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Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

AbstractPreclinical data demonstrated that combining an anti–programmed cell death 1 (PD-1) inhibitor with a cyclin-dependent kinase 9 (CDK9) inhibitor provided enhanced antitumor activity with no significant toxicities, suggesting this combination may be a potential therapeutic option. The multicohort, phase 1 KEYNOTE-155 study evaluated the safety and antitumor activity of the PD-1 inhibitor pembrolizumab plus the CDK9 inhibitor dinaciclib in patients with relapsed or refractory (rr) chronic lymphocytic leukemia (CLL), diffuse large B-cell lymphoma (DLBCL) and multiple myeloma (MM). Patients enrolled were ≥18 years of age with a confirmed diagnosis of CLL, DLBCL, or MM. The study included 2 phases: a dose-evaluation phase to determine dose-limiting toxicities and a signal-detection phase. Patients received pembrolizumab 200 mg every 3 weeks plus dinaciclib 7 mg/m2 on day 1 and 10 mg/m2 on day 8 of cycle 1 and 14 mg/m2 on days 1 and 8 of cycles 2 and later. Primary endpoint was safety, and a key secondary endpoint was objective response rate (ORR). Seventy-two patients were enrolled and received ≥1 dose of study treatment (CLL, n = 17; DLBCL, n = 38; MM, n = 17). Pembrolizumab plus dinaciclib was generally well tolerated and produced no unexpected toxicities. The ORRs were 29.4% (5/17, rrCLL), 21.1% (8/38, rrDLBCL), and 0% (0/17, rrMM), respectively. At data cutoff, all 72 patients had discontinued treatment, 38 (52.8%) because of progressive disease. These findings demonstrate activity with combination pembrolizumab plus dinaciclib and suggest that a careful and comprehensive approach to explore anti–PD-1 and CDK9 inhibitor combinations is warranted. This trial was registered at www.clinicaltrials.gov as NCT02684617.

Introduction: Failure to engraft donor cells is a devastating complication after allogeneic hematopoietic cell transplantation (HCT) while full engraftment remains a challenge in some recipients. Therapeutic approaches, such as recombinant hematopoietic growth factors, salvage only a minority of patients leaving affected patients at risk for recurrent infections and multiple blood products transfusions. PLX-R18 cells have been shown to mitigate bone marrow failure in rodent and non-human primate models. Further, these human placenta-derived mesenchymal-like adherent stromal cells secrete many cytokines after intramuscular (IM) injection that have been shown to stimulate growth and migration of bone marrow cells in vitro, e.g. MCP-1, IL-6, and IL-8. The initial results of the first cohort of this phase I trial were previously reported (ASH 2018 abstract 3379). Methods: Enrollment for this multi-center, open label, dose-escalation, phase I trial (ClinicalTrials.gov: NCT03002519) began in October 2017. Eligibility criteria included patients age ≥18 years who underwent either autologous (auto) or allogeneic (allo) HCT but suffered from incomplete hematopoietic recovery at least 3 months post-transplant, defined as failure to maintain either hemoglobin (Hb) >8g/dL and/or neutrophil count (ANC) >1,000/μL and/or platelet (PLT) count >50,000/μL. Other eligibility criteria included no evidence of underlying malignancy at time of enrollment, no active infection and no evidence of grade 3-4 acute or severe chronic GvHD. Subjects were enrolled into 3 dose-escalating cohorts: low-dose at 1M cells/kg (n=3), intermediate-dose at 2M cells/kg (n=6), and high-dose at 4M cells/kg (n=10). The specified dose of PLX-R18 cells was injected IM in multiple locations and given twice, 1 week apart. Cohorts were recruited sequentially, and progression to the next cohort was based on the safety assessment of its predecessor. Adverse event grading used the NCI CTCAE criteria. As of July 2020, all patients in cohorts 1 and 2 (3 & 6 patients, respectively) and 10 patients in cohort 3 were treated. Data were analyzed using the lmerTest package (ver. 3.1.0) in R (ver. 3.6.1) to produce baseline-adjusted least square means. As study is in progress and data collection ongoing, not all subjects have data on all parameters for all time points. Results: Data on 19 subjects (29-75 yrs) with either allo (n=17) or auto (n=2) HCT are reported herein. Not all patients reached the 9 month time point. Four patients died while on study and 2 withdrew consent within the 1 year follow up period. All deaths and other severe adverse events (SAEs) occurred due to progression of primary disease and were assessed as not related by investigators and sponsor. Most frequent related AEs were injection-site reactions. The table summarizes number of patients who improved from below the critical level, as defined above, at day 0 to above the critical level for a sustained period. Only those patients that were below the critical blood levels at day 0 are shown. To date, the majority of such patients improved to above the critical level after treatment. For example, 9 patients had ANC <1000/μL at day 0. Of the 4 patients for which data currently exists, all improved to ≥1000/μL at 9 months. The plots show changes in Hb, ANC and PLT up to 9 months following treatment. The dashed lines represent respective critical levels. Overall, there was improvement in the 3 parameters, with the greatest improvement observed in patients receiving the predicted optimal dose of 4M cells/kg. In this cohort, Hb levels increased from 9.29±0.5 to 13.19±1.2 (p=0.0019), ANC increased from 1.09±0.6 to 5.13±1.7 (p=0.018) and PLT increased from 45.7±10 to 175.9±28 (p=0.000012). Conclusions: Treatment with PLX-R18 is safe, well-tolerated and clearly effective in some patients. The most frequent AEs were reversible injection site reactions, all without sequelae. An overall improvement was observed in most patients, and among the high-dose cohort clinically impressive improvements in Hb, ANC and PLT were observed. The trial continues to follow up on patients. Upon completion, a large phase II trial, using the optimal dose, is considered for the same indication. Other attractive clinical areas for PLX-R18 therapy include acute radiation syndrome, bone marrow failure, aplastic anemia, myelofibrosis and with HCT as a "pan" cytokine to enhance rapid count recovery in all cells lines. Figure Disclosures Lazarus: Pluristem ltd: Consultancy. McGuirk:Astellas: Research Funding; Bellicum Pharmaceutical: Research Funding; Gamida Cell: Research Funding; Pluristem Ltd: Research Funding; Kite Pharmaceuticals: Consultancy, Honoraria, Research Funding, Speakers Bureau; Allo Vir: Consultancy, Honoraria, Research Funding; Juno Therapeutics: Consultancy, Honoraria, Research Funding; Novartis: Research Funding; Fresenius Biotech: Research Funding. Rowley:AbbVie: Current equity holder in publicly-traded company; FATE Therapeutics: Consultancy. Ofir:Pluristem: Current Employment. Shani:Pluristem ltd: Current Employment. Rowe:Pluristem ltd: Consultancy.