Page 1724 - Williams Hematology ( PDFDrive )

1698 Part XI: Malignant Lymphoid Diseases Chapter 104: Mature T-Cell and Natural Killer Cell Lymphomas 1699

Genomic and proteomic cluster analyses strongly suggest that suggesting improved remission durations. 22,15 The IPTCLP reported
ALK-positive and ALK-negative ALCL are two distinct disease entities. 5-year FFS and OS rates of 36 percent and 49 percent, respectively, for
3
CEBPB, PTPN12, SERPINA1, and BCL6 genes are typically overex- patients with ALK-negative ALCL (see Table 104–3). CD56 expres-
pressed in ALK-positive ALCL, and CCR7, CNTFR, interleukin (IL)-21, sion has been shown to be an independent favorable prognostic factor for
104
and IL-22 are overexpressed in ALK-negative ALCL. Based on com- ALK-negative ALCL, as has expression of DUSP22. 51,113
parative genomic hybridization and fluorescence in situ hybridization
for TP53 and ATM loci, gains of 17p and 17q24, and losses of 4q13–q21 ENTEROPATHY-ASSOCIATED T-CELL
and 11q14 are more common in ALK-positive tumors, whereas gains
112
of 1q and 6p21 are preferentially observed in ALK-negative tumors. LYMPHOMA
These differences are underscored by the different responses of these
two entities to therapy. Interestingly, cases of ALK-negative ALCL that DEFINITION
87
express DUSP22 appear to have a similar prognosis to ALK-positive Enteropathy-associated intestinal T-cell lymphoma (EATL) is a mature
ALCL, while those with TP63 expression are associated with especially T-cell lymphoma that presents within the gastrointestinal tract. The
poor prognosis. 51 World Health Organization divided EATL into two variants—type I
and type II—which are differentiated based on their histopathology. 116
TREATMENT AND PROGNOSIS
ALK-positive ALCL is the most chemosensitive of the T-cell lympho- EPIDEMIOLOGY
mas, with rates of survival and response similar to diffuse large B-cell
lymphomas. ALCL is commonly seen in the pediatric age group, where EATL constitutes approximately 2 to 10 percent of all PTCL and incidence
2–4
intensive anthracycline-based chemotherapy regimens have been varies by geographic distribution. The median patient age at diagnosis
116, 117
studied. 106,107 Approximately 90 percent of patients with ALK-positive is 55 to 65 years with a slight male predisposition. Type I EATL com-
116
ALCL treated with anthracycline-based chemotherapy achieve a tumor prises 60 to 80 percent of cases, is most common in patients who have
response, with 65 to 75 percent of pediatric patients remaining relapse- underlying celiac disease, and is strongly associated with the human leu-
free after 5 years. 76,108 Among adults, treatment with CHOP-based ther- kocyte antigen (HLA)-DQ2 haplotype. Among European patients with
116,118
apy has remained the most commonly used approach as more intensive EATL, 80 percent have type I EATL. Patients who have refractory
regimens, such as high-dose methotrexate, doxorubicin, cyclophos- celiac disease, which does not improve with a gluten-free diet, have a sig-
phamide, vincristine, prednisone, bleomycin (MACOP-B) and doxoru- nificantly higher risk of EATL. In particular, those with refractory celiac
bicin, cyclophosphamide, vindesine, bleomycin, and prednisone have disease who demonstrate a clonal expansion of abnormal intraepithelial
not shown superiority to CHOP-based therapy. 67,109 lymphocytes lacking CD3, CD8, and TCR markers, but expressing intra-
117
The IPI appears to be particularly helpful in risk-stratification of cellular CD3, have a significantly higher risk of developing EATL. In
ALK-positive ALCL, with some authorities suggesting that patients contrast, type II EATL, present in 20 to 40 percent of cases, is less fre-
116,119
with high risk ALK-positive ALCL should be treated similarly to those quently associated with celiac sprue and the HLA-DQ2 haplotype.
with other forms of PTCL (see Table 104–3). 2,3,110 The DSHNHL con-
cluded in a retrospectively assessment of seven phase II and phase III CLINICAL FINDINGS
trials that patients with ALK-positive ALCL who were 60 years of age The majority of patients with EATL present with acute abdominal
or younger and had a normal LDH, had an improved EFS but not OS symptoms that often require urgent or emergent surgical procedures,
21
if treated with CHOP plus etoposide, rather than CHOP alone. The resulting in diagnosis of the disease. EATL typically presents with
120
Groupe d’Étude des Lymphomes de l’Adulte (GELA) group has sug- ulcerative lesions of the jejunum or ileum which may perforate, though
gested that the prognostic significance of ALK expression is limited to other regions of the gastrointestinal tract may also be affected. As a
those older than age 40 years. After relapse, it appears that patients can result of the malabsorption that accompanies the disease, frequent pre-
67
be cured with intensive salvage therapy (including ASCT) at a higher senting signs and symptoms include weight loss, diarrhea, nausea, and
rate compared to other T-cell lymphomas. vomiting, accompanied by abdominal pain and bowel obstruction.
121
Brentuximab vedotin, which combines an anti-CD30 antibody The course can be fulminant; death may occur during treatment sec-
with monomethylauristatin E (MMAE) has demonstrated objective ondary to the consequences of intestinal perforation. Extraintestinal
responses in more than 80 percent of patients with relapsed/refractory presentation of EATL is rare, and there is little data on the manifes-
32
ALCL treated on a single-agent phase II trial. The FDA approved tations of cutaneous, neuromeningeal, or pulmonary presentations.
111
brentuximab vedotin for the treatment of relapsed ALCL in 2011. Systemic symptoms should be considered signs of clinical progression,
Brentuximab vedotin in combination with chemotherapy is being although they occur in less than 30 percent of patients with EATL. 124,129
explored as a first-line therapy in ALCL. Crizotinib, an inhibitor of ALK
tyrosine kinase that is FDA-approved for the treatment of ALK-positive
non–small cell lung cancer, has demonstrated encouraging responses LABORATORY FINDINGS
in small series of ALK-positive ALCL, leading to ongoing trials in Histopathology
relapsed/refractory ALCL. 44,45,112 The two types of EATL are recognized on the basis of the specific
ALK-negative ALCL typically presents with unfavorable features, immunophenotype: EATL type 1 is characterized by CD56 negativity
119
including stages III and IV disease, B-symptoms, high IPI scores, high and EATL type 2 exhibits CD56 expression. The histology of EATL
LDH serum levels, and expression of TP63. 51,114,115 The disease typically type I demonstrates mostly medium to large tumor cells with round
pursues an aggressive clinical course and is less responsive to chemo- or angulated vesicular nuclei, prominent nucleoli, and pale-staining
therapy than ALK-positive ALCL. It has been common practice to cytoplasm. There is often a moderate to abundant infiltrate of eosino-
treat patients with CHOP-like therapy, as with other forms of PTCL, as phils, histiocytes, and small lymphocytes. EATL type 1 characteristi-
123
discussed in the previous section Approach to Initial Therapy. Similar cally demonstrates the following immunophenotype: positive for CD3,
to PTCL-NOS, consolidation with ASCT in first remission is often con- CD7, CD103, and usually CD30, but negative for CD4, CD5, CD8, and
sidered for ALK-negative ALCL based upon large prospective studies CD56. The cells also exhibit a cytotoxic phenotype and are positive for

Kaushansky_chapter 104_p1693-1706.indd 1699 9/21/15 12:47 PM