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Dr. Younes highlights important lymphoma studies from ASCO


CURE asked Anas Younes, MD, professor in the department of lymphoma/myeloma, division of cancer medicine at MD 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 Clinical Oncology. For the 80,000 or so patients with Hodgkin and non-Hodgkin lymphoma who are diagnosed annually in the U.S., the largest oncology congress in the world, ASCO (American Society of Clinical Oncology), brought some good news and hope for the future. But as expected, several well-designed clinical studies also failed to demonstrate substantial benefits. Going through the large number of presentations, I will highlight the most important ones here. More is not better for newly diagnosed patients with advances stage diffuse large B cell lymphoma (DLBCL)DLBCL is a curable lymphoma. However, with current standard R-CHOP chemotherapy, the average cure rate of patients with advanced stage is approximately 50%. When patients relapse, they are treated with a second-line regimen, such as RICE or DHAP, and responding patients get autologous stem cell transplant (ASCT). This strategy can cure up to 50% of responding patients in the relapsed setting. So wouldn't it make sense to offer ASCT (or other forms of more intensive therapy) upfront rather than wait for relapsed disease? But four independent groups, using different strategies, reported that the answer is "No." Thus, RCHOP-21 remains the standard of care.In the first study from the United Kingdom, Cunningham et al compared dose-dense RCHOP given every 14 days (RCHOP14) with standard RCHOP-21 in 1080 patients. With a median follow up of 39 months, there was no difference in the overall response rate (88% for RCHOP-21 vs 90% for RCHOP-14), complete remission rate, progression free survival (PFS) or overall survival (OS) in the two treatment groups.Stiff et al compared CHOP-21 (or RCHOP-21) x 8 with CHOP/RCHOP x 6 followed by autologous stem cell transplant (ASCT) in 397 patients with high-intermediate or high-risk (HI/H) age-adjusted international prognostic index (IPI). Although there was a trend for improved PFS for the ASCT arm, there was no difference in OS (74% for chemo + ASCT vs 71% for chemo alone). This means that it did not matter whether a patient had ASCT upfront or at the time of relapsed disease. However, from a practical point of view, keeping ASCT for the time of relapse seems more appropriate. Schmitz et al also compared intensive front-line therapy with stem cell rescue using 3 sequential courses of R-Mega-CHOEP with R-CHOEP-14 in 306 young high-risk patients with aggressive B cell lymphoma and found no significant difference between the two treatment arms. Finally, Milpied and colleagues compared 8 cycles of RCHOP14 to a different regimen that incorporated ASCT and reported no difference between the two treatment approaches, and RCHOP14 was as good as the ASCT-containing regimen. Because RCHOP14 is as good as RCHOP21, as discussed above, the standard of care remains RCHOP21.Increasing impact of targeted therapy and small molecules So if more is not better, how do we improve on RCHOP21? Incorporating novel targeted therapy with RCHOP is the way to go. But for these trials to be successful, we need to incorporate biomarker analysis to preselect patients who are likely to benefit from these novel approaches. Some of these clinical trials have already started. Examples, RCHOP + lenalidomide, RCHOP + bortezomib, and RCHOP + everolimus. Patients are encouraged to participate in these clinical trials so we can hopefully improve the standard of care and move beyond RCHOP.The best example of successful targeted therapy in preselected patients based on biomarkers is the antibody drug conjugates (ADCs). In this strategy, a naked antibody is conjugated to a drug, or a toxic chemical, that binds to a specific receptor, internalize, and kill the tumor cell by releasing the toxic drug. At least one ADC, brentuximab vedotin (or SGN-35) is expected to gain FDA approval before the end of the year for the treatment of patients with relapsed Hodgkin lymphoma (HL) and anaplastic large cell lymphoma (ALCL).In a study of 102 patients with relapsed HL after failing stem cell transplant, the overall response rate was 75% and the CR rate was 34%. With a median follow up of 9 months, more than half of the patients who achieved CRs remain in remission. Brentuximab vedotin is currently being combined with ABVD in newly diagnosed patients with HL, and other combination studies will be conducted soon. The second study of brentuximab vedotin was in systemic ALCL. The response rate was 86% in 58 treated patients, with 53% achieving CRs. Tomorrow information on the duration of response will be presented demonstrating durable remissions for responding patients, especially those with CRs. A combination study of brentuximab vedotin with CHOP chemotherapy in newly diagnosed ALCL is currently enrolling patients.But sometimes less specific drugs may give better outcome, as long as toxicity is not increased. An example is lenalidomide, which works by several mechanisms, including antiangiogenesis, immune-stimulatory property, and direct anti-tumor effect. Lenalidomide alone has a good single-agent activity in patients with relapsed diffuse large B cell lymphoma (DLBCL) and follicular lymphoma (28% and 27% response rates, respectively). Because lenalidomide can enhance the immune response, it has been shown to be particularly active when combined with monoclonal antibodies, such as rituximab. With this background, two groups combined lenalidomide with rituximab (RR) alone or with RCHOP for the treatment of newly diagnosed indolent/follicular lymphoma and DLBCL. In the first trial, Samaniego et al from MD Anderson Cancer Center reported the RR regimen produced an overall response rate of 90% in 70 evaluable patients, with 60% achieving complete remissions (CRs). The overall response rate in 41 FL patients was 87% with the vast majority achieving CRs. These results compare favorably with chemotherapy-based frontline regimens, including RCHOP and R-bendamustine. A randomized study comparing RR with R-Chemo is under development. A second trail combined lenalidomide with standard RCHOP in a phase 1/2 study in patients with newly diagnosed DLBCL. Nowakowski et al from Mayo Clinic treated 30 patients with DLBCL or follicular lymphoma grade 3. Lenalidomide was given on days 1-10 of each cycle, and all patients required prophylaxis with pegfilgrastim. The investigators reported a response rate of 100% with CR rate of 83%. For comparison, the expected response rate with RCHOP alone is 84%-88% with CR rate of 63%-75%. So once again, there seems to be a benefit of combining lenalidomide with standard RCHOP, perhaps due to the enhancement of rituximab activity. Of course, more patients need to be enrolled on the phase 2 part, and if the data continue to hold, a randomized study will be required. As I discussed in my earlier post, as intensified front-line therapy failed to improve treatment outcome compared with standard RCHOP, progress will be made by incorporating targeted and biologic agents in smarter trials. The lenalidomide + RCHOP study is a good example.

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