Current Approaches to Therapy for Indolent Non-Hodgkin’s Lymphoma

Introduction

Progress in the treatment of indolent non-Hodgkin’s lymphoma has been limited over the past few decades and, despite the relatively long median survival of patients with non-Hodgkin’s lymphoma, this disorder remains incurable. The approach to treatment is generally determined by whether the disease is limited (stage I and non-bulky stage II) or advanced (bulky stage II, stages III and IV). In the 10% to 15% of patients with low-grade non-Hodgkin’s lymphoma who present with limited disease, radiation therapy has generally been recommended because it can produce a 10-year failure-free survival of 50% to 60%, with an overall survival of 60% to 80%.[1] However, whether even limited stage disease is curable by radiation therapy, with or without chemotherapy, is unclear.

A long-term follow-up study from Stanford included 177 patients with stage I and 104 with stage II follicular non-Hodgkin’s lymphoma at a median age of 53 years.[1] Patients were treated with radiotherapy and followed for a median of 7.7 years (the longest being 31 years). The median survival was 13.8 years. Over 10% of patients relapsed, however, after 10 or more years of being in remission.

Seymour et al[2] reported on 91 patients treated with combined modality therapy. The complete response rate was 99% and only 16 relapsed at a median follow-up of 60 months, but with no plateau on the relapse-free survival curve. Whether there is an advantage to initiating radiation therapy at diagnosis in patients with limited stage indolent non-Hodgkin’s lymphoma was examined by Soubeyran et al.[3] They described 26 patients with stage I follicular non-Hodgkin’s lymphoma who were not treated following excision, but were followed for a median of 6.3 years.

At that time, half were still free from recurrence; six relapsed only locally at a median of 4.2 years. Of 27 patients who received involved field radiation alone or with CVP (cyclophosphamide [Cytoxan, Neosar], vincristine [Oncovin], prednisone(Drug information on prednisone)), there were seven distant relapses. No plateau was apparent on the time-to-relapse curve. Therefore, although long-term disease control is possible, even limited disease may not be curable.

Advanced Disease

Although low-grade non-Hodgkin’s lymphomas are considered to be “indolent” tumors, the median time to progression in patients with advanced stage disease is 4 to 6 years, with an overall survival of 6 to 10 years.[4-6] Portlock et al[7] performed a retrospective analysis of 44 nonprotocol patients for whom therapy was deferred and compared their outcome to that of 112 previously untreated patients entered into prospective Stanford clinical studies. The median time to starting treatment for the 44 patients was 31 months, with 19 not needing treatment for as long as 104 months. The 4-year actuarial survival for the two groups did not differ.

In a study from the Groupe D’Etude des Lymphomes Folliculaires (GELF),[8] patients with a low tumor burden were randomized to observation, alpha-interferon, or prednimustine (Sterecyt). There was no difference in survival among the groups. At the National Cancer Institute, patients were randomized to observation alone or ProMACE/MOPP (prednisone, methotrexate(Drug information on methotrexate) [Rheumatrex], leucovorin, doxorubicin [Adriamycin], cyclophosphamide(Drug information on cyclophosphamide), etoposide [VePesid] and mechlorethamine [Mustargen], vincristine, procarbazine(Drug information on procarbazine) [Mutalone], prednisone chemotherapy). Those who achieved a complete response received total lymphoid irradiation. There is still no difference in survival with more than 13 years of follow-up (D. Longo, 2nd International Symposium on Malignant Lymphomas, Munich, 1998).

Since there is no apparent advantage to early intervention in patients with advanced stage disease, the decision to treat is generally based on the presence of increasing adenopathy, organ compromise, bone marrow failure, or constitutional symptoms. At the time these symptoms appear, the therapeutic options range from administering a single alkylating agent or a combination regimen (eg, CVP), to more aggressive approaches, with no clear evidence of a survival advantage for one treatment over the others. Even the frequency of complete responses with the same or different programs varies widely among series, reflecting differences in patient selection, and staging and evaluation techniques.

In an Eastern Cooperative Oncology Group (ECOG) trial,[4] there was no difference in complete response rates or survival duration with chlorambucil(Drug information on chlorambucil) (Leukeran) and prednisone (CP), CVP plus procarbazine (COPP), or carmustine(Drug information on carmustine) (BCNU) (BCVP), and no plateau of the time-to-progression curves. Other intensive regimens have failed to demonstrate benefit over less intensive programs. An early nonrandomized study in which more intensive therapy appeared to benefit patients with follicular mixed non-Hodgkin’s lymphoma compared with follicular small-cleaved cell non-Hodgkin’s lymphoma[9] was not confirmed.[6,10]

In an analysis of Southwest Oncology Group (SWOG) trials using cyclophosphamide, doxorubicin(Drug information on doxorubicin), vincristine, and prednisone (CHOP) to treat indolent histologies of non-Hodgkin’s lymphoma, the median durations of response and survival were no better than generally observed with a single alkylating agent.[6] The Lymphoma Group of Central Sweden randomized 259 patients to chlorambucil and prednisone or CHOP—CHOP achieved a higher response rate, but with no difference in survival.[11]

Relapsed and Refractory Disease

Relapse with low-grade non-Hodgkin’s lymphoma is inevitable. Although patients often respond again to the same or a similar induction regimen, the quality of their response becomes worse and the duration shorter. In a series from St. Bartholomew’s Hospital,[5] the response rate progressively decreased from 78% after first relapse to 48% after the fourth treatment, and the median duration of first remission was 31 months, compared with only 13 months for second remissions. The median survival following recurrence was 4 1/2 years with only eight of the 116 patients with recurrent disease dying of unrelated causes.

In another series, the median survival following relapse after an initial complete remission of a year or longer was only 5.9 years; median survival was 4.2 years after a partial response of at least a year, but only 2.4 years after an initial response shorter than a year.[12] Whereas most patients recur with a similar histology, there is a constant risk of undergoing a transformation to a high-grade non-Hodgkin’s lymphoma—generally considered an ominous event. If diagnosed and treated early, however, a small proportion of patients with transformed non-Hodgkin’s lymphoma may experience prolonged disease-free survival.[13]

A variety of aggressive combination regimens have been used to treat relapsed or refractory patients,[14-20] with no evidence of a major advantage from any of them.

New Treatment Approaches

New approaches being evaluated to improve the outcome of patients with advanced low-grade non-Hodgkin's lymphoma include new chemotherapy agents, biological therapies, and dose intensity with either allogeneic or autologous stem cell support.