Dose Escalation of Lenalidomide in Relapsed or Refractory Acute Leukemias

Abstract

Purpose Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes with deletion 5q. We report results of a phase I dose-escalation trial of lenalidomide in relapsed or refractory acute leukemia. Patients and Methods Thirty-one adults with acute myeloid leukemia (AML) and four adults with acute lymphoblastic leukemia (ALL) were enrolled. Lenalidomide was given orally at escalating doses of 25 to 75 mg daily on days 1 through 21 of 28-day cycles to determine the dose-limiting toxicity (DLT) and maximum-tolerated dose (MTD), as well as to provide pharmacokinetic and preliminary efficacy data. Results Patients had a median age of 63 years (range, 22 to 79 years) and a median of two prior therapies (range, one to four therapies). The DLT was fatigue; 50 mg/d was the MTD. Infectious complications were frequent. Plasma lenalidomide concentration increased proportionally with dose. In AML, five (16%) of 31 patients achieved complete remission (CR); three of three patients with cytogenetic abnormalities achieved cytogenetic CR (none with deletion 5q). Response duration ranged from 5.6 to 14 months. All responses occurred in AML with low presenting WBC count. No patient with ALL responded. Two of four patients who received lenalidomide as initial therapy for AML relapse after allogeneic transplantation achieved durable CR after development of cutaneous graft-versus-host disease, without donor leukocyte infusion. Conclusion Lenalidomide was safely escalated to 50 mg daily for 21 days, every 4 weeks, and was active with relatively low toxicity in patients with relapsed/refractory AML. Remissions achieved after transplantation suggest a possible immunomodulatory effect of lenalidomide, and results provide enthusiasm for further studies in AML, either alone or in combination with conventional agents or other immunotherapies.

IMiDs mobilize acute myeloid leukemia blasts to peripheral blood through downregulation of CXCR4 but fail to potentiate AraC/Idarubicin activity in preclinical models of non del5q/5q- AML

“…The clinical efficacy of lenalidomide has been explored as either low-dose or high-dose lenalidomide as monotherapy 50-54 and in combination with azacitidine 55,56 for both newly diagnosed and relapsed/refractory AML. Overall, these clinical trials were somewhat disappointing with CRR as low as 11%–20% and remission duration below 5–7 months.…”

Low-dose lenalidomide plus cytarabine induce complete remission that can be predicted by genetic profiling in elderly acute myeloid leukemia patients

“…Intensive induction chemotherapy is often unsuitable. 1 High-dose lenalidomide is effective in AML, alone 2,3 or in combination with azacitidine. [4][5][6] Biomarkers that are able to predict response to lenalidomide would be extremely useful.…”

“…Bone marrow evaluation was performed after 1, 2, 4 and 6 cycles. Responding patients experiencing a non-hematological toxicity 42 WHO received reduced courses (lenalidomide (10 mg) once daily (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14], and cytarabine (10 mg, subcutaneously) twice daily (days 1-10)). All patients were hospitalized for the first cycle.…”

“…Fehninger showed that high-dose lenalidomide (HDL, 50 mg/day), when administered up to two sequential 28-day cycles, is able to induce CR/CRi in 30% of untreated, older AML patients. 2 However, responses were restricted to patients with low circulating blast count (o1000 ml) at diagnosis, limiting this schedule to a minority. 2 Pollyea tested the efficacy of fixed dosage of azacitidine (75 mg/m 2 /day i.v.…”

“…2 However, responses were restricted to patients with low circulating blast count (o1000 ml) at diagnosis, limiting this schedule to a minority. 2 Pollyea tested the efficacy of fixed dosage of azacitidine (75 mg/m 2 /day i.v. for 7 days) followed by sequential lenalidomide (5, 10, 25 and 50 mg/day orally for 21 days) in a 42-day cycle, in 42 AML patients aged X60 years.…”