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2010 Lymphoma Research Findings Presented at the ASH Annual Meeting
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The 52nd Annual Meeting of the American Society of Hematology (ASH) was held December 4-7, 2010 at the Orange County Convention Center in Orlando, Florida. The conference was the venue for the presentation of much of the year’s breakthrough research on lymphoma and other blood-related disorders. The lymphoma community anxiously awaits the discoveries announced at ASH each year and the Lymphoma Research Foundation (LRF) has compiled summaries of the most important findings to provide a general understanding of the biggest advances in lymphoma research in 2010.

Phase II Trial of New Drug Brentuximab Vedotin (SGN-35) Presented With Promising Results for Hodgkin Lymphoma and Anaplastic Large Cell Lymphoma Patients
At perhaps the most anticipated and buzzed about lymphoma presentation at the 52nd American Society of Hematology (ASH) annual meeting, researchers from across the world introduced results from a Phase II study of brentuximab vedotin (SGN-35), a new drug with the potential to change the lives of patients with relapsed or refractory Hodgkin lymphoma (HL). People with relapsed or refractory HL have had few treatment options in the past few decades. The current standard of care includes combinations of radiation, chemotherapy and autologous stem cell transplantation (ASCT).
The study results showed 95 percent of patients demonstrating a decrease in their tumor measurements, and 34 percent achieving complete remission. Several LRF-associated researchers were a part of this study including Scientific Advisory Board (SAB) members Stephen M. Ansell, MD, PhD (Mayo Clinic), Joseph M. Connors, MD (British Columbia Cancer Agency) and Anas Younes, MD (University of Texas MD Anderson Cancer Center); MCLC member Ajay K. Gopal, MD (University of Washington/Fred Hutchinson Cancer Research Center); and Chicago Lymphoma Rounds steering committee member Scott E. Smith, MD, PhD, FACP (Loyola University Medical Center).“Up to 30% of all Hodgkin lymphoma patients will relapse. These patients have limited treatment options beyond autologous stem cell transplantation and represent a significant unmet medical need,” lead author Robert Chen, MD from the City of Hope in Duarte, CA said at a press briefing. “Based on these data, brentuximab vedotin has the potential to change the treatment paradigm for relapsed or refractory Hodgkin lymphoma patients and could be the first treatment approved for these patients in more than 30 years.”

Across 26 study centers, researchers treated 102 HL patients, ages 15 to 77 years (median 31 years), with relapsed or refractory disease, who all had previously undergone ASCT. The median number of prior chemotherapy regimens among the patients was four, and slightly more than half (53 percent) were female. Following the Phase I study, which showed tumor reduction in 50 percent of patients after being treated at the maximum tolerated dose of 1.8 mg/kg every third week, this study used the same dosing regimen for a total of 16 cycles of treatment. On average, the regimen lasted 27 weeks, ranging from three to 54. The investigators found that the regimen had manageable adverse side effects including low-grade peripheral sensory neuropathy, fatigue, nausea, neutropenia, diarrhea and fever. A total of 18 patients had to discontinue participation in the study due to adverse side effects.

“The response rate that is observed with brentuximab vedotin compares favorably to those reported with combination chemotherapy regimens in a similar patient population with less toxicity,” said Dr. Younes. “That’s the most important thing. Combining it with other active agents will hopefully further improve treatment outcomes for patients with Hodgkin lymphoma.”

In another linked study, researchers used brentuximab vedotin to treat anaplastic large cell lymphoma (ALCL), a rare aggressive T-cell lymphoma comprising only about three percent of all lymphomas in adults and between 10 and 30 percent of all lymphomas in children. Results concluded that 87 percent of patients demonstrated tumor shrinkage and 57 percent saw complete remission. LRF SAB members associated with this study were Ranjana Advani, MD (Stanford University Medical Center), Nancy L. Bartlett, MD (Washington University School of Medicine) and Dr. Connors.

Seattle Genetics, in partnership with Millennium: The Takeda Oncology Company, have plans to take the next step and apply for regulatory approval of brentuximab in the United States and Europe for treatment in both HL and ALCL.

Trial on Oral Drug, Panobinostat, for Relapsed/Refractory Hodgkin Lymphoma Finds Positive Results
A multicenter Phase II study on the oral drug Panobinostat (LBH589), found effective anti-tumor activity in post-transplant relapsed/refractory Hodgkin lymphoma (HL) patients. With a long history of having few treatment options and poor prognoses, people with relapsed/refractory HL should now have a wider array of protocol choices considering the onslaught of research presented at the 52nd American Society of Hematology annual meeting at the beginning of December.

The researchers, including Lymphoma Research Foundation (LRF) Scientific Advisory Board (SAB) member Anas Younes, MD (The University of Texas MD Anderson Cancer Center), concluded that the results of this single-arm trial, the largest ever conducted in this patient population, are “positive” and the long-term results seem promising.

“The advantage of this is that it’s an oral drug that can be taken as an outpatient without much interruption in the lifestyle of the patient,” said Dr. Younes. “It has a different side effect profile from common chemotherapies and the potential for enhancing the anti-cancer effects when combined with other active agents in the future.”

The study included 129 relapsed/refractory HL patients aged 18-75 years (median 32 years), with most already in their fifth line of treatment. Doses of panobinostat were administered at 40 mg three times a week, every week, in 21-day cycles.

Goals of the study included seeking an objective response rate, observing the time and duration of response, and monitoring progression-free and overall survival, while documenting safety and tolerability. Final results showed decreases in tumor size in 77 percent of patients. The average time it took for patients to respond to the treatment was 7.4 weeks and progression-free survival was seen at 5.7 months on average. Side effects observed were mostly low-grade, with some higher-grade thrombocytopenia, anemia and neutropenia experienced.

"It's impressive to see this response to Panobinostat in patients, many of whom have received multiple courses of chemotherapy," said lead author Anna Sureda, MD (Hospital de la Santa Creu i Sant Pau, Barcelona, Spain) in a press release. "The responses suggest LBH589, which has a very different mechanism of action than chemotherapy, has the potential to become a valuable treatment option for these patients."

Phase III Trial Compares ABVD and Stanford V Regimens’ Efficacy in Hodgkin Lymphoma
After analyzing and evaluating the two main treatment regimens currently available for Hodgkin lymphoma (HL), a team of researchers, including several Lymphoma Research Foundation (LRF) associated physicians, presented their results at the 52nd American Society of Hematology annual meeting at the beginning of December. They concluded that the combination of drugs known as ABVD should remain the standard of care, since the regimen known as Stanford V did not meet their failure free survival (FFS) objectives.

HL was not always as treatable as it is today. The development of the ABVD regimen in the 1970s was considered a dramatic development in the fight against the disease. Comprised of the drugs adriamycin (doxorubicin), bleomycin, vinblastine and dacarbazine, the combination was credited for producing a higher rate of overall response, less hematologic toxicity, better relapse-free survival and better outcomes after relapse in patients treated. In 1988, a new treatment protocol named Stanford V was developed with the objective of maintaining a high remission rate while reducing the incidence of acute and long term toxicity, pulmonary damage and sterility observed in the alternative treatment, as well as shortening the duration of chemotherapy. The individual agents include: mechlorethamine, a nitrogen mustard derivative; doxorubicin; vinblastine, an alkaloid cell toxin; vincristine; bleomycin; etoposide; and prednisone.

The study, headed up by Leo I. Gordon, MD, FACP (Northwestern University Feinberg School of Medicine), LRF Mantle Cell Lymphoma Consortium (MCLC) executive committee chair and Scientific Advisory Board (SAB) member was designed to detect a 10 percent improvement in FFS (from 64% to 74%) with Stanford V compared to ABVD. HL patients with advanced stage disease were randomly selected to receive either ABDV over six to eight cycles or Stanford V for 12 weeks. The 812 participants ranged in age from 16 to 83 (median 33) and slightly more than half (53%) were male.

They found similar response rates and toxicity between both regimens, with patients from both arms experiencing medium-grade neutropenia and patients on Stanford V experiencing slightly more lymphopenia and sensory neuropathy. Five-year overall survival was 88 percent for ABVD and 87 percent for Stanford V. Ultimately, Stanford V did not meet the group’s objective of 33 percent improvement in FFS. The researchers concluded that ABVD should remain the standard of care for HL. However, they also concluded that Stanford V, when prescribed with radiation, can be an acceptable alternative.

“These results mean that ABVD remains the standard of care for patients with advanced Hodgkin lymphoma and that ABVD plus radiation remains the standard for patients with bulky mediastinal disease,” said Dr. Gordon. “There may be some patients that could be treated with Stanford V, such as patients who are older with compromised cardiac and lung function, since lower doses of Adriamycin and Bleomycin are used in Stanford V.”

In addition to Dr. Gordon, other LRF-associated researchers included SAB chair Bruce D. Cheson, MD (Georgetown University Hospital); SAB immediate past-chair Richard I. Fisher, MD (James P. Wilmot Cancer Center); SAB members Randy D. Gascoyne, MD (British Columbia Cancer Agency), Nancy L. Bartlett, MD (Washington University School of Medicine), Joseph M. Connors, MD (British Columbia Cancer Agency), Ranjana Advani, MD (Stanford University), Brad Kahl, MD (University of Wisconsin), Jonathan W. Friedberg, MD (James P. Wilmot Cancer Center) and Thomas M. Habermann, MD (Mayo Clinic); and MCLC member Kristie A. Blum, MD (The Ohio State University).

Rituximab Reduces Need for New Treatment in Asymptomatic Follicular Lymphoma
Patients with asymptomatic, non-bulky follicular lymphoma (FL) have less of a chance of needing chemotherapy when treated at the time of diagnosis with rituximab, in comparison to a watch and wait strategy. These results, presented at the 52nd American Society of Hematology (ASH) annual meeting in early December, are based on a three-arm European study conducted over five years.

FL is a slow-growing, non-Hodgkin lymphoma (NHL) that affects white blood cells known as B-cells. Often, patients are managed with a “watchful waiting” strategy and not treated with drugs until the disease progresses. Rituximab, a targeted therapy drug that works with the immune system to kill diseased B-cells, has been shown to be effective for several NHLs and chronic lymphocytic leukemia (CLL).

Researchers enrolled 462 patients with Stage II through IV asymptomatic FL between 2004 and 2009 and randomly assigned each of them to one of three arms: A) watchful waiting, B) rituximab once a week for four weeks and C) rituximab once a week for four weeks followed by rituximab maintenance therapy (every two months for two years). In 2007, it became apparent to the researchers that maintenance therapy improved efficacy and arm B was eliminated.

Final analysis showed that patients treated with rituximab at the time of diagnosis were less likely to need chemotherapy or radiation therapy compared with patients who were on “watchful waiting.” While no difference in overall survival was found, fewer patients on the rituximab-containing arms B (20 percent) and C (9 percent) required chemotherapy or radiation therapy during the observation period of the trial, compared with those treated with watchful waiting, arm A (51 percent).

“These results will increase the options for the management of newly diagnosed patients with advanced asymptomatic follicular lymphoma, and it is likely that upfront [rituximab] therapy will prove popular with patients when compared with a watchful-waiting approach,” said the lead author Kirit M. Ardeshna, MD (University College London Hospitals, London, England) in a prepared statement.

Oliver W. Press, MD, PhD (Fred Hutchinson Cancer Research Center), Chair of LRF’s FL Consortium and Scientific Advisory Board member, was not involved with the study but feels that despite the promising results, more questions need to be asked and answered about these treatment strategies.

“Though these findings are very encouraging and will likely greatly influence management decisions for patients with FL, several questions concerning this study remain, since participants on the ‘watchful waiting’ arm were apparently not permitted to receive rituximab monotherapy as their first intervention following disease progression,” Dr. Press said.

New Standard of Care for MCL Patients Under 65 Years Recommended by European MCL Network Trial
Tremendous progress has been achieved in the fight against mantle cell lymphoma (MCL) over the past several years. MCL is an aggressive B-cell non-Hodgkin lymphoma for which survival rates have almost doubled from a median survival of three to more than five years. Prior studies have found that high-dose chemotherapy followed by an autologous stem cell transplant (ASCT) resulted in a significant increase in progression-free survival in patients with advanced stage MCL. Additionally, other studies have found that the addition of rituximab to CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) with or without high dose ARA-C (cytarabine) prior to an ASCT may significantly improve remission rates and progression-free survival.

In the results of its second randomized trial, the European MCL Network found that high-dose chemotherapy followed by an ASCT resulted in a significant increase in progression-free survival in patients less than 65 years of age with advanced stage MCL. The results were presented at the 52nd American Society of Hematology Annual Meeting in early December.

“Essentially this abstract establishes a new standard of care for younger MCL patients,” said Lymphoma Research Foundation (LRF) Scientific Advisory Board (SAB) member Martin Dreyling, MD, PD, the senior author on this study.

The multi-national study recruited 497 people with previously untreated stage II-IV MCL under the age of 65 years. Over a six year period, the patients were randomly treated in one of two arms. Control arm A consisted of six courses of CHOP plus rituximab followed by myeloablative radiochemotherapy and ASCT. Experimental arm B was made up of three alternating courses of CHOP and DHAP plus rituximab. This was followed by a high dose ARA-C containing myeloablative regimen and ASCT.

This study evaluated the time to treatment failure (TTF) of both regimens. Anything less than a major response (complete or partial) to induction therapy was considered treatment failure. After a median follow up of 27 months in the ARA-C arm and 49 months in the control arm, TTF had not yet been reached. At three years, the progression-free survival rate was about 65 percent in the control arm and 77 percent in the ARA-C arm. Overall survival was found to be similar in both treatment arms with median overall survival not yet reached.

"High-dose ARA-C chemotherapy should be part of the induction therapy along with rituximab and CHOP chemotherapy prior to an autologous stem cell transplant in order to improve outcomes without an increase in toxicity in these patients," lead author Olivier Hermine, MD, PhD, of Necker Hospital in Paris, said at an ASH news briefing.

12/2010

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