Phase 1 Trial of Flavopiridol and Lenalidomide In Patients with Previously Treated Chronic Lymphocytic Leukemia (CLL)

As a result of the previously demonstrated efficacy of the cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, in heavily pre-treated patients (pts) with bulky adenopathy and adverse cytogenetics, we conducted a phase I trial to determine the dose limiting toxicity (DLT) and maximum tolerated dose (MTD) of combined therapy. Both agents are active in pts with relapsed/refractory cytogenetically high risk CLL, utilize different novel mechanisms of action, and do not deplete T-cells, leading to the potential development of a well tolerated regimen for pts with del (17p13.1) and del (11q22.3) with greater efficacy and less infectious toxicity than observed with currently accepted fludarabine or alemtuzumab combinations.

Pts with histologically confirmed CLL relapsed after at least 1 prior therapy with a WBC ≤ 150,000/mm³, ANC ≥ 1000/mm³, platelets ≥ 30,000/mm³, and creatinine ≤ 1.5 mg/dL were enrolled. Treatment consisted of flavopiridol alone (30 mg/m² bolus + 50 mg/m² 4-hour continuous IV infusion (CIVI)) days 1, 8, and 15 of cycle 1 to decrease the pre-treatment disease burden and minimize the potential risks of simultaneous tumor flare and tumor lysis syndrome (TLS) with concurrent lenalidomide and flavopiridol. Starting in cycle 2, flavopiridol 30 mg/m² bolus + 30 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 28 days. All pts received 20 mg of dexamethasone 30 minutes prior to flavopiridol dosing and 4 mg of dexamethasone 24 hours after flavopiridol to minimize cytokine release symptoms.

Twenty-one pts (12 males) with a median age of 59 (range 42–71) previously treated with a median of 4 prior therapies (range 1–10) were enrolled. All pts received prior fludarabine, 9 pts were fludarabine refractory, no pts previously received flavopiridol, and 1 pt was previously treated with lenalidomide. Pts had Rai stage I/II (n=6) or IV (n=15) disease and 13 pts had bulky adenopathy ≥ 5 cm. Thirteen pts had del (17p13.1) and 8 pts had del (11q22.3). Seventeen pts completed two or more cycles of therapy (median 3, range 2–8), receiving 2.5 mg (n=6), 5.0 mg (n=7), and 7.5 mg (n=4) of lenalidomide. Four pts completed only one cycle of therapy and were removed prior to receiving lenalidomide due to progressive disease (n=2), TLS requiring dialysis (n=1), and grade 4 thrombocytopenia (n=1). 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 neutropenia (86%), diarrhea (62%), transaminitis reversible in ≤ 7 days (57%), anemia (38%), thrombocytopenia (38%), hyperglycemia (38%), infection without neutropenia (24%, cellulitis in 1 pt, pneumonia in 3 pts, and catheter-associated in 1 pt), febrile neutropenia (14%, unknown source in 2 pts and pneumonia in 1 pt), TLS not requiring dialysis (14%), and fatigue (14%). Grade 1 tumor flare occurred in 1 pt and did not require additional steroids or cessation of lenalidomide. In 15 evaluable pts who completed 1 or more cycles of combined lenalidomide and flavopiridol, partial responses were observed in 7 pts, including 4 pts with del (17p13.1), 3 pts with del (11q22.3), 5 fludarabine-refractory pts, 3 pts with bulky lymphadenopathy ≥ 5 cm, and 1 pt previously treated with lenalidomide.

Combined flavopiridol and lenalidomide is well tolerated, with activity in pts with previously treated, cytogenetically high-risk CLL. The MTD has not been reached and dose escalation continues.

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

Blum: Celgene: Research Funding. Off Label Use: The efficacy of the cyclin dependent kinase inhibitor, flavopiridol, and the immunomodulatory agent, lenalidomide, are under investigation in CLL.