Phase I/II Study of Lenalidomide, Intermediate Dose Dexamethasone and Low Dose Cyclophosphamide (RDC) for the Treatment of Patients with Primary Systemic Amyloidosis (AL).

Lenalidomide (R) is an IMiD with significant activity in patients with myeloma. Two recent series have shown that R, especially in combination with dexamethasone (D), is active in AL patients and can induce organ responses in one third of them. However, when R was administered at the standard dose of 25 mg PO QD it was associated with significant toxicity and almost all patients required dose reductions. Furthermore, there is evidence from myeloma trials that when R is combined with low dose D, early death and toxicity rates are improved. Finally, alkylating agents have activity in patients with AL. Based on the above we designed a phase I/II trial of lenalidomide, intermediate dose dexamethasone and low dose cyclophosphamide (RDC) in order to determine the maximum tolerated dose (MTD) and the hematologic and organ responses in patients with AL. Patients receive dexamethasone 20 mg days 1–4, cyclophosphamide is given on days 1–10 and lenalidomide on days 1–21 according to dose level (dose level 0: R 10 mg, C 50 mg, level 1: R 10 mg, C 100 mg, level 2: R 15 mg, C 100 mg, level 3: R 20 mg C 100mg, level 4:R 25 mg, C 100 mg). Patients are observed for 2 cycles of therapy for determination of Dose Limiting Toxicity (DLT). If no DLT is encountered in the first 3 patients at any dose level, 3 patients are enrolled at the next dose level. If >1 of 3 patients experience DLT, Maximum Tolerated Dose (MTD) is considered to have been exceeded. If 1 of 3 patients experiences DLT, 3 more patients are enrolled at the same dose level. If no more patients experience DLT (1 of 6), 3 patients are enrolled at the next dose level. If ≥ 2 of 6 patients experience DLT, MTD will be considered to have been exceeded. Patients with a creatinine ≤2.5 mg/dL and adequate hepatic function (total bilirubin <1.5 mg/dL, AST and ALT <2 x ULN or <5 x ULN if hepatic involvement is present) are enrolled. So far, 10 patients (6 previously untreated) have been included: 3 patients in dose level 0 and 7 patients in dose level 1. All patients receive DVT prophylaxis with aspirin 100 mg unless they are already on coumadine or LMWH for pre-existing DVT or other indications. No patient at dose level 0 experienced grade 3 toxicity. One patient in dose level 1 experienced grade 3 DVT; other toxicities were mainly hematologic (grade 2 thrombocytopenia and grade 3 neutropenia in one patient). Among 6 patients who are so far evaluable for hematologic response (3 in dose level 0 and 3 in dose level 1), 3 have achieved a PR (2 in dose level 0 and 1 in dose level 1). One patient, who started treatment at dose level 0, died due to progressive amyloidosis. The accrual in this study is ongoing, the MTD of the combination has not been reached and updated results will be presented at the meeting. On a compassionate basis, AL patients with a creatinine >2.5 mg/dL or on dialysis were treated with R at a dose adjusted according to their creatinine clearance (15 mg every other day for CrCl <30 ml/min, and for patients on dialysis 15 mg three times per week on the day after dialysis) with D 20 mg days 1–4 and C 50 mg days 1–10, every 28 days. Eight patients (two previously untreated) with severe renal failure (CrCl <30 ml/min), including 3 on dialysis, have been treated with RDC. Three patients received only 1 cycle of RDC and discontinued treatment due to toxicity (including one early death due to non-neutropenic infection and two due to fatigue grade 4). Other toxicities included fatigue grade 3 in 2 patients, grade 3 deterioration of renal function in 2 patients, diarrhea grade 3 in 2 patients, skin rash grade 3 in 1 patient, prolonged thrombocytopenia grade 3 in 1 patient. All but one patients who continued therapy required dose reduction of R. Four patients continue therapy with RDC with R at 10 mg three times per week and one at the initial dose of R (15 mg every other day) and have so far received 3–6 cycles. One patient on dialysis has a complete hematologic response with response of one affected organ (liver) and four have not reached yet criteria of hematologic response. The combination of R with intermediate dose D and low dose C appears feasible in patients with AL amyloidosis who have a creatinine less than 2.5 mg/dL and may induce hematologic responses. The completion of our study will define the MTD and the efficacy of this combination. However, in patients with severe renal impairment, R is associated with significant toxicity even when doses are adjusted for creatinine clearance according to published normogram.