Traditionally, economic evaluations of rituximab have been performed using data resulting from controlled clinical trials. These trial-based results provide valuable information, but they describe an idealized setting that may not be consistent with conditions observed in actual practice. It is also of interest to evaluate the experiences of actual lymphoma patients in order to measure the economic value of rituximab in a real-world setting.

A recent study, “Cost-Effectiveness of the Addition Of Rituximab To CHOP Chemotherapy In First-Line Treatment For Diffuse Large B-Cell Lymphoma In A Population-Based Observational Cohort In British Columbia, Canada”, published in Value in Health, evaluates the effect of rituximab on medical costs and survival for lymphoma patients receiving routine care in British Columbia. The study’s co-authors included cancer control researchers Stuart Peacock and Karissa Johnston of the Canadian Centre for Applied Research in Cancer Control (ARCC) and oncologist Joseph Connors of the British Columbia Cancer Agency.

Says Dr Peacock, co-director of the new ARCC centre, “New cancer treatments are often expensive and may offer modest improvements to length and quality of life compared to existing treatments. We found that for patients with diffuse large B-cell lymphoma adding rituximab to chemotherapy increases life expectancy and provides very good value for money.”

Value in Health (ISSN 1098-3015) publishes papers, concepts, and ideas that advance the field of pharmacoeconomics and outcomes research and help health care leaders to make decisions that are solidly evidence-based. The journal is published bi-monthly and has a regular readership of over 5,000 clinicians, decision-makers, and researchers worldwide.
Source
ISPOR

Two new studies suggest that the prolonged use of cancer drugs helped stunt the progress of the disease, a shift from the scheduled courses of treatment typically delivered to patients, The Wall Street Journal reports. For example, the drug Rituxan “cut the risk of cancer returning in certain lymphoma patients by half when used as a maintenance treatment for two years.” The studies show “how cancer is often becoming a chronic disease,” according to the Journal (Dooren and Winslow, 5/21).

The New York Times: “The studies on longer cancer treatment involve what is called maintenance therapy. It is a strategy for making cancer into a chronic disease like diabetes or hypertension, held in check by continuous use of medicines. Typically, cancer patients stop taking antitumor drugs once their tumors have shrunk or the disease goes into remission. They do not resume taking drugs until the tumor starts growing again. ” The Times notes that neither study has so far demonstrated that this type of treatment actually helps people live longer and cautions that long-term cancer drug use could have side effects and is expensive. A two-year supply of Rituxan costs $50,000 while one of the other drugs studied costs $6,000 a month (Pollack, 5/20).

This information was reprinted from kaiserhealthnews.org with kind permission from the Henry J. Kaiser Family Foundation. You can view the entire Kaiser Daily Health Policy Report, search the archives and sign up for email delivery at kaiserhealthnews.org.

Gleevec, one of the first targeted cancer therapies with wide success in CML patients, destroys most leukemic cells in the body, but in most patients, some cancerous cells remain and are measurable with sensitive molecular tests. These remaining cells are a source of relapse, according to the investigators, especially if Gleevec therapy is stopped.

In a pilot study published in Clinical Cancer Research, the Johns Hopkins investigators used a vaccine made from CML cells irradiated to halt their cancerous potential and genetically altered to produce an immune system stimulator called GM-CSF. The treated cells also carry molecules, called antigens, specific to CML cells, which prime the immune system to recognize and kill circulating CML cells.

The study vaccine was given to 19 CML patients with measurable cancer cells, despite taking Gleevec for at least one year. A series of 10 skin injections were given every three weeks for a total of four times. After a median of 72 months of follow-up, the number of remaining cancer cells declined in 13 patients, 12 of whom reached their lowest levels of residual cancer cells. In seven patients, CML became completely undetectable.

Because the study was conducted in a limited number of patients and not compared with other therapies, the researchers warn they cannot be sure that the responses were a result of the vaccine.

“We want to get rid of every last cancer cell in the body, and using cancer vaccines may be a good way to mop up residual disease,” says Hyam Levitsky, M.D., professor of oncology, medicine and urology at the Johns Hopkins Kimmel Cancer Center. More research to confirm and expand the results is needed, Levitsky said.

The investigators will be testing blood samples taken from the study patients to identify the precise antigens that the immune system is recognizing. With this information, they will tailor their vaccine for additional studies that monitor immune response more precisely.

Patients receiving the trial vaccine experienced relatively few side effects that included injection site pain and swelling, occasional muscle aches and mild fevers.

According to the investigators, most patients with CML will need to remain on Gleevec therapy for the rest of their lives. More than 90 percent of them will achieve remission, but about 10 to 15 percent of patients cannot tolerate the drug long term.

“Often patients have low blood cell counts, fluid retention, significant nausea and other gastrointestinal problems,” says B. Douglas Smith, M.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center. Secondary therapies, including dasatinib and nilotinib, also have many side effects.

Another common side effect of Gleevec, says Smith, is fatigue.

“Patients often tell me that they feel about 80 to 90 percent of what they should, and over time, this may have a big impact on their quality of life,” he says.

Gleevec also cannot be taken during pregnancy, and since one-third of CML patients are in their 20s and 30s, many patients hoping to start families would like to discontinue taking it.

“Ultimately, should this vaccine approach prove to be successful, the ability to get patients off lifelong Gleevec therapy would be a significant advance,” says Levitsky.

The research was funded by the National Institutes of Health.

Study contributors include Yvette Kasamon, Jeanne Kowalski, Christopher Gocke, Kathleen Murphy, Hua-Ling Tsai, Lu Qin, Christina Chia, Barbara Biedrzycki, and Richard Jones from Johns Hopkins; Carole Miller from St. Agnes Hospital; Elizabeth Garrett-Mayer from the Medical University of South Carolina; and Thomas Harding and Guang Haun Tu from Cell Genesys, Inc.

Under a licensing agreement between BioSante Pharmaceuticals Inc. and The Johns Hopkins University, Dr. Levitsky is entitled to a share of milestone payments and a share of royalty received by the university on sales of GVAX. Dr. Levitsky previously served as a paid consultant to Cell Genesys, which has since been acquired by BioSante Pharmaceuticals Inc. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies.

Findings published in today’s issue of Cancer Cell show that an experimental compound designed by a team of researchers from Weill Cornell Medical College, the University of Maryland and the Ontario Cancer Center at the University of Toronto may effectively block the cancer-causing actions of BCL6 by attaching to a critical “hot spot” on its surface, thus killing off the cancer cells.

“BCL6 mediates its cancer-causing actions by attaching to other proteins,” explains Dr. Ari Melnick, associate professor of medicine from the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College. “Traditionally protein-protein interactions have been viewed as being too difficult to block with small-molecule drugs.”

Accordingly, by observing the atomic scale structure of BCL6 attached to its partner proteins, Dr. Melnick and colleagues identified a critical “hot spot” that appeared to be amenable to designing a drug. Dr. Alexander Mackerell, from the University of Maryland, then used computational modeling to identify chemical structures that could attack this hot spot.

“We tested the ability of a large number of these chemicals to bind and block BCL6,” said Dr. Melnick, “and then Dr. Gilbert Privé, from the University of Toronto, performed nuclear magnetic resonance and X-ray crystallography studies to show that a specific BCL6 inhibitor compound hit exactly in the center of the predicted hot spot. Our results show that given the right scientific approach it is quite possible to design drugs against key protein regulatory factors like BCL6.”

Dr. Melnick’s group showed that the BCL6 inhibitor was specific for BCL6 and did not block other master regulators, and that the experimental drug could powerfully kill DLBCL cells derived from human patients with this disease. Remarkably, the compound was completely non-toxic to animals, and could powerfully suppress and improve survival in animal models.

“This means that if given as a therapeutic agent, the compound would be unlikely to have ill-effects on healthy normal cells, and therefore would not be expected to have significant side effects,” explains Dr. Melnick. “Since emerging data implicates BCL6 in other tumor types in addition to non-Hodgkin’s lymphoma, it is possible that BCL6-targeted therapy could benefit many other cancer patients.”

Dr. Melnick is among the physician-scientists supported by the Leukemia and Lymphoma Society’s (LLS) Scholar Award Program. Since 2005, LLS has funded research in Dr. Melnick’s laboratory, much of which has been focused on developing better treatments for patients with B-cell lymphomas. Dr. Melnick is also the leader of a Samuel Waxman Cancer Research Foundation Program Grant, which directly supported the effort to design small molecules for the BCL6 hot spot by the Melnick, Privé and Mackerell research team. The results of Dr. Melnick’s work in this area led the LLS to form a drug discovery partnership with Forma Therapeutics to improve these drugs so they can be used in human clinical trials for hematological malignant cancers.

The product showed an improvement in disease-free survival in a phase 3 clinical trial, which was reported at the American Society of Clinical Oncology (ASCO) 45th Annual Meeting, as reported by Medscape Oncology. Biovest says it plans to use these data to file for approval in the United States by mid-2010, and also plans to file for approval in Europe and Japan.

BiovaxID is personalized for each patient with a tumor-derived idiotype protein, and induces cellular immunity, which offers a different approach to treatment than existing immunotherapies. But the question of where it fits alongside existing therapy is the main issue, according to Ron Levy, MD, chief of oncology at Stanford University in California, and a pioneer in idiopathic vaccine development. He discussed the phase 3 data on BiovaxID at the ASCO meeting, and said that this trial showed that “the vaccine was effective in those patients in whom it was tested.” But since that trial began, many years ago, the treatment of lymphoma has changed substantially, in particular after the introduction of rituximab, which has had a huge impact on this disease. The question of what role BiovaxID could play in the current treatment of lymphoma will need further study, Dr. Levy said.

Another commentator suggested that future studies would need to compare the vaccine with rituximab and chemotherapy. Dr. Sonali Smith, MD, associate director of the lymphoma program at the University of Chicago Medical Center in Illinois, suggested that using the vaccine would be “cumbersome” because it necessitates taking a fresh biopsy to generate the individualized vaccine for each patient.

Almost 70% of patients had complete responses upon completion of consolidation therapy, which converted 40% of partial responses to complete ones, Umberto Vitolo, MD, of the University of Torino, told MedPage Today at the American Society of Hematology meeting.

He said the regimen was well tolerated, with relatively few grade III-IV adverse events reported.

“In elderly patients, the goal is to reduce the chemotherapy that patients sometimes don’t tolerate and in the meantime maintain the efficacy of the treatment,” he said. “This regimen led to nice results, even in patients older than 70 years and with two or more comorbidities, and they tolerated the regimen well. I think the results show that it is not appropriate not to give patients appropriate treatment only because of age.”

The findings came from a study to evaluate a therapeutic regimen that would offer efficacy and reduced toxicity for older patients with untreated grade I-IIIa follicular lymphoma.

The regimen consisted of four weekly administrations of chemoimmunotherapy (fludarabine-mitoxantrone-dexamethasone chemotherapy plus rituximab). Patients who achieved a complete or partial response were randomized to four consolidation doses of rituximab at months nine, 11, 13, and 15, or to observation.

Vitolo reported mature data from the chemoimmunotherapy phase of the trial. Follow-up was insufficient for analysis of the comparison between maintenance therapy and observation, he said.

Investigators at 33 Italian centers enrolled 242 patients ages 61 to 75, all of whom had stage 3-4 disease, bulky stage 2 disease, or stage 2 lymphoma with one or more adverse features.

Vitolo reported that 94% of the patients had grade 1-2 disease, while 86% had stage 3-4. More than half of the patients had bone marrow involvement, while 55% had high Follicular Lymphoma International Prognostic Index (FLIPI) scores, and 23% had two or more comorbid conditions.

The four cycles of chemoimmunotherapy led to complete responses in 55% of the patients, and partial responses in 37%. After rituximab consolidation therapy, 69% of the patients had achieved complete responses, and 18% had partial responses.

At diagnosis, 51% of the patients exhibited bcl-2 rearrangement in bone marrow by polymerase chain reaction assay. After chemoimmunotherapy, the proportion of bcl-2+ patients had decreased to 24%, followed by a decline to 11% after consolidation therapy.

The most common toxicity was neutropenia, which occurred in 65% of patients but was grade 3-4 severity in 25%.

The infection rate was 3% (<1% grade 3-4), and rituximab infusion reactions occurred in 6% of patients (<1% grade 3-4). Two toxic deaths occurred: one related to reactivation of hepatitis B infection and the other resulting from Stevens Johnson syndrome, Vitolo reported.

After a median follow-up of 22 months, the cohort had a two-year overall survival of 92%. The two-year PFS was 75%, including 85% in patients with FLIPI scores of 1 to 2 and 67% in patients with FLIPI scores of 3 or greater (P<0.001).

PFS was similar whether patients were younger or older than 70 and regardless of comorbidities.

Primary source: American Society of Hematology
Source reference: Vitolo U, et al “Rituximab maintenance versus observation after a short terml-chemoimmunotherapy (R-FND) as first-line treatment in elderly patients with advanced follicular lymphoma: Updated results and safety of the maintenance of an Intergruppo Italiano Linformi Randomized Trial” ASH 2009; Abstract 1706.
http://www.medpagetoday.com/HematologyOncology/Lymphoma/17386

Diffuse large B-cell lymphoma (DLBCL) originates in B cells, which are antibody-producing immune cells and one of the body’s key defense mechanisms. DLBCL is the most common form of non-Hodgkin’s lymphoma and represents about 30 percent of newly diagnosed cases. There are different subtypes of DLBCL that vary biologically and differ significantly in their rates of patient survival following chemotherapy. The activated B cell-like (ABC) subtype is the least responsive to currently available therapies.

When a normal B cell encounters a foreign substance, proteins on the cell surface known as B cell receptors (BCR) activate signaling pathways that tell the cell to survive and proliferate. A signaling pathway is a stepwise series of biochemical events that help regulate important cellular functions, such as proliferation and survival. Each pathway contains points at which normal signaling can become altered, causing cells to function abnormally. Alterations in signaling pathways have been found in many types of cancer cells. Previous research had suggested that BCR signaling might contribute to the development of lymphomas; however, direct genetic and functional evidence was lacking.

In the new study, researchers first used advanced laboratory techniques to identify critical points in the BCR signaling pathway that affect the survival of lymphoma cells. They found that interference with several individual components of this pathway caused lymphoma cells to die. Thus, ongoing BCR signaling – which the authors refer to as chronic active signaling – is necessary for ABC subtype DLBCL cell survival.

The team then looked for mutations in genes that encode these signaling pathway components in human DLBCL tumors. They found that about one-fifth of ABC subtype tumors had mutations in a BCR signaling component known as CD79B. The mutations increased BCR signaling by blocking a braking process that normally turns off the pathway in response to inhibitory signals.

“Our data provide important evidence that BCR signaling plays a crucial role in ABC DLBCL,” said study senior author Louis M. Staudt. M.D., Ph.D., of NCI’s Center for Cancer Research. “As such, this study opens up a wealth of therapeutic opportunities for this type of lymphoma and may eventually lead to clinical trials testing agents that target components of the BCR signaling pathway.” Indeed, the Staudt team found that dasatinib, a drug that is approved for the treatment of chronic myelogenous leukemia, could turn off BCR signaling by inhibiting the activity of one of the pathway’s components, a protein called BTK, thereby killing ABC subtype DLBCL cells that exhibit chronic active BCR signaling.

“However, more research is needed to understand the various biochemical mechanisms by which chronic, active BCR signaling begins,” said Staudt. “Tests will also need to be developed that can identify patients with cases of DLBCL that depend on chronic, active BCR signaling, so that we can rationally develop clinical trials with agents that inhibit the BCR pathway.”

Reference: Davis RE, et al. Chronic Active B Cell Receptor Signaling in Diffuse Large B Cell Lymphoma. Jan. 7, 2010. DOI: 10.1038/nature08638. Nature.

For more information on Dr. Staudt’s research, please go to http://ccr.cancer.gov/staff/staff.asp?profileid=5780

Promising results have led to the design of a clinical trial that will soon be under way to test a compound — called PU-H71 — in human patients. This compound is in a new class of drugs, called heat shock protein inhibitors.

Standard treatment for non-Hodgkin’s lymphoma includes radiation therapy, chemotherapy and monoclonal antibodies. Approximately 66,000 people are diagnosed in the United States each year and approximately 50 percent of patients will not be cured by current treatments.

The author’s results are published online today in the prestigious journal Nature Medicine.

“We observed almost complete tumor regression after treating the animals with PU-H71,” says Dr. Ari Melnick, associate professor of medicine from the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College. “I hope that clinical testing will have similar results for human participants.”

The research team discovered that a molecule called heat shock protein 90 (Hsp90) is necessary for the functioning of a protein called BCL-6, which is known to drive the activity of lymphoma tumor cells.

BCL-6 is the most commonly involved protein in diffuse large B-cell lymphomas, which is the most common form of non-Hodgkin’s lymphoma. Approximately 70 percent of these tumors test positive for BCL-6, making it a primary target for therapies.

Dr. Melnick and his team found that Hsp90 and BCL-6 joined together within cancer cells to form a complex. They also learned that Hsp90 binds directly to the gene responsible for producing the BCL-6 protein, which led them to believe that blocking Hsp90 would have a powerful effect on BCL-6 production within the cell and, therefore, tumor formation.

To prevent the two molecules from joining, the scientists tested the experimental drug, PU-H71, which was designed to block the activity of Hsp90. PU-H71 was developed by Dr. Gabriela Chiosis, a principal author of the study, from the Memorial Sloan-Kettering Cancer Center, in New York City. The scientific team discovered that exposing lymphoma cells to PU-H71 in laboratory experiments prevented the combination of the two molecules — killing lymphoma cells and inhibiting new cell reproduction.

“The next step was to test the findings in an animal model to see what kind of effect PU-H71 had,” explains Dr. Melnick. “We were excited to find that the treated animals’ tumors decreased in both size and weight, and that the animals had a significantly prolonged survival compared with controls.”

The researchers also found that PU-H71 had a very low toxicity in the animal models. Dr. Melnick believes that this may indicate that when tested in human patients, the drug will be well tolerated, with few side effects, such as damage to the bone marrow and immune system, which are common in cancer therapies.

Collaborators on the study include Leandro C. Cerchietti, Shao Ning Yang, Katerina Hatzi, Karen Bunting, Lucas Tsikitas, Alka Malik, Rita Shaknovich, all from Weill Cornell; Eloisi C. Lopes and Gabriela Chiosis, from Memorial Sloan-Kettering Cancer Center in New York City; Ana I. Robles, Jennifer Walling and Lyuba Varticovski, from the National Cancer Institute, National Institutes of Health, Bethesda, Md.; and Kapil Bhalla, from the Medical College of Georgia Cancer Center, Augusta, Ga.

This research is supported by the Leukemia and Lymphoma Society grant S-7032-04, U.S. National Cancer Institute grant R01-CA10434, and the Chemotherapy Foundation and in part by the Intramural Research Program of the U.S. National Institutes of Health National Cancer Institute Center for Cancer Research. This work was also supported by the Translational and Integrative Medicine Research Fund and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center.

Source
Weill Cornell Medical College

Treatment of swince flu is effective. Swine flu A (H1N1), Seasonal flu A (H1N1), Seasonal flu A (H3N2) and Seasonal flu (type B) are all sensitive to Zanamivr. All (but seasonal flu A) are sensitive to Oseltamivr.

H1N1 Epidemic Update
During influenza week 47 (November 22-28, 2009), influenza activity continued to decrease in the United States.[4] More than 99% of strains that were subtyped were 2009 influenza A (H1N1).

Summary:

1. Virtually all influenza at this time is swine flu. Seasonal flu has not started.
2. The number of outpatient visits for influenza-like illnesses is 3.7%, which is above the national baseline of 2.3% but lower than earlier reports. Hospitalizations and deaths due to influenza are down.
3. The second wave is subsiding, but there is still widespread illness in 25 states.
4. Resistance testing shows that 15 of 1540 (less than 1%) 2009 H1N1 strains were resistant to oseltamivir. Nearly all 15 had previous exposure to oseltamivir.
5. Oseltamivir is still active against nearly all strains, especially in patients who have not had oseltamivir exposure.
6. Pediatric deaths attributed to this influenza strain in the United States now total 198, including 34 in children younger than 2 years of age. Of these, 89 had cultures of normally sterile sites and 28/89 (31%) showed bacterial superinfections involving a predictable menu of pathogens.
7. There is increasing concern and attention on bacterial superinfections. Clues are (1) biphasic course, (2) elevated WBC, (3) x-ray showing lobar consolidation, and (4) sputum showing the likely pathogens: pneumococcus, Staphylococcus aureus, or Group A streptococcus.

Promising results have led to the design of a clinical trial that will soon be under way to test a compound — called PU-H71 — in human patients. This compound is in a new class of drugs, called heat shock protein inhibitors.

Standard treatment for non-Hodgkin’s lymphoma includes radiation therapy, chemotherapy and monoclonal antibodies. Approximately 66,000 people are diagnosed in the United States each year and approximately 50 percent of patients will not be cured by current treatments.

The author’s results are published online November 22 in the journal Nature Medicine.

“We observed almost complete tumor regression after treating the animals with PU-H71,” says Dr. Ari Melnick, associate professor of medicine from the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College. “I hope that clinical testing will have similar results for human participants.”

The research team discovered that a molecule called heat shock protein 90 (Hsp90) is necessary for the functioning of a protein called BCL-6, which is known to drive the activity of lymphoma tumor cells.

BCL-6 is the most commonly involved protein in diffuse large B-cell lymphomas, which is the most common form of non-Hodgkin’s lymphoma. Approximately 70 percent of these tumors test positive for BCL-6, making it a primary target for therapies.

Dr. Melnick and his team found that Hsp90 and BCL-6 joined together within cancer cells to form a complex. They also learned that Hsp90 binds directly to the gene responsible for producing the BCL-6 protein, which led them to believe that blocking Hsp90 would have a powerful effect on BCL-6 production within the cell and, therefore, tumor formation.

To prevent the two molecules from joining, the scientists tested the experimental drug, PU-H71, which was designed to block the activity of Hsp90. PU-H71 was developed by Dr. Gabriela Chiosis, a principal author of the study, from the Memorial Sloan-Kettering Cancer Center, in New York City. The scientific team discovered that exposing lymphoma cells to PU-H71 in laboratory experiments prevented the combination of the two molecules — killing lymphoma cells and inhibiting new cell reproduction.

“The next step was to test the findings in an animal model to see what kind of effect PU-H71 had,” explains Dr. Melnick. “We were excited to find that the treated animals’ tumors decreased in both size and weight, and that the animals had a significantly prolonged survival compared with controls.”

The researchers also found that PU-H71 had a very low toxicity in the animal models. Dr. Melnick believes that this may indicate that when tested in human patients, the drug will be well tolerated, with few side effects, such as damage to the bone marrow and immune system, which are common in cancer therapies.

Collaborators on the study include Leandro C. Cerchietti, Shao Ning Yang, Katerina Hatzi, Karen Bunting, Lucas Tsikitas, Alka Malik, Rita Shaknovich, all from Weill Cornell; Eloisi C. Lopes and Gabriela Chiosis, from Memorial Sloan-Kettering Cancer Center in New York City; Ana I. Robles, Jennifer Walling and Lyuba Varticovski, from the National Cancer Institute, National Institutes of Health, Bethesda, Md.; and Kapil Bhalla, from the Medical College of Georgia Cancer Center, Augusta, Ga.

This research is supported by the Leukemia and Lymphoma Society grant S-7032-04, U.S. National Cancer Institute grant R01-CA10434, and the Chemotherapy Foundation and in part by the Intramural Research Program of the U.S. National Institutes of Health National Cancer Institute Center for Cancer Research. This work was also supported by the Translational and Integrative Medicine Research Fund and the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center.

Reference: http://news.med.cornell.edu/wcmc/wcmc_2009/11_22_09.shtml