnormality seen commonly in the pediatric age Yp11.3 (pseudoautosomal region 1), or a 320-kb interstitial deletion
group but extremely rarely in the adult age group is a cryptic trans- centromeric of CRLF2 resulting in P2RY8–CRLF2 fusion. CRLF2
location, the t(12;21)(p13;q22) (ETV6-RUNX1). When present, it overexpression is frequently associated with activating mutations of
is associated with a favorable prognosis. Leukemias that harbor rear- JAK1/ JAK2, IL7R, or deletion of the JAK-STAT negative regulator
rangements of the mixed-lineage leukemia (MLL) gene at chromo- SH2B3, resulting in activation of JAK-STAT signaling. JAK-STAT
some 11q23, most notably t(4;11)(q21;q23), present with high WBC signaling activation also occurs in a second category of Ph-like ALL
counts and frequent CNS involvement, and are associated with poor with JAK2/EPOR rearrangements. The third broad category of
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clinical outcomes. Ph ALL associated with t(9;22)(q34;q11.2) is seen Ph-like ALL involves ABL1, ABL2, CSF1R, and PDGRB, described