Activity of Combined Flavopiridol and Lenalidomide in Patients with Cytogenetically High Risk Chronic Lymphocytic Leukemia (CLL): Updated Results of a Phase I Trial,

The cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, are active in heavily pre-treated CLL patients (pts) with bulky adenopathy and adverse cytogenetics, although dose escalation of these two agents has been limited by tumor lysis syndrome (TLS) and tumor flare. Furthermore, these agents do not deplete T-cells, and combination therapy may result in greater efficacy and less infectious toxicity than observed with fludarabine or alemtuzumab combinations. Methods: We conducted a phase I trial of combined flavopiridol and lenalidomide in pts with CLL relapsed after at least 1 prior therapy, WBC < 150,000/mm³, ANC > 1000/mm³, platelets > 30,000/mm³, and creatinine < 1.5 mg/dL. Treatment consisted of flavopiridol alone, 30 mg/m² bolus + 30–50 mg/m² 4-hour continuous IV infusion (CIVI) days 1, 8, and 15 of cycle 1. Starting in cycle 2, flavopiridol 30 mg/m² bolus + 30–50 mg/m² 4-hour CIVI days 3, 10, and 17 was combined with lenalidomide 2.5, 5.0, 7.5, 10, 15, or 25 mg days 1–21 every 35 days. All pts received 20 and 4 mg of dexamethasone 30 minutes prior to and 24 hours after flavopiridol, respectively, to minimize cytokine release symptoms. Pegfilgrastim was administered on day 18 of cycles 2–8. Results : Thirty pts (18 males) with a median age of 60 (range 42–74) previously treated with a median of 3 prior therapies (range 1–10) were enrolled. All pts received prior fludarabine and 40% were fludarabine refractory. Seventy-three percent of patients were Rai stages III-IV, 60% pts had bulky adenopathy > 5 cm, 60% pts had del(17p13.1), 37% pts had del(11q22.3), and 83% pts had a complex karotype. Twenty-five pts completed two or more cycles of therapy (median 3.5, range 1–8). Five pts completed only one cycle of therapy and were removed prior to receiving lenalidomide due to progressive disease (n=2), TLS requiring dialysis (n=2), and grade 4 thrombocytopenia (n=1). Pts received 2.5 mg (n=6), 5.0 mg (n=7), 7.5 mg (n=4), and 10 mg (n=3) of lenalidomide with 30 mg/m² bolus + 30 mg/m² 4-hour CIVI flavopiridol and 5 patients have received 10 mg of lenalidomide with 30 mg/m² bolus + 50 mg/m² 4-hour CIVI flavopiridol. DLT consisting of grade 3–4 transaminitis persisting > 7 days occurred in 2 pts treated with 2.5 mg (n=1) and 5.0 mg of lenalidomide (n=1), respectively. Grade 3–4 toxicities consisted of thrombocytopenia (60%), diarrhea (57%), transient transaminitis (47%), neutropenia (47%), hyperglycemia (47%), infection (43%, pneumonia in 5 pts, upper respiratory tract infection in 2 pts, cellulitis in 1 pt, herpes simplex stomatitis in 1 pt, oral candidiasis in 1 pt, catheter-associated in 1 pt, and febrile neutropenia without a source in 2 pts), hypokalemia (37%), anemia (33%), hypophosphatemia (33%), hypocalcemia (17%), hyperkalemia (17%), TLS requiring dialysis (7%), tumor flare (3%), and rash (3%). In 23 evaluable pts who completed 1 or more cycles of combined lenalidomide and flavopiridol, partial responses were observed in 13 pts (57%), including 7 pts with del(17p13.1), 6 pts with del(11q22.3), 9 pts with complex cytogenetics, 5 fludarabine-refractory pts, and 6 pts with bulky lymphadenopathy. Six pts were able to proceed to allogeneic transplant after 1–3 cycles, and 4 of these pts remain in remission. Median PFS and OS are 7 months (range 0–24 months; 95% CI 5, 11) and 23 months (range 0–27 months; 95% CI 13, 27), respectively. No significant differences have been observed in the single agent and combination PK parameters (AUC, Cmax, T ½, and Clearance) of lenalidomide and flavopiridol. Conclusions: Combined flavopiridol and lenalidomide is well tolerated without increased risks of TLS or tumor flare, with significant activity in pts with bulky, cytogenetically high-risk CLL. This combination regimen could be utilized to de-bulk high risk pts prior to stem cell transplantation or prior to other oral therapies. The MTD has not been reached and dose escalation continues at a lenalidomide dose that exceeds the single agent MTD in CLL of 5 mg (Maddocks et al, Blood 114: abstract 3445, 2009). Future evaluation of continued maintenance lenalidomide after initial combination therapy is planned.

This trial is supported by NCI 1R21 CA133875, NCI P50-CA140158, NCI K23 CA109004, NCI U01 CA076576, LLS SCOR 7080–06, and the D. Warren Brown Foundation.

Off Label Use: Flavopiridol and lenalidomide are off-label for the treatment of CLL.