Poly (ADP-ribose) polymerase-1 (PARP1) as a therapeutic target in acute myeloid leukemia and myelodysplastic syndrome.

Poly (ADP-ribose) polymerase-1 (PARP1) is a key mediator of various forms of DNA damage repair and plays an important role in the progression of several cancer types. The enzyme is activated by binding to DNA single-strand and double-strand breaks. Its contribution to chromatin remodeling makes PARP1 crucial for gene expression regulation. Inhibition of its activity with small molecules, leads to the synthetic lethal effect by impeding DNA repair in the treatment of cancer cells. At first PARP1 inhibitors (PARPi) were developed to target BRCA mutated cancer cells. Currently, PARPi are being studied to be used in a broader variety of patients either as single agents or in combination with chemotherapy, antiangiogenic agents, ionizing radiation, and immune checkpoint inhibitors. Ongoing clinical trials on olaparib, rucaparib, niraparib, veliparib and the most recent talazoparib show the advantage of these agents in overcoming PARPi resistance and underline their efficacy in targeted treatment of several hematologic malignancies. In this review, focusing on the crucial role of PARP1 in physiological and pathological effects in myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), we give an outline of the enzyme's mechanisms of action and its role in the pathophysiology and prognosis of MDS/AML and we analyze the available data on the use of PARPi, highlighting their promising advances in clinical application.

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Immune Therapies for Myelodysplastic Syndromes and Acute Myeloid Leukemia

Cancers ◽

10.3390/cancers13195026 ◽

2021 ◽

Vol 13 (19) ◽

pp. 5026

Author(s):

Sargam Kapoor ◽

Grace Champion ◽

Aparna Basu ◽

Anu Mariampillai ◽

Matthew J. Olnes

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Myelodysplastic Syndromes ◽

Myeloid Leukemia ◽

Molecular Mechanisms ◽

Checkpoint Inhibitors ◽

Hematologic Malignancies ◽

Suppressive Therapy ◽

Immune Therapies ◽

Acute Myeloid

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are hematologic malignancies arising from the bone marrow. Despite recent advances in treating these diseases, patients with higher-risk MDS and AML continue to have a poor prognosis with limited survival. It has long been recognized that there is an immune component to the pathogenesis of MDS and AML, but until recently, immune therapies have played a limited role in treating these diseases. Immune suppressive therapy exhibits durable clinical responses in selected patients with MDS, but the question of which patients are most suitable for this treatment remains unclear. Over the past decade, there has been remarkable progress in identifying genomic features of MDS and AML, which has led to an improved discernment of the molecular pathogenesis of these diseases. An improved understanding of immune and inflammatory molecular mechanisms of MDS and AML have also recently revealed novel therapeutic targets. Emerging treatments for MDS and AML include monoclonal antibodies such as immune checkpoint inhibitors, bispecific T-cell-engaging antibodies, antibody drug conjugates, vaccine therapies, and cellular therapeutics including chimeric antigen receptor T-cells and NK cells. In this review, we provide an overview of the current understanding of immune dysregulation in MDS and AML and an update on novel immune therapies for these bone marrow malignancies.

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Unique ethnic features of DDX41 mutations in patients with idiopathic cytopenia of undetermined significance, myelodysplastic syndrome, or acute myeloid leukemia

Haematologica ◽

10.3324/haematol.2020.270553 ◽

2021 ◽

Author(s):

Eun-Ji Choi ◽

Young-Uk Cho ◽

Eun-Hye Hur ◽

Seongsoo Jang ◽

Nayoung Kim ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Normal Karyotype ◽

Hematologic Malignancies ◽

Genetic Characteristics ◽

Male Predominance ◽

Korean Patients ◽

Acute Myeloid ◽

Undetermined Significance

DDX41 mutations are associated with hematologic malignancies including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), but the incidence in idiopathic cytopenia of undetermined significance (ICUS) is unknown. We investigated the incidence, genetic characteristics, and clinical features of DDX41 mutations in Korean patients with ICUS, MDS, or AML. We performed targeted deep sequencing of 61 genes including DDX41 in 457 patients with ICUS (n=75), MDS (n=210), or AML (n=172). The germline DDX41 mutations with causality were identified in 28 (6.1%) patients, of whom 27 (96.4%) had somatic mutations in the other position of DDX41. Germline origins of the DDX41 mutations were confirmed in all of the 11 patients who performed germline-based testing. Of the germline DDX41 mutations, p.V152G (n=10) was most common, followed by p.Y259C (n=8), p.A500fs (n=6), and p.E7* (n=3). Compared with non-mutated patients, DDX41-mutated patients showed male predominance, old age, normal karyotype, low leukocyte count, and hypocellular marrow at diagnosis. Three of the 4 ICUS patients with germline DDX41 mutations progressed to MDS. DDX41 mutations in Korean patients showed a high incidence and distinct mutation patterns, in that p.V152G was a unique germline variant. ICUS harboring germline DDX41 mutations may be regarded as a hereditary myeloid neoplasm. Germline DDX41 mutations are not uncommon and should be explored when treating the patients with myeloid malignancies.

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Salvaged Cord Blood Transplantation For 19 Patients With Progressive Hematologic Malignancies

Blood ◽

10.1182/blood.v122.21.5532.5532 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5532-5532

Author(s):

Sun Zimin ◽

Yao Wen ◽

Zheng Changcheng ◽

Tong Juan ◽

Liu Huilan ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Cord Blood ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Cord Blood Transplantation ◽

Hematologic Malignancies ◽

Refractory Anemia ◽

Blood Transplantation ◽

Acute Myeloid

Abstract Few clinical studies have investigated the role of salvaged unrelated cord blood transplantation (CBT) for progressive hematologic malignancies. The aim of this report is to identify the potential benefits of unrelated CBT in progressive hematologic malignancies.19 consecutive patients with progressive myeloid and lymphoid malignancies who received salvaged CBT following myeloablative conditioning regimens (12 TBI/CY/Ara-C, 6 Bu / CY / Ara-C, and 1 Bu /CY) from July 2005 to December 2012 were analyzed retrospectively. Of the 19 patients, 6 suffered from acute myeloid leukemia(AML), 5 acute lymphoid leukemia(ALL),：1 acute mixed lineage leukemia (AMLL), 1 myelodysplastic syndrome-refractory anemia with excess blasts(MDS-RAEB), 2 acute myeloid leukemia transformed from myelodysplastic syndrome, and 4 lymphoma, all of them in non-remission (NR) before transplantation. Median age of them were 13（range 6-32）years and median body weight were 45 (range 18–73 ) kg. All patients received 1 CBT unit ≤2 loci HLA-mismatched with the recipient. Infused TNC was 4.07（range 2.76-6.02）×107/kg and CD34+ stem cell 2.08（range 0.99-8.65）×105/kg. All patients were engrafted with neutrophil exceeded 0.5×109/L on median day +17（range 14-37d）and plt counts of＞20×109/L on median day +35 (range 17-70d). 10 patients (52.6%) experienced pre-engraftment syndrome (PES) and 3 (15.8%) patients progressed to acute GVHD. The incidence of Ⅱ-Ⅳ aGVHD and cGVHD were 10.5% and 21.1%. With a median follow up of 10(range 1-58) months，10 cases survived and 2 relapsed．The estimated 2 year overall survival (OS), disease-free survival (DFS) and non-relapse mortality (NRM) rate was 45.6%, 34.2% and 39.8%. Salvaged CBT might be a promising modality for treatment of progressive hematologic malignancies, even with high leukemia burden. Disclosures: No relevant conflicts of interest to declare.

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