Purine Analogs

The purine analogs pentostatin (deoxycoformycin), fludarabine, and cladribine (2-chlorodeoxyadeno-sine/2-CdA) are a group of structurally similar drugs that are active agents in the therapy of T-cell lymphomas.

T-cells have high levels of adenosine deaminase (ADA), a key enzyme involved in purine metabolism, and as ADA inhibitors, these drugs produce DNA damage and impairment of DNA repair. As single agents, the purine analogs are relatively well tolerated, with myelosuppres-sion being usually mild, although it tends to be more severe with cladribine than with pentostatin. Of note is the fact that these agents produce lymphopenia and immunosuppression, occasionally resulting in the development of opportunistic infections.

Several studies have demonstrated that pentostatin has activity against T-cell lymphoma (Table 60.3). Investigators at the Royal Marsden Hospital in London demonstrated that pentostatin has activity in post-thymic mature T-cell malignancies. Mercieca et al.98 obtained an overall response rate of 32% for 145 patients treated with pentostatin for a variety of mature T-cell tumors, most of whom had disease considered relapsed or refractory to anthracycline-containing regimens or alkylating agents. The median overall duration of response was 6 months, ranging from 3 to 66 months. For the 55 patients with T-PLL, 5 achieved a CR and 20 achieved a PR, lasting from 3 to 16 months (median 6 months), for an overall response rate of 45%. For the 16 patients with SS, 3 experienced a CR and 7 had PRs, ranging from 3 to 66 months (median 9 months), for an overall response rate of 62%. However, 13 patients with other types of CTCL, including 5 with MF, did not respond to pentostatin. Nonethless, of the four patients with circulating Sezary cells without skin involvement, two (50%) had PRs in terms of improvement in peripheral lymphocytosis and bone marrow function. Two of the five patients with LGLL leukemia also achieved a CR, one lasting 18 months and the other lasting 12 months. However, other subsets of T-cell disease in this study had lower response rates to pentostatin. Two of the 25 patients with ATLL achieved a CR, one lasting 33 months and the other died of an opportunistic infection while still in CR 5 months after stopping drug treatment; another achieved a PR lasting 5 months, with an overall response rate of 12%. Meanwhile, 27 patients with PTCL were treated, with 5 PRs and no CR, for an overall response rate of 19%. The duration of response was from 3 to 28 months, with a median response duration of 9 months. There was no statistically significant difference in the response rates of previously untreated patients compared to those for patients previously treated with one or more regimens (35% vs 29%, respectively), with histologic subtype being the single most important factor influencing results.

Other investigators have studied pentostatin for patients with relapsed CTCL or PTCL with prominent cutaneous manifestations.104 Of the 24 patients evaluable for response, six (25%) patients had CR and 11 (46%) patients had PR. Ten of 14 (71%) patients with SS, four of six (66%) with tumor stage MF, and three of three with PTCL responded. Although the median response duration of the patients with tumor-stage MF was only 2 months (range 1-2 months) and 3.5 months for SS patients, there were two SS patients with prolonged responses lasting greater than 1 year. One of the three PTCL patients had an ongoing CR at 20 months. The most common side effect observed in these patients who had received a median of three prior therapies (range 1-12) was significant lowering of CD4 counts, and several subsequently developed herpes zoster infection.

Recently, investigators at MD Anderson Cancer Center treated 14 patients with relapsed noncutaneous T-cell lymphomas with pentostatin, and reported details regarding its lymphopenic effects.107 One patient (7%) had a CR and six (43%) had PRs, with the median PFS result for responders being 6 months (range 2-15 months). A significant reduction in circulating CD26+ T lymphocytes was observed in treated patients, potentially associated with immunosupres-sion. In one patient with PR, the decrease in the levels of CD26+ T lymphocytes was associated with genital herpes reactivation, while resolution of this opportunistic infection was associated with a recovery in CD26+ T-cell levels, once pentostatin was discontinued. Since CD4+CD26+ T lymphocytes are memory helper T cells, the selective loss of CD26+ T cells in lymphoma patients treated with pentostatin has important clinical implications, and may partly explain the relatively high incidence of opportunistic infections observed in patients receiving this agent.

The other purine analogs, cladribine and fludara-bine, also have activity in T-cell lymphomas, although relatively limited data are available. One study involving 25 patients with relapsed or refractory cutaneous T-cell lymphoproliferative disorders (24 MF or SS and 1 Ki-1 + ALCL) showed that 2-CdA treatment resulted in a 24% response rate, with 3 patients (12%) having a CR with a median duration of 4.5 months (range 2.5-16 months) and three patients having a PR with a median duration of 2 months (range 2-4 months). The most significant toxicities were myelosuppression and infection, with opportunistic infections occurring in a significant percentage of patients.108 109 Another study also demonstrated 2-CdA activity in T-cell lymphomas, as 22 patients with such varied diagnoses as T-LGLL, T-PLL, T-CLL, SS, MF, and PTCL who were treated with 2-CdA had a response rate of 41%. Four responders (18%) had CRs (1 T-PLL, 1 MF, and 2 T-LGLL) while five patients (23%) had PRs (2 T-CLL, 1 SS, and 2 PTCL). All patients with PR and one CR patient developed relapses at a median of 7 months (range 5-26 months), while three patients with CR remain in remission at 30+, 36+, and 54+ months. The median overall survival was 12 months, and the main toxicities were fever and infec-tion.110 To date, there is only limited published data to suggest that fludarabine has single-agent activity in certain subsets of T-cell lymphoma, particularly MF.111112

Several investigators have studied purine-analog-containing combination therapies for T-cell tumors. In a phase II study of 41 patients with advanced MF/SS, the combination of pentostatin and intermittent highdose recombinant interferon alfa-2a resulted in CR in two and PR in 15 patients, for an overall response rate of 41%. The PFS duration for responders was 13.1 months, and common toxicities for this combination included opportunistic infection and interferon-related constitutional symptoms.113 The combination of flu-darabine and interferon alfa-2a was also tested in another phase II trial of 35 patients with advanced MF/SS, with 4 CRs and 14 PRs for an overall response rate of 51%.114 The median PFS duration for responders was 5.9 months, with three of the CRs still in remission after 18-35 months. Significant toxicities included constitutional symptoms, neutropenia, and infections. Another study with 12 patients with advanced refractory primary CTCL demonstrated that treatment with the combination of fludarabine and cyclophosphamide resulted in 1 CR and 4 PRs for an overall response rate of 42%. The mean duration of response was 10 months, with bone marrow toxicity being the common and significant side effect.115 Finally, the combination of flu-darabine, mitoxantrone, and dexamethasone has produced 1 CR that has lasted 15 months after treatment cessation in a patient with aggressive subcutaneous panniculitislike T-cell lymphoma.116

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