Studies highlight progress in lymphoma, pose more questions


CURE asked Anas Younes, MD, professor in the department of lymphoma/myeloma, division of cancer medicine at M.D. Anderson Cancer Center in Houston, and a CURE advisory board member, for his thoughts on the lymphoma advancements announced at this year's American Society of Hematology.I finally got to blog on what is news at this year's ASH meeting in San Diego. Almost 20,000 people attended the meeting, and more than 1,000 studies were presented on hematologic malignancies and benign hematologic disorders. But for lymphoma, I think the most important studies are the following three. That is not to say that other studies are not significant, but I think the following ones have a more relevant impact on the treatment of lymphoma. I will explain why.A Phase III Randomized Intergroup Trial (SWOG S0016) of CHOP Chemotherapy Plus Rituximab Vs. CHOP Chemotherapy Plus Iodine-131-Tositumomab for the Treatment of Newly Diagnosed Follicular Non-Hodgkin's LymphomaWe all know that radioimmunotherapy (RIT) is active therapy for lymphoma. Two drugs (Iodine-131-Tositumomab (Bexxar) and ibritumomab tiuxetan (Zevalin) are already approved by the FDA for the treatment of relapsed follicular and indolent lymphoma. But in clinical practice, the use of RIT has been relatively modest compared to other newly approved drugs. Despite the documented safety of these agents, there is still a perception among oncologists and patients that these agents are not as safe as other drugs. Many of us wanted to see whether the use of RIT may improve patients' survival, which has not been shown in a randomized study. If so, such data would certainly re-energize the RIT field. This phase 3 randomized study was positioned to answer such a question. Unfortunately, there was no difference between RCHOP and CHOP followed by Bexxar. I am sure many experts will try to dissect the data in many different ways, including whether this data is applicable to all RITs or just Bexxar. Should we do another randomized study with Zevalin? May be with rituximab maintenance? Should we include rituximab in both treatment arms as part of the induction? But at the end of the day, this trial as good as it is, will not help move RIT forward. With the current competitive environment that includes many new promising agents that have minimal side effects, I think the use of RIT, as we currently know it, will continue to decline.Frontline Therapy with Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin LymphomaBrentuximab vedotin (or SGN-35) has produces 75 percent response rate in heavily pre-treated patients with relapsed Hodgkin lymphoma (HL). So, it makes sense to move it up front and test in newly diagnosed patients whose tumors are less resistant to therapy. Because HL is highly curable with chemotherapy, such as ABVD, it is unethical to test brentuximab alone in these patients. Instead, it makes more sense to add it to ABVD hoping the combined brentuximab + ABVD will be more effective. However, to prove the point, multiple steps needed to be taken. The first step was the core of this clinical trial: Is it safe to combine brentuximab with ABVD, and what is the optimal dose that we can use in such combination? Because ABVD is the standard regimen, it is kept intact while the doses of brentuximab are escalated to maximum dose. During the conduct of this study, an increase in the incidence of lung complications were observed, which were similar to bleomicin toxicity: shortness of breath, dry cough and lung infiltrate. This toxicity was reversible in 9 of 10 patients with simple measures that included discontinuation of bleomycin and administration of steroids. But because bleomycin is the weakest drug in the ABVD regimen, and usually associated with unpredictable lung toxicity, it was eliminated to generate a brentuximab + AVD combination. At the time of the study presentation, brentuximab + AVD was not associated with any lung toxicity.What was presented at ASH and was not in the printed abstract is the results of interim PET scan results after two cycles of therapy. With ABVD alone, we typically see 20 percent to 30 percent of the patients continue to have PET positive scans after 2 cycles, which usually correlate with bad prognosis. In contrast, after 2 cycles of brentuximab-based therapy (with ABVD or AVD), only 3 percent of the patients had positive PET. So these results look very encouraging, but of course we need more time and longer follow up to find out what this all means. Obviously, the ultimate test will be to compare the standard ABVD with the new regimen brentuximab + AVD in a randomized trial. This study is planned for the end of 2012. The outcome of such trial may indeed change the standard of care for patients with HL.The Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study and The Bruton's Tyrosine Kinase Inhibitor PCI-32765 Is Highly Active As Single-Agent Therapy in Previously-Treated Mantle Cell Lymphoma (MCL): Preliminary Results of a Phase II TrialThere is a lot of buzz about the promising clinical results with the oral small molecule inhibitor PCI-32765, which inhibits an enzyme called Bruton kinase. Last year, there was emerging data from a phase 1 study that also got a lot of attention. This year, the early results are now confirmed in a larger number of patients with CLL and MCL, both are practically incurable lymphoid malignancies. In CLL, a 70 percent response rate was seen in 27 patients treated with 420 mg daily. This single-agent activity data is so impressive, so a randomized phase 3 study is being planned. In MCL, results from an ongoing phase 2 study reported a response rate of 67 percent, which is also very impressive for a single agent in this disease. If this data continues to hold as more patients are enrolled, a phase 3 randomized study in relapsed MCL will be the obvious next step. There is a clear need for new agents for patients with MCL, and PCI-32765 may as well what we all have been waiting for!

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