Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS

Hemato-Oncology, Dutch-Belgian; Sakk, Swiss Grp Clinical Canc Res; Ossenkoppele, Gert J.; Breems, Dimitri; Stuessi, Georg; Norden, Yvette van; Bargetzi, Mario; Biemond, Bart J.; Borne, Peter A. von dem; Chalandon, Yves; Cloos, Jacqueline; Deeren, Dries; Fehr, Martin; Gjertsen, Bjørn Tore; Graux, Carlos; Huls, Gerwin; Janssen, Jeroen; Jaspers, Aurélie; Jongen‐Lavrencic, Mojca; Jongh, Eva de; Klein, Saskia K.; Klift, Marjolein van der; Kooy, Marinus van Marwijk; Maertens, Johan; Micheaux, L.; Poel, Marjolein W. M. van der; Rhenen, Anna van; Tick, Lidwine W.; Valk, Peter J.M.; Vekemans, Marie Christiane; Velden, Walter J.F.M. van der; Weerdt, Okke de; Pabst, Thomas; Manz, Markus G.; Löwenberg, Bob

doi:10.1038/s41375-020-0725-0

Cited by 20 publications

(19 citation statements)

References 24 publications

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“…Historically, remission rates with salvage chemotherapy have been reported at 16%-25%. 4 In this phase one study, we found that lenalidomide given for 21 days in combination with 21 Although the combination was well tolerated, addition of lenalidomide did not improve the CR/CRi rate, event-free survival or OS. Given the importance of sequencing these drugs, future studies would be warranted to investigate the impact of pretreatment with higher doses of lenalidomide.…”

Section: Discussionmentioning

confidence: 80%

“…Lenalidomide enhanced apoptotic priming in vivo and dynamic BH3 profiling assay was suggested as a biomarker to predict response to combination. Embarking on this encouraging mechanistic data, a recent phase two study of 222 newly diagnosed older AML patients compared standard 7 + 3 induction chemotherapy with or without lenalidomide at a dose of 20 mg daily on days 1‐21 21 . Although the combination was well tolerated, addition of lenalidomide did not improve the CR/CRi rate, event‐free survival or OS.…”

Section: Discussionmentioning

confidence: 99%

“…12 The drug was also tested in the first-line setting as a single agent or in combination with other chemotherapy regimens for previously untreated AML. [13][14][15][16][17][18][19][20][21] Given the clinical activity of single agent lenalidomide in AML and preclinical studies suggestive of synergy with chemotherapy, we conducted a phase one study of lenalidomide in combination with cytarabine and idarubicin re-induction chemotherapy, to evaluate the safety and tolerability of this combination in patients with R/R AML and high-risk MDS.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, lenalidomide in combination with MEC re‐induction therapy in R/R AML resulted in 34% (12/35) CR rate with MTD of 50 mg daily 12 . The drug was also tested in the first‐line setting as a single agent or in combination with other chemotherapy regimens for previously untreated AML 13‐21 …”

Section: Introductionmentioning

confidence: 99%

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A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

et al. 2020

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Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) have poor outcomes and hematopoietic cell transplantation (HCT) is the only curative treatment. New targeted therapies improved survival in select patients with specific mutations, however management of patients without these molecular alterations is an unmet need. We conducted a phase one study of lenalidomide in combination with cytarabine/idarubicin salvage chemotherapy in patients with R/R AML and high-risk myelodysplastic syndromes. A total of 33 patients were enrolled in the study (30 AML, 3 MDS), and treated at three dose levels with 3 + 3 design. Doselimiting toxicity (DLT) was seen in eight patients, including four hematologic DLTs. The most commonly observed non-hematologic serious adverse events were febrile neutropenia, rash, sepsis and renal injury. Dose level −1, consisting of 25 mg/d lenalidomide D1-21, 1 g/m 2 cytarabine D5-8, and 8 mg/m 2 idarubicin D5-7 was determined to be the maximum tolerated dose. Note, 15/33 (45%) of patients were able to receive pre-planned 21 days of lenalidomide. Overall, 18 patients achieved complete remission (CR) (n = 14) or CR with incomplete count recovery (CRi) (n = 4) with total CR/CRi rate of 56%. The 1-year and 2-year overall survival (OS) were 24% and 10%, respectively. Among responders, 10/18 underwent allogeneic HCT and had a 1-year OS of 40%. There was no molecular pattern associated with response. These data demonstrate that the combination had clinical activity in R/R AML. This regimen should be further investigated for patients who relapsed after HCT, and as a bridge therapy to HCT. (ClinicalTrials. gov identifier: NCT01132586).

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Section: Discussionmentioning

confidence: 80%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

et al. 2020

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“…Compared with conventional intensive chemotherapy, the treatment protocol used by the authors produced higher hematologic CR rates in patients with a very poor cytogenetics risk but the response duration was short. Moreover, the Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK) conducted a randomized phase 2 study [ 42 ] with or without lenalidomide at a dose of 20 mg/day 1–21. In the second cycle, patients received cytarabine 1000 mg/m 2 twice daily on days 1–6 with or without lenalidomide (20 mg/day 1–21).…”

Section: Lenalidomidementioning

confidence: 99%

Immunomodulatory Drugs in Acute Myeloid Leukemia Treatment

Piccolomo

Schifone

Strafella

et al. 2020

Cancers

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Immunomodulatory drugs (IMiDs) are analogs of thalidomide. They have immunomodulatory, antiangiogenic and proapoptotic properties and exert a role in regulating the tumor microenvironment. Recently IMiDs have been investigated for their pleiotropic properties and their therapeutic applications in both solid tumors (melanoma, prostate carcinoma and differentiated thyroid cancer) and hematological malignancies. Nowadays, they are applied in de novo and relapsed/refractory multiple myeloma, in myelodysplastic syndrome, in del5q syndrome with specific use of lenalidomide and B-cell lymphoma. Several studies have been conducted in the last few years to explore IMiDs possible use in acute myeloid leukemia treatment. Here we report the mechanisms of action of IMiDs in acute myeloid leukemia and their potential future therapeutic application in this disease.

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Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort

Brune

Stüssi²,

Lundberg

et al. 2021

Ann Hematol

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This translational study aimed at gaining insight into the effects of lenalidomide in acute myeloid leukemia (AML). Forty-one AML patients aged 66 or older of the Swiss cohort of the HOVON-103 AML/SAKK30/10 study were included. After randomization, they received standard induction chemotherapy with or without lenalidomide. Bone marrow biopsies at diagnosis and before the 2nd induction cycle were obtained to assess the therapeutic impact on leukemic blasts and microenvironment. Increased bone marrow angiogenesis, as assessed by microvessel density (MVD), was found at AML diagnosis and differed significantly between the WHO categories. Morphological analysis revealed a higher initial MVD in AML with myelodysplasia-related changes (AML-MRC) and a more substantial decrease of microvascularization after lenalidomide exposure. A slight increase of T-bet-positive TH1-equivalents was identifiable under lenalidomide. In the subgroup of patients with AML-MRC, the progression-free survival differed between the two treatment regimens, showing a potential but not significant benefit of lenalidomide. We found no correlation between the cereblon genotype (the target of lenalidomide) and treatment response or prognosis. In conclusion, addition of lenalidomide may be beneficial to elderly patients suffering from AML-MRC, where it leads to a reduction of microvascularization and, probably, to an intensified specific T cell-driven anti-leukemic response.

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Lenalidomide added to standard intensive treatment for older patients with AML and high-risk MDS

Abstract: Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. Leukemia

Cited by 20 publications

References 24 publications

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

A phase I study of lenalidomide plus chemotherapy with idarubicin and cytarabine in patients with relapsed or refractory acute myeloid leukemia and high‐risk myelodysplastic syndrome

Immunomodulatory Drugs in Acute Myeloid Leukemia Treatment

Effects of lenalidomide on the bone marrow microenvironment in acute myeloid leukemia: Translational analysis of the HOVON103 AML/SAKK30/10 Swiss trial cohort

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