Speaker: Jeffrey E. Lancet, MD, Assistant Professor of Medicine, James P. Wilmot Cancer Center, Rochester School of Medicine and Dentistry, and Admitting Physician, Strong Memorial Hospital, Rochester, New York.

Interim results from a phase 2 clinical trial indicate that tip-farnab (Zarnestra™, Johnson & Johnson), a novel farnesyl transferase inhibitor, has beneficial activity in previously untreated poor-risk patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS).

Farnesyl transferase inhibitors, which competitively block farnesyl protein transferase, are being developed and tested across a wide range of refractory acute leukemias. In this study, patients with poor-risk AML, MDS, or chronic myelo-monocytic leukemia (CMML), were eligible.
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A total of 104 patients—94 with AML, four with MDS, and six with CMML—received tipfarnib 600 mg twice daily for 21 days, followed by a one- to three-week recovery period. Up to four cycles of the drug were permitted in patients with CRs. The primary endpoint was the overall response rate; secondary endpoints included toxicity rates and the determination of various molecular genetic and chemical correlates.

In the 92 patients who were evaluable for response, the overall response rate (RR + PR) was 33%. In patients older than

75 years of age, the overall response rate was 36%, with 26% having CRs and 10% having PRs. Overall, CRs occurred in 19 patients (21%) of this population. The median duration of response in the patients with CRs was 5.8 months.

The median overall survival was eight months for all patients. In the responders (CR + PR), however, the overall survival rate was not reached, with more than 60% of patients still alive at 15 months. In the nonresponders, the median overall survival was five months. Nine patients died during the study. The only serious drug-related adverse event was grade 4 toxicity, manifested mainly as neutropenic infection in 12 of 96 patients (13°%).

Arsenic Trioxide in Myelodysplastic Syndrome

Speaker: Norbert Vey, MD, Hematologist, Department of Hematology, Institut Paoli-Calmette, Marseille, France, and Spokesperson for the Groupe-Francais des Myelodysplasies, France.
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Preliminary results from a phase 2 clinical study suggest that an outpatient arsenic trioxide (Trisenox®, Cell Therapeutics, Inc. [CTI]) regimen is safe, well tolerated, and effective in patients with myelodysplastic syndrome (MDS).

Arsenic trioxide was given as a one-hour intravenous infusion, with a loading dose of 0.30 mg/kg per day for five days and a maintenance dose of 0.25 mg/kg per day twice a week for 15 or more weeks as an outpatient treatment. Disease assessment was performed every eight weeks.

The primary study objective was to determine the percentage of lower-risk patients who achieved major hematologic improvement after arsenic trioxide treatment and the percentage of higher-risk patients who achieved a complete or a partial remission or a major hematologic response after treatment. According to modified International Working Group criteria, the response must be maintained for 56 or more days.

A total of 82 patients with MDS were enrolled in the study; 74 patients (27 with a lower risk and 47 with a higher risk) were evaluable for response. Treatment with arsenic trioxide resulted in major or minor hematologic responses in almost 25% of patients with low-risk and high-risk myelodysplasia, and an additional 30 high-risk patients had stable disease for at least two months. Among the evaluable patients, 16 (22%), including 10 higher-risk and six lower-risk patients, achieved definite hematologic responses, with nine major and one minor responses in the higher-risk patients and three major and three minor responses in the lower-risk patients.

Responses were observed across all hematologic lineages in higher-risk patients and in two lineages in lower-risk patients, including major and minor erythroid, platelet, and neutrophil lineages. Eight of the patients with hematologic responses became transfusion-independent; two additional patients decreased their dependence on transfusions by 50%. Responses to arsenic trioxide were durable, lasting from 59 to 322 days during the study. The median duration of response was 107 days.

Renal Impairment with Multiple Myeloma Therapy

Speaker: Tahir Latif, MD, Fellow in Hematology/Oncology, Cleveland Clinic Myeloma Program, The Cleveland Clinic Foundation, Cleveland, Ohio.

An analysis of the relationship between renal impairment and bisphosphonate therapy, as part of a treatment regimen under study in patients with multiple myeloma, suggests that there was no difference in the incidence of renal impairment in patients who were receiving combination therapy with thalidomide (Thalomid®, Celgene) and bisphosphonate therapy with either zoledronic acid (Zometa®, Novartis) or pamidronate (Aredia®, Novartis). Although previous studies had shown a similar 1% incidence of renal impairment in multiple myeloma patients receiving either zoledronic acid or pamidronate as bisphosphonate therapy, a possible adverse interaction between thalidomide and zoledronic acid has been suggested, resulting in a higher incidence of renal impair-ment—up to 20%—in these patients. suhagra

To elucidate this relationship between thalidomide and bis-phosphonates, investigators included all 80 patients with multiple myeloma who were enrolled in a phase 2 trial in a separate analysis to evaluate the safety and toxicity of lipo-somal doxorubicin (Adriamycin®), vincristine, and dexa-methasone (Decadron®, Merck) in combination with thalido-mide with three months of follow-up. Early in the trial, two patients died of myocardial infarction and progressive disease, respectively, and were excluded.

The decision to initiate monthly bisphosphonate therapy was made by the treating physician. In 75 evaluable patients, 31 received pamidronate, 26 received zoledronic acid, and 18 received no bisphosphonate therapy. Eleven of the 75 evalu-able patients developed renal impairment during the study. Of these patients, four of the 31 were taking pamidronate, five of the 26 were taking zoledronic acid, and two of the 18 had no exposure to bisphosphonate therapy.

There was no overall difference in the prevalence of renal impairment between patients with newly diagnosed disease and previously treated patients or between the type of bisphosphonates used. Renal impairment was related to progressive disease in five patients, to dehydration or infection in two patients, and to bisphosphonate therapy in the remaining four patients.
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Because most of the episodes of renal impairment were multifactorial, it is possible that aggressive treatment of confounding factors (such as infection, dehydration, and progression of disease) might prevent permanent renal dysfunction. Renal impairment, which was considered to be solely related to bisphosphonate therapy, almost always improved after patients discontinued taking the offending bisphospho-nate and were switched to an alternative agent.

Category: Diseases / Tags: Hematology, Lymphoma, Pregnancy Loss, Tipfarnab

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