A Phase II Trial of Pulse Dosing Lenalidomide: 3 Weeks On 3 Weeks off in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma.

Abstract 3427

Poster Board III-315

Lenalidomide (L) trials in relapsed chronic lymphocytic leukemia (CLL) have shown promising results when the drug was given continuously or with short interruptions. Here we present data from a phase II clinical trial (ClinicalTrials.gov Identifier: NCT00465127) in which L was given for 3 weeks followed by a 3 week drug-free period. This dosing scheme was devised based on the hypothesis that immune stimulatory effects might be more effective when L is pulsed and to determine whether an extended recovery period would reduce toxicities, especially myelosuppression. This single center, investigator initiated trial, enrolled patients with CLL or small lymphocytic lymphoma, who had relapsed after standard of care therapy, had a neutrophil count >500/ul and a platelet count >20,000/ul. The primary endpoint of the study was response after 4 cycles of L. Patients with at least a partial response were allowed to receive up to 4 additional cycles. The starting dose for the first 10 patients was 20 mg daily; it was then lowered to 10 mg daily because of toxicities observed in other L trials for CLL. A dosage increase was allowed after cycle 2 if blood counts permitted. TLS prophylaxis with allopurinol was mandated during cycle 1-3. Deep venous thrombosis (DVT) prophylaxis was not mandated unless risk factors were present. Ibuprofen and corticosteroids were allowed to treat inflammatory symptoms. The planed accrual goal has been reached (27 patients). Patient characteristics were: median age 64 years (36-78), median number of prior therapies was 3 (range 1-7), 14 patients (52%) were in Rai stage III-IV, 14 patients (52%) had del 17p, 18 patients (67%) had bulky disease, 12 out of 22 patients (55%) were ZAP70+, and in 13 of 18 patients (72%) the CLL clone expressed unmutated immune globulin VH genes (>98% germline). 26 patients received at least 1 cycle of therapy (range 2-8) and could be evaluated for toxicity, 1 patient never started treatment. Toxicities included Gr 3/4 neutropenia in 20 patients (77%) that worsened with cumulative cycles, 3 patients (12%) developed febrile neutropenia and G-CSF was given to 20 patients (77%), mostly in later cycles; Gr 3/4 thombocytopenia in 8 patients (31%); and DVTs (Gr 3) in 5 patients (19%). A cytokine release syndrome (CRS), that includes reactions labeled as tumor flare syndrome, was observed in 19 patients (73%) in cycle 1, including Gr 3/4 reactions in 5 patients (19%). The CRS recurred in 11 (42%), 5 (19%) and 3 patients (12%) in cycles 2, 3, and 4 respectively. No case of tumor lysis syndrome was observed. Non-neutropenic infections were seen in 13 patients (50%), mainly Gr 1/2, but 1 patient died from S. pneumoniae sepsis at the end of cycle 4. CD4 lymphopenia Gr 3/4 occurred in 9 patients (35%) and one patient with Gr 4 developed CMV colitis. 18 patients received at least 4 cycles of L and were evaluable for response: 6 (33%) had partial response (PR), 9 (50%) stable disease, and 3 (17%) progressive disease. 5 of 6 patients with PR (84%) had a del 17p and bulky disease. Once treatment was stopped, duration of response was short (median 3.5 months, range 1-13). 6 patients (26%) could not complete 4 cycles of L; 2 because of autoimmune complications, 3 because of side effects, and 1 because of PD in cycle 3. In summary, L cycled 3 weeks on, 3 weeks off induced responses, all partial, in 33% of relapsed CLL patients, comparable to previous studies using other dosing strategies. We observed remarkably good activity in patients with 17p deletion and bulky nodal disease. Unfortunately, pulse dosing of L did not lead to reduced toxicities and myelosuppression remained a major concern and was worsening with cumulative cycles. Notable additional toxicities of L in CLL indentified in this study included CD4 lymphopenia, in one case complicated by CMV colitis, and a 19% incidence of DVTs. Once L was discontinued, the duration of response was short, suggesting a need for continued therapy in patients who are able to tolerate the drug.