BALTIMOREFludarabine (Fludara) and cyclophosphamide(Drug information on cyclophosphamide) are highly active agents for indolent lymphomas, but when given in combination, opportunistic infections such as Pneumocystis carinii pneumonia (PCP) and herpes zoster may be dose limiting.
A phase II trial has now shown that this combination can be given safely without lowering efficacy. Ian Flinn, MD, of Johns Hopkins University Oncology Center, presented the findings of the multicenter trial at the ASH meeting.
Lowering the Dose
Dr. Flinn pointed out that previous combination regimens including nucleoside analogs (such as fludarabine) have been marred by increased toxicity. A phase I ECOG study of fludarabine/cyclophosphamide in low-grade lymphoma by Hochester et al suggested good response rates at all dose levels.
Therefore, he said, we chose the lower dose to pursue in our phase II study, along with maximizing supportive care.
Dr. Flinn and his colleagues at Johns Hopkins and Walter Reed Army Medical Center felt that by lowering the dosages of cyclophosphamide and fludarabine and giving PCP prophylaxis, they could maintain the combinations efficacy while minimizing adverse events.
The phase II trial included 39 patients (median age, 53 years): 52% had follicular lymphoma; 25% had mantle cell lymphoma; and 20% had other lymphomas. Eligibility criteria included no previous malignancy or HIV infection and noncontiguous stage IIA-IV disease.
Patients were given fludarabine, 20 mg/m² on days 1 to 5; cyclophosphamide, 600 mg/m² on day 1; G-CSF (Neupogen) 5 µg/kg/d for 8 days until recovery; and TMP-SMX (Bactrim double-strength) by mouth twice a day on Monday, Wednesday, and Friday. The regimen was repeated every 28 days.
The patients were treated to best response or six cycles, Dr. Flinn said. Bone marrow transplant candidates received only four cycles.
Of 38 patients evaluable for response, results were as follows: follicular lymphoma, 63% complete response, 32% partial response; mantle cell, 36% complete response, 45% partial response; other, 50% complete response, 38% partial response.
Hematopoietic toxicity was mild, as were nausea, vomiting, and alopecia, Dr. Flinn said. Notable toxicities were cryptococcal pneumonia (one patient); unexplained focal seizures 30 days after the fourth chemotherapy cycle, which did not recur (one patient); grade 4 pulmonary toxicity (one patient); and secondary organ failure of uncertain etiology leading to death (one patient).
The researchers concluded that this combination produced a complete response rate in excess of that achieved using standard therapies, and that use of infectious disease prophylaxis and growth factor support led to an acceptable toxicity profile.