Successful Management (Mgt) of Hyperkalemia Associated with Tumor Lysis Syndrome (TLS) in Refractory Chronic Lymphocytic Leukemia (CLL) Patients (pts) Receiving Flavopiridol on an Active Pharmacologically Derived Schedule.

Introduction: Flavopiridol, a synthetic flavone with marked clinical efficacy in refractory high risk CLL, can cause overwhelming TLS with hyperkalemia. Accrual to a National Cancer Institute (NCI) sponsored phase 1 trial of flavopiridol (NCI 5746) was held for TLS with uncontrolled hyperkalemia in 2 of 3 pts at the cohort 2 dose. An algorithm for hyperkalemia mgt was instituted, and accrual resumed. An additional 14 pts were treated with dose level 1 (30mg/m² 30-min IV bolus followed by 4 hr IV infusion of 30 mg/m² weekly x 4 every 6 wks for up to 6 cycles). This regimen had marked activity (43% PR) and improved safety. A third cohort with dose escalation to 50 mg/m² for the 4 hr infusion in pts with <50% disease reduction after 1 cycle was initiated. We report the mgt of hyperkalemia in these 19 pts in cohort 3.

Methods: Potentially nephrotoxic drugs were held. The 1^st cycle and 1st dose of the 2nd cycle were given in-patient (inpt). Premedications included allopurinol and calcium acetate. Inpatients (Inpts) received IV alkalinization for 10 hr prior to flavopiridol, and rasburicase 0.15 mg/kg 2 hr prior to flavopiridol. Serum monitoring was done pretreatment, after the loading dose, hourly during and for 4 hr after flavopiridol for inpts (hourly for 2–3 hr afterwards for outpts). Serum monitoring was more frequent if potassium (K) levels exceeded 5.0 mmol/L. Rapid, accurate result reporting (less than 30 min from draw) was achieved with use of a critical care laboratory. Serum K levels were managed accordingly.

Results: To date 19 pts have received 116 inpt doses (range 1–6/pt) of flavopiridol and 78 outpt doses (range 3–11/pt). Out of 194 infusions, 7 resulted in hyperkalemia which required hemodialysis/CVVHD; 2 occurred in 1 pt at the start of cycle 1 and upon dose escalation. All inpt doses required interventions in addition to premedications to prevent hyperkalemia. Incidence of hyperkalemia as rated by NCI Common Toxicity Criteria V 3.0 was low. Hyperkalemia incidence in 116 inpt doses was: grade (gr) 1, 0.086% (N=10) gr 2, 0.026% (N=3); gr 3, 0.008% (N=1); gr 4, 0.04% (N=5). Similarly, outpt hyperkalemia was uncommon. Of 78 outpt doses only 14% (N=11) resulted in gr 1 hyperkalemia and only 1 pt required admission for IV fluids and monitoring. The hyperkalemia mgt algorithm for 78 outpt doses required 44% (N=35) to have pre-treatment Kx, 61% (N=48) to have additional Kx, and 29% (N=19) to have IV interventions.

Conclusion: Aggressive monitoring and adherence to this hyperkalemia algorithm during flavopiridol therapy has reduced the incidence of hyperkalemia and the need for hemodialysis. The safety of this highly active treatment for resistant, high risk CLL has improved with the algorithm, so that outpt treatment is now feasible. Further development of flavopiridol in this indication is warranted.