Page 1545 - Hematology_ Basic Principles and Practice ( PDFDrive )

1372 Part VII Hematologic Malignancies

or plaque disease demonstrate efficacy similar to that of topical achieving a CR. The median response duration was 15 months.
mechlorethamine. For limited patch disease, there was a failure-free Common adverse events included nausea/vomiting in over 56% of
rate of 90% at 3 years. For more extensive patch-stage disease, the patients, asthenia in 44%, and diarrhea in 14%, but again grade 3
freedom from treatment failure rate at 3 years was 62%. Some toxicities were much less frequent, but also included fatigue in 6%.
patients have been managed for as long as 10 years with topical The HDACI have been linked to cardiac abnormalities and especially
carmustine. Side effects of contact dermatitis are less frequent with arrhythmias. However, in this large trial, events such as cardiac
this agent, but systemic side effects, mainly leukopenia, are more failure, atrioventricular block, and ventricular tachycardia were rare,
common. This drug may be helpful for the treatment of patients who occurring typically in less than 1% of patients. Avoiding other drugs
do not tolerate topical mechlorethamine, because there is no cross- that may also cause cardiac arrhythmias seems prudent in patients
sensitivity. A topical agent undergoing clinical investigation in a phase treated with HDACI. The second confirmatory trial was led by
Ib multi-center, double-blind, placebo-controlled, randomized trial investigators at the National Cancer Institute. Seventy one patients
in early-stage CTCL patients is the hydroxamic acid HDAC inhibitor (87% with stage IIB or higher) with heavily pretreated MF/SS
SHP-141. A 2014 update reported that six of the 18 patients enrolled (median four prior treatments) were treated with romidepsin at the
had achieved a clinical objective response (>50% improvement by same dose as described earlier. Again the overall RR was 34% with
CAILS) and incremental weekly CAILS improvement throughout 6% CR. Although GI disturbances and fatigue were common in this
the dosing period. Time to response was noted to be as early as day trial in over 40% of patients, myelosuppression was seen more fre-
7. Skin biopsy histology revealed increased dermal acetylation, and quently, with 5%–10% of patients experiencing grade 3 neutropenia
pharmacokinetics results confirmed lack of SHP-141 peripheral and thrombocytopenia. Cardiac arrhythmias were again uncommon,
blood exposure. but T-wave/ST changes were seen in the majority of patients, and
Hamminga et al performed one of the few prospective trials grade 1 QTc prolongation was seen in 10% of patients.
comparing total-skin electron beam radiation to topical mechloretha- In general then, toxicity to romidepsin and vorinostat has included
mine. A total of 42 patients with MF localized to the skin (no docu- alterations in the cardiac conduction that could potentially predispose
mented nodal or visceral involvement) were treated. Patients were not to arrhythmias, and treatment of patients has required ongoing
randomized to their treatment; rather, the physician based the deci- telemetry monitoring in some trials, but no evidence for acute or
sion on patient health, availability of the linear accelerator, and the chronic impairment in cardiac function has been noted. Vorinostat
distance the patient lived from the clinic. In patients with minimal therapy led to drug-related grade 1 electrocardiographic changes in
skin disease, no difference in outcome was observed. In more five patients and grade 2 in one patient. Therefore it appears safe to
advanced skin disease, a trend toward superior initial response was use these agents in the outpatient setting with a periodic assessment
seen with electron beam therapy, but there was a high relapse rate in of cardiac rhythm and QTc interval with an electrocardiogram base.
those patients, necessitating subsequent therapy. Unfortunately, romidepsin has been shown to be a substrate for
the MDR protein (a P-glycoprotein) and upregulates the expression
of MDR1. Preliminary molecular analyses confirmed the upregula-
Systemic Chemotherapy tion of MDR1. These data suggest that when resistance to this agent
develops, other chemotherapeutic drugs handled by MDR1 may be
Currently systemic chemotherapy is reserved for those patients with rendered ineffective. Several patients demonstrated increased surface
relapsed or refractory disease after topical interventions or for those expression of the CD25 component of the high-affinity IL-2 receptor
patients with advanced nodal or visceral disease at presentation. Many after treatment. This protein is a target for denileukin diftitox (DD),
of the patients treated with chemotherapy have also previously been discussed elsewhere in this chapter as a therapy for MF, suggesting
treated with cytokine-based or other nontraditional chemotherapeu- that strategies for combination therapy approaches could be devised
tic agents before systemic chemotherapy is considered. With that to enhance responses to both agents.
in mind, a number of trials have been published reporting results
using agents developed many years ago for other indications but Approved Chemotherapy Agents for Cancer But not
still in use for the treatment of MF/SS today. Recently, novel agents for CTCL
are being increasingly studied for efficacy in MF/SS based upon a Older agents studied previously include alkylating agents such as
rationale developed with molecular or proteomic data. An example chlorambucil or cisplatin, the microtubule inhibitors etoposide,
of such agents is the HDACI. Vorinostat (SAHA) has been approved vincristine, and vinblastine, or the antitumor antibiotics, such as
by the FDA for the treatment of the cutaneous manifestations of bleomycin and doxorubicin. In general, the RRs are modest, and
CTCL in patients in whom bexarotene therapy (see Retinoids) has duration of response is typically less than 6 months.
failed, and a related HDAC inhibitor, romidepsin (depsipeptide or McDonald and Bertino reported particularly good results with the
FR901228), has been approved for the treatment of both CTCL antimetabolite methotrexate administered intravenously followed by
and PTCL. oral citrovorum factor. Patients received 1–5 mg/kg of intravenous
methotrexate every 5 days. If a patient tolerated the lowest dose, each
Approved Chemotherapy Agents for CTCL subsequent dose was escalated. After five intravenous doses, patients
Vorinostat 400 mg daily orally was tested in an open-label trial of 74 were switched to oral methotrexate (25–50 mg) with oral citrovorum
patients who had progressed on at least two prior systemic therapies. as weekly maintenance. All 11 patients achieved “good” or better
The ORR (skin only) was 29.5%, with 1 CR and 18 PRs. Common clearing (>60%) for a median duration of 24 months. Mucositis and
adverse events included diarrhea (49%) and fatigue (46%). Grade 3 skin ulcerations were the most significant toxicity witnessed. Myelo-
events were less common but included fatigue (5%), deep venous suppression was mild in general. The related compound, trimetrexate
thromboses/pulmonary emboli (5%), and thrombocytopenia (4%). has also been reported to be effective in treating CTCL.
Reports from the National Cancer Institute with romidepsin have As discussed previously, a newer folate analogue, pralatrexate, has
provided confirmatory results of the use of this class of agent for the also been shown to have substantial activity against PTCL. In early-
treatment of patients with T-cell lymphomas, including some with phase trials several patients with CTCL were felt to benefit, and
MF/SS. In several phase I and II trials, 10 of 20 patients with MF/ therefore a trial was designed specifically for MF/SS patients to
SS appeared to have had a PR. Two additional clinical trials demon- identify an effective and tolerable dose. Starting with a dose
2
strated activity in CTCL. In a large, multicenter, open-label phase II de-escalation design at 30 mg/m /week intravenously for 3 of 4
2
trial of romidepsin, 96 patients with relapsed stage IB–IVA MF/SS weeks, ultimately 15 mg/m /week was identified as the recommended
(71% had stage IIB or higher) received standard dosing of 14 mg/ dosage for further exploration. Twenty nine patients received this
2
m , on days 1, 8, and 15 every 28 days. Importantly in these trials, dose for a median of four cycles, and the ORR was 45% (1 CR
total disease burden, not just skin involvement, was assessed to unconfirmed [CRu]/12 PR). No median response duration had been
determine the RRs. The overall RR was 34%, with 7% of patients identified at the time of publication but ranged from 1 day to 372