NcXHF

NOVEL TREATMENTS FOR T-CELL LYMPHOMA
patients underwent front-line consolidative ASCT. 55 The
combination schedule is currently being compared with
CHOP for patients with CD30 PTCL in the phase III
ECHELON-2 study (NCT01777152).
CEOP Plus Pralatrexate
Advani et al reported preliminary results from the T-cell consortium
trial of CEOP (cyclophosphamide/etoposide/vincristine/
prednisone) alternating with pralatrexate in newly diagnosed
patients with PTCL. 56 Etoposide was substituted for doxorubicin
because of data suggesting improved effıcacy (discussed
above) and the lack of proven benefıt for anthracyclines. CEOP
was administered in the standard fashion, with pralatrexate administered
at 30 mg/m 2 intravenously on days 15, 22, 29; up to 6
cycles in total were planned and growth factor support was
mandatory. The goal was to improve the CR rate to facilitate
optional ASCT, which was allowed at the investigator’s discretion.
The ORR was 70% (CR 45%) and the 1-year EFS was 48%.
Observed toxicities of grade 3 or greater included hematologic
events, sepsis, and mucositis.
CHOEP Plus HDAC Inhibitors
The French cooperative group LYSARC (Lymphoma Academic
Research Organization) performed a phase Ib/II study
of CHOP with romidepsin in 35 patients with treatmentnaive
PTCL. CHOP218 was given at standard doses, with
the dose of romidepsin escalated (phase II dose 12 mg/m 2 on
days 1 and 8 in a 21-day cycle). The major adverse events
were, predictably, hematologic: grade 3 or greater neutropenia
(38%), thrombocytopenia (19%), and anemia (9%). The
ORR was 68% (CR 51%) and the estimated PFS at 18 months
was 57%. 57 This combination is being tested in a randomized
phase III study (NCT01796002). The Italian Cooperative
Group is performing an ongoing phase I/II study of romidepsin
in combination with CHOEP followed by ASCT
(NCT02223208). Because of its activity in cutaneous T-cell
lymphoma, 58,59 Oki et al. tested the combination of the orally
available pan-HDAC inhibitor vorinostat with CHOP in a
small phase I study of 14 newly diagnosed patients with
PTCL. 60 Toxicities were comparable to those expected from
standard CHOP, with the exception of mild diarrhea in approximately
half of all patients treated. All 12 patients who completed
therapy achieved a CR (93% of total population) suggesting that
this promising combination warrants further evaluation. A
multicenter phase I study evaluating the combination of CHOP
with belinostat is in progress (NCT01839097).
CHOP Plus Alemtuzumab
Alemtuzumab has also been explored in combination with
CHOP-like therapy in three separate phase II multicenter European
studies with markedly different treatment schedules. 61-63
The Italian study used 8 doses of CHOP-14 with 30 mg alemtuzumab
given intravenously at 2-week intervals (total 240 mg) 62 ;
the HOVON (Dutch-Belgian Hemato-Oncology Group) study
also used CHOP-14, but intensifıed alemtuzumab with three
30-mg doses per cycle (total 720 mg) 63 ; the DSHNHL study used
alemtuzumab (133 mg over 4 weeks) as consolidation following
CHOP induction (with etoposide for patients older than 60) in
41 patients with newly diagnosed PTCL. 61 In all three studies,
serious opportunistic infectious complications such as CMV
reactivation, disseminated zoster and tuberculosis JC virus
encephalitis, invasive fungal infections, and EBV-associated
lymphoproliferative disease were observed despite aggressive
chemoprophylaxis. Although comparisons between small
phase II studies in heterogeneous disease groups are diffıcult,
it appeared that both the ORR and rate of infection of
grade 3 or greater were proportional to the cumulative dose of
alemtuzumab administered. The ongoing ACT-1 (NCT00646854)
and ACT-2 (EudraCT 2007-000821-23) phase III studies
are randomized comparisons of CHOP alemtuzumab in
PTCL in younger (with ASCT consolidation) and older patients
respectively.
BIOLOGIC DOUBLETS IN THE RELAPSED SETTING
Moving beyond the traditional “CHOPX” development
pathway are a plethora of studies testing combinations of
novel agents and eschewing chemotherapy altogether. At
present, these biologic doublets are mostly being tested in the
relapsed/refractory setting. A selection of such studies is presented
in Table 3. We anticipate that the most promising
combinations will be investigated in chemotherapy-free
front-line protocols, as is currently underway in B-cell
lymphoma. At the present time, results from most of these
protocols are not mature. Hopfınger et al explored the combination
of lenalidomide, vorinostat (400 mg daily, fıxed
dose), and dexamethasone in a phase I/II study and found
that the maximum tolerated dose (MTD) of lenalidomide in
the combination was only 5 mg daily. 64 Planned dose escalation
was aborted because of grade 3 thrombocytopenia and
stroke at the 10-mg dose of lenalidomide. Probably because
of the low tolerated dose of lenalidomide, activity was modest
(ORR 25%, median PFS 2.2 months). Tan et al recently reported
on a phase II study of the HDAC inhibitor panobinostat
with the proteasome inhibitor bortezomib in patients
with pretreated PTCL. 65 The main toxicities were hematologic,
diarrhea, fatigue, and peripheral sensory neuropathy;
among 23 evaluable patients, the ORR was 43% (CR 22%)
with fıve patients successfully bridged to allogeneic stem cell
transplantation.
Several combination studies are underway using romidepsin
in combination with other biologic agents. There are
preclinical data suggesting potent synergism between romidepsin
and alisertib in T-cell lymphomas, 66 an observation
supported by preliminary results from a phase I study of the
combination being performed at The University of Texas
MD Anderson Cancer Center. 67 Among the included histologies,
activity seems most promising in PTCL, with a CR observed
at the lowest dose level and ORR of 1/3 (33%). This
study is ongoing and the expansion cohort will be restricted
to patients with PTCL. Romidepsin is also being explored in
combination with several other nonchemotherapic agents,
including lenalidomide, 5-azacitidine, and pralatrexate, with
promising early results. Preliminary results from a phase I/II
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