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1696 Part XI: Malignant Lymphoid Diseases Chapter 104: Mature T-Cell and Natural Killer Cell Lymphomas 1697

subjects younger than age 60 years in a prospective study evaluating For patients who are transplantation-eligible, allogeneic transplan-
upfront stem cell transplantation for PTCL. In this phase II study, tation should be considered in the relapsed/refractory setting. Once
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patients received biweekly CHOEP followed by ASCT for the respond- a donor is identified, intensive salvage chemotherapy options should
ers. The ORR to CHOEP was 82 percent with a CR rate of 51 percent. be considered, including ICE (ifosfamide, carboplatin, etoposide) or
Although one must be cautious when comparing results from differ- DHAP (dexamethasone, cytarabine, cisplatinum), as they have a high
ent study populations, these results appear superior to those reported potential to induce major remissions that will optimize outcomes after
30
by Reimer and colleagues for patients treated with CHOP followed by transplantation. However, these regimens are generally only tolerated
ASCT, who achieved CR in only 39 percent of cases. 15 for three to four cycles and should be followed promptly by consoli-
There are no randomized trials assessing the controversial dation with transplantation. Both myeloablative and reduced intensity
approach of performing ASCT in first remission for PTCL, although allogeneic stem cell transplantation have demonstrated up to 60 percent
several prospective studies suggest the benefit of this strategy. The afore- 3-year PFS. 37–39 The role of ASCT in relapsed/refractory PTCL is con-
mentioned Nordic study enrolled 160 patients with PTCL, including troversial. Several series suggest that ASCT rarely results in long-term
39 percent with PTCL-NOS, 19 percent with ALK-negative ALCL, and disease control of PTCL, with the exception of patients with ALCL. 34,35
19 percent with AITL, while excluding ALK-positive ALCL. Patients Other series, however, including registry data from the Center for Inter-
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were treated with CHOEP for six cycles (etoposide was omitted for national Blood and Marrow Transplant Research, report more salutary
patients >60 years of age) and those in CR or partial response (PR) pro- results for ASCT after relapse. 36
ceeded to high-dose therapy with carmustine, etoposide, cytarabine, For patients who are not transplantation-eligible, the goals of treat-
and melphalan (or cyclophosphamide) and ASCT. By intent-to-treat ment are palliative, and therapy should be geared toward maintaining
analysis, 71 percent of patients underwent ASCT and the 5-year OS and quantity and quality of life. Options for treatment include romidep-
PFS were 51 percent and 44 percent. Reimer and colleagues conducted sin, belinostat, pralatrexate, gemcitabine, bendamustine, and alemtu-
the second largest prospective study evaluating ASCT in first remission zumab. 26–29,40–42 In addition, brentuximab vedotin should be considered
following CHOP, enrolling 83 patients. A 3-year OS rate of 48 per- as the first choice for relapsed CD30-expressing ALCL patients, who
15
cent was observed by intent-to-treat analysis. For those who were trans- have not previously received this agent. 21–33
planted (66 percent of patients enrolled) outcomes were considerably In view of the heterogeneity of PTCL, there is an increasing inter-
more favorable with a 3-year OS of 71 percent. In a retrospective anal- est in individualizing therapy based on histology and other factors.
ysis performed at Memorial Sloan Kettering Cancer Center to evaluate For example, brentuximab vedotin, a CD30 antibody–drug conjugate,
patients treated with the intent to transplant in first remission, interim induced responses in patient with relapsed or refractory ALCL as well
PET imaging was found to be the most powerful predictor of outcome. as those with CD30-positive AITL and PTCL-NOS. 32,33 Similarly, cri-
Of the 53 percent of patients who had a negative interim PET scan after zotinib, an ALK inhibitor, demonstrated significant activity in a small
four cycles, 59 percent were progression free after 5 years, including number of patients with relapsed ALK-positive ALCL and is being fur-
53 percent of those with IPI of 3 or greater. 23 ther investigated. 43–45 The histone deacetylase (HDAC) inhibitors, such
as belinostat and romidepsin, appear to have preferential activity and
APPROACH TO RELAPSED OR REFRACTORY duration of response in patients with AITL (see Table 104–4). 27,29
Gene-expression profiling has identified molecular classifiers that
THERAPY improve classification and prognostication in ALK-negative ALCL,
There are no randomized data or standard of care to guide treatment AITL, and PTCL-NOS. 46–49 Furthermore, additional translocations
of patients with relapsed or refractory PTCL. In the largest series of and recurrent mutations have been identified that may help better
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patients with PTCL-NOS, AITL, and ALCL treated from 1976 to 2010, classify PTCLs and identify potential treatment targets. Next-genera-
those with relapsed or refractory disease who did not proceed to hemato- tion sequencing has identified a novel translocation within ALK-neg-
poietic stem cell transplant demonstrated a median OS of 5.5 months. ative ALCL, t(6;7), which potentially identifies a unique entity within
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However, the outlook for this patient population may improve as several ALK-negative ALCL associated with a better prognosis. This muta-
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new agents have been approved for this setting, including romidepsin, tion typically leads to reduced expression of the DUSP22 gene, which
belinostat, and pralatrexate. 28,29 In addition, brentuximab vedotin is likely functions as a tumor suppressor. A translocation producing an
listed in the National Comprehensive Cancer Network (NCCN) com- ITK-SYK fusion gene, t(5;9), was initially found in a subset of PTCL-
pendium of appropriate therapeutic agents for CD30-positive T-cell NOS cases. SYK expression was subsequently evaluated in 141 PTCL
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lymphomas (Table 104–4). 30–33 cases by immunohistochemistry and found to be overexpressed in
TABLE 104–4. Overall Response Rate to Agents FDA Approved for Relapsed/Refractory Peripheral T-Cell Lymphoma
Subtype Pralatrexate* Romidepsin † Belinostat ‡ Brentuximab Vedotin §¶
PTCL-NOS 31% 29% 23% 33%
AITL 8% 30% 46% 50%
ALCL 29% 24% 15% 86%
AITL, angioimmunoblastic T-cell lymphoma; ALCL, anaplastic large cell lymphoma; PTCL, peripheral T-cell lymphoma; PTCL-NOS, peripheral
T-cell lymphoma, not otherwise specified.
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*Data extrapolated from OA O’Connor, B Pro, L Pinter-Brown, et al.
† Data extrapolated from B Coiffier, B Pro, HM Prince, et al.
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‡ Data extrapolated from S Horwitz, W Jurczak, A Van Hoof, et al. and OA O’Connor, T Masszi, KJ Savage, et al.
29
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§ Data extrapolated from B Pro, R Advani, P Brice, et al. and SM Horwitz, RH Advani, NL Bartlett, et al.
32
¶ Brentuximab vedotin is National Comprehensive Cancer Network (NCCN) Compendium listed for relapsed/refractory CD30+ PTCL.

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