Clinical, molecular, and prognostic comparisons between CCUS and lower-risk MDS: a study of 187 molecularly annotated patients

Li, Marissa; Binder, Moritz; Lasho, Terra L.; Ferrer, Alejandro; Gangat, Naseema; Al‐Kali, Aref; Mangaonkar, Abhishek A.; Elliott, Michelle; Pardanani, Animesh; Wolanskyj, Alexandra P.; Howard, Matthew T.; King, Rebecca; Shah, Mithun Vinod; Alkhateeb, Hassan B.; Begna, Kebede H.; Tefferi, Ayalew; Finke, Christy; Oliveira, Jennifer L.; Ketterling, Rhett P.; Olteanu, Horatiu; Patnaik, Mrinal M.

doi:10.1182/bloodadvances.2020003976

Cited by 32 publications

(31 citation statements)

References 15 publications

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“…These findings were consistent with previous observations that mutations in genes coding for splicing factors and epigenetic modulators were early events in the evolution of MDS 1,20. A recent clinical, molecular, and prognostic comparison study from Mayo Clinic demonstrated low-grade MDS patients were likely to carry more SF3B1 mutation and similar mutation distribution in TET2, DNMT3A, ASXL1, and SRSF2 compared with CCUS patients 21. Our study showed similar findings.…”

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confidence: 93%

Morphologic, immunophenotypic, and molecular genetic comparison study in patients with clonal cytopenia of undetermined significance, myelodysplastic syndrome, and acute myeloid leukemia with myelodysplasia‐related changes: A single institution experience

Gao

Hyter

Zhang

et al. 2022

Int J Lab Hematology

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Introduction Next‐generation sequencing (NGS) analysis showed clonal cytopenia of undetermined significance (CCUS) as an immediate precursor to myelodysplastic syndrome (MDS). Methods We evaluated and compared morphologic, multiparametric flow cytometry (MFC), and molecular genetic findings in patients with CCUS (n = 37), MDS (n = 75), and acute myeloid leukemia with myelodysplasia‐related changes (AML‐MRC, n = 24). Results CCUS patients showed variable MFC abnormalities including >2% CD34+ myeloblasts (5.8%), altered antigen expression on myeloblasts, monocytes, and granulocytes (1.2, 1.5, and 0.2/case), abnormal maturation of myeloblasts (45.8%), decreased hematogones (17.6%), and decreased side scatter (SSC) of granulocytes (11.4%). CCUS patients with high‐risk mutations showed significantly more MFC abnormalities. However, CCUS patients with >20% variant allelic fraction (VAF) did not show more MFC aberrations than the rest of the group. MDS patients showed significantly more MFC abnormalities compared with CCUS patients (p = 7.8E‐05–0.047). Low‐grade MDS patients showed significantly fewer MFC abnormalities compared with high‐grade MDS or AML‐MRC patients (p = 1.89E‐05–0.04). AML‐MRC patients showed significantly elevated blast counts, more antigen aberrations, decreased hematogones, and decreased SSC of granulocytes compared with CCUS patients (p = 2.0E‐05–0.01). CCUS patients carried predominantly TET2/DNMT3A/ASXL1 mutations. They harbored fewer mutations in gene coding splicing factors compared with MDS patients (p = .0001–.02) and fewer mutations in tumor suppressor and transcription factor genes compared with AML‐MRC patients (p = .0006–.02). Conclusions CCUS is an immediate precursor to low‐grade MDS. The progression from CCUS to MDS to AML‐MRC is a stepwise process that requires acquisition of mutations in splicing, transcription factor, and tumor suppressor genes with accumulations of additional MFC abnormalities.

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confidence: 93%

Morphologic, immunophenotypic, and molecular genetic comparison study in patients with clonal cytopenia of undetermined significance, myelodysplastic syndrome, and acute myeloid leukemia with myelodysplasia‐related changes: A single institution experience

Gao

Hyter

Zhang

et al. 2022

Int J Lab Hematology

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“…3 ), DNMT3A 7(14%), SRSF2 66(12%), RUNX1 4 (8%), and TP53 3 (6%). In contrast, the most common PVs in CCUS [ 9 ] were TET2 (21%), SRSF2 (12%), DNMT3A (7%), ZRSR2 (7%), and U2AF1 (6%) and the most common PV in t-MN were TP53 (26%), TET2 (8%), ASXL1 (7%), DNMT3A (6%), SRSF2 (4%) and IDH1 (4%). Thus, the genetic landscape of t-CC is distinct from t-MN as well as compared to the recently described cohort of CCUS patients [ 9 ].…”

Section: Resultsmentioning

confidence: 99%

“…The evidence of clonality in patients with otherwise unexplained cytopenia, impart a 17–27% risk of developing a subsequent myeloid neoplasm [ 9 – 11 ]. However, these studies did not assess the impact of prior DNA-damaging therapies, which is one of the strongest known risk factors for myeloid neoplasms [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…On the other hand, the survival of t-CC patients was significantly superior compared to t-MN patients. In the de novo context, an argument can be made that the clear distinction between CCUS and low-risk MDS (LR-MDS) may be of little importance; as observation is the preferred option for both entities [ 1 ], and there is no difference in survival [ 9 ]. This is in stark contrast with our findings as t-CC appears to have superior survival compared to all t-MN phenotypes, including t-MDS with no increase in blasts.…”

Section: Discussionmentioning

confidence: 99%

“…While studying t-MN patients, we encountered patients who had received DNA-damaging therapy and developed unexplained cytopenia with clonal abnormality, without morphological evidence of a myeloid neoplasm (i.e., CCUS). As a vast majority of patients in the CHIP, ICUS, or CCUS cohorts did not receive prior DNA-damaging therapies [ 2 , 9 – 11 ], the significance of CCUS following such therapies and its outcomes is not known. We hypothesized that clonal cytopenia following DNA-damaging therapy (therapy-related clonal cytopenia or t-CC) is a distinct entity from the WHO-defined t-MN.…”

Section: Introductionmentioning

confidence: 99%

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Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

et al. 2022

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Therapy-related myeloid neoplasms (t-MN) are aggressive leukemia that develops as a complication of prior exposure to DNA-damaging agents. Clonal cytopenia of undetermined significance (CCUS) is a precursor of de novo myeloid neoplasms. Characteristics of CCUS that develop following cytotoxic therapies (therapy-related clonal cytopenia, t-CC) and outcomes following t-CC have not been described. We identified 33 patients with t-CC and compared to a cohort of the WHO-defined t-MN (n = 309). t-CC had a distinct genetic and cytogenetic profile: pathogenic variants (PV) in TET2 and SRSF2 were enriched in t-CC, whereas TP53 PV was more common in t-MN. Ten (30%) t-CC patients developed a subsequent t-MN, with a cumulative incidence of 13%, 23%, and 50% at 6 months, 1, and 5 years, respectively. At t-MN progression, 44% of evaluable patients had identifiable clonal evolution. The median survival following t-CC was significantly superior compared all t-MN phenotype including t-MDS with <5% bone marrow blasts (124.5 vs. 16.3 months, P < 0.001) respectively. The presence of cytogenetic abnormality and the absence of variants in DNMT3A, TET2, or ASXL1 (DTA-genes) were associated with a higher likelihood of developing a subsequent t-MN and an inferior survival. We describe a putative precursor entity of t-MN with distinct features and outcomes.

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Remarkable stability in clonal hematopoiesis involving leukemia‐driver genes in patients without underlying myeloid neoplasms

et al. 2021

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Herein, we report the first case of PBL treated with the anti-PD1 monoclonal antibody pembrolizumab at standard doses approved for use in patients with relapsed or refractory Hodgkin lymphoma. The expression of PDL1 in the malignant cells and the tumor-associated macrophages served as the biological basis for our intervention. No treatment intervention is without potential toxicity, however. Our patient experienced a number of adverse events probably related to PD1 blockade. Cardiomyopathy with LVEF at 10% developed after 18 cycles of pembrolizumab therapy prompting permanent discontinuation. Cardiomyopathy with left ventricular systolic dysfunction appears to be a late adverse event associated with PD1 blocking agents. 8 Fortunately, the cardiomyopathy improved after drug discontinuation.Our experience suggest that anti-PD1 monoclonal antibody therapy could be effective in the management of patients with PBL with PDL1 expression, especially in patients who might not be optimal candidates for combination chemotherapy or autologous stem cell transplantation.

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Clinical, molecular, and prognostic comparisons between CCUS and lower-risk MDS: a study of 187 molecularly annotated patients

Cited by 32 publications

References 15 publications

Morphologic, immunophenotypic, and molecular genetic comparison study in patients with clonal cytopenia of undetermined significance, myelodysplastic syndrome, and acute myeloid leukemia with myelodysplasia‐related changes: A single institution experience

Morphologic, immunophenotypic, and molecular genetic comparison study in patients with clonal cytopenia of undetermined significance, myelodysplastic syndrome, and acute myeloid leukemia with myelodysplasia‐related changes: A single institution experience

Therapy-related clonal cytopenia as a precursor to therapy-related myeloid neoplasms

Remarkable stability in clonal hematopoiesis involving leukemia‐driver genes in patients without underlying myeloid neoplasms

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