Dose Escalation of Lenalidomide in Relapsed or Refractory Acute Leukemias

Division of Hematology, The Ohio State University and The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA.
Journal of Clinical Oncology (Impact Factor: 18.43). 10/2010; 28(33):4919-25. DOI: 10.1200/JCO.2010.30.3339
Source: PubMed


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.
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.
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.
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.

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Available from: Jason Chandler, Jul 28, 2015
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    • "A phase 1 study in relapsed/refractory AML patients also indicated that lenalidomide can be tolerated up to 50 mg daily, but there were no CR's in the del5q population. Those that did respond had low presenting white cell counts suggesting limited efficacy as monotherapy in proliferative disease [8] Additionally, the Nordic group had similar findings when they assessed lenalidomide monotherapy up to 20 mg daily in a phase 2 study for MDS/AML patients with any form of chromosome 5 abnormality and noted no response in patients with TP53 mutation [9]. More recently a phase 1 study of sequential therapy with azacitidine and lenalidomide has identified an alternative approach capable of inducing haematological improvement and complete cytogenetic remissions, although has significant haematological toxicity [10]. "
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    ABSTRACT: Patients with high risk myelodysplasia (HR-MDS) and acute myeloid leukaemia (AML) with chromosomal changes involving deletion of the long arm of chromosome 5 (del5q), especially with complex karyotype, rarely have a durable response to combination chemotherapy. In the subgroup with monosomal karyotype there are no long term survivors (Fang et al., 2011) [1]. Recent experience indicates that the incidence of del5q in AML is ~20–30%, with only 20–25% of patients achieving complete remission (CR) (Farag et al., 2006) [2]. Additionally, therapy has significant toxicity, with induction death rates ~20% even in younger patients (Juliusson et al., 2009) [3]. This lack of efficacy provides the clinical rationale for combination/sequential therapy with Lenalidomide and combination chemotherapy. Dose dependent haematological toxicity is the major safety concern with such a combination protocol. Therefore we conducted a phase 2 study, AML Len5 (ISRCTN58492795), to assess safety, tolerability and efficacy of lenalidomide monotherapy, followed by lenalidomide with intensive chemotherapy in patients with primary/relapsed/refractory high risk MDS or AML with abnormalities of chromosome 5.
    Leukemia Research Reports 08/2013; 2(2):70–74. DOI:10.1016/j.lrr.2013.07.003
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    • "Interestingly, 2 of 4 patients who had relapsed after an allogeneic stem cell transplant developed acute graft versus host disease of the skin and durable CR. Toxicities included fatigue and infection, but high dose lenalidomide was relatively well-tolerated.41 SWOG conducted a phase II clinical trial for untreated elderly patients with 5q deletion with or without additional cytogenetic abnormalities. "
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    Clinical Medicine Insights: Oncology 05/2012; 6:205-17. DOI:10.4137/CMO.S7244
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    ABSTRACT: There are a significant number of patients diagnosed with acute leukemia who either fail to achieve remission or who relapse thereafter. Challenges in treating this patient population include accurately assessing prognosis of disease and whether remission can be achieved; assessing the ability of patients to tolerate aggressive salvage therapies; choosing a salvage therapy that is most likely to succeed; and identifying suitable patients for hematopoietic stem cell transplantation. Despite the development of a variety of new investigational therapies, relapsed or refractory acute myeloid Leukemia remains a difficult clinical problem. Clinicians will need to consider all currently available approaches, including cytotoxic chemotherapy, targeted agents, and allogeneic stem cell transplantation, to optimize outcomes.
    04/2011; 2(2):73-82. DOI:10.1177/2040620711402533
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