Lenalidomide and Rituximab in Combination As Initial Treatment of Chronic Lymphocytic Leukemia: Initial Results of a Phase II Study

Background.

Lenalidomide (Len) is an immunomodulatory drug with single agent activity in patients (pts) with treatment-naïve (TN) CLL, (overall response rate (ORR) 56-65%, Chen JCO 2011, Ferrajoli Blood 2011). Given the encouraging results of the combination of Len and rituximab (R) in relapsed CLL, we explored this combination as initial therapy. TN pts could derive greater benefit than relapsed pts from Len + R given their less compromised immune function.

Methods.

Fifty-eight pts were enrolled between 01/2012 and the present time. All patients had treatment indications per IWCLL 2008 criteria, WHO performance status ≤2 and adequate hepatic and renal function. Patients with HIV, hepatitis B or C infection were excluded.

Treatment consisted of R 375 mg/m² IV given weekly for 4 weeks then monthly during months (mo) 3-12 and Len 10 mg PO/day from day 9 for 24 mo. Allopurinol 300 mg PO daily was given for the first 2 weeks. No pts received antibiotic or DVT prophylaxis. Use of growth factors was allowed according to ASCO guidelines. Responses were assessed (2008 IWG criteria) at mo 3, 6 and every 6mo thereafter.

Results.

Forty-eight patients are evaluable for response and toxicity (8 too early, 1 lost to follow-up and 1 diagnosed with metastatic colonic adenocarcinoma within 1 week of study entry). Median age was 66 yrs (42-79). 29 (59%) pts were ≥age 65. 22 pts (46%) had Rai stage III-IV disease. Median β₂M level was 3.8 mg/dL (1.4-10.5). 24/37 pts (65%) had unmutated IGHV gene and 31 pts (65%) expressed ZAP-70. 4 pts (8%) had del(17p) and 15 pts (32%) del(11q).

Forty pts responded (ORR 83%). 7 pts (14.6%) achieved CR (1 MRD negative) and 33 (68.8%) achieved PR (including 7 nodular PRs). Median time to CR was 11mo (range 5-27). 5 pts discontinued therapy before the 3mo evaluation (4 due to toxicity and 1 due to unrelated co-morbidities). Six pts discontinued between 3 and 6mo (4 for refractory disease and 2 for toxicity after achieving PR). ORR was similar for patients with mutated and unmutated IGHV gene (85 vs 83%, p=0.96), age ≥65 and <65 (85 v 82%, p=0.8) and those with β₂M <4.0 vs ≥4.0 (89 vs 75%, p=0.19). No difference in ORR was observed according to FISH; 3 of 4 pts (75%) with del(17p),11/15 (73%) with del(11q) and 25/28 (89%) of pts with other FISH characteristcs responded, p=0.38. There was a trend toward inferior ORR for patients with complex metaphase cytogenetics (≥3 distinct abnormalities) compared to pts without (2/6 = 33% v 88%, p=0.052). Given the small number of events, subgroup analysis could not be performed for time to treatment failure (TTF) and survival endpoints.

47 pts are alive; one died from pneumonia 3mo after treatment discontinuation. Median TTF and survival have not been reached in evaluable pts at a median follow up of 11mo (range 3-30). (figure)

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The most common treatment-related hematological adverse event was neutropenia [grade (G) 3 in 11 pts (23%) and G4 in 13 (27%)]. G3 thrombocytopenia occurred in 6 pts (13%) and G3 anemia in 4 pts (8%). G3-4 infectious episodes occurred in 5 pts (10%) and other G3 non-hematologic toxicities were uncommon (tumor lysis syndrome, pulmonary embolism (PE), rash and rituximab infusion reaction were each experienced by 1 pt). Ten pts discontinued therapy due to toxicities: persistent G2 rash in 4 pts, G2 DVT in 2 pts, G3 neutropenia in 2 pts and G3 PE, G2 recurrent infections and G2 fatigue in 1 pt, respectively). Pts ceasing therapy due to toxicity received a median of 4 courses of treatment (range 2-18). Median time to progression or next treatment after cessation of Len+R was 2.8mo (0-14).

Median baseline IgG was 654mg/dL (range 216-1510). There was no significant change in IgG from baseline to 6 or 12mo and a trend toward an increased IgG at 24mo, median %change 13.5%, p=0.062.

Conclusions.

Len + R achieves high ORR, comparing favorably with our historical Len monotherapy cohort. Similar efficacy was seen in older pts and in pts with unfavorable baseline characteristics, with the potential exception of patients with complex cytogenetics. Treatment was equally well tolerated in younger and older pts. Myelosuppression was frequently observed, but serious infections were uncommon. An increase in IgG levels was observed in pts undergoing Len monotherapy following completion of rituximab infusions.