Phase I trial of dose escalation with growth factor support in patients with previously untreated diffuse aggressive lymphomas: Determination of the maximum-tolerated dose of ProMACE-CytaBOM

Purpose: The aim of this study was to determine the maximum-tolerated dose (MTD) of cyclophosphamide, doxorubicin, etoposide, prednisone, bleomycin, cytarabine, methotrexate, and leucovorin (ProMACE-CytaBOM) when the myelotoxic drugs cyclophosphamide, doxorubicin, etoposide, and cytarabine are escalated. Patients and Methods: Thirty-eight eligible patients with diffuse aggressive non-Hodgkin's lymphoma were treated on a phase I trial of dose escalation using the ProMACE-CytaBOM regimen and granulocyte-macrophage colony-stimulating factor (GM-CSF; Schering, Kenilworth, NJ). Patients were treated with recombinant (r)GM-CSF 10 μg/kg/d subcutaneously from day 9 to 19. Twenty-seven patients had stage IV disease, four had stage III, and seven had bulky stage II. Half of the patients had bone marrow involvement. The median age was 45 years. Results: We found that the MTD was 200% for the escalated drugs in this regimen (although we never escalated above the MTD or defined by dose-limiting toxicity) and that the normalized dose-intensity (NDI; defined as the ratio of the received dose-intensity to the 100% dose- intensity of ProMACE-CytaBOM) decreased with each cycle and was lower for the day-8 drug (cytarabine) than for the day- 1 drugs. The complete response (CR) rate was 66%, and 92% of patients who achieved CR are alive without disease with a median follow-up time for survival of 3.6 years. Conclusion: The MTD of cyclophosphamide, doxorubicin, etoposide, and cytarabine in the ProMACE- CytaBOM regimen given with growth factor support is 200%, and this dose should be tested in larger phase II trials.