Page 1547 - Hematology_ Basic Principles and Practice ( PDFDrive )

1374 Part VII Hematologic Malignancies

myelosuppression than the other agents. This myelosuppression may CTCL, new drugs continue to be tested. On the basis of the
even be more significant when the agent is used to treat T-lymphocyte clinical evidence of possible activity in early-phase testing, several
disorders compared with B-cell diseases. In the study by Betticher drugs have been evaluated. In a phase II trial of 44 patients with
et al, significant reductions in neutrophils and lymphocyte counts relapsed MF or PTCL (unspecified), a dose of gemcitabine was
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occurred in 46% and 41% of patients, respectively. In a study of administered at 1200 mg/m over 30 minutes for 3 weeks every 28
2-CdA, we reduced the days of therapy delivered by continuous days. There were five (11%) CRs and 26 (59%) PRs (overall RR,
infusion to 5 days from the usual 7 because of a perception that the 70.5%). The median duration of response ranged from 15 months
toxicity, primarily prolonged thrombocytopenia, was unacceptable. for CRs to 10 months for those patients with PR. There appeared
These results suggest that patients treated with these agents should to be no difference in response type between patients with MF and
be carefully evaluated for infectious complications, especially oppor- PTCL. In a second trial at the MD Anderson Cancer Center with
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tunistic infections, and that prophylactic antibiotic therapy should gemcitabine administered similarly but at a dose of 1000 mg/m ,
be considered during and after therapy if significant immunosuppres- investigators documented a 68% overall RR (17 of 25), with two
sion is documented. In addition, one should carefully consider the patients developing a CR. Toxicity included myelosuppression in
value of continuing to administer cycles of therapy if there is no the majority of patients and development of a hemolytic uremic
evidence of further improvement in clinical response, because of the syndrome in two older adult patients. Most recently, gemcitabine
risk for suddenly developing prolonged cytopenias that may limit was studied as a first-line systemic treatment in 27 patients with
future therapeutic approaches. In general it is not apparent that one stage T3 or T4 MF/SS. The overall RR was 70% (19 of 27), with six
purine antimetabolite is dramatically superior from these studies, CRs. The median time to progression was 10 months. Toxicity was
although DCF has a slightly higher overall RR. It has been observed generally mild.
repeatedly in these studies that occasional patients with SS may have The camptothecins are a family of compounds that inhibit topoi-
striking and durable responses to treatment, but ideally other agents somerase I, an enzyme required for unwinding strands of DNA for
emerging may allow for higher RRs with less toxicity in this transcription and replication. In early-phase studies it was recognized
population. that the administration of 9-aminocamptothecin (9-AC) by continu-
A relatively new class of antineoplastic agents, the proteasome ous infusion was required to maintain a drug concentration above a
inhibitors, also have activity in CTCL. In vitro activity of bort- threshold level, which coupled with duration of exposure was impor-
ezomib has been demonstrated against CTCL cell lines, thought tant to ensure adequate inhibition of the target enzyme. In these
to be due to a decrease in NFκB expression observed, and this studies at appropriate concentrations, activity was identified in
reduction resulted in marked increase in spontaneous apoptosis. NHLs, and it was therefore evaluated in MF/SS. We undertook a
These data formed the rationale for performing a clinical trial. trial of intravenous 9-AC in patients with MF/SS. The trial was
Zinzani et al reported a small phase II trial of 10 evaluable patients prematurely closed after 12 patients received 30 cycles. There were
with stage IV or greater MF. In this limited sample, there was one two PRs (17%) in a heavily pretreated population of patients;
CR and six PR observed, with a range of response durations of however, six of the 12 patients (50%) developed indwelling catheter
7–14 months at the time of the report. Toxicity was as expected, infections, and three patients died 4–8 weeks after the last dose of
with nearly 20% of patients experiencing grade 3 neutropenia and 9-AC. The toxicity was deemed too excessive to justify this dose,
thrombocytopenia. Additional studies are ongoing with this agent route, and schedule of administration. This study nicely demonstrates
in combination with other agents for histologically aggressive T-cell the hazards of chemotherapy in this patient population, including
lymphomas. the underlying risk for infection and the relative contraindication to
Combination chemotherapy has often been employed for MF/SS indwelling catheters (hence a bias toward agents administered as short
patients with advanced disease at presentation or with progression. infusions through peripheral catheters, or oral agents, and the impor-
Usually alkylating agents are used, in combination with doxorubicin tance of prophylactic antibiotics if excessive invasive procedures are
or vinca alkaloids. Response rates of 80%–100% have been achieved, anticipated).
with longer durations of remission than observed with single-agent Another drug empirically tested for the treatment of MF/SS is
therapy. There have been no trials comparing different aggressive pegylated doxorubicin based on the historic activity of doxorubicin
combination regimens. High RRs with perhaps less toxicity have been against NHLs. The process of encapsulating the doxorubicin in
observed in treating other NHLs using infusional combination regi- pegylated liposomes creates stable, long circulating carriers of the
mens such as EPOCH (etoposide, prednisone, vincristine [Oncovin], drug that result in greater tumor cell uptake versus normal cell
cyclophosphamide, and hydroxydaunomycin). A trial in CTCL sug- uptake. This may reduce normal cardiotoxicity and myelosuppres-
gested comparable activity to a bolus schedule, with greater risk for sion. The drug is approved for use against Kaposi sarcoma but has
febrile neutropenia and bacteremia associated with indwelling cath- been evaluated in a small group of patients with MF in Europe. Six
eters required for the infusion. patients in this pilot study received pegylated liposomal doxorubicin
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It is our philosophy that this disease behaves similarly to other at 20 mg/m every 4 weeks. Four patients achieved a CR and one
low-grade lymphomas (e.g., B-cell type), with periods of remission other patient achieved a PR. The overall RR was 83%. The median
becoming shorter with subsequent therapeutic interventions. duration of response was not reported. Grade 3 adverse events were
However, as noted, advanced-stage MF is associated with a relatively few and included one patient with lymphopenia and two with
short median life expectancy. Patients with significant nodal involve- anemia. No other severe adverse effects were noted. A larger retro-
ment or extensive skin disease (T4 in particular) have median life spective multicenter report of this agent administered intravenously
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expectancies of 30–55 months. A driving force in the development at 20–40 mg/m every 2–3 weeks in 34 patients has also been con-
of treatments for this disease is the goal of altering the natural history ducted. Overall, 15 patients achieved a CR and 15 achieved a PR
for this group of poor-prognosis patients, or for delaying the develop- (RR of 88%), with EFS of 12 months. Toxicity was similarly
ment of poor-prognosis disease. There is no clinical trial of any manageable.
modality that has demonstrated a survival benefit compared with a The ability to biopsy skin lesions for studies of tumor cells in MF/
control group. Kaye et al demonstrated more than a decade ago that SS has resulted in this disease being a favorable setting for the evalu-
combination chemotherapy (and total-skin electron beam radiation ation of candidate therapeutic agents and exploration of rational
therapy) did not provide a more favorable survival or even clinically therapeutic development. These studies have allowed investigators to
significant delays in time to recurrence for patients, compared with test new drugs at appropriate dosages with a correct schedule of
standard palliative, less aggressive therapies. New drugs or approaches administration, and to generate, prove, or refute hypotheses regarding
are still being developed with the goal of altering the disease state in mechanism of action or resistance. A number of studies of such agents
poor-prognosis patients. have been completed and may lead to further drug testing in search
Because of the pressing need to identify new strategies to provide of enhanced therapeutic activity in MF or perhaps achieve cure
more durable remissions or even curative therapy for advanced of MF.