The indolent lymphomas, previously known as low-grade lymphomas, are a group of disorders whose main clinical features are as follows: (1) they have a high frequency of advanced presentation (70% of patients present with stage IV disease by virtue of its common involvement of the bone marrow); (2) they show exquisite sensitivity to chemotherapy but also a continuous relapse pattern following standard therapy, except in the case of early-stage disease; and (3) they have the potential for histologic transformation into a more aggressive cell type, such as diffuse large-cell lymphoma.
From the pathobiological standpoint, there is considerable heterogeneity among these disorders. Within the category of indolent non-Hodgkins lymphoma (NHL), we include various histologic categories: small lymphocytic lymphoma (SLL), follicular small cleaved-cell lymphoma, and follicular mixed lymphoma, as defined in the Working Formulation. Equivalent disorders in the Revised European-American Lymphoma (REAL) classification are small lymphocytic, follicular center-cell grade 1, and follicular center-cell grade 2 lymphoma. The follicular NHLs usually harbor the t(14;18) translocation, which results in a mutation of the bcl-2 oncogene, whereas the SLLs resemble the chronic lymphocytic leukemias more closely, which commonly express trisomy 12.
While much has been learned recently about the biological features of the indolent lymphomas, progress in their clinical management has not kept pace. The stage IV presentations have remained, by and large, incurable disorders. Nevertheless, some important advances in management made during the past decade offer hope that we might be closer to developing a cure (Table 1). Interferon has been proven in both randomized and nonrandomized studies to prolong failure-free survival and perhaps overall survival.[1-4] The purine nucleoside analogs, introduced later, have also demonstrated important activity against indolent lymphomas, both as single agents and in combination with other drugs.
At M. D. Anderson Cancer Center, we adapted the polymerase chain reaction (PCR) assay to detect rearranged bcl-2 cells in the blood and marrow. We have been able to detect minimal residual disease in follicular lymphomas, thus allowing the assessment of the response to treatment in a more meaningful way. Finally, the recent discovery that a monoclonal antibody directed against the CD20 antigen, which is expressed in B lymphocytes as well as in B-cell lymphomas, is capable of producing a high response rate in the salvage setting has equipped us with a new therapeutic agent with a different mechanism of action.
The potentially significant impact of all of these new advances on the front-line management of these disorders encourages optimism. This article reviews the contribution of the purine nucleoside analogs to the current management of relapsed indolent NHL, and focuses on the role of pentostatin (Nipent) in that management.
The Purine Nucleoside Analogs
FludaraThe first of the purine nucleoside analogs to show significant activity in indolent NHL was fludarabine (Fludara). Shortly after its effect on chronic lymphocytic leukemia was demonstrated, Grever et al used fludarabine in patients with indolent lymphomas and found it to also be active against these disorders.[M. Grever, personal communication, 1990] These results were rapidly confirmed by other research groups, including ours.[5-7] In a more definitive phase II trial conducted at M. D. Anderson Cancer Center, we defined specifically its activity in follicular lymphomas.
Sixty-seven patients who had received a median of three previous chemotherapy regimens were treated with a dose of 25 mg/m² of fludarabine, administered intravenously over 30 minutes daily for 5 days every 3 to 4 weeks. Activity was identified in follicular small cleaved-cell lymphoma (62% response rate), follicular mixed small- and large-cell lymphoma (80%), and follicular large-cell lymphoma (100%), as well as in SLL (33%), transformed lymphoma (33%), and mycosis fungoides (40%). Interestingly, no activity was observed in 20 patients with aggressive lymphomas.[6-8] Currently, the activity of fludarabine is being explored in front-line combinations with other active agents, such as mitoxantrone(Drug information on mitoxantrone) (Novantrone) and dexamethasone(Drug information on dexamethasone) (FND regimen), as well as with cyclophosphamide(Drug information on cyclophosphamide) (Cytoxan, Neosar).
CladribineIn addition, 2-chlorodeoxyadenosine (cladribine [Leustatin]) has also demonstrated activity in chronic lymphocytic leukemia[10,11] and more recently in indolent NHL.[12,13] Hoffman et al described 21 patients treated with at least one cycle of cladribine(Drug information on cladribine). Of these, five had follicular low-grade lymphoma; four, SLL; five, SLL with plasmacytoid differentiation; one, follicular large-cell lymphoma; and six, diffuse small cleaved-cell lymphoma. Of the 21 patients treated, 9 (43%) responded. Durable responses of up to 29+ months were observed, and seven of nine responders were still in remission at the time of this report.
The study by Saven et al focused on previously untreated cases of follicular lymphoma: 15 patients had SLL (8 with plasmacytoid features), 10 follicular small cleaved-cell lymphoma, one monocytoid B cell, one mantle cell, and one mucosa-associated lymphoid tissue. A total of 26 patients were evaluable and nine achieved a complete remission: four with SLL, three with follicular small cleaved-cell lymphoma, one with mantle-cell lymphoma, and one with mucosa-associated lymphoid tissue. Another 14 patients demonstrated a partial response, for an overall response rate of 88%. The median response duration was 10 months.
One drawback of cladribine, at least when used following the traditional dose and schedule, is its cumulative toxicity, which interferes with repeated administration of therapy. Thus, treatment is usually limited to one or two courses. No comparative studies of cladribine and fludarabine have been conducted, so we do not know which of the two is more active in indolent NHL. It also remains to be seen whether these agents are cross-resistant. However, extrapolating from the results in chronic lymphocytic leukemia, there appears to be significant cross-resistance between these purine nucleoside analogs. Furthermore, although cladribine has been effective in chronic lymphocytic leukemia, again, no comparative studies have been conducted to determine whether cladribine or fludarabine is more active.
Interestingly, investigators at M. D. Anderson have shown that cladribine has important activity in Waldenströms macroglobulinemia.[16,17] Of 26 patients treated, 22 (85%) responded to two courses of cladribine administered by continuous infusion at 0.1 mg/kg/d for 7 days. There were three complete remissions and 19 partial responses. At a median follow-up of 13 months, five patients have relapsed, and all retreated patients have responded again to cladribine.
PentostatinOf the three purine nucleoside analogs, pentostatin (Nipent) has received the least attention with regard to its role in the management of indolent NHL. There is enough information on its use in hairy cell leukemia to indicate activity, but only preliminary evidence of any activity in chronic lymphocytic leukemia. Although the data in the literature appear to indicate that fludarabine and cladribine are more active, this conclusion could be flawed because many of the studies investigating pentostatin in indolent NHL have contained a large number of patients previously treated with the other purine analogs. As these agents are most likely cross-resistant, it is unfair to conclude that pentostatin is less active.
Furthermore, in all of these trials, pentostatin was administered at 4 mg/m² as a single dose repeated every 1 to 2 weeks. Recently, there has been interest in using a more protracted schedule similar to the one used for fludarabine and cladribine. Thus, a new schedule is being explored in which pentostatin is administered at an intravenous dose of 2 mg/m²/d for 5 days. The rationale for this schedule is that even though pentostatin inhibits the activity of the enzyme adenosine(Drug information on adenosine) deaminase very effectively on the single-dose schedule, the cells are capable of recovering quickly. Adenosine deaminase, whose inhibition is likely responsible for pentostatins antitumor activity, is replenished soon after the drug disappears from the circulation. Although the schedule used in the trials conducted in indolent NHL might not be optimal, pentostatin has nevertheless shown significant activity in these disorders (Table 2).[18-21]
In conclusion, using intermittent schedules, pentostatin has shown excellent activity in hairy cell leukemia and reasonably good activity in heavily pretreated patients with advanced chronic lymphocytic leukemia.[10,11] More data are needed to confirm the effectiveness of a daily ´ 5 schedule of pentostatin in chronic lymphocytic leukemia and in indolent B-NHL. A study comparing pentostatin with fludarabine could better define the role of this agent in indolent NHL.