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Kara Vonasek, Spectrum Science
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Aislinn Raedy, American Society of Hematology
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MODIFIED CANCER THERAPY REGIMENS OFFER SUCCESSFUL TREATMENTS FOR LYMPHOMA WITH FEW SIDE EFFECTS

(SAN DIEGO, December 6, 2004) – While chemotherapy and radiation therapy regimens have proven to be the most effective treatments to fight cancer, many patients find that the powerful side effects take a great toll on the body while trying to rid it of disease.

In several studies presented at the 46th Annual Meeting of the American Society of Hematology, researchers have addressed new options to treat patients suffering from lymphoma, a cancer of the blood system, both in terms of treatment alternatives and intensity of therapy.

Intensification of Chemotherapy and Concomitant Reduction of Radiotherapy Dose in Intermediate Stage Hodgkin's Lymphoma: Results of the Fourth Interim Analysis of the HD 11 Trial of the GHSG [Abstract 1308]; Reduction of Combined Modality Treatment Intensity in Early Stage Hodgkin's Lymphoma: Interim Analysis of the HD 10 Trial of the GHSG [Abstract 1307]

Current treatments for intermediate stage (early unfavorable) Hodgkin's lymphoma (HL) involve a combination regimen of chemotherapy (generally ABVD, a combination cycle of the medicines adriamycin, bleomycin, vinblastine, and dacarbazine) followed by radiation therapy (IF). While remission rates are high with this treatment, failure rates are still of concern.

In this study, researchers from the University of Cologne modified the intensity of the therapy to achieve better results. To complete the trial, the research team utilized a new regimen (BEACOPP, a new dose-escalated and accelerated regimen) to intensify the chemotherapy arm of treatment while reducing the dosage of radiation therapy. The four arms compared the standard treatment (AVBD) with radiation therapy at 30 and 20 GY (gray, a unit measuring radiation), to the BEACOPP regimen with radiation therapy at 30 and 20 GY.

Of the 1,047 patients evaluated for chemotherapy and 982 for radiation therapy, 95.1 percent of patients reached complete disease remission. After two years of observation, overall survival (OS) was 97.4 percent and freedom from treatment failure (FFTF) was 89.9 percent. For both OS and FFTF, the researchers found no significant differences between the chemotherapy regimens or radiation dosage levels.

The relapse rate of the trial was 5.9 percent, and two percent of patients suffered progression. The most frequent hematologic toxicity was leukopenia (low white blood cell count), which occurred in 33 percent of the patients. The most frequent toxicity in radiation therapy, dysphagia (difficulty swallowing), was found in 5.6 percent of patients.

“We are encouraged by the results of this trial and feel that the accurate combination of therapy regimens and intensity of dosage will offer our patients the most successful treatment,” said Volker Diehl, M.D. of the University of Cologne and lead author of the study. “We hope to further intensify the chemotherapy side of this treatment to evaluate for an even better success rate.”

In a second study from the University of Cologne, researchers used the same regimen and found positive results. In the study, the cycles of ABVD and doses of radiation therapy were both reduced in 1,131 HL patients with early stage disease, of which 847 were analyzed. The patients were randomized into four arms: four cycles of ABVD with radiation (30 GY or 20 GY), or two cycles of ABVD with radiation (30 GY or 20 GY).

After an average of two years of observation, OS and FFTF rates were 98.5 percent and 96.6 percent, respectively. In total, 98.4 percent of the patients reached complete remission, and progressive disease or no change was observed in just 0.9 percent of the patients. No statistical differences in OS or FFTF were seen between the two sets of AVBD cycles, or between the two doses of radiation therapy. The most common grade 3 to 4 toxicity was leukopenia (low white blood cell count) in 19 percent of the patients.

“Since the adverse events were minimal, the results here suggest that the intensity of therapy might be further reduced in terms of cycles as well as doses,” said Dr. Diehl. “This is a good sign for our patients suffering from Hodgkin's lymphoma, who may be experiencing severe side effects as a result of their intense therapy regimens.”

Efficacy and Late Effects of Stanford V Chemotherapy and Radiotherapy in Untreated Hodgkin's Disease: Mature Data in Early and Advanced Stage Patients [Abstract 308]

This study by a group of researchers at Stanford University evaluated the effectiveness of a new treatment regimen for patients suffering from early and advanced stage Hodgkin's disease. The regimen involved a chemotherapy combination called the "Stanford V" (doxorubicin, vinblastine, nitrogen mustard, vincristine, bleomycin, etoposide, and prednisone) with differing levels of radiation therapy.

A total of 87 patients with stage I-IIA disease (without massive tumors in the chest) received eight weeks of Stanford V chemotherapy with 30 GY (gray, a unit measuring radiation) radiation therapy, while 169 patients with bulky stage II, III, or IV disease (massive tumors in the chest or widespread disease) received 12 weeks of Stanford V chemotherapy with 36 GY radiation therapy to tumors > 5 cm. When needed, the team supplemented the chemotherapy regimen with G-CSF (Granulocyte Colony Stimulating Factor, an approved treatment to increase white blood cell count) to maintain dose intensity after the first dose reduction or delay.

In the study, no cases of secondary myelodysplasia (improper production of blood cells)/leukemia or non-Hodgkin's lymphoma have occurred. To date, 25 percent of treated patients have conceived offspring after the completion of treatment. Among 24 of the patients whose disease progressed (four with early stage and 20 with advanced stage disease), 16 (67 percent) were treated successfully with second-line therapy and the majority of relapses were successfully treated secondarily.

The average observation time in the study was 5.7 years for early stage and 6.9 years for advanced stage patients. Major acute toxicities were grade 3 to 4 neutropenia (abnormally low level of a particular white blood cell that kills bacteria) and constipation.

"In our study, the Stanford V and radiation therapy regimen was encouragingly effective, with preservation of fertility in this disease involving young patients," said Sandra J. Horning, M.D., of Stanford University and lead author of the study. "We believe these results merit further testing in a large randomized trial such as one sponsored by the National Cancer Institute in the U.S. and Canada.”

A Multicenter Experience with Single Agent Bortezomib in Non-Hodgkin's Lymphoma Reveals Marked Differences in Sub-Type Sensitivity to Proteasome Inhibition [Abstract 607]

Studies of the various cancers and even sub-types of the same cancer have discovered dramatically different responses to treatment. In this study, researchers found similar results studying the utility of the targeted chemotherapy treatment bortezomib in patients with non-Hodgkin's lymphoma.

An average of four cycles of treatment were administered at doses of 1.5mg/m2 to 51 patients, all but one of whom had received prior treatment: 19 patients with follicular lymphoma (FL); 23 with mantle cell lymphoma (MCL); five patients with small lymphocytic lymphoma (SLL); and four with marginal zone lymphoma (MZL).

The overall response rate in the study was 55 percent, though the team noted considerable variability in response rates and time to response among the subtypes. In the SLL group, only one of five patients experienced partial remission, though it was achieved by all four patients in the MZL group. Of the 23 patients with MCL, the response rate was 56 percent, and in the FL group, the response rate was 60 percent, including one complete response and one unconfirmed complete response.

The most common grade 3 toxicity experienced was lymphopenia (low lymphocyte blood cell count), and three patients experienced grade 3 sensory neuropathy (loss of sensation).

“These results clearly demonstrate the potential for a novel drug, bortezomib, in treating certain kinds of non-Hodgkin's lymphoma,” said Owen A. O’Connor, M.D., Ph.D., of Memorial Sloan-Kettering Cancer Center and lead author of the study. “Importantly, it helps to clarify the differences in response among patient with different sub-types of lymphoma, which may provide clues into how best to tailor targeted therapies for our patients.”

The sub-types of lymphoma in this study are caused by cancerous B-cell lymphocytes, the cells which produce antibodies to fight infections in the body. Follicular lymphoma is a systemic disease characterized by a follicular pattern of growth throughout the body.

Mantle cell lymphomas are derived from separate areas of the lymph node and are characteristically associated with resistance to chemotherapy. Small lymphocytic lymphoma presents with extensive lymph node enlargement and bone marrow involvement. In contrast, marginal zone lymphomas occur both in lymph nodes and in glands throughout the body (e.g. gastrointestinal tract, thyroid, and parathyroid, often times appearing in the spleen as well). Many of these cancers are considered indolent lymphomas (except mantle cell lymphoma), which are typically incurable, chronic diseases.

The American Cancer Society predicts that there will be nearly 55,000 new cases of non-Hodgkin's lymphoma (NHL) in this country in 2004, and that more than 19,000 people will die of the disease. More than nine out of 10 cases of NHL occur in adults. Hodgkin's disease, a less common form of lymphoma, will be diagnosed in nearly 8,000 people in the U.S. this year.

The American Society of Hematology 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.

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