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 Progress and Promise in the Treatment of Indolent Lymphomas
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The Oncologist, Vol. 7, No. 3, 217-225, June 2002
© 2002 AlphaMed Press

MAYO CLINIC HEMATOLOGY/ONCOLOGY REVIEW: PART 1

Progress and Promise in the Treatment of Indolent Lymphomas

Peter McLaughlin

University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence: Peter McLaughlin, M.D., The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 429, Houston, TX 77030, USA. Telephone: 713-792-2860; Fax: 713-794-5656; e-mail: pmclaugh{at}mail.mdanderson.org


   LEARNING OBJECTIVES
Top
 Learning Objectives
Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
After completing this course, the reader will be able to:

  1. Describe subsets of patients with indolent lymphoma for whom cure may be a realistic goal.
  2. Describe the ways by which the polymerase chain reaction for bcl-2 can be utilized to monitor patients with follicular lymphoma.
  3. Identify immunotherapy approaches that have shown promising results for patients with indolent lymphoma.

Access and take the CME test online and receive one hour of AMA PRA category 1 credit at CME.TheOncologist.com


   ABSTRACT
Top
 Learning Objectives
 Abstract
Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
In the era of conventional alkylating agent-based chemotherapy, advanced stage indolent lymphoma has been considered incurable. The failure of our traditional therapies to cure these patients, coupled with the indolent course of the disease and the elderly population affected, has fostered a nihilistic attitude about the treatment of these diseases. Twenty years ago, in the absence of interesting alternatives to alkylating agents, judicious use and reuse of alkylators was perhaps the best we could do. There are now many reasons for optimism and excitement in the treatment of these diseases, including the availability of promising agents such as interferon-{alpha}, the nucleoside analogues, and rituximab. Radioimmunotherapy will also likely play a role in future therapy programs. Allogeneic stem cell transplantation is a high-risk approach that is not an option for all patients, but it has the potential to cure patients, even in the setting of relapse. Mini-allogeneic transplantation may permit an approach to allogeneic transplantation that is better tolerated than standard transplant strategies. In addition to these therapy options, biological insights have provided new options for monitoring patients. Molecular monitoring (polymerase chain reaction for bcl-2) is a stringent measure of short-term treatment efficacy, and one that correlates with durability of remission, i.e., it is a surrogate marker by which to judge treatment efficacy. There used to be a limited number of conventional treatment approaches, which consistently failed. The pendulum has swung. There are now many promising new options. It is time to plan and conduct trials that are geared for success.

Key Words. Follicular lymphoma • bcl-2 • Fludarabine • Rituximab • Interferon-{alpha}


   INTRODUCTION
Top
 Learning Objectives
 Abstract
 Introduction
Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
The indolent lymphomas represent about 35% of all malignant lymphomas [1]. In general, these diseases are characterized by a slow clinical pace and by responsiveness to a variety of treatment approaches. However, relapse is essentially inevitable following treatment with conventional therapy, so these diseases are considered to be incurable in most instances.

The current review focuses on promising newer treatment approaches and on results with some traditional treatment approaches that challenge the belief that patients with indolent lymphoma are uniformly incurable. The treatment results summarized here, as in other reviews [2–4], pertain most clearly to patients with follicular lymphoma, who represent the majority of patients with indolent lymphoma. Other indolent small lymphocytic lymphomas are becoming more clearly recognized, including marginal zone lymphomas and the fascinating mucosa-associated lymphoid tissue lymphomas [5–7]. As the unique clinical features of these diseases become more clearly understood, it seems likely that specific treatment nuances will emerge [8].


   THERAPEUTIC NIHILISM...COUNTERPRODUCTIVE?
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
A nihilistic attitude about treatment of these diseases is prevalent, based on the failure of traditional therapies to cure these patients, coupled with the indolent course of the disease and the elderly population that is often affected. Observation without therapy has been popular in selected patients who are asymptomatic and do not have immediately threatening disease. Guidelines for the selection of patients for this "watch and wait" approach are not as clearly defined or as widely agreed upon as are those for patients with chronic lymphocytic leukemia (CLL) [9]. However, several studies have demonstrated feasibility of the watch and wait approach [10–12]. The cornerstone of this management approach is that standard therapies do not cure these patients. If and when curative strategies emerge for these diseases, the watch and wait strategy may become counterproductive. As illustrated in Table 1Go, there are some scenarios in which observation without therapy is not advisable, notably for patients with stage I-II disease, who are potentially curable with involved field radiation therapy approaches [13–15]. Although only about 15% of patients with indolent lymphoma present with limited-stage disease, the potential for cure of these patients is an opportunity that should be seized.


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  		Table 1. Indolent lymphoma: pros and cons for treatment or deferral of treatment, by stage
 
One of the common arguments for deferral of therapy relates to the elderly population that is affected by indolent lymphoma, for whom a gentle approach is often advocated as the most humane approach. However, it is sobering to recognize how devastating indolent lymphoma can be in this age group. Weisdorf et al. assessed survival outcomes for elderly patients with indolent lymphoma, compared with age-matched controls, and have reported a tenfold higher risk of dying within a year for patients who have indolent lymphoma (Table 2Go) [16]. For patients over age 70, the risk of dying within a year approaches 50% for patients with indolent lymphoma. These indolent lymphomas are life-threatening diseases. Deferral of therapy may spare some short-term treatment-related toxicities, but it does not save lives.


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  		Table 2. Age-adjusted mortality for indolent lymphoma patients over age 60, compared with age-matched controls
 

   SMALL BUT IMPORTANT SUBSETS OF PATIENTS WHO MAY BE CURED
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
As already mentioned, patients with stage I-II indolent lymphoma are potentially curable with involved field radiation therapy. Numerous investigators have recorded remarkably similar results, with an apparent failure-free survival plateau at about 35%-40% that emerges after about 5 years for patients managed with involved field radiation therapy. Although late relapses certainly can occur, it appears that many of these patients may indeed be cured. Attempts to increase the fraction of patients who are potentially cured have included the use of total lymphoid radiation instead of involved field, and the incorporation of chemotherapy with involved field radiation. With the latter approach, we have reported that the fraction of patients in long-term remission at 5 years can be increased to about 75% [17,18]. To date, though, involved field radiation remains the accepted standard approach for stage I-II indolent lymphoma.

Another, even more impressive, demonstration of the potential curability of patients with indolent lymphoma is provided by allogeneic stem cell transplantation results for patients with relapsed disease. van Besien et al. have recently analyzed long-term results for 113 International Bone Marrow Transplant Registry patients, and reported a 45% long-term disease-free survival rate, with a plateau that is very suggestive of cure for these patients [19]. This approach is not a realistic option for all patients, and it carries substantial risks, including a 30% treatment-related mortality rate in the first year. However, the daunting aspects of allogeneic transplant are counterbalanced by the very impressive treatment outcomes. If "mini-allo" transplant strategies can reduce the early mortality rate and preserve the long-term disease control rate, it may become increasingly attractive to consider allogeneic transplantation for patients with recurrent indolent lymphoma [20].


   NEW TREATMENT OPTIONS...BETTER RESULTS?
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
To judge the new therapies, perspective is needed on the benefits and the limitations of older alkylating agent-based therapy approaches. These standard therapies have been effective in the short run, with good rates of remission. But with all standard therapy, durable remissions are rare; the majority of patients relapse within 2-3 years after standard therapy (Table 3Go) [21–28].


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  		Table 3. Indolent NHL: selected chemotherapy results{dagger}
 
The literature provides mixed signals on virtually every therapy issue. Even the end points by which to judge efficacy of treatment have been a matter of debate: "complete response (CR)" is illusory, even when stringently defined; reports on duration of failure-free or relapse-free survival can be greatly influenced by the frequency that sites such as the bone marrow are monitored; and the most important goal, overall survival, is influenced by numerous salvage therapy decisions, not just the initial treatment choice. Some consensus has been reached on some of these issues. As a spin-off from the rituximab pivotal trial analysis [29], uniform response criteria and end points have been proposed [30]. As discussed later, molecular monitoring provides an additional level of sensitivity for the detection of subclinical residual disease.

Many investigators, even advocates of watchful waiting [31], agree that once therapy is started, the goal should be the attainment of CR or good partial response (PR) [23]. In many trials, combination chemotherapy has been found to induce remission more quickly and perhaps more often than single-agent therapy [23,24]; yet single-agent therapy is still favored by many [24]. While the contribution of doxorubicin is controversial [21], a meta-analysis has suggested that the favorable impact of interferon is most obvious in the context of relatively intensive doxorubicin-containing chemotherapy [32]. Most analyses indicate that treatment is more often successful when the tumor burden is low. But many of these issues are still debated.

Some have suggested, based on the above observations, that it might be optimal to start therapy relatively early, and to employ a combination chemotherapy regimen plus interferon. However, this is a hypothesis that remains controversial. The flaw might not be in the hypothesis, but in the reliance on alkylating agent-based therapy.

In the past 15-20 years, a number of new effective agents have become available for patients with indolent lymphoma. In single-agent trials, interferon-{alpha}, the nucleoside analogues, fludarabine and 2-chlorodeoxyadenosine, and the chimeric anti-CD20 monoclonal antibody, rituximab, have all demonstrated response rates of 40%-50% [33–36]. These encouraging single-agent results have led to the incorporation of these agents into combination programs.

Interferon has been incorporated into combination chemotherapy programs either as a maintenance strategy or as concurrent therapy. Most studies have shown a favorable impact of interferon on failure-free survival but not on overall survival [37–39]. Some studies have shown no impact at all [26]. Two studies have shown an impact both on failure-free survival and overall survival [25,28], including an important randomized trial from the Groupe d'Etude des Lymphomes Folliculaires (GELF) group (Table 3Go). Regrettably, many practitioners feel that the modest favorable impact of interferon is offset by the fatigue and other side effects of the drug, even though a quality-of-life analysis has concluded that the incorporation of interferon is worthwhile [40].

Numerous studies have incorporated nucleoside analogues into combination chemotherapy regimens. There is an appealing theoretical basis for the use of a DNA-damaging agent in combination with fludarabine, since fludarabine inhibits key DNA repair enzymes, thereby theoretically enhancing the effects of the DNA-damaging agent [41–45]. Some proof of this theoretical principal is provided by in vitro experiments using CLL cells, in which a measurable but transient impact of activated cyclophosphamide was prolonged by concurrent exposure to fludarabine [46]. It is likely that the encouraging results observed with the combination of fludarabine, mitoxantrone, and dexamethasone (FND) [47], as well as the impressive treatment results with fludarabine and cyclophosphamide (FC) [48,49], are explained at least in part by this favorable interaction of fludarabine when given in conjunction with a DNA-damaging agent, such as cyclophosphamide, or an intercalator, such as mitoxantrone.


   BCL-2 AND "MOLECULAR REMISSION"
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
The bcl-2 gene is rearranged in 80%-90% of patients with follicular lymphoma [50]. Overexpression of Bcl-2 confers longevity to malignant cells, as well as resistance to many chemotherapeutic agents [51–53]. In follicular lymphomas, the overexpression of Bcl-2 is related to the t(14;18) translocation, which results in the juxtaposition of the bcl-2 gene with immunoglobulin heavy chain gene enhancer elements. Other mechanisms can also lead to dysregulated Bcl-2 expression; a number of other malignancies, including non-small cell lung cancer, breast cancer, prostate cancer, and melanoma, among others, can have overexpression of Bcl-2. In all of these situations, the overexpression of Bcl-2 confers longevity and chemoresistance to the tumor cells. Disruption of this Bcl-2 overexpression with antisense bcl-2 oligonucleotide therapy could, therefore, have an important impact on these malignancies [54]. In lymphoma, Webb et al. have demonstrated the feasibility of this approach and reported some responses, even in phase I trials [55]. The broad potential of this strategy in other malignancies is suggested by experimental work in which bcl-2 antisense therapy conferred chemosensitivity to resistant melanoma cells [56].

The bcl-2 insight that is uniquely relevant to follicular lymphoma patients is the use of the polymerase chain reaction (PCR) to monitor patients for subclinical disease. The application of the PCR technique to patients with bcl-2 gene rearrangement was first demonstrated by Lee et al. [57]. For patients whose tumors have this gene rearrangement, the PCR technique is substantially more sensitive than light microscopy, flow cytometry, or even Southern blotting in detecting subclinical residual disease [58].

The availability of PCR for bcl-2 has generated interest in "molecular remission," wherein eradication of detectable cells bearing the bcl-2 gene rearrangement is achieved. The first sobering observation about molecular remission was that it was almost unattainable with standard therapy. In a group of 212 patients referred to the Dana Farber Cancer Institute for stem cell transplant, Gribben et al. reported that only 1 out of the 212 was induced into molecular remission following conventional cytoreductive chemotherapy (Table 4Go) [59]. However, following high-dose therapy and stem cell transplant, the same investigators found that molecular remission can be attained, and that patients who achieved molecular remission had more durable remissions following transplant than patients who failed to achieve molecular remission [60]. Thus, this threshold of molecular remission, although difficult to achieve, is attainable and is a relevant end point that correlates with more durable remission.


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  		Table 4. Most standard-dose chemotherapy does not induce molecular remission [59]
 
As noted above, it had appeared to be a difficult task to induce molecular remission with conventional dose chemotherapy. The first demonstration that molecular remission was attainable in a meaningful number of patients with a conventional-dose regimen was with an alternating triple therapy (ATT) regimen [61]. Long-term follow-up of those patients and others has revealed that molecular remission following conventional-dose chemotherapy correlates with durable remission, as it does following transplant strategies [62]. Recent encouraging results have appeared from several investigators showing that molecular remission can be attained with several new treatment approaches, including strategies that utilize monoclonal antibody therapy (Table 5Go) [63–65].


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  		Table 5. Molecular remission with conventional-dose therapy in indolent lymphoma
 

   ANTI-CD20 MONOCLONAL ANTIBODIES AND OTHER IMMUNOTHERAPY APPROACHES
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
Conclusion
 References
 
Most normal and lymphomatous B-cells express the surface protein CD20; rituximab is a chimeric anti-CD20 monoclonal antibody that was developed to target B-cells [66]. As a single agent, it has been effective and well tolerated, as demonstrated initially in trials for patients with indolent lymphoma, and shortly thereafter in patients with aggressive lymphomas as well [36,67–69]. In addition to the obvious importance of its efficacy, a notable aspect of the success of rituximab therapy is the good tolerance of this agent. Partly by virtue of this good tolerance, some traditionally difficult to treat subsets of patients, namely the elderly and those who have had prior bone marrow transplantation, have had treatment results that are as good as the results for younger or less extensively treated patients [36].

Some categories of lymphoma have been less responsive to rituximab than others; for example, patients with small lymphocytic lymphoma have had less encouraging treatment results with rituximab than those with follicular lymphoma. The explanation for this observation is probably multifaceted. The malignant cells of CLL and small lymphocytic lymphoma have less dense expression of the CD20 protein on the cell surface than do follicular lymphoma cells [70]. Thus, it might be speculated that the antibody less effectively targets these tumor cells. However, pharmacokinetic observations indicate that rituximab is more promptly cleared from the circulation in patients with small lymphocytic lymphoma than in follicular lymphoma patients, suggesting that there may an "antigen sink" phenomenon [36,71]. These pharmacokinetic observations have, in turn, prompted dose-escalation trials of rituximab in CLL, with the demonstration of higher response rates than at the standard lymphoma dose and schedule [72,73]. Notably, even after these dose-escalation trials, the maximum tolerated dose of rituximab remains undefined.

Since the mechanism of action of rituximab is different than for standard chemotherapeutic agents, and since its toxicities are modest and nonoverlapping with those of standard chemotherapy, combination trials with rituximab and other therapies have been pursued. Cytokines have been combined with rituximab, to exploit the possible upregulation of the CD20 target after exposure to cytokines or to increase populations of effector cells that mediate some of the antitumor effects of rituximab. Chemotherapeutic combinations with rituximab have been based partly on the fact that nonoverlapping toxicities warrant combination approaches. There is also evidence of sensitization by rituximab to the cytotoxic effects of some chemotherapeutic agents [74]. In combination with chemotherapy, rituximab has been well tolerated; ongoing trials suggest that rituximab can add to the impact of chemotherapy [64,75–78]. The R-CHOP program for elderly patients with diffuse large B-cell lymphoma, as reported by Coiffier et al., is of particular interest [76]. Other regimens that have been successfully combined with rituximab include the FND program, for patients with indolent lymphoma [77], and the hyper-CVAD program for patients with mantle cell lymphoma [78].

In addition to rituximab, other unconjugated monoclonal antibodies are becoming available or are being developed [79]. Another exciting application of monoclonal antibody therapy is to use the antibody as a delivery system, conjugated to a radioisotope or a toxin. Results with radioimmunotherapy (RIT) approaches have been encouraging [80–83]. Since some radiation exposure of the marrow is to be expected with RIT, myelosuppression does occur with RIT. Both nonmyeloablative dose schedules and myeloablative doses with stem cell support have been quite successful.

The success of myeloablative RIT approaches [83] dovetails with other reports of impressive disease control following high-dose therapy followed by stem cell transplant [84]. Indeed, RIT may be preferable to total body irradiation (TBI) in preparative programs [85]. The significant prolongation of disease-free survival that can occur with the autologous transplantation strategy [86] is tempered by the realization that these patients are likely still not cured, and by the observation that myelodysplasia may occur in about 15% of patients, perhaps especially those who receive TBI [87]. Allogeneic transplant strategies are being explored with heightened interest because of the potential for cure that has been observed, and the hope that mini-allo transplant strategies will be better tolerated. An impressive demonstration of the importance of the graft-versus-lymphoma effect of allogeneic transplantation is provided by experience with patients who receive donor lymphocyte infusions (without further chemotherapy) when they have relapsed posttransplant. The radiographic and even molecular responses that can be achieved in this setting provide conclusive evidence that the immunologic effect of the allogeneic stem cell transplant strategy is a key to the efficacy of these programs [20,88].

Vaccine strategies represent an immunotherapeutic approach aimed at boosting the immune system of the host, rather than replacing it as is done with allogeneic transplantation. Research is ongoing to simplify the production of vaccines and to augment the response of the host to the vaccine [89,90]. Simultaneously, trials are under way to try to define the appropriate place for vaccination in an overall treatment approach, taking into consideration both the necessary lag time to prepare a vaccine from a patient's biopsy sample, and the need to achieve some cytoreduction so that the vaccine can be utilized at a time when the patient is close to a "minimal residual disease" status [91]. A unifying theme in many of these new approaches is the exploitation of immunologic defenses in the treatment strategy.


   CONCLUSION
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
References
 
With alkylating agent-based therapy approaches for patients with indolent lymphoma, transient control but ultimate failure was the rule. A number of promising new treatment options are now available. The time is right to plan and conduct trials that are geared for success.


   ACKNOWLEDGMENT
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 
Supported in part by National Cancer Institute Core Grant No. CA16672 awarded to The University of Texas M.D. Anderson Cancer Center.

Grant/research support provided by Immunex Corporation, Berlex Laboratories, IDEC Pharmaceuticals, Genentech, Schering-Plough, Integrated Therapeutics, and Amgen Inc. Consultant support from Immunex Corporation, IDEC and Genentech Pharmaceuticals. Speakers bureau support came from Catalyst Communication, Immunex Corporation Speakers Bureau, Health Science Communications, Network for Medical Communication and Research, International Meeting and Science, Inc. National Initiatives, and ProEd Communications.

Presented in part at the Mayo Clinic's 11th Annual Hematology/Oncology Reviews, State-of-the-Art Treatment of Hematology/Oncology Treatments, Amelia Island, Florida, August 16-19, 2001.


   REFERENCES
Top
 Learning Objectives
 Abstract
 Introduction
 Therapeutic...
 Small But Important Subsets...
 New Treatment Options...Better...
 bcl-2 and "Molecular Remission"
 Anti-CD20 Monoclonal Antibodies...
 Conclusion
 References
 

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Received November 20, 2001; accepted for publication March 4, 2002.




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