Venetoclax is approved for adult patients with chronic lymphocytic leukemia and acute myeloid leukemia. Expanding its use to the pediatric population is currently under investigation, but more robust data are needed. We retrospectively analyzed the safety and efficacy of venetoclax in children/AYA with ALL/LBL. We identified 18 patients (T-cell ALL, n = 7; T-cell LBL, n = 6; B-cell ALL, n = 5) aged 6–22 years. No new venetoclax safety signals were identified; the most common toxicity was myelosuppression. No deaths occurred within 30 days from the start of the therapy. A mean of 2.6 (range 0–8) prior lines of therapy were given. The mean duration of venetoclax was 4.06 months (range 0.2–24.67 months). Complete remission was achieved in 11 (61%) patients. Of the eight patients who remain alive, four are continuing on venetoclax combination therapy, and four proceeded to hematopoietic stem cell transplantation. Three patients who initially achieved CR, later relapsed, and are deceased. Nine patients are deceased, and one patient was lost to follow-up. Overall survival is 9.14 months (range 1.1–33.1), and progression-free survival is 7.34 months (range 0.2–33.1). This is the largest cohort of pediatric/AYA patients who received venetoclax for ALL/LBL. Our data support the consideration of venetoclax-based regimens in pediatric patients with R/R ALL/LBL and its investigation as upfront therapy for T-cell ALL/LBL.

The BCL-2 inhibitor venetoclax improves survival for adult patients with acute myeloid leukemia (AML) in combination with lower-intensity therapies, but its benefit in pediatric patients with AML remains unclear. We retrospectively reviewed two Texas Medical Center institutions’ experience with venetoclax in 43 pediatric patients with AML; median age 17 years (range, 0.6–21). This population was highly refractory; 44% of patients (n = 19) had ≥3 prior lines of therapy, 37% (n = 16) had received a prior bone marrow transplant, and 81% (n = 35) had unfavorable genetics KMT2A (n = 17), WT1 (n = 13), FLT3-ITD (n = 10), monosomy 7 (n = 5), TP53 (n = 3), Inv(3) (n = 3), IDH1/2 (n = 2), monosomy 5 (n = 1), NUP98 (n = 1) and ASXL1 (n = 1). The majority (86%) received venetoclax with a hypomethylating agent. Grade 3 or 4 adverse events included febrile neutropenia in 37% (n = 16), non-febrile neutropenia in 12% (n = 5), anemia in 14% (n = 6), and thrombocytopenia in 14% (n = 6). Of 40 patients evaluable for response, 10 patients (25%) achieved complete response (CR), 6 patients (15%) achieved CR with incomplete blood count recovery (CRi), and 2 patients (5%) had a partial response, (CR/CRi composite = 40%; ORR = 45%). Eleven (25%) patients received a hematopoietic stem cell transplant following venetoclax combination therapy, and six remain alive (median follow-up time 33.6 months). Median event-free survival and overall survival duration was 3.7 months and 8.7 months, respectively. Our findings suggest that in pediatric patients with AML, venetoclax is well-tolerated, with a safety profile similar to that in adults. More studies are needed to establish an optimal venetoclax-based regimen for the pediatric population.

Background : Although in recent clinical trials the 5-year event-free survival rates for pediatric Acute Myeloid Leukemia (AML) range between 49% and 64%, relapse still occurs in up to one-third of cases. Long-term outcomes of children with relapsed or refractory disease remain poor, with overall survival under 40%. Novel drugs directed toward distinct pathways and new molecular targets are required to continue improving outcomes for this aggressive hematological disease. Use of the BCL-2 inhibitor, venetoclax, has improved overall and event-free survival in adult patients with newly diagnosed, intensive-chemotherapy ineligible AML, however, its effects in pediatric AML patients remain unclear. We reviewed our multi-institutional experience with venetoclax in this population. Methods : We performed a retrospective review of patients ages 0 to 23 y/o with AML and treated with at least one cycle of venetoclax at either MD Anderson Cancer Center or Texas Children's Hospital prior to May 2021. Flow cytometry was used to assess morphology and response to therapy. Adverse events (AEs) associated with venetoclax were graded according to the Common Terminology Criteria for Adverse Events version 5.0. Descriptive statistics were used to report efficacy and toxicity data. Results : 46 patients with AML who received venetoclax-containing regimens were identified. There was a similar proportion of males and females (52% and 48%) and most were Caucasian (48%). The median age was 21 years (range, 1-23) with eight patients (17%) <12 years of age. The most common AML subtype was M2 (30%; n=14) and the most common genetic mutations were FLT3-ITD (15%; n=7) and KMT2A (26%; n=12). Eight (17%) patients received venetoclax within front-line therapy and 38 (83%) as part of therapy for relapsed or refractory disease. Patients received a median of 2 therapies (range, 0-7) before venetoclax, with ten patients (22%) receiving at least four lines of prior therapy and twenty (43%) at least one prior allogeneic transplant. Venetoclax was combined with a hypomethylating agent in 28 (61%) patients. Dosing varied significantly ranging from 34-479 mg/m2 with 20% (n=9) requiring dose reduction due to concomitant use of azole antifungals. The most common grade 3/4 AE's observed included febrile neutropenia (41%; n=19), neutropenia (35%; n=16), anemia (20%; n=9), and thrombocytopenia (33%; n=15). No patients discontinued treatment because of AEs. The overall response rate in the 38 patients evaluated for disease at the end of cycle 1 was 53% (n=20). Complete remission (CR) or complete remission with incomplete blood count recovery (CRi) was achieved in 42% (n=16) of patients. Among those with CR/CRi, 9 (56%) were MRD negative. Of those sixteen, 4 (25%) had received venetoclax as front-line therapy. In total, seventeen patients (37%) were able to successfully transition to hematopoietic stem cell transplant. The median follow-up time was 8.5 months. Median progression-free survival (PFS) was 5.5 months (range, 0.13-36.61) and overall survival (OS) was 10 months (range, 0.13-36.61). Patients who received venetoclax as part of front-line therapy had a median PFS of 16.8 months (range, 0.72-17.5) and OS of 16.8 months (range, 0.72-28.75) with 4 (50%) patients still in ongoing remission. Conclusion : Our findings suggest that in pediatric and early young adults, venetoclax is well-tolerated with a variety of cytotoxic agents and has a safety profile similar to that in adults. Patients should be monitored closely for prolonged myelosuppression and febrile neutropenia. As dosing varied significantly in our cohort, more studies are needed to establish an optimal dose in the pediatric population. Longer follow-up is expected to provide more insight on the improvement venetoclax may have on overall and progression-free survival. Figure 1 Figure 1. Disclosures Kadia: Sanofi-Aventis: Consultancy; Dalichi Sankyo: Consultancy; Genentech: Consultancy, Other: Grant/research support; Genfleet: Other; AstraZeneca: Other; Astellas: Other; Pulmotech: Other; Cure: Speakers Bureau; Cellonkos: Other; Jazz: Consultancy; Pfizer: Consultancy, Other; Ascentage: Other; Novartis: Consultancy; Liberum: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support. Konopleva: Cellectis: Other: grant support; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support; KisoJi: Research Funding; Calithera: Other: grant support, Research Funding; Rafael Pharmaceuticals: Other: grant support, Research Funding; Ascentage: Other: grant support, Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Stemline Therapeutics: Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding. DiNardo: Takeda: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; ImmuneOnc: Honoraria, Research Funding; AbbVie: Consultancy, Research Funding; Forma: Honoraria, Research Funding; Agios/Servier: Consultancy, Honoraria, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Daver: Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Sevier: Consultancy, Research Funding; Novartis: Consultancy; Astellas: Consultancy, Research Funding; Glycomimetics: Research Funding; Novimmune: Research Funding; Hanmi: Research Funding; Genentech: Consultancy, Research Funding; Trillium: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; FATE Therapeutics: Research Funding; ImmunoGen: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; Trovagene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding. Short: AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy; NGMBio: Consultancy; Novartis: Honoraria; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Issa: Kura Oncology: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding; Novartis: Consultancy, Research Funding. Ravandi: Amgen: Honoraria, Research Funding; Xencor: Honoraria, Research Funding; Taiho: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Agios: Honoraria, Research Funding; Novartis: Honoraria; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Prelude: Research Funding; Astex: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding. Kantarjian: Ascentage: Research Funding; Astra Zeneca: Honoraria; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Ipsen Pharmaceuticals: Honoraria; NOVA Research: Honoraria; Novartis: Honoraria, Research Funding; Immunogen: Research Funding; Astellas Health: Honoraria; BMS: Research Funding; Aptitude Health: Honoraria; Jazz: Research Funding; AbbVie: Honoraria, Research Funding; Precision Biosciences: Honoraria; Amgen: Honoraria, Research Funding; Taiho Pharmaceutical Canada: Honoraria.

Background: Single-cell RNA-seq has emerged as an innovative technology used to study complex tissues and characterize cell types, states, and lineages at a single-cell level. Rapid adoption of this technology has led to a flurry of research creating single-cell atlases for many organs, cancers, and developmental models. Despite the tremendous success of this technology, sarcomas, rare cancers of mesenchymal origin, have not yet widely benefited from the adoption of single-cell RNA-seq. Due to their rarity, obtaining fresh clinical specimens is challenging. Single-nucleus RNA-seq could remove limitations from obtaining fresh tissue and enable immediate processing of archival tissue. However, biases may exist during dissociation of either fresh or frozen specimens that can hinder reproducible results and introduce technical or biological artifacts. Results: To address these questions, we systematically assessed dissociation methods across different sarcoma subtypes. Here, we compare gene expression from single-cell and single-nucleus RNA-sequencing of 125,831 whole-cells and nuclei from Ewing′s sarcoma, desmoplastic small round cell tumor, and osteosarcoma patient-derived xenografts. We detected warm dissociation artifacts from single-cell samples and gene length bias in single-nucleus samples. Classic sarcoma gene signatures were observed regardless of dissociation method. Finally, we show that dissociation method biases can be computationally corrected. Conclusions: We highlighted transcriptional biases, including warm dissociation and gene-length biases, introduced by any dissociation method for various sarcoma subtypes. This work will inform researchers on choice of dissociation method and careful interpretation of data due to dissociation biases.

No abstract