'R-Squared' Rates 98% Response in Lymphoma Patients

Bruce D. Cheson, MD; Nathan H. Fowler, MD


December 19, 2012

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Bruce D. Cheson, MD: Hello. I'm Bruce Cheson, Deputy Chief of Hematology-Oncology and Head of Hematology at Georgetown University Hospital and the Lombardi Comprehensive Cancer Center in Washington, DC. Welcome to this edition of Medscape Oncology Insights, from the 2012 annual meeting of the American Society of Hematology (ASH) in Atlanta. I am delighted today to be joined by my former fellow, Dr. Nathan Fowler, who has moved up in the world and is Assistant Professor and Co-director of Clinical Research in the Department of Lymphoma at the University of Texas MD Anderson Cancer Center in Houston, Texas. Welcome Nathan. It's great to have you here. We are in a new era. The world is changing. That chemotherapy stuff may be on its way out.

Nathan H. Fowler, MD: We hope so.

Augmenting Response With Rituximab

Dr. Cheson: At this meeting, you are presenting the so-called "final results"[1] of the data on the regimen of rituximab and lenalidomide, affectionately known as "R-squared." Tell us about the regimen, how it developed, and what the results are.

Dr. Fowler: Data show that lenalidomide may work to modulate the immune microenvironment. Some of these data come from preclinical studies; some early animal studies have shown that it's possible that this drug can repair some mechanisms of recognition within the microenvironment, basically allowing a patient's immune cells to recognize tumor cells.

The idea was that by combining this drug with a monoclonal antibody such as rituximab we could augment the response that we are seeing with rituximab in certain types of lymphoma. We initially designed a pilot study. The first 30 patients who were enrolled had follicular lymphoma, small lymphocytic lymphoma (SLL), or marginal zone lymphoma. We presented our initial results with the combination of lenalidomide and rituximab at the 2009 meeting of ASH.[2] In that early poster, we saw pretty dramatic responses. In the follicular lymphoma subset, we saw 100% complete response, although it was a small number -- 7 patients. At that time, we became very interested in the potential for this combination. We approached the sponsor of the study and asked them to expand the study to include approximately 110 patients weighted in the follicular lymphoma group. We planned to enroll 50 patients with follicular lymphoma, 30 patients with SLL, and 30 patients with marginal zone lymphoma. We have now completed accrual. All the patients have completed the planned treatment, and we will be presenting the final results at ASH in a couple days.

Dr. Cheson: What was the dosing schedule?

Dr. Fowler: The dose is based on our early experience in myeloma, chronic lymphocytic leukemia (CLL), and mantle cell lymphoma. We used lenalidomide 20 mg daily for 21 days out of a 28-day cycle. We dosed patients with a standard dose of rituximab, 375 mg on day 1 of each 28-day cycle. When we first designed this study, we planned to give patients 6 months of treatment. As the study was enrolling, data from the CLL group showed that responses tended to peak a little later in patients, especially those with SLL, so we amended the study to allow patients to receive up to 12 months of the regimen if they were deriving clinical benefit. This was a small change as the study went on. About two thirds of our patients had 6 months of treatment, and 25 patients had 12 months.

Dr. Cheson: What did you find?

Dr. Fowler: As we had hoped, the results of the larger cohort mirrored what we had seen in the original first 30 patients. The response rate in follicular lymphoma was pretty much universal: 45 of 46 patients with follicular lymphoma responded. Our overall response rate was 98%. The complete response rate was just as impressive: 87% of patients with follicular lymphoma responded. Nearly all patients (93%-94%) were also PET negative by the time they finished their treatment. So, we were very pleased.

We have followed these patients. At a median follow-up of 2 years, our progression-free survival in patients with follicular lymphoma is 81%. We have been pleased so far with the results.

Dr. Cheson: Is the total duration of lenalidomide now 1 year?

Dr. Fowler: We allowed patients to go on to 12 months of treatment if they were deriving clinical benefit. The patients with follicular lymphoma, because most of them hit complete response quite early, stopped at 6 months. Most patients in the group whose progression-free survival was 81% at 2 years received only 6 months of treatment. Only 1 or 2 patients with follicular lymphoma received more than 6 months. Twenty-five patients out of the entire group of 110 were treated for 12 months, but those were mainly patients with SLL who were not yet in a complete response at 6 months.

What About the Rash?

Dr. Cheson: We have used a lot of lenalidomide, and there are some untoward effects: rash, fatigue, and other effects. What types of toxicity did the patients experience?

Dr. Fowler: The most common side effect that we saw, and the one that was most concerning to patients, was rash. We saw rash in about half of the patients. Most of the time it occurred in the first cycle, and most of the time it was self-limited. We saw 8 patients who had grade 3 or 4 rash (a rash that covers more than 50% of the body). But only 1 patient had to leave the study because of rash. Most of these rashes, even the grade 3 rashes, resolved with supportive care. We used low-dose steroids and antihistamines in some patients. In most patients, the rash was well controlled with supportive care.

Dr. Cheson: When you had your poster, I had a poster right next to it, and we began to talk about the rash. It hadn't been seen in myeloma and other clinical situations, and all of a sudden we were seeing it. Why is the rash so much more prominent in the indolent lymphoid malignancies than in other settings?

Dr. Fowler: We are still trying to figure that out. If you look at the studies of lenalidomide as a single agent with low-grade lymphoma, they didn't see the same incidence of rash. The Mayo Clinic group reported rash but it only occurred in 20%-30% of patients. We wondered whether adding rituximab would worsen this rash. The rash could be an immune effect, caused by cytokine release or a histamine reaction in the skin. There could be a reason that the rash is worsened by adding other immune therapies such as rituximab, but it's too early to know.

Dr. Cheson: I have 2 other questions about that. First, did you use much allopurinol?

Dr. Fowler: We did not use allopurinol in any patient.

Dr. Cheson: In some situations, the rash seems to portend a good outcome. Have you observed a correlation between rash and outcome?

Dr. Fowler: Fortunately, most of the patients responded, and we couldn't correlate the presence of rash with response. As we follow these patients longer, it will be interesting to see whether the incidence of rash corresponds with early relapse. At least with respect to response events, we didn't see a correlation.

Can We Get Rid of Chemo?

Dr. Cheson: This regimen has become very popular. In fact, in CALGB (now called Alliance) we completed a similar trial and are writing up an abstract of the data. It is becoming the backbone of a number of regimens, including another trial that you're involved in, which is an international study along the lines of "Can we get rid of chemotherapy?" Tell us about the study.

Dr. Fowler: This is one of the most exciting things about where we are in the development of new drugs for low-grade lymphoma. We may be getting close to getting rid of chemotherapy for patients with follicular lymphoma and SLL. The design of this study is to take the R-squared regimen (lenalidomide and rituximab) and compare it with R-chemo (rituximab and chemotherapy). This will be the first randomized study for newly diagnosed patients comparing a completely biologic regimen vs rituximab plus chemotherapy.

Dr. Cheson: What is the name of the study?

Dr. Fowler: RELEVANCE, for "rituximab lenalidomide vs any chemotherapy." We allow investigators to "pick their poison." It can be R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone], R-CVP [rituximab, cyclophosphamide, vincristine, prednisone] or R-bendamustine [rituximab plus bendamustine]. We will compare those regimens with lenalidomide and rituximab. Half of the patients will get the combination R-squared and half will get R-chemo. The primary endpoint will be progression-free survival, which is both good and bad. Even with R-chemo, the patients take a long time to relapse, so the primary endpoint is probably going to be several years out.

Dr. Cheson: This is one of the most important -- and most courageous -- studies to try to finally eliminate chemotherapy. How well is it accruing?

Dr. Fowler: We put our first patient on the study in December 2011. This is an international study. It's a collaboration between groups in Germany, Australia, Canada, and the United States. We are just ramping up now. We have opened only about half of the planned study sites. Our accrual is matching what we anticipated at 12 months, just over 100 patients. That should increase exponentially when we open all of our sites in the United States.

Dr. Cheson: When do you project to complete accrual?

Dr. Fowler: In 2 to 2.5 years we are hoping to have accrual near-complete.

A New Wave of Drug Development

Dr. Cheson: While this is happening, many others are using R-squared as a backbone and adding other agents to it. For example, in our frontline follicular study that we are going to be opening, is R-squared plus ibrutinib. We have a couple of studies that we are getting ready to do, hopefully with R-squared plus the PI3 kinase inhibitor GS1101. At our institution, we are probably going to be doing R-squared plus another novel kinase inhibitor which will remain unrevealed at the present time. How are you involved in this new wave of drug development?

Dr. Fowler: This is an exciting time to be doing what we are doing. This is really a renaissance in the treatment of non-Hodgkin lymphomas. Many new drugs that are targeted biologic agents have significant activity in many of our patients. As we move forward, we are going to see combinations of these new biologics. Many of them are oral drugs, and many have very mild side-effect profiles that are going to move forward quickly into clinical studies. I have been lucky to be involved in the development of ibrutinib, which has shown remarkable activity in multiple different histologies with little toxicity. Several other exciting drugs target the PI3 kinase delta and gamma pathway, and these drugs will quickly be combined with other biologics as we move forward.

Dr. Cheson: Put on your foresight hat and spy glasses. Five years from now, what kind of discussion will we have? Will we ask, "What was chemotherapy?"

Dr. Fowler: I hope so. I like to give this talk to patients when I see them the first time. Look at all the new drugs that are coming out. Only one of the drugs that has been US Food and Drug Administration-approved in the last 5 years is a chemotherapy agent, and that's a drug that was invented 50 years ago.

Bendamustine is a very active drug in lymphoma, but I'm hopeful that when we talk about this 5 or 10 years, we can look at each other and at our patients and say, "We don't need chemotherapy." "You are not going to need chemotherapy." Much like many other chronic diseases, if we can't cure this disease, at least we can control it and patients can lead a normal life without many side effects when we start treatment.

Dr. Cheson: We are at a historic point in new drug and therapeutic development in patients with lymphoma and many other cancers as well. People like you are in the forefront of bringing this new world to patients with lymphoma. Nathan, thank you for joining me here. To the audience, thank you for joining us for this edition of Medscape Oncology Insights. This is Bruce Cheson signing off from ASH 2012 in Atlanta.