Current front-line regimens for previously untreated CLL typically include fludarabine (F) and rituximab (R), with or without cyclophosphamide, based on the results of single and multicenter trials demonstrating ORR of > 90% (CR 44–70%). Nevertheless, relapse is inevitable. In phase II studies lenalidomide (L) has shown ORR of 32–47% (CR 7–9%) in relapsed/refractory CLL. Given these findings, we proposed following FR therapy with L in previously untreated CLL patients to determine if CR rate and PFS can be improved upon. This study is the first of FR followed by L monotherapy in patients (pts) with untreated CLL.
Pts were eligible for this 2-stage Phase II study with untreated CLL requiring therapy, a performance status < 2, and adequate organ function. Pts received R 375 mg/m2 IV on D1 and F 25 mg/m2 IV D1–5 for 3 cycles. Pts with a CR/PR received 3 more cycles of FR followed by 3 cycles of L 5 mg po daily D1–21, which was increased to 10 mg with Cycle 2 if tolerated. Pts with stable (SD) or progressive disease (PD) after 3 cycles of FR were switched to L 5 mg po daily D1–21, which was increased to 10 mg with Cycle 2 if tolerated. Pts with SD or better after 3 cycles of L received another 3 cycles. Pts with PD were removed. The primary endpoint was the CR rate with FR followed by L monotherapy.
Of 22 pts on study, the median age was 61 years (range: 41–78), 68% were male, 27% were Rai Stage III/IV, 73% were CD38+, and 18% had a b-2 microglobulin level > 4. Of the 21 pts evaluated for ZAP-70, 36% had expression > 20%. Four pts had sole del 13q and 4 had normal cytogenetics. Of the remaining 14 patients, the majority had greater than 1 cytogenetic abnormality, 3 of which were del 17p and 7 del 11q. Pts completed a median of 10 cycles of therapy. The median time to response was 7 months (Range: 6–8 months). ORR with FR was 77.2% (CR 22.7%). With the addition of L in 15 patients, 3 pts (including both normal and complex cytogenetics) converted from a PR to CR, increasing the CR rate to 36.4%. ORRs by cytogenetics were: del 17p 33.3% (CR 0%), del 11q 85.7% (CR 28.5%), normal 75% (CR 25%), and del 13q 100% (CR 50%). L was unable to produce a response in the two pts refractory to FR. As shown in Fig 1, the estimated median progression-free survival was 34.4 months. One pt developed breast cancer and one pt developed Hodgkin's lymphoma after completing FR alone. The most common > Grade 3 adverse events were neutropenia, lymphopenia, and leucopenia. Less frequent >Grade 3 adverse events included thrombocytopenia, neutropenic fever, infection, and anemia. One pt suffered a fatal septic shock. The most common reasons for withdrawing from study were rash and fatigue.
In our single-institution study of FR followed by L in untreated CLL, we were unable to achieve the previously reported CR rates with fludarabine-based regimens, nor were we able to reach our statistical endpoint of a CR of 48% in order to proceed to stage II. Our data were likely inferior as the majority of our pts were CD38 positive and half had poor-risk cytogenetics. L monotherapy appeared to improve the quality of response in pts with a response to FR. This regimen is currently being studied in the North American Intergroup trial (CALGB 10404).
Off Label Use: Lenalidomide has not yet been approved for treatment of CLL. It has shown preliminary efficacy as a single agent in CLL in the relapsed refractory setting. We are investigating it's efficacy in the front line setting. Jamshed:Celgene: Speakers Bureau. Broome:Alexion: Speakers Bureau. Cohen:Teva: Honoraria; Amgen: Honoraria. Cheson:Celgene: Consultancy; Genentech: Consultancy.
Asterisk with author names denotes non-ASH members.