Management of indolent lymphoma

When selecting initial therapy for patients with indolent lymphoma, I consider many factors, including the patient’s age, comorbidities, how aggressively the disease is behaving, the extent of the lymphadenopathy, the LDH level, whether the patient is symptomatic and needs quick relief and how many downstream options I want to leave open for later.

In a patient who is symptomatic or has several adverse prognostic factors, I am more aggressive and likely to include an anthracycline up front, so I use something like R-CHOP. In an older patient, who has heart disease or in a patient who doesn’t need a quick response, I might select R-CVP.

I tend not to use fludarabine in the first-line setting for follicular lymphoma because of its profound immunosuppressive effects and the effect it seems to have on the stem cell population. In some patients, it also impairs marrow health, which may impact how well the patient will tolerate future treatments.

Role of watchful waiting in patients with follicular lymphoma

One of the controversies in treating indolent or follicular lymphoma is whether watchful waiting is appropriate at this time, given the newer, less toxic agents. However, based on the existing data, I believe watchful waiting remains a reasonable management strategy. Prospective studies have shown that many patients with indolent lymphoma will not require therapy for many years — in some cases, as long as five or 10 years. Those patients are sometimes included in treatment trials, and they can make data look very good. I don’t believe those patients should be subjected to the toxicities of unnecessary treatments.

In patients who received four weekly doses of rituximab and had less than a partial response — let’s call it a minor response — I have tried four more doses of rituximab. For the most part, I have found that to be ineffective; however, I’m not talking about a huge personal experience, so I can’t draw too many conclusions.

On rare occasions, I have been able to convert a nonresponder to a responder with this strategy. I will continue to try it in selected circumstances, particularly in patients for whom chemotherapy is an unattractive option, such as elderly patients or those with diabetes or heart disease.

Clinical trials of maintenance rituximab

Rituximab maintenance has been proven to prolong remission, whether it’s given as a single agent or after chemotherapy. Hainsworth reported on a Phase II trial with rituximab maintenance given in four weekly doses every six months for two years, and the maintenance therapy kept patients in remission longer than just a one-time dosing (Hainsworth 2003). In addition, a trial conducted in Europe randomly assigned patients to a maintenance strategy versus a one-time dosing strategy, and the patients who received the maintenance strategy experienced longer remissions (Marinus 2004).

In ECOG-E1496, a Phase III trial, patients were randomly assigned to maintenance rituximab versus observation following CVP chemotherapy. The data showed an impressive benefit for rituximab maintenance (Hochster 2004). Patients in the maintenance arm experienced remissions that lasted approximately two and a half years longer.

However, the patients in that trial received CVP chemotherapy without rituximab, and today almost every patient receives chemotherapy plus rituximab as part of their initial therapy. Whether rituximab maintenance adds a similar benefit for patients who receive rituximab with their chemotherapy is totally unknown. Investigators in Great Britain are launching a trial evaluating R-CVP followed by rituximab maintenance versus observation in the first-line setting in an attempt to address that very issue.

ECOG-E4402: RESORT trial of maintenance rituximab
(see page 4, figure 1.2)

Design and endpoints

The RESORT trial is designed to determine whether, after induction rituximab, it’s better to give rituximab on a predetermined schedule or on an as-needed basis. Eight weeks after patients receive a traditional dosing of rituximab — 375 mg/m² weekly for four weeks — they are restaged. Patients with a partial or complete response are randomly assigned to either the re-treatment arm of four weekly doses of rituximab upon disease progression, provided the time to progression is more than six months, or the scheduled maintenance arm, where they receive a single dose of rituximab every 12 weeks until progression.

The primary endpoint is time to rituximab resistance. We want to answer such questions as: Which strategy prolongs the period of time during which the patient benefits from rituximab? Will they develop resistance to rituximab faster with one strategy versus the other? Secondary endpoints include time to first chemotherapy and survival.

Survival is not the primary endpoint because in any indolent lymphoma trial, patients move on to second-, third- and fourth-line therapies. It then becomes difficult to determine the contribution of the first-line treatment to their overall survival when it is confounded by the six other treatments they received after that.

Correlative science studies

The RESORT trial is an excellent opportunity to address questions relating to predictors of response to rituximab because these patients have had no prior lymphoma therapy and rituximab is the only treatment they receive. Rituximab is an IgG subclass 1 antibody, and known human polymorphisms exist that have a better or worse affinity to such antibodies. Approximately 15 percent to 20 percent of the population has a favorable polymorphism for rituximab.

The remaining population has a less favorable polymorphism, but the exact impact of that polymorphism on response rates and time to progression is not consistent across small studies. In the RESORT trial, we will examine the polymorphism status of the patients and try to clarify this issue.

We will also evaluate the pharmacokinetics of rituximab, measuring serum levels at several key points. The scheduled maintenance arm consists of a single dose every three months. We want to determine if that dosing can maintain serum levels above 25 micrograms per mL.

We will also measure serum levels at the time of progression to see if patients are progressing while they have measurable serum levels. Most of us would conclude that a patient is truly rituximab refractory if the disease is growing despite measurable serum levels.

Tissue arrays are another area we will be evaluating in the RESORT trial. We will take the paraffin blocks and examine immune system factors present in the lymph node at diagnosis. An article published in the New England Journal of Medicine in 2004 examined RNA microarray patterns in follicular lymphoma, and attempted to correlate gene expression profiles with prognosis (Dave 2004).

The paper suggested that it’s not the genes that are turned on or off in the tumor cells that make a difference, rather it’s the genes that are turned on and off in the cells around the tumor cells — the macrophages and the T cells. How well an individual’s immune system recognizes the lymphoma might have an important impact on the patient’s ultimate prognosis and outcome and, if that were true, then immunotherapies such as antibodies or vaccines would be important to examine.

Nonproctocol use of maintenance rituximab

When I treat a patient with single-agent rituximab without chemotherapy, I administer four weekly doses and then evaluate the response. If the patient responds and experiences a nice remission, I re-treat them when they recur with four weekly doses and repeat that strategy as long as the drug is working. I do not use a maintenance strategy off protocol because I don’t believe we have evidence that it’s superior.

Phase II trial: First-line therapy for follicular lymphoma with Zevalin followed by rituximab

At the University of Wisconsin, we are conducting a 35-patient, Phase II trial evaluating Zevalin radioimmunotherapy followed by maintenance rituximab for patients with intermediate or high-risk disease, as determined by the Follicular Lymphoma International Prognostic Index (FLIPI) score.

The FLIPI score for follicular lymphoma is a little different than the IPI for aggressive lymphomas. The FLIPI score is based on five clinical factors at diagnosis, and the acronym to remember them is NOLASH: (1) NO is for nodes; five or more nodal groups is an adverse feature. (2) L is for LDH; if elevated, it’s an adverse feature. (3) A is for age; if the patient is over 60, it’s an adverse feature. (4) S is for Stage; Stage III or IV disease is an adverse feature. (5) H is for hemoglobin; if less than 12, it’s an adverse feature.

Patients with zero to one features are considered low risk, two features are considered intermediate risk and three to five features are considered high risk. This trial is restricted to patients with intermediate- or high-risk disease because some risks may be associated with this therapy. We did not want to expose patients at low risk to that potential; however, I believe the five- and 10-year survival rates for patients at intermediate or high risk justify this approach in these patients.

Patients enrolled in the trial will receive a single dose of Zevalin and then be restaged at three and six months. Patients who are responding will receive four weekly doses of rituximab at the six-month mark and then a single dose every three months until disease progression. In this trial and in the RESORT trial, the maintenance strategy is indefinite. The stopping points for the other maintenance trials — nine months and two years — are completely arbitrary, and I felt it was time to push the envelope. I don’t know if our strategy will prove to be better, and I believe it would be wrong to use it off protocol.

We will evaluate the two-year, event-free survival in addition to the median event-free survival. It could take four or five years to determine the median event-free survival, which is a long time to wait. Therefore, it’s prespecified that if the median two-year, event-free survival is 80 percent or better, that would be good enough to consider a larger trial.

Pilot trial of modified hyper-CVAD with rituximab in patients with mantle cell lymphoma

We reported a pilot study at ASH in 2004 in which 20 patients with untreated mantle cell lymphoma received a modified hyper-CVAD regimen followed by rituximab maintenance (Kahl 2004). Patients have a very difficult experience tolerating the toxicities of the traditional hyper-CVAD regimen, so we removed the cytarabine and methotrexate.

We added rituximab to the induction regimen and then followed it with four weekly doses of rituximab every six months for two years, which I refer to as consolidation rather than maintenance, because it’s given for a fixed period of time. We found the modified regimen to be very tolerable, and our two-year, event-free survival rate is currently over 70 percent, which is quite good for mantle cell lymphoma (3.1).

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