Combination Lenalidomide and Azacitidine: A Novel Salvage Therapy in Patients Who Relapse After Allogeneic Stem-Cell Transplantation for Acute Myeloid Leukemia
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PURPOSE: Salvage options for patients who relapse after allogeneic stem-cell transplantation (allo-SCT) for acute myeloid leukemia (AML) and myelodysplasia (MDS) remain limited, and novel treatment strategies are required. Both lenalidomide (LEN) and azacitidine (AZA) possess significant antitumor activity effect in AML. Administration of LEN post-transplantation is associated with excessive rates of graft-versus-host disease (GVHD), but AZA has been shown to ameliorate GVHD in murine transplantation models. We therefore examined the tolerability and activity of combined LEN/AZA administration in post-transplantation relapse. PATIENTS AND METHODS: Twenty-nine patients who had relapsed after allo-SCT for AML (n = 24) or MDS (n = 5) were treated with sequential AZA (75 mg/m 2 for 7 days) followed by escalating doses of LEN on days 10 to 30. Dose allocation and maximum tolerated dose (MTD) estimation were guided by a modified Bayesian continuous reassessment method (CRM). RESULTS: Sequential AZA and LEN therapy was well tolerated. The MTD of post-transplantation LEN, in combination with AZA, was determined as 25 mg daily. Three patients developed grade 2 to 4 GVHD. There was no GVHD-related mortality. Seven of 15 (47%) patients achieved a major clinical response after LEN/AZA therapy. CD8+ T cells demonstrated impaired interferon-γ/tumor necrosis factor–α production at relapse, which was not reversed during LEN/AZA administration. CONCLUSION: We conclude LEN can be administered safely post-allograft in conjunction with AZA, 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 MTD assessment and provided additional flexibility. Combined LEN/AZA therapy represents a novel and active salvage therapy in patients who had relapsed post-allograft.
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In 2020, pomalidomide was approved by the FDA for the treatment of Kaposi sarcoma, an endothelial cell-derived solid tumour caused by human herpesvirus 8 infection, based on data from a phase I/II trial that demonstrated an ORR of 73% in patients with newly diagnosed Kaposi sarcoma.
“In 2020, pomalidomide was approved by the FDA for the treatment of KS, an endothelial cell-derived solid tumour caused by human herpesvirus 8 (HHV8) infection110, based on data from a phase I/II trial that demonstrated an ORR of 73% in patients with newly diagnosed KS22.”
From Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide (2021) · cites this paper as [110]
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Cancer therapies based on targeted protein degradation — lessons learned with lenalidomide
Jan, M., Sperling, A. S., & Ebert, B. L. (2021) · Nature Reviews Clinical Oncology · doi:10.1038/s41571-021-00479-z · Cited by 137 · see citing works
- Authors
- Craddock, C., Slade, D., De Santo, C., Wheat, R., Ferguson, P., Hodgkinson, A., Brock, K., Cavenagh, J., Ingram, W., Dennis, M., Malladi, R., Siddique, S., Mussai, F., & Yap, C.
- Affiliations
- Novartis (Switzerland) (CH)
- University of Birmingham, Birmingham, United Kingdom
- Corresponding author
- Craddock, Charles
- ORCID
- Venue
- Journal of Clinical Oncology
- Published
- 2019-03-01
- Volume
- 37
- Issue
- 7
- Pages
- 580-588
- ISSN
- 0732-183X (ISSN-L)
- 1527-7755
- PMC
- PMC6494237
- OpenAlex
- W2909224113
- Cited by
- 73
- References
- 30
- Citations by year
- 2026: 3 · 2025: 7 · 2024: 11 · 2023: 5 · 2022: 12 · 2021: 14 · 2020: 12 · 2019: 9
- FWCI
- 8.29
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by
- Locations
- Journal of Clinical Oncology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- University of Birmingham Research Portal (University of Birmingham) (submittedVersion, cc-by)
- Funders
- Celgene
- Cancer Research UK (C22436/A15958)
- Blood Cancer UK (13019)
- Imperial Experimental Cancer Medicine Centre
- Topics
- Health Sciences › Medicine › Hematology › Acute Myeloid Leukemia Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinoids in leukemia and cellular processes
- Keywords
- lenalidomide, azacitidine, salvage therapy, acute myeloid leukemia, myelodysplastic syndrome, relapse after allogeneic stem cell transplantation, graft-versus-host disease, T cell exhaustion, CD8+ T cells, interferon-gamma, TNF-α, maximum tolerated dose, combination therapy
- MeSH terms
- Lenalidomide, Adolescent, Adult, Aged, Antineoplastic Combined Chemotherapy Protocols, Azacitidine, Female, United Kingdom, Humans, Male, Middle Aged, Prospective Studies, Recurrence, Time Factors, Transplantation, Homologous, Leukemia, Myeloid, Acute, Salvage Therapy, Treatment Failure, Maximum Tolerated Dose, Stem Cell Transplantation, Young Adult
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