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Chapter 85 T-Cell Lymphomas 1373

days. Mucositis (17% grade 3), skin toxicity (7% grade 3), and fatigue TABLE Response Rates Observed in Clinical Trials With
(3% grade 3) were common with the use of this agent at the recom- 85.7 Purine Antimetabolite Agents
mended dose. To date no comparison trials of pralatrexate to metho-
trexate have been performed to assess the relative cost and benefit Drug Overall Response Rate (%) Reference
differences. DCF 66 119
Subsequently, the benefits of adding 5-fluorouracil to the
methotrexate-based regimen, exploiting the synergy between these DCF 100 120
agents, were evaluated. The methotrexate was administered as a DCF 54 121
2
24-hour continuous infusion at 60 mg/m . Immediately after this DCF 66 122
infusion, 5-flourouracil (20 mg/kg every 24 hours) was continu- Fludarabine 18 123
2
ously infused for 36–48 hours. Oral citrovorum factor (10 mg/m )
was administered intravenously 6 hours after cessation of the 2-CdA 28 124
methotrexate infusion and then orally for five additional doses. The 2-CdA 38 125
2
methotrexate dose was escalated to a maximum of 120 mg/m , as 2-CdA 18 126
allowed by toxicity and response. Ten patients were treated for an
average duration of 33 months (range, 3–78 months). The number of 2-CdA 100 127
cycles administered ranged from 5 to 45. All patients achieved a PR. 2-CdA, 2-chlorodeoxyadenosine; DCF, 2′-deoxycoformycin.
Initial cycles were given every 5–8 days. Once a good response was
achieved, cycles were administered every 3 months as maintenance.
Other groups anecdotally reported success with low doses of oral
methotrexate. In general these regimens appear to be fairly well A number of studies treating patients with MF/SS have been
tolerated. performed with these drugs. Table 85.7 shows the results in these
The purine antimetabolites have been shown to be active in the studies. Four studies used DCF as a single agent at doses ranging
2
treatment of MF/SS. These compounds do not have a single mecha- from 3.75 to 10 mg/m daily for three doses every 21–28 days.
nism of action, but all ultimately interfere with intracellular regula- Twenty five patients with MF/SS were included in these studies;
tion of deoxyribonucleotide pools and this imbalance partially overall, three CRs (12%) and 12 PRs (48%) were documented. The
explains the cytotoxicity. This family of drugs includes 2′-deoxyco- fourth study represents the largest phase II experience reported for
formycin (DCF), fludarabine phosphate, and 2-chlorodeoxyadenosine the treatment of MF/SS and other CTCLs. Twenty-seven eligible
2
(2-CdA). patients were treated for 3 consecutive days at 3.75 mg/m /day.
2
DCF is a transition state inhibitor of adenosine deaminase. Inhibi- Essentially, 80% of the doses were delivered at 3.75 or 5.0 mg/m /
tion of this enzyme, necessary for the conversion of adenosine to day. Twenty one of 24 response-evaluable patients had SS (14
inosine, results in accumulation of 2-deoxy–ATP and subsequent patients), tumor-stage MF (six patients), or large-cell transformation
inhibition of the enzyme ribonucleotide diphosphate reductase neces- of MF (one patient). Patients had failed a median of three prior
sary for DNA synthesis in dividing cells. DCF is also effective against treatments before enrollment. The overall RR for patients with MF/
cells in the resting state, where ribonucleotide diphosphate reductase SS was 66% (five CRs and nine PRs). Most responses were short lived
levels are barely detectable. It has been shown that deoxy-ATP because the median duration of response in patients with tumor-stage
accumulation in resting lymphocytes results in increased DNA strand disease was 2 months (range, 1–2 months) and the median duration
2+
2+
breaks over time; this results in the activation of Ca /Mg -dependent of response in erythrodermic disease was 3.5 months (no range given,
endonuclease that produces double-stranded DNA breaks at internu- but two patients had responses of at least 17 months).
cleosomal regions and also activation of a poly-adenosine diphosphate The use of fludarabine for the treatment of MF/SS has also been
(ADP)–ribose polymerase that consumes nicotinamide adenine assessed in a single, large phase II trial by Von Hoff et al. They treated
dinucleotide and adenosine triphosphate (ATP). These perturbations 33 patients who were good-risk disease (i.e., no prior systemic
lead to apoptotic cell death. therapy) or poor-risk disease (i.e., prior systemic therapy) with
2
Fludarabine phosphate represents the fluorinated derivative of fludarabine alone at doses of 25 and 18 mg/m for the two groups,
adenine arabinoside (ara-A). This compound was known to retain respectively. One complete response and five PRs were obtained for
cytotoxic action against leukemias and was resistant to degradation an overall RR of 18%.
by adenosine deaminase. Solubility was poor, however, unless the 2-CdA has been evaluated as a single agent for the treatment of
5′-monophosphate derivative was used; hence, fludarabine mono- MF/SS in 21 patients who had failed at least one prior therapy. There
phosphate is the 5′-monophosphate form of F-ara-A. Similar to the were three CRs and three PRs (overall RR of 29%). The median
mechanism of action of cytarabine or ara-A, fludarabine phosphate duration of response in this heavily pretreated group, however, was
requires phosphorylation by deoxycytidine kinase to the active tri- only 4 months. Three other groups have also reported results in small
phosphate metabolite F-ara-ATP. Again, this triphosphate derivative numbers of MF patients. A total of 21 patients were reported when
inhibits ribonucleotide reductase, resulting in nucleotide pool imbal- the studies are pooled. Seven patients achieved responses, giving an
ances, which prevent DNA repair and ultimately cause apoptosis. overall ORR of 33%, remarkably similar to results from the prior
2-CdA represents another chemical modification of deoxy- large, single-institution study.
adenosine, which renders the drug resistant to adenosine deaminase. The similarity in mechanism of action of these compounds would
After activation by deoxycytidine kinase, the triphosphate derivative suggest that toxicity associated with the various compounds would
similarly inhibits ribonucleotide reductase and accumulates intracel- be similar. This has definitely not been the case, however. There are
lularly, perturbing the deoxyribonucleotide pool balance, resulting in distinct differences in the spectrum of acute and chronic toxicities
DNA damage and cell death. with these agents. DCF and fludarabine are associated with higher
Enzymes such as cytoplasmic 5′-nucleotidase catalyze the degrada- rates of nausea or vomiting and alopecia than commonly associated
tion of the active triphosphate derivatives discussed earlier. Cells with with 2-CdA. The most significant toxicities with DCF and fludara-
relatively greater levels of the activation enzymes versus degradation bine, however, are neurotoxicity and immunosuppression. Approxi-
enzymes were identified as likely clinical targets. Lymphoid disorders mately 15% of patients developed sepsis, and 10% developed an
make good targets for these agents because they contain high levels opportunistic infection, such as disseminated toxoplasmosis, cyto-
of deoxycytidine kinase and low levels of 5′-nucleotidase and depend megalovirus infection, Pneumocystis carinii pneumonia, atypical
on polymerase-α for DNA repair. Because it was known that mycobacterial infection, and fungemia in studies. Another 15%
T-lymphoblastoid cell lines were most sensitive to these drugs, it was developed severe neurotoxicity in the form of confusion, motor weak-
thought that T-lymphocyte disorders would be sensitive in vivo to ness, paresthesias, and CNS demyelination. Treatment with 2-CdA
these agents. is extremely well tolerated initially but may result in somewhat greater