Lymphoma And Multiple Myeloma

Both G-CSF and GM-CSF have been tested in prospective, randomized trials in patients with lymphomas, in an effort to reduce morbidity and mortality associated with infectious complications, and to potentially improve response rates and therapeutic outcome. Results of an updated meta-analysis of 12 prospective, randomized, controlled (placebo or no prophylaxis) trials have recently been published. The findings support the use of G-CSF/GM-CSF, especially in older patients who are receiving treatment for non-Hodgkin's lymphoma. In the meta-analysis, the relative risk of febrile neutropenia (RR 0.74) and infection (0.74) were both reduced. Other potential study endpoints, such as antibiotic use, infection-related mortality, and overall outcome, were not affected.42

Recently, a pegylated, longer-acting version of G-CSF had been tested in a phase II randomized trial of patients receiving salvage chemotherapy for refractory non-Hodgkin's or Hodgkin's lymphomas. Chemotherapy consisting of ESHAP (etoposide, cisplatin, ARA-C and methylprednisolone) was followed by administration of filgrastim daily single dose of 5 ^g/kg versus pegfilgrastim given once 100 ^g/kg. The incidence and duration of grade 4 neutropenias were similar between the two groups, revealing equivalent effects of single administration of the pegylated compound versus a median of 11 injections of filgrastim.43 The concept of dose-dense chemotherapy is based on the assumption that, although rapid reduction of tumor mass promotes faster tumor regrowth, sensitivity to the effects of chemotherapy agents may also increase during such periods.44 Hence, the goal of this therapeutic strategy is to deliver chemotherapy in the shortest possible interval. To test this theory, the German High-Grade Lymphoma Study Group compared six cycles of CHOP (cyclophosphamide, doxoru-bicin, Vincristine, and prednisone) given either every 21 days, or every 14 days (this latter schedule was supported with G-CSF). These investigators also attempted to answer whether the addition of etoposide to CHOP would result in improved outcome. Based on this 2 X 2 factorial design, two parallel studies (in patients aged 60 or less vs patients aged over 60 years) were carried out. Patients receiving CHOP every 2 weeks were prescribed G-CSF for 10 days, starting on day 4, based on the expected high incidence of significant neutrope-nia. In patients aged over 60 years, complete response rates were higher (76.1% vs 60.1%) and relative risk reduction for event-free and overall survival was significantly greater (0.66, p = 0.003; 0.58, p < 0.001) in those treated on the dose-dense, every 2-week schedule. The addition of etoposide was associated with increased toxicity and no obvious benefit. Hence, further trials to expand and confirm the role of dose-dense delivery of CHOP are ongoing, and these studies are also incorporating rituximab into the treatment arms.11 The ASCO growth factor guidelines regarding both primary and secondary prophylaxis of neutropenia and, similarly, guidelines regarding chemotherapy-associated anemia, apply to patients with multiple myeloma.410 Evaluation of epoetin beta in a randomized, double-blind, controlled study in transfusion-dependent patients with multiple myeloma (the study also included patients with chronic lymphocytic leukemia and low-grade malignant lymphoma) revealed that transfusion-free and severe anemia-free survival were significantly better, with a risk reduction of 43% and 51%, respectively, in patients receiving epoietin beta at a dose of 150 IU/kg three times a week for a period of 16 weeks, versus control. Approximately 2/3 of patients receiving epoietin beta responded, versus 27% in the placebo group. Quality of life was also significantly improved and correlated with a rise of >2 g/dL of hemoglobin.41

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