Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia

Molina, John C; Asare, Julie M.; Tuschong, Laura M.; West, Robert R.; Calvo, Katherine R.; Persky, Rebecca; Boyce, Alison M.; Hammoud, Dima A.; Holland, Steven M.; Hickstein, Dennis D.; Shah, Nirali N.

doi:10.1002/pbc.28865

Cited by 6 publications

(3 citation statements)

References 33 publications

(70 reference statements)

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“…Common mutations are those found in ≥3 patients in this study or >5% in other studies of myeloid malignancies. Mutations in patient 78 have also been described in Molina et al 67 NA indicates that WES was not performed (supplemental Table 1). BMT, bone marrow transplant.…”

Section: Resultsmentioning

confidence: 65%

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ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

et al. 2022

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GATA2 Deficiency patients harbor de novo or inherited germline mutations in the GATA2 transcription factor gene, predisposing them to myeloid malignancies. There is considerable variation in disease progression, even among family members with the same mutation in GATA2. We investigated somatic mutations in 106 patients with GATA2 Deficiency to identify acquired mutations that are associated with myeloid malignancies. Myelodysplastic Syndrome (MDS) was the most common diagnosis (~44%), followed by GATA2 bone marrow immunodeficiency disorder (G2BMID) (~37%). Thirteen percent of the cohort had GATA2 mutations but displayed no disease manifestations. There were no correlations between patient age or sex with disease progression or survival. Cytogenetic analyses showed a high incidence of abnormalities (~43%)- notably trisomy 8 (~23%) and monosomy 7 (~12%), but these changes did not correlate with lower survival. Somatic mutations in ASXL1 and STAG2 were detected in ~25% of patients, though these mutations were rarely concomitant. Mutations in DNMT3A were found in ~10% of patients. These somatic mutations were found similarly in G2BMID and MDS, suggesting clonal hematopoiesis in early stages of disease, before the onset of MDS. ASXL1 mutations conferred a lower survival probability and were more prevalent in female patients. STAG2 mutations also conferred a lower survival probability, but did not show a statistically significant sex bias. There was a conspicuous absence of many commonly mutated genes associated with myeloid malignancies, including TET2, IDH1/2, and the splicing factor genes. Notably, somatic mutations in chromatin-related genes and cohesin genes characterized disease progression in GATA2 Deficiency

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Section: Resultsmentioning

confidence: 65%

Section: Resultsmentioning

confidence: 65%

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

et al. 2022

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“…One patient with AML in first complete remission remains in complete remission nearly 4 years after URD HSCT. A 15‐year‐old with CMML received two cycles of venetoclax and decitabine pre‐HSCT; he remains in remission two years after HRD 12 . One asymptomatic patient with 10% myeloblasts and trisomy 8 on a routine screening bone marrow also was in remission following two cycles of venetoclax/decitabine and remains in remission nearly two years following URD HSCT.…”

Section: Resultsmentioning

confidence: 99%

Donor source and post‐transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency

et al. 2021

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Summary GATA2 deficiency was described in 2011, and shortly thereafter allogeneic hematopoietic stem cell transplantation (HSCT) was shown to reverse the hematologic disease phenotype. However, there remain major unanswered questions regarding the type of conditioning regimen, type of donors, and graft‐versus‐host disease (GVHD) prophylaxis. We report 59 patients with GATA2 mutations undergoing HSCT at National Institutes of Health between 2013 and 2020. Primary endpoints were engraftment, reverse of the clinical phenotype, secondary endpoints were overall survival (OS), event‐free survival (EFS), and the incidence of acute and chronic GVHD. The OS and EFS at 4 years were 85·1% and 82·1% respectively. Ninety‐six percent of surviving patients had reversal of the hematologic disease phenotype by one‐year post‐transplant. Incidence of grade III‐IV aGVHD in matched related donor (MRD) and matched unrelated donor recipients (URD) patients receiving Tacrolimus/Methotrexate for GVHD prophylaxis was 32%. In contrast, in the MRD and URD who received post‐transplant cyclophosphamide (PT/Cy), no patient developed grade III‐IV aGVHD. Six percent of haploidentical related donor (HRD) recipients developed grade III‐IV aGVHD. In summary, a busulfan‐based HSCT regimen in GATA2 deficiency reverses the hematologic disease phenotype, and the use of PT/Cy reduced the risk of both aGVHD and cGVHD.

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The spectrum of GATA2 deficiency syndrome

Hickstein

Calvo

2023

Blood

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Inherited or de novo germline heterozygous mutations in the gene encoding the transcription factor GATA2 lead to its deficiency; this results in a constellation of clinical features including infections with non-tuberculous mycobacterial, bacterial, fungal, and human papilloma virus infections, lymphedema, pulmonary alveolar proteinosis, and myelodysplasia. The onset, or even the presence, of disease is highly variable, even in kindreds with the identical mutation in GATA2. The clinical manifestations result from the loss of a multilineage progenitor which gives rise to B-lymphocytes, monocytes, Natural Killer (NK) cells and dendritic cells, leading to cytopenias of these lineages, and subsequent infections. The bone marrow failure is typically characterized by hypocellularity; dysplasia may be absent or subtle, but typically evolves into multilineage dysplasia with prominent dysmegakaryopoiesis, followed in some instances by progression to myeloid malignancies, specifically myelodysplastic syndrome (MDS), acute myelogenous leukemia (AML), and chronic myelomonocytic leukemia (CMML). The latter three malignancies often occur in the setting of monosomy 7, trisomy 8, and acquired mutations in ASXL1 or STAG2. Importantly, myeloid malignancy may represent the primary presentation of disease without recognition of other syndromic features. Allogeneic hematopoietic stem cell transplantation (HSCT) results in reversal of the phenotype. There remain important unanswered questions in GATA2 deficiency including: 1) why do some family members remain asymptomatic despite harboring deleterious mutations in GATA2, 2) what are the genetic changes that lead to myeloid progression, 3) what causes the apparent genetic anticipation, and 4) what is the role of preemptive HSCT.

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Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia

Cited by 6 publications

References 33 publications

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

ASXL1 and STAG2 are common mutations in GATA2 deficiency patients with bone marrow disease and myelodysplastic syndrome

Donor source and post‐transplantation cyclophosphamide influence outcome in allogeneic stem cell transplantation for GATA2 deficiency

The spectrum of GATA2 deficiency syndrome

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