CHICAGO—The optimal treatment for newly diagnosed indolent non-Hodgkin’s lymphoma (NHL) has not been determined.
But lenalidomide has been shown to have single-agent activity in indolent NHL, and rituximab is effective alone and in combination with chemotherapy, and a Phase II study from the University of Texas MD Anderson Cancer Center has now evaluated the efficacy and safety of both of these biologic agents as front-line treatment in patients with untreated, Stage III/IV indolent NHL.
Response rates to date with 45 evaluable patients were 89% overall and 73% complete, principal investigator Nathan Fowler, MD, Assistant Professor in the Department of Lymphoma/Myeloma, reported here at the ASCO Annual Meeting.
In the subset of patients with follicular lymphoma, the overall response rate with 28 patients was 97% and the complete response rate was 86%.
Other subset response rates were 80% in small lymphocytic NHL and 73% in marginal zone lymphomas, for an overall response rate of 89% for the study.
The patients, all with untreated low-grade B-cell non-Hodgkin’s lymphoma, received 20 mg/day of lenalidomide on Days 1-21, and rituximab at 375 mg/m2 on Day 1 of each 28-day cycle for up to six cycles. Median age was 56; and 57% of the patients were male.
Dr. Fowler said this Phase II trial is targeted to accrue 110 patients. At the time of his report, there were 74 on the trial, with data on the 45 evaluable patients who had completed six cycles.
“Because the response rates are so dramatic between cycle three and cycle six, we’re holding off on reporting response rates [in the patients not reported on here] until patients complete their treatment, because otherwise it skews the data,” Dr. Fowler said in an interview during the poster discussion session.
“Unlike with other types of chemotherapy regimens, I think patients need extended exposure to this regimen to get optimal response.”
But he said unconfirmed complete response rates after three cycles were about 28%, jumping to about 48% after six cycles.
All the response rates were “really, really high, compared with historical standards,” Dr. Fowler said. “In the patients with low-grade lymphoma we’ve seen not only very high overall response rates, but also complete response rates.
“And we saw very minimal toxicities, either hematologic, or non-hematologic toxicity. Most of our patients who had evidence of follicular disease in the bone marrow converted with six cycles of therapy.”
Grade 3/4 adverse events included neutropenia in 21% of patients, thrombocytopenia in 13%, rash in 13%, and thrombosis in 4%. One patient had relapsed, at 16 months of treatment.
“We’re very encouraged by the high CR rate, but whether that translates for a long progression-free survival is yet to be seen,” he said.
Unconfirmed CR (CRU)
Dr. Fowler said that in some patients with low-grade lymphoma, the tumor will shrink by 90% but there will still be a residual mass, which is probably just fibrotic tissue.
“As long as the tumor mass shrinks by more than 75% by CT scan, we call it a complete response. It’s unconfirmed because that residual mass has not been biopsied.”
He said his institution does not use PET scans to measure responses, but “if we did PET on these patients, we could potentially get rid of the CRU, because if a residual mass is PET-negative it converts to a CR.” The problem with low-grade lymphoma, he said, is that there is no real accepted standard-of-care. Some patients are under observation only, others receive rituximab as a single agent, and still others might receive bendamustine with rituximab or R-CHOP. He said much depends on the patient’s pre-treatment risk factors.
In this study about half of the patients had bulky disease or had criteria for treatment per European standards or per the University of Guelph criteria, with what many would consider need-to-treat criteria, he said. “In other words, these weren’t all patients that had very indolent disease and you could have watched without treatment, a lot were high-risk. But even in that subset of patients we saw very high CR rates.”
Dr. Fowler said the lenalidomide-rituximab regimen is the most common protocol for any patient with low-grade lymphoma treated at MD Anderson. Obviously some patients do receive standard-of-care treatment, he said, and would not get this regimen because it is a clinical trial protocol or they do not want to go on a trial.
Dr. Fowler said he hopes this regimen will become a new standard-of-care for untreated, low-grade lymphomas, “but of course that will require a randomized trial.”
The Discussant for the study, Nancy L. Bartlett, MD, Associate Professor in the Department of Medicine, Oncology Division, at Washington University Medical School in St. Louis, called the lenalidomide-rituximab combination “a very interesting approach, from the standpoint that it is extremely well tolerated and its very high overall response rates and CR rates—but obviously we need to see if these are durable.”
For comparison, she noted that single-agent response for lenalidomide in a recent study in relapsed indolent NHL was 27% for follicular lymphoma and 22% for small lymphocytic lymphoma, with 70% of responses ongoing at 15 to 28 months (WitzigT et al: JCO 2009; 27:5404-5409).
Dr. Bartlett said it is unknown how lenalidomide works in lymphoma, but from in-vitro data it appears that the potential mechanism is repair of the T-cell immunologic synapse dysfunction induced by follicular and diffuse large B-cell lymphoma cells. In addition, lenalidomide enhances rituximab-induced killing of NHL via NK cell- and monocyte-mediated antibody-dependent cell-mediated cytotoxicity, she explained.