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New Chemotherapy Combinations and Alternatives for Blood Cancers Offer Patients Better Results, Improved Quality of Life

Posted on: Monday, 11 December 2006, 12:00 CST

ORLANDO, Fla., Dec. 11 /PRNewswire/ -- While chemotherapy has been a standard of care for cancer patients for decades, doctors have struggled with the dangerous side effects of the toxic therapy, focusing their research on therapies that can produce the same results without causing additional harm. This is particularly important in blood cancers like leukemia and lymphoma, and three studies being presented today at the 48th Annual Meeting of the American Society of Hematology (ASH(TM)) suggest that novel compounds may be used alone or in combination with current therapies to treat blood cancers like leukemia and lymphoma without reducing quality of life. The studies examine new targeted compounds that have shown promise in a range of disorders and solid tumors, as well as combination therapy with chemotherapy and non- chemotherapy options.

"Current research in blood-borne disease treatments has expanded beyond just efficacy to incorporate the importance of patient quality of life," said Kenneth Kaushansky, MD, Vice President of ASH and Helen M. Ranney Professor and Chair of the Department of Medicine, University of California, San Diego. "We hope that by working together now to test a variety of promising therapies in development and comparing them to standards of care, we will deliver better quality treatment and cures for patients in the future."

MK-0457, a Novel Aurora Kinase and BCR-ABL Inhibitor, Is Active Against BCR-ABL T315I Mutant Chronic Myelogenous Leukemia (CML) [Abstract #163]

*This abstract is being presented on Monday, December 11, 2006, 7:30 a.m. (EST) prior to the press conference at 11:00 a.m. It is embargoed for release until the time of initial presentation.

Researchers are continually examining new ways to treat leukemia and other cancers of the blood system, with the goal of finding options that help patients fight the disease without compromising quality of life. In this study, a new molecule, MK-0457, offers a "targeted" approach to treating the disease with minimal side effects.

MK-0457 is a compound that targets chronic myeloid leukemia (CML) and other types of leukemia by inhibiting aurora kinases (cell development enzymes) and BCR-ABL, an oncogene that when further altered promotes uncontrolled cell growth and disease progression in leukemia. In previous research, MK-0457 has been successful in blocking the progression of a normal cell growth cycle, inducing apoptosis (programmed cell death) in a range of human tumors, and inhibiting tumor growth in early leukemia models. It has also previously demonstrated promising in vitro activity against normal or mutated BCR-ABL-containing cells, including the T315I BCR-ABL mutation, which causes resistance to powerful anti-leukemia therapies, including imatinib, dasatinib, and nilotinib.

Researchers from M. D. Anderson Cancer Center and Duke University conducted a phase I study of MK-0457 in more than 40 patients, 15 of whom had refractory CML and a history of accelerated or blastic phase disease (progression of the disease to an advanced phase) and 11 of whom carried the T315I BCR-ABL mutation. Patients received the therapy by continuous five-day intravenous infusion every two to three weeks at dose ranges of 8, 12, 16, 20, 24, 28, 32, or 40 mg/m(2)/hr, for an average of three months therapy to date.

All eleven BCR-ABL T315I mutant CML patients responded to the therapy, with one major and four minor hematologic responses, and one complete and two partial cytogenetic responses. One patient received 15 cycles of therapy and continues to receive treatment. No serious drug-related, non-hematologic toxicity was observed.

"MK-0457 is a unique compound that shows clinical activity in a very refractory subpopulation of CML patients," said Francis Giles, MD, Developmental Therapeutics Section, M. D. Anderson Cancer Center, Houston, Texas, and leader of the study. "It was very well tolerated and warrants further evaluation both alone and in combination with other BCR-ABL inhibitors in CML and in other types of leukemia."

Benefit of Rituximab Addition to High-Dose Programs with Autograft for B- Cell Lymphoma: A Multicenter GITIL Survey on 957 Patients [Abstract #207]

*This abstract is being presented on Monday, December 11, 2006, 8:00 a.m. (EST) prior to the press conference at 11:00 a.m. It is embargoed for release until the time of initial presentation.

As has been demonstrated in hundreds of clinical trials over the past nine years, rituximab has greatly improved the treatment success for patients with non-Hodgkin lymphoma, specifically B-cell lymphoma. While past studies have shown it can be effectively combined with conventional chemotherapy regimens, the current study finds that rituximab can also be added to high-dose chemotherapy regimens with autograft (bone marrow or stem cell transplantation) to improve treatment outcomes. High-dose chemotherapy kills cancer cells and destroys bone marrow, so it is often followed by autograft to rescue bone marrow function.

Medical records were collected from 957 high-risk B-cell lymphoma patients receiving a high-dose sequential (HDS) chemotherapy regimen at ten Italian centers associated with the Gruppo Italiano Terapie Innovative nei Linfomi (GITIL). All patients entered the HDS-protocols due to very unfavorable clinical features. Half of patients (n=483) received HDS with rituximab (R+), and the other half (n=474) received HDS without rituxmiab (R-). Most patients concluded the intensive program with autograft in the final phase (87 percent and 86 percent among R+ and R-, respectively).

Five-year overall survival (OS) and event-free survival (EFS) rates were estimated at 66 percent and 55 percent, respectively, with patients treated at diagnosis having significantly better outcomes (5-yr OS: 72 percent, EFS: 61 percent) compared to patients treated at first or subsequent relapse (5-yr OS: 56 percent, EFS: 45 percent). Adding rituximab to HDS significantly improved the outcome for all patient subtypes, including those treated at diagnosis and relapse, and those with low-grade and intermediate/high-grade disease. Overall, the long-term survival without any evidence of disease (EFS) is projected to be 65 percent for R+ vs. 41 percent for R- among patients with the low-grade histological subtype and 64 percent for R+ vs. 52 percent for R- among those with the intermediate/high-grade subtypes.

"The fact that approximately two-thirds of the patients treated at diagnosis were alive and over half did not experience any sign of disease after five years is extremely promising, especially given that overall survival rates for B-cell lymphoma patients presenting with poor prognostic features have traditionally been low," said Corrado Tarella, MD, Div. Universitaria Ematologia, University of Turin. "The main message, however, is that rituximab definitely improves the efficacy of intensive treatments with autograft in high-risk B-cell lymphoma. What makes the study particularly relevant is the large number of patients, evaluated in a multicenter setting. Finally, the study underscores the need for more research into the addition of rituximab to treatment regimens other than conventional chemotherapy, which may ultimately lead to better patient outcomes in the future."

The EGFR-Inhibitor Erlotinib Induces Apoptosis in Neoplastic Cells of Myelodysplastic Syndrome (MDS) and Acute Myeloid Leukemia (AML), an Effect Determined by the Expression Level of Nucleophosmin (NPM) [Abstract #856]

Targeted therapies were originally designed to block specific substances that help tumor cells grow and spread. Nevertheless, previous studies have demonstrated that a variety of targeted therapies exhibit off-target effects, meaning they are able to fight tumor cells despite the absence of the respective target. Evaluating a potential off-target effect of erlotinib -- which was initially designed to attack the epidermal growth factor receptor (EGFR) in the neoplastic cells of solid tumors -- a team of researchers in France tested the drug's in vitro effects on cells of patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML).

The team demonstrated that erlotinib exhibits an off-target effect by inducing programmed cell death (apoptosis) in ex vivo cells of patients diagnosed with MDS (n=4) and AML (n=6). Cells were treated with erlotinib (1 mu M to 10 mu M) and were analyzed for up to six days, using healthy bone marrow cells as controls. Importantly, erlotinib was able to kill tumor cells and exhibited no toxicity toward healthy bone marrow cells.

In order to define the mechanisms of erlotinib's off-target effect in myeloid neoplasms, the impact of the drug was tested in erlotinib-sensitive and -resistant cell lines, where the team was able to determine the crucial role of the protein nucleophosmin -- whose prognostic significance in AML was recently identified. By decreasing the expression of this protein, not only was erlotinib's apoptosis-inducing effect enhanced in sensitive cells, sensitivity was also established in otherwise erlotinib-resistant cells. As a result, the team confirmed that an increased expression of nucleophosmin promotes resistance to erlotinib.

"We were impressed by discovering erlotinib's ability to induce cell death in neoplastic cells of MDS and AML, while it is obviously sparing normal bone marrow cells. This result is of particular interest considering the favorable toxicity profile of the drug, as demonstrated previously in the clinical studies carried out to assess its efficacy in solid tumors," said Simone Boehrer, MD, Institut Gustave Roussy, France, and lead author of the study. "This study therefore merits additional research into erlotinib for the treatment of MDS, AML, and other related blood disorders."

The American Society of Hematology (http://www.hematology.org/) is the world's largest professional society concerned with the causes and treatment of blood disorders. Its mission is to further the understanding, diagnosis, treatment, and prevention of disorders affecting blood, bone marrow, and the immunologic, hemostatic, and vascular systems, by promoting research, clinical care, education, training, and advocacy in hematology.

American Society of Hematology

CONTACT: Leslie Humbel of Spectrum Science Communications,+1-202-955-6222, lhumbel@spectrumscience.com; or Laura Stark of AmericanSociety of Hematology, +1-202-776-0544, lstark@hematology.org; On-site(12/9-12/13): +1-407-685-5405

Web site: http://www.hematology.org/

Source: PRNewswire

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