ECOG-E4402: Maintenance rituximab compared to rituximab retreatment upon disease progression in patients with low tumor burden indolent lymphomas

In patients with low-risk indolent lymphomas, the RESORT trial (ECOG-E4402) is comparing scheduled maintenance rituximab to retreatment with rituximab upon disease progression. The trial is attempting to determine if it is better to receive rituximab continuously and prevent relapse or to receive rituximab upon disease progression and be able to obtain the benefit of a response down the road. The endpoint for this trial is the duration of time to rituximab resistance.

Dosing and scheduling of rituximab

We arrived at the dose of rituximab on a fairly empiric basis. We escalated the dose and did not reach a dose-limiting toxicity (Maloney 1994, 1997). In fact, much higher doses of rituximab can probably be administered without any apparent dose-limiting toxicity, at least in patients with lymphoma. Studies from MD Anderson in patients with low-grade lymphomas (mostly chronic lymphocytic leukemia) — suggest that a higher dose may be more active (O’Brien 2001, Keating 2000). I’m skeptical about those approaches, so I still use the standard dose of 375 mg/m²; however, some are pushing the dose to 500 mg/m² or even higher.

A rituximab schedule of 375 mg/m² weekly for four doses is most widely used. Although rituximab is FDA-approved for eight consecutive doses, I never recommend that schedule. My interpretation of the data is that absolutely no benefit exists for eight doses compared to four doses; however, additional rituximab on a maintenance schedule clearly can delay the time to progression in patients with follicular lymphoma treated with rituximab monotherapy up front.

The maintenance rituximab schedules were derived from two trials. The Hainsworth trial used four doses of rituximab every six months for two years in patients who were responding (Hainsworth 2002). The Swiss trial (3.1) employed one dose every other month for four doses (Ghielmini 2004). Both of those schedules were found to extend the time to progression. ECOG-E4402 will evaluate a maintenance schedule of one dose every three months, so I will use either one of those schedules at the standard dose of 375 mg/m². But for now, we don’t yet know whether a maintenance dose every other month for four doses is better than four doses every six months for two years.

Using the Follicular Lymphoma International Prognostic Index to make treatment decisions

In my own practice, I utilize the Follicular Lymphoma International Prognostic Index (FLIPI), which defines five factors that increase the risk of poor outcomes in patients with follicular lymphoma (Solal-Celigny 2004). If the patients are at high risk on the FLIPI, I favor treatment with chemotherapy plus rituximab. If the patients are at low risk, certainly chemotherapy plus rituximab could be used, but they are the ideal patients for rituximab monotherapy.

In patients who are at low risk on the FLIPI, expectant management is another option. Patients who have a long history (three to five years) of lymph nodes that haven’t changed are much more comfortable with expectant management. Patients who have a sudden appearance of multiple lymph nodes have more rapidly progressing disease, and it would be more difficult to consider expectant management. If I do try expectant management in that setting, I watch closely and as soon as kinetic activity of the lymphoma occurs, I initiate treatment.

Nonmyeloablative allogeneic stem cell transplantation

As opposed to using high-dose chemo/radiotherapy to eliminate the malignancy, a nonmyeloablative stem cell transplant basically harnesses the power of the donor’s immune system to attack the cancer. We are using immunosuppressive treatments and then stem cells from a human leukocyte antigen (HLA)- matched sibling or unrelated donor. This new immune system, as it grafts and grows, eliminates the host’s bone marrow function and also generates an antitumor effect.

We’ve had excellent success in patients with mantle cell, follicular and aggressive lymphomas using this T-cell therapy from the donor to eradicate the underlying malignancy. This is a valid treatment option for patients, especially once they’ve exhausted the more tolerable and safer treatments. I would never use this approach early on for patients with follicular lymphoma; however, after patients have failed an autologous transplant, a nonmyeloablative allogeneic transplant offers an opportunity to salvage their disease and possibly provide a long-term cure.

Graft-versus-host disease in patients treated with a nonmyeloablative allogeneic transplant

Graft-versus-host disease (GVHD) is the biggest complication associated with a nonmyeloablative allogeneic transplant from a related or an unrelated donor. A nonmyeloablative transplant requires some graft-versus-host response to be able to obtain a graft-versus-tumor response.

About 40 percent of patients develop acute GVHD, which occurs mostly in the skin and GI tract. The majority of patients have Grade I or II GVHD, which is readily treatable; about 10 percent develop more serious Grade III or IV GVHD, which is life-threatening. In most studies, two-year mortality from GVHD and its complications is 20 to 25 percent.

Sequencing therapies in patients with follicular lymphoma

In a typical patient with advanced, aggressive follicular lymphoma who requires treatment because of hematologic compromise (eg, a low platelet count) or a rapidly progressing tumor, I would utilize CHOP plus rituximab if I could not enroll them in a clinical trial. One could argue whether CVP plus rituximab would be as good, but I believe evidence exists of synergistic activity with some of the components of chemotherapy. Therefore, I like to use CHOP plus rituximab to obtain a complete remission. I don’t use maintenance rituximab following a rituximab plus chemotherapy regimen, but I follow the patients closely.

If the patient relapses after five or six years, I’m inclined to use rituximab monotherapy. If the patient relapses very quickly, I consider them to be more chemotherapy-resistant, and I am more likely to treat them with reinduction chemotherapy, harvest their stem cells and perform an autologous transplant in second remission. I like to determine a patient’s HLA type at the time of their first relapse to determine whether they have a matched sibling, because that would provide an option further down the road.

If they don’t have a matched sibling, I try to determine how likely it will be to find a matched unrelated donor. If the likelihood is high, I keep open the option of a nonmyeloablative transplant in the future. If the likelihood is low, then I’m more aggressive with the type of autologous transplant regimen used.

Management of patients with diffuse large B-cell lymphoma

For more than 20 years, CHOP was the standard of care for adult patients with DLBCL. The introduction of rituximab has clearly shifted that treatment paradigm. Now the standard of care is rituximab with each of the six to eight cycles of CHOP. Can we do better? Several studies suggest that other chemotherapy regimens (eg, CHOP plus etoposide [CHOEP]) or alternative ways of administering CHOP (eg, every 2 weeks or dose-dense) may be better than CHOP.

I’m excited about a clinical trial that will be conducted in the cooperative groups comparing dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (EPOCH) plus rituximab to CHOP plus rituximab. Some data suggest that infusional chemotherapy with the EPOCH regimen might be better than bolus chemotherapy.

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