Page 1532 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 85 T-Cell Lymphomas 1359

regimen, and then the tolerability and activity in a subpopulation of most common adverse events were infusion reactions (89%) and skin
patients with PTCL. rashes (63%), which were manageable and reversible in all cases.
Albeit relatively early, this study demonstrated clinically meaningful
antitumor activity in patients with relapsed aggressive ATL, with an
Brentuximab Vedotin acceptable toxicity profile. Another study in 2014 evaluated 37
patients with relapsed CCR4+ PTCL. The authors noted objective
Monoclonal antibodies have emerged as potentially important new responses for 35% of the patients including 14% with a CR. The
therapeutic tools in the treatment of many subtypes of NHL. Mono- ORR was 34% in patients with PTCL (three of 16 for PTCL-NOS,
clonal antibodies are now being developed against a host of other cell six of 12 for AITL, and one of one for ALCL, ALK negative). The
surface proteins, including the chemokine receptor CCR4, and other median PFS and OS for patients with PTCL were 2 months (8.2
surface proteins such as CD4 and more recently CD30. CD30 (also months for PTCL responders) and 14.2 months, respectively. Inter-
known as TNFRSF8) is a 120-kD transmembrane protein of the estingly, the total ORR did not significantly correlate with CCR4
tumor necrosis factor family and a known tumor marker found on expression level. Further investigation of KW-0761 for treatment of
many kinds of lymphoma. The receptor is found on the surface of ATL and other T-cell neoplasms are now warranted.
only activated T cells, and some B cells. CD30 is found on virtually
all cases of ALCL, and the majority of cases of Hodgkin lymphoma
(HL), where it is seen on the surface of the Reed-Sternberg cell. It is Miscellaneous Agents
also expressed by several nonlymphoid malignancies, including
embryonal carcinoma and some cases of non-small–cell lung cancer. The drugs mentioned earlier all represent agents that have been
Clinical trials with the chimeric anti-CD30 monoclonal antibody studied in a reasonable number of patients with T-cell lymphoma,
were uniformly disappointing in patients with ALCL and HL. For and have been approved by regulatory agencies for select diseases. In
example, among 38 patients with HL and 41 patients with ALCL addition to these there are other agents with very early and potentially
treated with SGN-30, no responses were seen in patients with HL, promising signals of activity in PTCL.
whereas two patients with ALCL achieved a CR. Similar results have
been reported with other anti-CD30 monoclonal antibodies. Proteasome Inhibitors
Conjugation of small molecules to highly targeted monoclonal The proteasome inhibitors, including bortezomib and carfilzomib,
antibodies to create an antibody–drug conjugate offers a promising have marked activity in multiple myeloma and mantle cell lymphoma.
way to deliver highly toxic drugs to select populations of cells. The Although the experience in PTCL is modest, 10 patients with CTCL
conjugation of a highly potent antimicrotubule agent, monomethyl and two with PTCL were treated with bortezomib at a dose of
2
auristatin E to the anti-CD30 monoclonal antibody creates a novel 1.3 mg/m on a day 1, 4, 8, and 11 schedule. Although the ORR
antibody–drug conjugate called SGN-35, or brentuximab vedotin. was reported to be 67%, dramatic responses were seen in patients
Clinical trials of this drug in patients with HL and ALCL have with advanced CTCL, and one of the two patients with PTCL
demonstrated remarkable activity in these CD30-expressing diseases. experienced a CR. Emerging data have now demonstrated that the
A pivotal trial of brentuximab vedotin in patients with relapsed or proteasome inhibitors potently synergize with the HDACIs and
refractory ALCL produced an ORR of 86%, with a CR rate of 57%. pralatrexate, which is now leading to combination studies in patients
These remissions were found to be very durable, with a median with PTCL.
response duration of 12.6 months and a median duration of response
among patients in CR of 13.2 months. The majority of patients Immunomodulatory Drugs
enrolled in the study exhibited poor prognostic features: 72% of Another novel class of drugs with a signal of activity in the T-cell
patients had ALK-negative ALCL, 63% of patients were refractory lymphomas includes the immunomodulatory drug lenalidomide.
to front-line therapy, and 22% of patients had never responded to This class of drugs is thought to increase the immunologic synapse
any prior therapy. These results recently led the FDA to grant acceler- by increasing NK cell activity against the lymphoma cells. In one
ated approval to brentuximab vedotin in patients with ALCL. A report, lenalidomide was administered orally for 21 days on a 28-day
subsequent experience in non-ALCL PTCL (n = 35 patients), essen- cycle at a dose of 25 mg daily in 24 patients with relapsed or refrac-
tially restricted to PTCL-NOS and AITL, revealed an ORR of 41% tory PTCL with an ORR of 30% being reported (seven responses
(24% with a CR), with a median PFS and duration of response of among 23 evaluable patients), with no CR. Responses were seen in
2.6 months and 7.6 months, respectively. Ongoing studies are now patients with ALCL, AITL, and PTCL-NOS. The median PFS was
exploring the benefits of this drug in combination with standard 96 days. Similar results were reported among 10 patients with relapsed
upfront chemotherapy regimens such as CHOP. and refractory PTCL-NOS, where three CRs were reported.
Alisertib (Aurora A Kinase Inhibitor)
KW-0761 Preliminary reports from a phase II study of a novel aurora A kinase
inhibitor, MLN8237/alisertib, in patients with aggressive NHL have
Another novel cell surface protein for which there is now a targeted recently demonstrated activity in patients with PTCL. An initial
drug is the CCR4 chemokine receptor, which is encoded by the phase II trial of alisertib in patients with B- and T-cell lymphoma
CCR4 gene. CCR4 has also recently been designated CD194. The demonstrated an ORR of 27%, and in eight patients with PTCL, a
CCR4 protein belongs to the G-protein–coupled receptor family and RR of 50%. Recently, SWOG-1108 evaluated alisertib in 37 patients
is a receptor for many different cytokines that influence the behavior with PTCL in the relapsed and refractory setting. In this study, Barr
of leukocytes. CCR4 is known to be expressed on Th2 cells and regu- et al reported two CRs and seven PRs, with an ORR of 24% and
latory T cells. Several studies have demonstrated that CCR4 is 33%, respectively, for the most common subtypes (PTCL-NOS,
expressed at relatively high levels on select T-cell neoplasms, including AITL, and ALCL). The LUMIERE trial, which is a phase III study
HTLV-1 ATLL. KW-0761 is a defucosylated humanized IgG1 anti- of alisertib versus investigator’s choice (pralatrexate, romidepsin,
CCR4 monoclonal antibody that enhances antibody-dependent gemcitabine) in relapsed/refractory PTCL has recently closed and we
cellular cytotoxicity and has been evaluated in multicenter phase I eagerly await these results.
and II studies in patients with relapsed, aggressive CCR4+ ATL.
Patients received intravenous infusions of KW-0761 once a week Bendamustine
for 8 weeks at a dose of 1.0 mg/kg. The phase II study of KW-0761 The BENTLY trial evaluated bendamustine in 60 patients with
was conducted in 28 patients with relapsed or refractory ATL. The relapsed or refractory PTCL. The ORR was 50%, including a CR
overall RR was 50%, including eight complete responses, and the rate of 28% and a PR rate of 22%. The drug showed consistent
median PFS and OS were 5.2 and 13.7 months, respectively. The efficacy independent of major disease characteristics. The median