Page 1550 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 85 T-Cell Lymphomas 1377

hypotension, chest pain or dyspnea, and a vascular leak syndrome). that could be explained by findings from another study suggesting
Based on this trial the drug was approved for the treatment of that alemtuzumab depletes all T cells in the blood but only the central
relapsed/refractory CD25-expressing CTCL. memory T cells of the skin.
Recently, two dose levels of DD were compared with placebo in Another target of therapy for MF/SS is CD30. As noted earlier,
patients with stage IA–III disease. This clinical trial is one of the larger this antigen is expressed in a variety of malignancies, including
studies conducted in MF/SS to date and provides interesting infor- advanced HL, ALCL, and often the lesions of tumor-stage or trans-
mation because it is one of the few to include a placebo control arm. formed MF (tMF). As previously discussed, brentuximab vedotin
Overall, 144 patients were enrolled, all with 20% or higher expression (SGN-35) is an antibody to CD30 conjugated via a highly stable
of CD25 on a skin biopsy specimen and randomized in a 1 : 1 : 1 protease-cleavable linker to a derivative of auristatin E (monomethyl
fashion to either 18 µg/kg DD, 9 µg/kg DD, or the placebo, with auristatin E), which inhibits microtubules and induces apoptosis in
the primary endpoint being overall RR. The RRs were 49.1%, target cells. It has been approved for the treatment of relapsed HL
37.85%, and 15.9%, respectively, and both DD dose arms were and systemic ALCL that express CD30. There are now efforts under-
statistically superior to the placebo. PFS (median >2 years) in the DD way to determine its efficacy in primary cutaneous ALCL and MF.
arms was also superior compared with placebo (median 4 months). Several preliminary studies have been reported. Investigators at
Moderately severe and severe adverse events were both greater in the Stanford led a trial of this molecule in MF/SS with all levels of
DD arms than placebo, but there was no dose effect with regard to expression of CD30. At the time of the preliminary report, 15
safety. patients with MF/SS (13 stage IIB–IV MF/SS, nine with large-cell
Because of the toxicity spectrum of DD, we limit the use of this transformation) were included. Seven of the patients had less than
agent to patients who have failed several systemic agents (often 10% CD30 expression, seven had 10%–50% expression, and one
bexarotene and IFN) previously and have more threatening disease had more than 50% expression by immunohistochemical analysis.
such as the presence of skin tumors or nodal involvement. It is An objective response was observed in 60% of the patients and in all
important to note that the pivotal trials did not allow concomitant cohorts by expression level of CD30. Toxicity was generally mild,
use of corticosteroids to prevent nausea and infusional reactions. including fatigue, peripheral neuropathy, rash, and infusion reactions.
Subsequently, a retrospective case review of patients pretreated with Two patients with pretreatment expression of CD30 developed
corticosteroids suggested a more favorable toxicity profile and a RR antigen loss during treatment. In a phase II trial, in which SGN-35
of nearly 60%. The nature of the trial limited the conclusions to be was administered at 1.8 mg/kg every 3 weeks for up to eight cycles
drawn but suggested that aggressive pretreatment with steroids made to 19 heavily pretreated MF/SS patients with variable CD30 expres-
this drug easier to administer to patients with advanced relapsed MF. sion, an ORR of 68% and median EFS of 27 weeks were reported.
+
However, this drug is currently not available. A newer version of the In another phase II trial involving 48 relapsed/refractory CD30
drug has been developed with improved manufacturing characteris- CTCL patients (including patients with PC-ALCL, LyP, and MF)
tics, but is only now entering clinical trials to determine if these who received SGN-35, a 71% ORR was reported (100% ORR
changes have altered clinical activity. among the PC-ALCL and LyP patients). Neither of these studies
demonstrated a correlation between response to SGN-35 and degree
Approved Targeted Agents for Cancer But Not for of CD30 expression, and response was noted even among cases with
Cutaneous T-Cell Lymphoma minimal expression of CD30. AEs observed in both studies included
Targeted therapies against unique tumor antigens continue to be peripheral neuropathy, rash, diarrhea, and fatigue. Currently, patients
+
tested, such as the recombinant DNA-derived humanized monoclo- with relapsed CD30 MF or PC-ALCL are being enrolled in a
nal antibody alemtuzumab. This antibody is directed against CD52, multicenter, open-label phase III trial, which compares BV to physi-
which is present on the surface of normal and malignant B and T cian’s choice of either bexarotene or methotrexate (ClinicalTrials.gov
cells, and presumably works through antibody-dependent cellular identifier: NCT01578499).
cytotoxicity and activation of complement-dependent cytolysis, but
may also induce apoptosis without complement activation. A number
of trials of this agent in various stages of MF/SS have been reported. Investigational Approaches
The initial phase II study using alemtuzumab in 50 patients with
low-grade NHL, including eight patients with MF, demonstrated a Because of the chronic relapsing nature of MF, new therapies with
50% RR in MF (four of eight patients, two CR). In a phase II different mechanisms of action are needed to circumvent tumor
multicenter study of 22 patients with advanced MF (n = 15) and SS resistance. A variety of such approaches are under investigation. These
(n = 7) refractory to PUVA, radiotherapy, or systemic chemotherapy, include the use of existing or newly developed retinoid compounds
intravenous treatment with 30 mg alemtuzumab three times a week or combinations of retinoids with other agents. Other combination
for 12 weeks resulted in an ORR of 55%, with 32% of patients in modalities under study include retinoids, IFNs, and chemotherapy
CR and 23% in PR. Higher RRs were demonstrated in patients with or radiation therapy, and total-skin electron beam radiotherapy fol-
erythroderma and those with fewer previous treatment regimens. lowed by photopheresis or chemotherapy. Given the lack of benefits
Both patients with tumor-stage disease had progressive disease on of combination chemotherapy and radiotherapy previously, the role
alemtuzumab. Kennedy et al studied the efficacy of alemtuzumab in of such approaches should remain investigational. Another less toxic
CTCL patients (stage IIB–IV) and demonstrated a PR in three combination approach has been the simultaneous administration of
(38%), with infectious complications in seven of eight patients. Two IFN and phototherapy. An overall RR of 92% has been observed with
of the responders had SS, and these findings support our perspective this combination in all stages of patients, many of whom had been
that alemtuzumab may be most helpful in patients with erythroder- previously treated with other therapies.
mic MF and SS. We then conducted a trial in 19 heavily pretreated Another approach to the therapy of this disease has involved new
patients with erythrodermic MF or frank SS. In this trial the patients drugs to exploit the biologic characteristics of these neoplastic cells.
received a variety of subcutaneous, intravenous, or both routes of For example, Notch signaling has been shown to be dysregulated in
administration. The overall RR was 84% (47% CR and 37% PR). a variety of T-lymphocyte neoplasms. It has also been shown that
Median PFS was 6 months, but median overall survival was 41 Notch1 is expressed in tumor cells in many advanced-stage patients
months despite the advanced-stage disease and extensive prior therapy. with MF/SS. There are specific inhibitors of Notch signaling that
We did not experience the dramatic infectious or cardiac events some induce apoptosis in MF/SS cell lines, and this is an elegant example
investigators have reported, likely because of the routine inclusion of of how these molecular breakthroughs could be exploited to develop
prophylactic antiviral, antifungal, and antipneumocystis agents. A new approaches to the treatment of this disease. Other examples of
multicenter retrospective analysis of 39 patients with advanced MF recent or ongoing efforts to target aberrant molecular pathways in
(n = 6) or SS (n = 23) indicated that the SS patients experienced a CTCL include clinical trials involving the use of PI3K inhibition and
higher RR and longer median time to progression, an observation selective inhibition of nuclear export (ClinicalTrials.gov identifier: