NcXHF

NOVEL TREATMENTS FOR T-CELL LYMPHOMA
of stable disease (SD) among three evaluable patients. 85 A
phase II study in PTCL (and other histologies) is planned.
Immune Checkpoint Inhibitors
PD-1 is an immune checkpoint receptor that inhibits T-cell
activation upon binding to its ligand PD-L1, which is overexpressed
in many lymphoid malignancies. Antibodies specifıc
for PD-1, such as nivolumab, thus induce antitumor
T-cell activation and are highly active in Hodgkin lymphoma.
86 PD-L1 is known to play an important role in the
tumor microenvironment in PTCL, providing a preclinical
rationale for PD-1 inhibitors in these conditions. 87 A phase I
study in heavily pretreated patients with NHL including 23
patients with T-cell lymphoma recently reported a favorable
toxicity profıle and ORR of 17%. However, among patients
with PTCL, the ORR was 2/5 (40%). 88
ALK Inhibitors
For patients with ALK ALCL, the EML4-ALK fusion oncogene
provides an attractive target. Crizotinib, the fırstgeneration
ALK inhibitor, was used in a phase Ib study of 15
patients with ALK lymphomas (14 with ALK ALCL). 89
The main toxicities were diarrhea, vomiting, and visual impairment;
the ORR was 60%. This agent is being tested in a
phase I/II study in combination with chemotherapy in untreated
patients (NCT01979536) and in a study of relapsed/
refractory ALK ALCL (NCT00939770). As with many
tyrosine kinase inhibitors, secondary resistance has been reported
and second-generation agents such as ceritinib
(LDK378) will undoubtedly be explored in patients who experience
treatment failure. 90-93 A phase I study that includes
an arm enrolling patients with ALK malignancies other
than lung cancer is in progress (NCT01283516).
TOWARD MOLECULAR STRATIFICATION IN PTCL
Gene expression profıling (GEP) has advanced our understanding
of the classifıcation, 92 prognostic stratifıcation, and
molecular pathogenesis of T-cell lymphomas. The Mayo
group recently described two genetic subsets of ALK ALCL
with disparate clinical outcomes: patients with rearrangements
in DUSP22 (at the 6p25.3 locus, found in 30% of cases)
had excellent outcomes, comparable to those of ALK
ALCL, whereas those with TP63 rearrangement (on 3q28,
seen in 8% cases) had dismal prognosis. 93 Several recurrent
somatic mutations in genes such as TET2, 94 IDH2, 77 and
RHOA 95,96 have been described, although their clinical relevance
requires further investigation. In PTCL-NOS, a recurrent
t(5;9)(q33;q22) translocation resulting in a ITK-SYK
fusion gene and SYK overexpression was described in a subset
of patients with follicular histology. 97 Finally, small nucleolar
RNA (snoRNAs) have been shown to have potential
diagnostic and prognostic signifıcance in PTCL. 98 Further
development and more widespread utilization of these technologies
are clearly needed to deliver on the promise of true
precision medicine for patients with T-cell lymphomas.
CONCLUSION
Cooperative studies in the last 5 years have successfully enabled
the rapid completion of phase I/II studies and brought four new
drugs for patients with T-cell lymphoma to the clinic. Continuing
efforts are needed to complete confırmatory randomized
phase III studies in combination with chemotherapy. The development
of chemotherapy-free regimens using the most active
biologic agents in PTCL will be a critical focus of research efforts
in the future. Additional efforts to develop molecular targeted
approaches are also clearly needed in order to rationally select a
treatment plan that would be predicted to have the highest effıcacy
for a particular patient.
Disclosures of Potential Conflicts of Interest
Relationships are considered self-held and compensated unless otherwise noted. Relationships marked “L” indicate leadership positions. Relationships marked “I” are those held by an immediate
family member; those marked “B” are held by the author and an immediate family member. Institutional relationships are marked “Inst.” Relationships marked “U” are uncompensated.
Employment: None. Leadership Position: None. Stock or Other Ownership Interests: None. Honoraria: Michelle A. Fanale, Plexus, Research to Practice,
Seattle Genetics, Takeda. Consulting or Advisory Role: Michelle A. Fanale, Acetylon Pharmaceuticals, Amgen, Clarient, Spectrum Pharmaceuticals.
Speakers’ Bureau: None. Research Funding: Michelle A. Fanale, Bristol-Myers Squibb, Celgene, Genentech, Gilead Sciences, MedImmune, Millennium,
Molecular Templates, Novartis, Seattle Genetics. Yasuhiro Oki, Curis, Seattle Genetics, Novartis, Janssen Pharmaceuticals, Infinity, Millennium, Cell Medica,
Spectrum Pharmaceuticals. Patents, Royalties, or Other Intellectual Property: None. Expert Testimony: None. Travel, Accommodations, Expenses:
Michelle A. Fanale, Plexus, Research to Practice, Spectrum Pharmaceuticals, Takeda. Yasuhiro Oki, DAVAOncology. Other Relationships: None.
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