Lenalidomide Plus Hypomethylating Agent as a Treatment Option in Acute Myeloid Leukemia With Recurrent Genetic Abnormalities—AML With inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

Merz, Lauren E.; Perissinotti, Anthony J.; Marini, Bernard L.; Burke, Patrick W.; Crouch, A. D.; Erba, Harry P.; Bixby, Dale

doi:10.1016/j.clml.2019.09.615

Cited by 3 publications

(5 citation statements)

References 17 publications

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“…13 We reported single agent activity of lenalidomide in AML patients with isolated trisomy 13 9,29 and another brief report demonstrated clinical activity of lenalidomide in combination with hypomethylating agents in AML patients with inv(3). 30 Due to the low frequency of these abnormalities in AML, lenalidomide clinical trials including the present study lack the statistical power to analyze individual karyotypic abnormalities.…”

Section: Discussionmentioning

confidence: 88%

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: 88%

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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“…HMA decreases methylation leading to increased expression of tumor suppressor genes and improved control of the malignancy. 12,19 HMA are FDA approved for the treatment of MDS in adult patients. In pediatrics, in this setting, they are given off-label.…”

Section: Discussionmentioning

confidence: 99%

“…Hematologic malignancies have known hypermethylation expression, which silences tumor suppressor genes. HMA decreases methylation leading to increased expression of tumor suppressor genes and improved control of the malignancy 12,19. HMA are FDA approved for the treatment of MDS in adult patients.…”

Section: Discussionmentioning

confidence: 99%

“…They are seen in younger patients and are associated with a poor prognosis and poor response to standard chemotherapy. 12 There are a few case reports in the literature describing myeloid neoplasms that developed in patients actively receiving treatment for ALL and unfortunately resulted in the death of the patients, demonstrating the high-risk nature of rapid onset t-MDS. [13][14][15] Hispanic patients have an increased risk of death from AML compared with non-Hispanic whites.…”

Section: Discussionmentioning

confidence: 99%

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A Pediatric Case of Treatment-related Myelodysplastic Syndrome While on Therapy for Pre-B Acute Lymphoblastic Leukemia

McElroy

Myers

Flatt

2023

Journal of Pediatric Hematology/Oncology

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Background: Treatment-related myelodysplastic syndrome (t-MDS) is a rare late effect of cancer therapy. After alkylating agents, this typically occurs years after completion of therapy. Treatment of t-MDS in pediatrics is an allogeneic stem cell transplant, however, the prognosis remains poor. Observations: This case demonstrates t-MDS developing in a patient receiving treatment for pre-B acute lymphoblastic leukemia. This patient was treated with a combination of hematopoietic stem cell transplant and hypomethylating agents. Conclusions: These agents should be considered for use in patients with t-MDS, before transplant to limit additional chemotherapy and as maintenance therapy post-transplant to reduce the risk of relapse.

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“… 45 Notwithstanding, the use of lenalidomide has been suggested as a possible adjunct to hypomethylating agents in the treatment of inv(3)/t(3;3) AML patients. 46 …”

Section: Discussionmentioning

confidence: 99%

Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia

et al. 2021

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Deregulation of the EVI1 proto-oncogene by the GATA2 distal hematopoietic enhancer (G2DHE) is a key event in high-risk acute myeloid leukemia carrying 3q21q26 aberrations (3q-AML). Upon chromosomal rearrangement, G2DHE acquires characteristics of a super-enhancer and causes overexpression of EVI1 at 3q26.2. However, the transcription factor (TF) complex of G2DHE remains poorly characterized. The aim of this study was to unravel key components of G2DHE-bound TFs involved in the deregulation of EVI1. We have identified several CEBPA and RUNX1 binding sites to be enriched and critical for G2DHE function in 3q-AML cells. Using ChIP-SICAP (ChIP followed by selective isolation of chromatin-associated proteins), a panel of chromatin interactors of RUNX1 and CEBPA were detected in 3q-AML, including PARP1 and IKZF1. PARP1 inhibition (PARPi) caused a reduction of EVI1 expression and a decrease in EVI1–G2DHE interaction frequency, highlighting the involvement of PARP1 in oncogenic super-enhancer formation. Furthermore, 3q-AML cells were highly sensitive to PARPi and displayed morphological changes with higher rates of differentiation and apoptosis as well as depletion of CD34 + cells. In summary, integrative analysis of the 3q-AML super-enhancer complex identified CEBPA and RUNX1 associated proteins and nominated PARP1 as a potential new therapeutic target in EVI1 + 3q-AML.

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Lenalidomide Plus Hypomethylating Agent as a Treatment Option in Acute Myeloid Leukemia With Recurrent Genetic Abnormalities—AML With inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM

Cited by 3 publications

References 17 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

A Pediatric Case of Treatment-related Myelodysplastic Syndrome While on Therapy for Pre-B Acute Lymphoblastic Leukemia

Identification of therapeutic targets of the hijacked super-enhancer complex in EVI1-rearranged leukemia

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