A phase II study was conducted to evaluate the safety and efficacy of fludarabine, cytarabine (ara-C), cyclophosphamide, cisplatin and GM-CSF (FACPGM) treatment in patients with Richter's syndrome (RS), refractory prolymphocytic leukemia (PLL) or refractory non-Hodgkin's lymphoma (NHL). Twenty-two patients with RS, refractory PLL, or refractory NHL were entered into this trial between March 1997 and February 2001. Median age was 62 years (42-74); 77% were over 60 years of age. Histologic diagnosis was large cell NHL transformation in 15 patients with CLL, immunoblastic transformation of CLL in one, refractory PLL in three, and refractory NHL in three patients. Treatment consisted of fludarabine 30mg/m2 (days 1-3), ara-C 0.5g/m2 (days 3-4), cyclophosphamide 250 mg/m2 (days 2-4), cisplatin 15 mg/m2 IV CI (days 1-4) with GM-CSF 250 microg/m2 from day 5 to recovery of neutrophils and antibiotic prophylaxis. Patients with response were to receive a maximum of six cycles of therapy. Eighteen patients were evaluable for response; one patient achieved a complete remission (5%), 12 stable disease/no response (67%) and five patients had progressive disease (28%). The median survival was 2.2 months (range, 1-19); the median failure-free survival was 1.5 months (range, 0.5-18.6). Grade III/IV toxicities were as follows: anemia in 62% of cycles; leucopoenia in 66%; granulocytopenia in 90%; thrombocytopenia in 83%; hyperbilirubinemia in 14%; hyperuricemia in 17%; hyponatremia in 17%; hypokalemia in 14%; hypophosphatemia in 10%; hypoalbulinemia in 14%; hypocalcemia in 7%; and hypercalcemia in 3%. One (3%) patient developed cardiac failure. Forty-one percent of the cycles were complicated with fever, 34% with non-neutropenic fever, and 55% cycles with infections (fungal 31%; bacterial 57%; HSV 6%; VZV 6%). FACPGM had very limited activity and significant toxicity in a cohort of patients with heavily pretreated refractory lymphoproliferative disorders.