Chlorambucil in indolent mantle cell lymphoma – just another old drug for a new disease?

Keywords:

• Mantle cell lymphoma
• chlorambucil (Leukeran)
• indolent lymphomas

Mantle cell lymphoma (MCL) is a distinct subtype of malignant lymphoma characterized by the chromosomal translocation t (11; 14) (q13; q32) resulting in constitutional over expression of cyclin D1 and an aggressive clinical course with a continuous relapse pattern and a median survival of only 3–5 years [1]. Recently, a subset of 15% long term survivors has been identified with a rather indolent clinical course even after receiving conventional treatment strategies only. However the upfront identification of these cases still remains a challenge although their more benign clinical course may in retrospect have been predicted in some cases on the basis of cytological morphology and a nodular pattern on histopathology [2,3,4].

The alkylating agent chlorambucil, an aromatic derivative of nitrogen mustard and functionally a cell cycle phase non-specific agent was first introduced for the treatment of lymphoproliferative disorders and chronic lymphocytic leukemia (CLL) over 50 years ago and pioneered in particular in the UK by Galton and colleagues [5]. The drug is well absorbed after oral administration and rapidly metabolized to phenylacetic acid mustard with low urinary excretion and elimination. For years it remained the most popular drug for the treatment of CLL and was first given orally continuously in standard dosages until the disease was controlled or until toxicity intervened [5]. Low rates of complete remission were obtained with chlorambucil but about 60% response rates were commonly achieved. During the 1960s different dosage schedules were used and pulses of oral chlorambucil were commonly given. Using this regimen responses were comparable to those obtained with the daily doses but less toxicity was reported [5].

In the 1970s chlorambucil was used in combination with prednisone, in different schedules in a bi-weekly or monthly manner or as daily or monthly oral doses, by a number of different groups and response rates of 37 - 47% were obtained. However although adequate responses were achieved and responding patients appeared to live longer, there was no great advantage gained in terms of median overall survival [6].

Since then the addition of the anti- CD20 monoclonal antibody - rituximab (mabthera) [7] to different chemotherapeutic regimens and especially fludarabine and/cyclophosphamide with or without mitoxantrone has resulted in improved overall survival and because of this has most recently been accepted worldwide as the gold standard for therapy of CLL [8]. However, it should be noted that a recent study in elderly patients showed that fludarabine, although considered to be a more effective agent for CLL, resulted in a trend towards worse overall survival when compared to chlorambucil [9]. So in recent years there is a renewed interest in this drug and it has found its way back into clinical trials once again particularly in the above category of patients in combination with rituximab [10].

In this issue of Leukemia & Lymphoma, Sanchalas and Pangalis et al report on a combined regimen employing chlorambucil followed by rituximab maintenance for one year in 20 previously untreated patients with mantle cell lymphoma [11]. The treatment was very well tolerated without any serious hematological toxicities or any febrile neutropenic episodes. The response rate was remarkable with 95% responses (90% CR, 5% PR) and among patients in CR, 78% presented a molecular remission. Even more importantly an impressive 3 year progression-free survival of 89% was observed. How can these remarkable results be explained when dose-intensified regimens with a high dose Ara-C containing induction and subsequent autologous transplantation has recently been proposed as the new treatment standard for younger patients? [12] In this respect it is well known that in MCL, the clinical course may vary widely according to clinical (MIPI) and biological risk factors and cell proliferation is particularly important in this regard [1]. Accordingly, it is difficult to compare the results of regimens applied in different phase II studies. In keeping with these concepts, 19 of 20 patients in this study had a low risk or intermediate MIPI score and in fact some authors have even suggested a watch and wait strategy in such low risk patients [13]. However, if therapy has to be initiated the combination of rituximab and chlorambucil represents a very attractive therapeutic approach with very few side effects even when compared to the recently presented data on bendamustine in indolent and mantle cell lymphoma [14].

Current studies of the European MCL Network are evaluating various post-induction strategies such as rituximab maintenance as applied in this study [11] attempting to further extend the normally short-lived remission durations after conventional immuno-chemotherapy only. In contrast, autologous transplantation remains the current standard approach in younger patients and has also been applied accordingly in the study reported here [11]. Optimizing the treatment approach based on the individual risk profile may finally bring mantle cell lymphoma back into the category of “low grade” lymphomas from where it started as centrocytic lymphoma about four decades ago in the original Kiel classification! [4].