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Emerging lymphoma and myeloma treatments focus on improving individual patient response

(SAN DIEGO, December 11, 2011) Lymphoma and myeloma are both malignant diseases that arise from lymphocytes, a subset of blood cells, and commonly involve lymph nodes and the bone marrow. Although considerable progress has been made in the treatment of these diseases, they remain a significant challenge for patients and their hematologists. New research introducing unique treatment approaches and targets for lymphoma and myeloma will be presented today at the 53rd Annual Meeting of the American Society of Hematology.

"New insights into the biology of the hematologic malignancies, especially lymphoma and multiple myeloma, are facilitating the design of novel treatment strategies," said Jane N. Winter, MD, moderator of the press conference and Professor of Medicine in the Division of Hematology-Oncology at Northwestern University Feinberg School of Medicine in Chicago. "With new therapies that reflect our improved understanding of the molecular basis of these diseases, we are seeing valuable improvements in outcomes for patients."

This press conference will take place on Sunday, December 11, at 8:00 a.m. PST.

Cereblon Expression is Required for the Anti-Myeloma Activity of Lenalidomide and Pomalidomide [Abstract 127]

A new study uncovers the genetic mechanisms that regulate whether commonly used immune-modulating drugs for multiple myeloma, known as IMiDs, will work in certain patients who may be less responsive to therapy.

Thalidomide became well-known in the early 1960s for its link to severe birth defects when administered to pregnant mothers to treat morning sickness; however, in 1999, investigators discovered that the drug worked well in about one-third of patients with multiple myeloma (MM). Since this discovery, thalidomide and other drugs like it (such as lenalidomide and pomalidomide, together known as IMiDs) have proven to be highly effective in the treatment of blood cancers like MM.

The exact mechanisms and targets through which these therapies work to enhance immune response or kill cancer cells has been largely unknown; therefore, it has been challenging to understand which patients to treat and to distinguish the positive properties of these drugs from the side effects. After recent research identified a specific protein known as cereblon as a primary mediator of the birth defects caused by thalidomide, a hypothesis emerged that cereblon may also be responsible for the anti-tumor properties of IMiDs.

To test whether the presence of cereblon in myeloma cells might be partly responsible for resistance or response to MM treatment, and thus may potentially serve as a target for therapeutic intervention, researchers examined MM cell lines resistant to IMiDs and found that expression of the cereblon gene was either low or entirely absent, suggesting a possible link between resistance to IMiDs and presence of the protein.

The team then lowered the level of cereblon expression in five human-derived MM cell lines, which caused the cell lines to become almost completely resistant to lenalidomide (compared with control cell lines) yet remain sensitive to other myeloma therapies such as melphalan, dexamethasone, and bortezomib. The investigators then examined the DNA of 10 MM patients who were resistant to IMiD therapy and found low levels of cereblon expression in eight of those 10 patients, further emphasizing that cereblon expression appears necessary for IMiDs to work properly. Interestingly, some resistant patients had normal cereblon levels, suggesting that while cereblon may be an absolute requirement for response, there are likely other mechanisms present that play a role in drug resistance.

"These findings help us understand which patients may be more or less likely to respond to therapy and will allow us to focus on other ways we can target cereblon as a possible biomarker to improve treatment and patient outcomes in multiple myeloma," said senior author Keith Stewart, MD, Professor of Medicine in the Division of Hematology-Oncology at Mayo Clinic in Scottsdale, Ariz. "This work also suggests that we can begin to isolate the cause of birth defects from the anti-cancer properties in order to develop safer drugs in the future."

Yuan Xiao Zhu, PhD, will present this study in an oral presentation on Sunday, December 11, at 4:30 p.m. PST at the San Diego Convention Center in Room 6DE.

Final Analysis of a Randomized Comparison of ABVD Chemotherapy with a Strategy that Includes Radiation Therapy (RT) in Patients with Limited-Stage Hodgkin Lymphoma (HL): NCIC CTG/ECOG HD.6 [Abstract 590]

New research concludes that patients with limited-stage Hodgkin lymphoma treated with a standard chemotherapy regimen have better overall survival rates compared with those receiving a radiation-based treatment.

Patients with limited-stage Hodgkin lymphoma (HL) are often treated with combination therapy containing chemotherapy plus radiation (RT). While this therapy is successful in controlling HL, these patients remain challenged by potential long-term complications of radiation exposure such as heart conditions or subsequent cancers.

To determine if HL patients treated with standard chemotherapy (ABVD) have better long-term survival than those treated with radiation-based therapy, researchers from Canada's NCIC Clinical Trials Group (NCIC CTG) designed a trial comparing the 12-year overall survival (OS) between the two groups. The Eastern Cooperative Oncology Group (ECOG) also participated in the trial. Along with overall survival, the trial also examined secondary survival factors, including freedom from disease progression (FFDP) and event-free survival (EFS).

Approximately 400 patients with non-bulky (small tumor size) clinical stage I-IIA HL were stratified into low- and high-risk groups and randomized into two treatment arms: those who received ABVD and those who received extended-field RT (with or without ABVD). By comparing survival rates of the two treatment arms, researchers found that at 12 years, participants treated with ABVD had better OS (94%) than those treated with radiation-based therapy (87%). However, patients treated with RT had better FFDP than those who were randomized to ABVD alone, a finding that was aligned with previous results of short-term success rates using RT. Researchers did not find a significant difference in EFS between the groups.

When analyzing results specifically for high-risk patients, who may carry a poorer prognosis, the findings were generally similar to the primary analysis, with higher OS rates observed in the ABVD treatment arm group (92%) when compared to the ABVD plus RT group (81%). Late effects of treatment, such as heart conditions or secondary cancers, were also less frequent in patients treated with ABVD alone.

"The results of our study suggest that in the long-term patients with limited-stage HL may be better served by a treatment approach that uses chemotherapy without radiation, as this method seems to be associated with fewer deaths from other causes," said lead author Ralph M. Meyer, MD, Director of the NCIC CTG. "After 12 years of follow-up, we have gained valuable and reliable insights about the long-term value of specific therapeutic interventions to help clinicians make more informed treatment decisions and better manage the possible risks for their patients."

Data from this study are updated from a five-year outcomes study published in 2005. The study was made possible through NCIC CTG's grant funding from the Canadian Cancer Society Research Institute. The NCIC CTG and ECOG each receive grant funding support from the U.S. National Cancer Institute.

Dr. Meyer will present this study in an oral presentation on Monday, December 12, at 3:00 p.m. PST at the San Diego Convention Center in Ballroom 20A.

Randomized Phase II Trial Comparing GA101 (Obinutuzumab) with Rituximab in Patients with Relapsed CD20+ Indolent B-Cell Non-Hodgkin Lymphoma: Preliminary Analysis of the GAUSS Study [Abstract 269]

The first clinical trial to directly compare rituximab with the new anti-CD20 monoclonal antibody obinutuzumab for the treatment of relapsed non-Hodgkin lymphoma (NHL) has shown higher response rates for patients treated with the novel therapy.

NHL survival rates have increased dramatically in the last several decades because of such proven and effective targeted therapies as rituximab that aim directly at the key molecular features of the disease. Despite advances in NHL treatment, hematologists continue to be challenged by drug resistance and disease relapses among their patients. Obinutuzumab, also known as GA101, is a new investigational therapy and the first type II bio-engineered monoclonal antibody specifically targeting CD20 (a prominent lymphoma biomarker) to be studied for use in NHL. Early research with GA101 has shown potential anti-lymphoma activity, but no studies have compared the results against current clinical options directly.

To compare the efficacy and safety of GA101 versus rituximab in patients with relapsed NHL, an international Phase II clinical trial was undertaken measuring overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety outcomes among patients on both treatments. A total of 175 patients were randomized to receive four weekly injections of either GA101 or rituximab with response to treatment assessed between 28 and 42 days after the last dose. Those patients who responded to treatment received ongoing doses of GA101 or rituximab every two months for up to two years.

After a complete assessment by both investigators and an independent radiology review, trial data revealed that treatment with GA101 resulted in higher response rates in patients compared to treatment with rituximab. The ORR for GA101 was 33.3 percent versus 44.6 percent for rituximab, and the complete remission (or unconfirmed complete remission) rate in the GA101 arm was 12.2 percent compared to 5.3 percent for rituximab.

Overall, GA101 was well tolerated by most study participants. Although patients on GA101 treatment had a higher rate of infusion reactions, which are a common complication of treatment with monoclonal antibodies, they were generally considered mild and did not result in significant differences in treatment discontinuation. A greater number of patients in the rituximab arm experienced severe adverse events during the four-week induction period (nine patients vs. five GA101 patients). Severe adverse events in GA101 patients included infusion reactions, neutropenia with fever, pleural effusion (a build-up of fluid in the lung tissue), and kidney stones. Finally, more rituximab-treated patients than GA101-treated patients discontinued therapy during the induction period.

"This is the first head-to-head trial of a novel anti-CD20 monoclonal antibody, GA101, against rituximab and we are encouraged to see a trend toward higher response rates without appreciable differences in safety," said lead author Laurie H. Sehn, MD, MPH, Clinical Associate Professor in the Division of Medical Oncology at the University of British Columbia and the British Columbia Cancer Agency, Center for Lymphoid Cancer in Vancouver, Canada. "Given the promising efficacy of this drug, definitive Phase III studies evaluating its benefit are warranted and are currently underway."

Dr. Sehn will present this study in an oral presentation on Monday, December 12, at 8:00 a.m. PST at the San Diego Conventino Center in Ballroom 20A.

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 [Abstract 983]

A recent update of a multicenter Phase Ib/II clinical trial concludes that the novel Bruton's Tyrosine Kinase (BTK) inhibitor PCI-32765 may be an important new targeted treatment approach for patients with chronic lymphocytic leukemia (CLL).

Tyrosine kinase enzymes are important targets for cancer research because they function as "on/off switches" in many cell functions and can signal cells to either maintain normal functioning or to grow uncontrollably, leading to cancer. BTK in particular is largely responsible for the signaling that drives normal B-cell development, making it a primary target for research on B-cell malignancies such as non-Hodgkin lymphoma (NHL).

PCI-32765 is an orally-administered BTK inhibitor that induces apoptosis, or programmed cell suicide, and inhibits function of malignant B-cells. Earlier promising studies of PCI-32765 have shown that the compound may be highly active and tolerable in patients with CLL.

The current analysis summarizes results of an ongoing study using PCI-32756 as a treatment for patients with relapsed CLL. Two cohorts of CLL patients were treated with PCI-32765 at doses of either 420 mg (n=27) or 840 mg (n=34) daily for 28-day cycles until they showed signs of disease progression. Nearly three-fourths (72%) of participating patients had at least one high-risk feature, indicating that they may not respond well to treatment.

After a review of the current analysis, researchers concluded that PCI-32765 was associated with high rates of six-month progression-free survival in patients with relapsed CLL. At 10 months follow-up, 70 percent of patients in the 420 mg treatment group achieved an objective response to therapy (previously reported as 48%), and 44 percent of the patients in the 840 mg cohort achieved an objective response at six months follow-up. An additional 19 percent of the 420 mg cohort and 35 percent of the 840 mg cohort had a nodal partial response, meaning their disease responded to therapy as represented by a 50 percent or greater reduction in lymph node size, but some lymph nodules persisted. Importantly, 82 percent of patients remain on treatment, and only 8 percent have experienced progressive disease.

Two patients discontinued the trial because of adverse events, and six patients required a dose reduction. The most frequently reported adverse events included diarrhea, fatigue, nausea, and ecchymosis (apparent skin bruising). Serious adverse events (SAEs, which are considered relatively common among this immune-compromised patient population) occurred in 38 percent of patients, with 10 percent considered potentially related to treatment. Grade ≥3 severe AEs considered potentially related to treatment occurred in 21 percent of patients. In addition, the majority of patients experienced high lymphocyte count, an event well-documented with this type of treatment, during the first two months of treatment that resolved over time.

"Our results suggest that PC-32765 has the potential to be highly effective and tolerable, and, more importantly, appears to be working well in patients with poor prognoses," said lead author Susan O'Brien, MD, Professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston. "As we become better equipped to target specific cellular functions, it is our hope that therapies like PCI-32765 will become effective interventions to manage disease in patients with CLL."

Dr. O'Brien will present this study in an oral presentation on Tuesday, December 13, at 8:30 a.m. PST at the San Diego Convention Center in Ballroom 20A.


Contact: Lindsey Love
American Society of Hematology

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