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Supplementary Figure from Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia

Supplementary Table from Distinct Patterns of Clonal Evolution Drive Myelodysplastic Syndrome Progression to Secondary Acute Myeloid Leukemia

Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications.Significance:Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level.See related article by Menssen et al., p. 330 (31).See related commentary by Romine and van Galen, p. 270.This article is highlighted in the In This Issue feature, p. 265

Clonal evolution in myelodysplastic syndrome (MDS) can result in clinical progression and secondary acute myeloid leukemia (sAML). To dissect changes in clonal architecture associated with this progression, we performed single-cell genotyping of paired MDS and sAML samples from 18 patients. Analysis of single-cell genotypes revealed patient-specific clonal evolution and enabled the assessment of single-cell mutational cooccurrence. We discovered that changes in clonal architecture proceed via distinct patterns, classified as static or dynamic, with dynamic clonal architectures having a more proliferative phenotype by blast count fold change. Proteogenomic analysis of a subset of patients confirmed that pathogenic mutations were primarily confined to primitive and mature myeloid cells, though we also identify rare but present mutations in lymphocyte subsets. Single-cell transcriptomic analysis of paired sample sets further identified gene sets and signaling pathways involved in two cases of progression. Together, these data define serial changes in the MDS clonal landscape with clinical and therapeutic implications.Significance:Precise clonal trajectories in MDS progression are made possible by single-cell genomic sequencing. Here we use this technology to uncover the patterns of clonal architecture and clonal evolution that drive the transformation to secondary AML. We further define the phenotypic and transcriptional changes of disease progression at the single-cell level.See related article by Menssen et al., p. 330 (31).See related commentary by Romine and van Galen, p. 270.This article is highlighted in the In This Issue feature, p. 265

TPS4611 Background: The utilization of neoadjuvant immune checkpoint inhibitor (ICI) therapy, including anti-PD1/L1 agents, prior to radical cystectomy (RC), is an emerging paradigm in muscle invasive bladder cancer (MIBC). Pathologic complete responses (pCR) have been observed in 25-40% of patients with neoadjuvant PD1/L1 inhibitor monotherapy for cisplatin-ineligible MIBC. In situ vaccination using stereotactic body radiation therapy (SBRT) may augment T-cell responses to tumor-specific antigens through immunogenic cell death. Sasanlimab (PF-06801591) is a humanized IgG monoclonal antibody that targets PD-1 selectively, for which there are both Phase 1 data and ongoing Phase 3 trials in early-stage urothelial carcinoma. There exists a strong rationale to evaluate a novel strategy of combination neoadjuvant ICI therapy with SBRT as an in situ vaccine to improve loco-regional control and decrease the risk of distant recurrence in cisplatin-ineligible patients with MIBC. Methods: This is a prospective, investigator-initiated, single-arm, single-institution, phase II trial that evaluates neoadjuvant sasanlimab in combination with SBRT as neoadjuvant therapy for patients with MIBC before RC. Eligibility requires patients to be cisplatin-ineligible (one of the following: ECOG-PS=2, creatinine clearance