NcXHF

CHEAH, OKI, AND FANALE
a similar median PFS of 2 months, 44 although the limited
DOR suggests that mogamulizumab might be best suited for
combination studies. However, one possible exception may
be the highly aggressive and chemorefractory disease adult
T-cell lymphoma/leukemia. Ishida et al performed a phase II
study of mogamulizumab in 28 patients with relapsed/refractory
disease, in which the ORR was 50% with median PFS and
OS of 5.2 and 13.7 months respectively. 45
Lenalidomide
The immunomodulatory drug lenalidomide has substantial
activity in myeloma and B-cell lymphomas. 46,47 Three small
studies have explored lenalidomide (25 mg administered
orally for days 1 to 21 of a 28-day cycle) in patients with relapsed/refractory
PTCL, with a reported ORR of 22% to 39%
(CR 8% to 30%). 48-50 Although the median DOR in the largest
study of 54 patients was only 3.6 months, there was a nonsignifıcant
trend toward higher response rates among the subset
of patients with AITL. 48
Alisertib
Aurora A kinase regulates mitotic entry and spindle formation;
it is overexpressed in aggressive lymphomas and has a
potential role in oncogenesis. 51 The orally available, smallmolecule
competitive inhibitor alisertib induces cytotoxicity
in a range of solid and hematologic tumors. 52 Friedberg et al
performed a multicenter phase II study of alisertib in 48 patients
with heavily pretreated aggressive lymphomas. 53 Although
the ORR was 27% overall, it was 4/8 (50%) among
patients with T-cell lymphoma, with 3/4 (75%) maintaining a
response for more than 1 year at the time of reporting. Subsequently,
the SWOG1108 phase II study extended this observation
in an additional 37 heavily pretreated patients with
a range of PTCL subtypes. 54 Alisertib was administered at a
dosage of 50 mg twice daily for 7 days in a 21-day cycle. The
most common adverse events (AEs) of grade 3 or greater
were hematologic, observed in approximately one-third of
patients; febrile neutropenia was seen in 14%. The ORR was
24% overall and 31% in patients with PTCL-NOS. As a pathway
to potential approval, an ongoing international phase III
registration study is comparing alisertib to investigators
choice (gemcitabine, pralatrexate, or romidepsin) in patients
with PCTL (NCT01482962).
MOVING NOVEL AGENTS INTO THE FRONT LINE
With many drugs demonstrating effıcacy in relapsed/refractory
PTCL, integrating agents into front-line therapy is a major
focus of drug development efforts. The conventional
approach has been to be combine novel agents with chemotherapy
in an attempt to discover an “R-CHOP” equivalent
for PTCL; a summary of these studies is provided in Table 2.
CHOP/CHP Plus Brentuximab Vedotin
Because of the promising single-agent activity of brentuximab,
a phase I study of CHOP without vincristine (CHP)
and with brentuximab was designed to minimize the overlapping
toxicity of peripheral sensory neuropathy. This study
enrolled 39 patients with CD30 PTCL, although most (32
patients) had ALCL. 55 Two schedules of administration were
used: BV2 followed by CHOP6 (sequential, 13 patients)
or BV given concurrently with CHP (combination, 26 patients).
The sequential arm was closed by the sponsor after
two patients who responded to BV progressed during CHOP.
Toxicity was similar between the schedules and manageable;
the most common AE overall was peripheral neuropathy
(31% with grade 3 in the combination group), followed by
hematologic febrile neutropenia (21% in the combination
group), fatigue, nausea, and GI disturbance. The combination
was highly active, with an ORR of 85% and 100% (CR,
62% and 88%) and 1-year PFS of 77% and 71% in the sequential
and combination groups, respectively, and none of these
TABLE 2. Summary of Selected Chemotherapy/Novel Agent Combinations for Untreated Peripheral T-Cell
Lymphoma
Combination Study Group Major Histologies Phase n ORR CRR PFS OS
CHOP romidepsin 57 LYSARC NR Ib/II 35 68% 51% 18 mo 57% 18 mo 76%
CHOP vorinostat 60 MDACC PTCL-NOS 5, AITL 5, ALCL 4 I 14 93% 93% 2 yr 79% 2 yr 81%
CHOP-14 alemtuzumab 62 GITIL PTCL-NOS 14, AITL 6, ALCL 3 II 24 75% 71% 2 yr 48% 2 yr 53%
CHOP alemtuzumab 63 HOVON PTCL-NOS 10, AITL 6 II 20 90% 60% 2 yr 27%* 2 yr 55%
CHO(E)P alemtuzumab 61 DSHNHL PTCL-NOS 21, AITL 11, ALCL 4 II 41 61% 58% 3 yr 32% 3 yr 62%
CHP brentuximab vedotin 55 U.S./European multicenter ALCL 32, PTCL-NOS 2, ATLL 2, AITL 2 I 39 100%** 88%** 1 yr 71%** 1 yr 88%**
CEOP pralatrexate 56 T-cell consortium PTCL-NOS 21, AITL 8, ALCL 4 II 33 70% 45% 1 yr 48%ˆ 1 yr 80%
CHOP denileukin diffitox 99 U.S. multicenter PTCL-NOS 19, AITL 10, ALCL 8 II 49 65% 50% 2 yr 43% 2 yr 65%
CHOP bortezomib 74 CISL PTCL-NOS 16, ENKTL 10, AITL 8 II 46 76% 65% 3 yr 35% 3 yr 47%
Abbreviations: ORR, objective response rate; CRR, complete response rate; DOR, duration of response; NR, not reported; CHOP, cyclophosphamide/doxorubicin/vincristine/prednisone; ICE,
ifosfamide/carboplatin/etoposide; CHP, cyclophosphamide/doxorubicin/prednisone; CEOP, cyclophosphamide/etoposide/doxorubicin, prednisone; CHOEP, cyclophosphamide, doxorubicin, vincristine/
etoposide/prednisone; LYSARC, Lymphoma Academic Research Organization; MDACC, MD Anderson Cancer Center; GITIL, Italian Group for Innovative Lymphoma Therapies; HOVON, Dutch-Belgian
Haemato-Oncology Group; CISL, Consortium for Improving the Survival of Lymphoma; PTCL-NOS, peripheral T-cell lymphoma not otherwise specified; AITL, angioimmunoblastic T-cell lymphoma;
ALCL, anaplastic large cell lymphoma; ATLL, adult T-cell leukemia/lymphoma; ENKTL, extranodal NK/T-cell lymphoma.
*Event-free survival.
**Results for combination CHP brentuximab arm.
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