Preliminary Results of a Phase I Study of Lenalidomide in Relapsed Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia (CLL) is a disease characterized by both humoral and cellular immune defects. Lenalidamide is an immunomodulatory drug that has clinical activity in multiple myeloma and myelodysplastic syndrome. Although the exact mechanism of action is unknown, lenalidomide has been reported to promote cellular and innate immune activation; interfere with the tumor microenvironment, angiogenesis, and cytokine production; and induce the tumor suppressor gene SPARC. Two prior phase II studies in patients with relapsed/refractory CLL using higher doses of lenalidomide have shown clinical activity (Chanan-Khan et al J CLin Oncol 2006; Ferrajoli et al Blood 2008), although 58% of patients developed tumor flare and two patients developed acute tumor lysis in the former and 27% of patients developed tumor flare in the latter. In addition, a phase II study of lenalidomide in previously untreated, symptomatic CLL patients (Chen et al ASH 2008) demonstrated clinical activity using lower doses of lenalidomide after acute tumor lysis was seen at higher doses. We present preliminary data of a phase I dose escalation study of lenalidomide to determine the maximum tolerated dose (MTD), toxicities and preliminary efficacy in patients with relapsed CLL.

Eligibility criteria included patients with a diagnosis of B-cell CLL or SLL requiring therapy, who previously received treatment with one or more chemotherapy regimens, had an absolute lymphocyte count < 200,000, and an ECOG performance status 0-2. Patients were treated with lenalidomide daily days 1-21 of a 28 day cycle at a starting dose of 25 mg.

Three patients were enrolled at the starting dose of 25 mg and have previously been reported (Andritsos et el J Clin Oncol 2009). One patient was treated off study per protocol. Three of these patients experienced significant tumor flare, resulting in one death, and the fourth patient developed grade 3 neutropenia with sepsis. The protocol was amended to reduce the dose of lenalidomide and include an intrapatient dose escalation (Table 1). The starting dose was 2.5 mg. Fourteen patients have been accrued since the amendment. Eight males and six females were enrolled with median age of 57 (range 37-73) and median number of prior therapies of 4.5 (range 1-9). Dose limiting toxicity (DLT) occurred in 3 of 6 patients treated in the cohort receiving 2.5 mg daily week 1, 5 mg week 2, and 7.5 mg week 3 and thereafter. Dexamethasone prophylaxis (4mg/day) was administered for 7 days. DLT included grade 4 thrombocytopenia in one patient, grade 4 neutropenia in one patient, grade 3 neutropenia with pneumonia in one patient and grade 2 tumor flare in one patient. All of these patients were heavily pre-treated. Non-DLT hematologic toxicities included grade 3 anemia (2) and grade 3-4 neutropenia (3). Non-DLT hematologic toxicity included grade 2 tumor flare (1), grade 3 hemolysis (1), grade 3 pneumonia (3) and grade 3 fatigue (1). Two patients experienced tumor flare at the 2.5 mg dose level prior to initiating corticosteroids on day 3. To date, ten patients are evaluable for response. One patient treated at the highest dose level who was subsequently dose reduced to 5 mg had a partial response, and 2 patients had stable disease. 5 patients treated at 5 mg continuous dosing (the MTD) had stable disease. 2 patients had progressive disease at continuous dosing of 5 mg and 7.5 mg. Evidence of B-cell activation in vivo was observed including up-regulation of multiple NF-κB target genes. In one patient with lenalidomide induced tumor flare and associated hypercalcemia, treatment-induced tumor PTH-RP production was noted that reversed with cessation of therapy.

Lenalidomide can induce tumor flare even at very low doses in patients with active CLL. The MTD of lenalidomide in heavily pre-treated CLL patients is 2.5 mg orally daily week one escalating to 5 mg orally daily for subsequent weeks with continuous dosing. We have limited our dose escalation of lenalidomide to less heavily treated patients and accrual continues. Our laboratory data suggest that B-cell activation may correlate with development of tumor flare and other toxicities including hypercalcemia observed in a subset of CLL patients.

Off Label Use: Lenalidomide, an immunomodulatory agent approved in MM and MDS, is used in this phase I clinical study to determine maximum tolerated dose and toxicities in CLL. Blum:Celgene: Research Funding. Andritsos:Celgene: Research Funding.