Page 1549 - Hematology_ Basic Principles and Practice ( PDFDrive )

1376 Part VII Hematologic Malignancies

induce a host immune response to the reinfused altered Sézary cells, Vitamin A Derivatives Not Approved for CTCL
possibly through activation of circulating dendritic cells. This theory There has been a resurgence of interest in retinoids for the treatment
would explain the findings of some investigators that patients without of hematologic malignancies with the approval of all-trans retinoic
leukemic involvement do poorly with such therapy. This treatment acid (ATRA) for acute promyelocytic leukemia. ATRA has been
modality has resulted in the best results in SS patients with erythro- studied in 33 patients with relapsed MF who had not had prior
+
2
derma of short duration and with adequate CD8 blood counts. exposure to oral retinoids. Patients received 45 mg/m daily in two
Several other groups have reported their experiences with photo- divided doses for up to 2 years. In 29 evaluable patients, five responses
pheresis. When the data are analyzed on an intent-to-treat basis, were observed (one CR, four PRs) for an ORR of 17% with a median
overall RRs of 36%–52% were observed. Only 12%–18% achieved duration of response of 4.5 months. Another seven patients (24%)
CR. These investigators attempted to wean patients from therapy as had stable disease. The most common toxicities included headache
clearing of lesions was documented. Ultimately, most responders (37%) and mucous membrane dryness (80%). Only one patient
developed recurrent disease. Many trials are underway combining experienced severe elevation of lipid levels. ATRA works through
extracorporeal photopheresis with other active modalities. binding to specific retinoic acid receptors (RARs; RAR family α, β,
Toxicity is mild and includes occasional nausea, erythematous and γ), which then bind to retinoic acid response elements located
flares, and temperature elevations. Patients may develop hypotension upstream of gene promoters, providing transcriptional control of
during leukapheresis, which usually responds to saline infusions. proteins.
Approved Vitamin A Derivatives for CTCL
Interferons A second family of receptors, the retinoid X family of receptors
(RXR), has been identified. Bexarotene is a synthetic retinoid that
IFN-α is an active agent for the treatment of MF. Dosages and routes selectively binds this family of receptors. Unfortunately, as is the case
of administration have differed among studies. Initially, high-dose with the retinoids that bind the RAR family of receptors, the expres-
IFN was used, with maximum doses of 36–50 million International sion of which genes that are altered to achieve the clinical benefits
Units (IU). Bunn et al and Olsen et al independently demonstrated observed remains unknown. This compound has been tested in sepa-
2
complete RRs of 10%–27% in heavily pretreated patients. The dura- rate trials of early- and advanced-stage patients. At the 300 mg/m
tion of response was only 5.5 months. Later trials of untreated dosage daily (dose recommended by the FDA), 54% of the 94
patients with doses of 3–18 million IU given subcutaneously daily advanced-stage patients in an open-label phase II study responded to
have demonstrated RRs of 80%–92%. From all these studies, it therapy (2% CRs). The median duration of response was 299 days.
appears that a reasonable and tolerable single-agent dose is 12 million The early disease trial showed similar RRs. The toxicity spectrum is
2
IU/m administered subcutaneously daily. We recommend starting at somewhat different from the RAR-specific retinoids, including more
3 million IU and gradually increasing as treatment is tolerated by the frequent severe elevations of lipid levels (although rarely associated
patient. with pancreatitis), hypothyroidism, and less frequent headaches and
In a single trial, the results of treatment of 16 refractory CTCL dry mucous membranes. The compound can also be used topically.
patients with IFN-γ were reported. Five patients experienced PRs A phase I/II trial of the topical bexarotene demonstrated a 63% RR
(RR, 31%) with a median duration of 10 months (range, 3–32+ (21% clinical CRs) in primarily early-stage patients with lesional
months). application. Toxicity was mostly local irritation with erythema.
Side effects of all IFNs are dose dependent. Most common adverse The favorable toxicity profile has led to a number of combination
effects are constitutional symptoms, consisting of fever, chills, myal- modality trials using retinoids. Some of these small trials have com-
gias, malaise, and anorexia. Rarely, cytopenias, elevations of liver bined retinoids with IFN-α and have reported RRs of 40%–50%.
function test results, renal dysfunction, cardiac dysfunction, or Combinations of retinoids with PUVA have been suggested to result
changes in mental status can be seen. Patients need to be monitored in clinical benefit in less time with less exposure to ultraviolet radia-
closely while on IFN. tion. These experiences have been generally limited and often
A retrospective analysis of a CTCL database, including 198 MF/ uncontrolled, making definitive conclusions impossible. Larger ran-
SS patients undergoing systemic therapies, revealed a median time to domized trials are needed to determine if routine use of such combi-
next treatment for single- or multiagent chemotherapy of 3.9 months nations should be undertaken outside of an investigational trial.
(95% CI, 3.2–5.1), compared with 8.7 months for IFN-α (95% CI,
6.0–18.0, p < .00001). This study suggests that the use of conven-
tional chemotherapy regimens should be delayed until other options Monoclonal Antibodies
are exhausted.
Targeted therapy has become a reality for the treatment of many types
of cancer, including MF/SS. Although the most common approach
Retinoids has been with the use of antibodies that target antigens expressed by
the tumor cells (e.g., rituximab), another class of compounds known
Vitamin A and its natural and synthetic analogues are known as reti- as recombinant fusion proteins has been developed, the prototype being
noids. These compounds have diverse biologic effects, influencing DD, for the treatment of CTCL.
differentiation and proliferation of a number of structures during
development. In addition, some compounds have been shown to Approved Monoclonal Antibodies for Cutaneous
influence immune function. Clinically, a number of approved formu- T-Cell Lymphoma
lations have demonstrated efficacy in MF and SS. DD is a single-chain protein in which the receptor-binding domain
Many of the trials of retinoids for MF/SS were performed decades of native diphtheria toxin is replaced by the sequences encoding the
ago with limited patient numbers. Treatment with isotretinoin IL-2 gene (CD25). Once this molecule binds to the high-affinity IL-2
(13-cis-retinoic acid), a nonaromatic retinoid, has been associated receptor, the fusion toxin is internalized by receptor-mediated endo-
with clinical benefit in a number of trials. Overall objective responses cytosis and is proteolytically cleaved within endosomes to liberate the
have been described in 33 of 56 patients treated in three clinical trials. free ADP-ribosyl transferase activity of diphtheria toxin into the
A monoaromatic retinoid compound, etretinate, did not achieve cytosol, where it then inhibits protein synthesis.
similar results when tested as monotherapy for MF in several trials In early phase I studies with DD, the RR of CTCL patients who
but did show efficacy in a trial for the treatment of parapsoriasis en demonstrated at least 20% expression of the IL-2 receptor was 30%.
plaques. A polyaromatic retinoid demonstrated efficacy in a small A phase III study comparing various dose levels of DD demonstrated
trial. Objective responses were observed in three of six patients (one a similar RR, but there was significant toxicity that led to a high
CR and two PRs). dropout rate (constitutional symptoms, infusional reactions such as