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Combination Azacitidine and Lenalidomide as Salvage Therapy for Relapsed AML After Allogeneic Stem Cell Transplantation

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Key Points

  • The maximum tolerated dose of posttransplantation lenalidomide in combination with azacitidine was determined to be 25 mg daily.
  • Major clinical response was observed in 7 of 15 patients receiving at least 3 cycles of azacitidine/lenalidomide.

In a phase I trial reported in the Journal of Clinical Oncology, Craddock et al found evidence that the sequential combination of azacitidine and lenalidomide may be an effective salvage therapy in patients with acute myeloid leukemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT). As noted by the investigators, lenalidomide given posttransplantation is associated with excessive rates of graft-vs-host disease, with there being preclinical evidence that azacitidine may reduce this complication.

The study included 29 patients who had relapsed after allo-SCT for AML (n = 24) or myelodysplasia (MDS, n = 5). Patients received azacitidine (75 mg/m2 for 7 days) followed by escalating doses of lenalidomide (2.5–35 mg) on days 10 to 30. Dose allocation and maximum tolerated dose estimation were guided by use of a modified Bayesian continuous reassessment method (CRM) dose-toxicity model. The maximum tolerated dose was defined as the dose level with an estimated dose-limiting toxicity rate closest to 20%.

Maximum Tolerated Dose and Responses

The maximum tolerated dose of posttransplantation lenalidomide in combination with azacitidine was determined to be 25 mg daily. Three patients developed grade 2 to 4 graft-vs-host disease, with no related mortality being observed.

Major clinical response was observed in 7 (47%) of 15 patients receiving at least 3 cycles of treatment, including 6 patients with AML and 1 with MDS. No correlation between dose of lenalidomide and response rate was observed. The response rate was 24% among 29 patients receiving at least 1 dose of azacitidine/lenalidomide. Median overall survival was 27 months in responders vs 10 months in nonresponders (P = .004).

CD8-positive T cells exhibited impaired interferon-γ/tumor necrosis factor-α production at relapse, with no reversal of this impairment being observed during azacitidine/lenalidomide treatment.

The investigators concluded, “We conclude [lenalidomide] can be administered safely postallograft in conjunction with [azacitidine], and this combination demonstrates clinical activity in relapsed AML/MDS without reversing biologic features of T-cell exhaustion. The use of a CRM model delivered improved efficiency in [maximum tolerated dose] assessment and provided additional flexibility. Combined [lenalidomide/azacitidine] therapy represents a novel and active salvage therapy in patients who had relapsed postallograft.”

Charles Craddock, MD, of the Centre for Clinical Haematology, Queen Elizabeth Hospital, Birmingham, is the corresponding author for the Journal of Clinical Oncology article.

Disclosure: The study was supported Bloodwise, Cancer Research UK and Cancer Research UK Cure Leukaemia, and Celgene. The study authors’ full disclosures can be found at jco.ascopubs.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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