Cytoneme signaling provides essential contributions to mammalian tissue patterning.

During development, morphogens pattern tissues by instructing cell fate across long distances. Directly visualizing morphogen transport in situ has been inaccessible, so the molecular mechanisms ensuring successful morphogen delivery remain unclear. To tackle this longstanding problem, we developed a mouse model for compromised sonic hedgehog (SHH) morphogen delivery and discovered that endocytic recycling promotes SHH loading into signaling filopodia called cytonemes. We optimized methods to preserve in vivo cytonemes for advanced microscopy and show endogenous SHH localized to cytonemes in developing mouse neural tubes. Depletion of SHH from neural tube cytonemes alters neuronal cell fates and compromises neurodevelopment. Mutation of the filopodial motor myosin 10 (MYO10) reduces cytoneme length and density, which corrupts neuronal signaling activity of both SHH and WNT. Combined, these results demonstrate that cytoneme-based signal transport provides essential contributions to morphogen dispersion during mammalian tissue development and suggest MYO10 is a key regulator of cytoneme function.

Nivolumab+AVD in Advanced-Stage Classic Hodgkin's Lymphoma.

BACKGROUND: Incorporating brentuximab vedotin into the treatment of advanced-stage classic Hodgkin's lymphoma improves outcomes in adult and pediatric patients. However, brentuximab vedotin increases the toxic effects of treatment in adults, more than half of pediatric patients who receive the drug undergo consolidative radiation, and relapse remains a challenge. Programmed death 1 blockade is effective in Hodgkin's lymphoma, including in preliminary studies involving previously untreated patients. METHODS: We conducted a phase 3, multicenter, open-label, randomized trial involving patients at least 12 years of age with stage III or IV newly diagnosed Hodgkin's lymphoma. Patients were randomly assigned to receive brentuximab vedotin with doxorubicin, vinblastine, and dacarbazine (BV+AVD) or nivolumab with doxorubicin, vinblastine, and dacarbazine (N+AVD). Prespecified patients could receive radiation therapy directed to residual metabolically active lesions. The primary end point was progression-free survival, defined as the time from randomization to the first observation of progressive disease or death from any cause. RESULTS: Of 994 patients who underwent randomization, 970 were included in the intention-to-treat population for efficacy analyses. At the second planned interim analysis, with a median follow-up of 12.1 months, the threshold for efficacy was crossed, indicating that N+AVD significantly improved progression-free survival as compared with BV+AVD (hazard ratio for disease progression or death, 0.48; 99% confidence interval [CI], 0.27 to 0.87; two-sided P = 0.001). Owing to the short follow-up time, we repeated the analysis with longer follow-up; with a median follow-up of 2.1 years (range, 0 to 4.2 years), the 2-year progression-free survival was 92% (95% CI, 89 to 94) with N+AVD, as compared with 83% (95% CI, 79 to 86) with BV+AVD (hazard ratio for disease progression or death, 0.45; 95% CI, 0.30 to 0.65). Overall, 7 patients received radiation therapy. Immune-related adverse events were infrequent with nivolumab; brentuximab vedotin was associated with more treatment discontinuation. CONCLUSIONS: N+AVD resulted in longer progression-free survival than BV+AVD in adolescents and adults with stage III or IV advanced-stage classic Hodgkin's lymphoma and had a better side-effect profile. (Funded by the National Cancer Institute of the National Institutes of Health and others; S1826 ClinicalTrials.gov number, NCT03907488.).

LAG-3 Inhibitory Receptor Expression Identifies Immunosuppressive Natural Regulatory Plasma Cells.

B lymphocytes can suppress immunity through interleukin (IL)-10 production in infectious, autoimmune, and malignant diseases. Here, we have identified a natural plasma cell subset that distinctively expresses the inhibitory receptor LAG-3 and mediates this function in vivo. These plasma cells also express the inhibitory receptors CD200, PD-L1, and PD-L2. They develop from various B cell subsets in a B cell receptor (BCR)-dependent manner independently of microbiota in naive mice. After challenge they upregulate IL-10 expression via a Toll-like receptor-driven mechanism within hours and without proliferating. This function is associated with a unique transcriptome and epigenome, including the lowest amount of DNA methylation at the Il10 locus compared to other B cell subsets. Their augmented accumulation in naive mutant mice with increased BCR signaling correlates with the inhibition of memory T cell formation and vaccine efficacy after challenge. These natural regulatory plasma cells may be of broad relevance for disease intervention.

Glofitamab stimulates immune cell infiltration of CNS tumors and induces clinical responses in secondary CNS lymphoma.

ABSTRACT: Although CD20×CD3 bispecific antibodies are effective against systemic B-cell lymphomas, their efficacy in central nervous system (CNS) lymphoma is unknown. Here, we report the CD20×CD3 bispecific glofitamab penetrates the blood-brain barrier, stimulates immune-cell infiltration of CNS tumors, and induces clinical responses in patients with secondary CNS.

LXRα Promotes Abdominal Aortic Aneurysm Formation Through UHRF1 Epigenetic Modification of miR-26b-3p.

BACKGROUND: Abdominal aortic aneurysm (AAA) is a severe aortic disease without effective pharmacological approaches. The nuclear hormone receptor LXRα (liver X receptor α), encoded by the NR1H3 gene, serves as a critical transcriptional mediator linked to several vascular pathologies, but its role in AAA remains elusive. METHODS: Through integrated analyses of human and murine AAA gene expression microarray data sets, we identified NR1H3 as a candidate gene regulating AAA formation. To investigate the role of LXRα in AAA formation, we used global Nr1h3-knockout and vascular smooth muscle cell-specific Nr1h3-knockout mice in 2 AAA mouse models induced with angiotensin II (1000 ng·kg·min; 28 days) or calcium chloride (CaCl2; 0.5 mol/L; 42 days). RESULTS: Upregulated LXRα was observed in the aortas of patients with AAA and in angiotensin II- or CaCl2-treated mice. Global or vascular smooth muscle cell-specific Nr1h3 knockout inhibited AAA formation in 2 mouse models. Loss of LXRα function prevented extracellular matrix degeneration, inflammation, and vascular smooth muscle cell phenotypic switching. Uhrf1, an epigenetic master regulator, was identified as a direct target gene of LXRα by integrated analysis of transcriptome sequencing and chromatin immunoprecipitation sequencing. Susceptibility to AAA development was consistently enhanced by UHRF1 (ubiquitin-like containing PHD and RING finger domains 1) in both angiotensin II- and CaCl2-induced mouse models. We then determined the CpG methylation status and promoter accessibility of UHRF1-mediated genes using CUT&Tag (cleavage under targets and tagmentation), RRBS (reduced representation bisulfite sequencing), and ATAC-seq (assay for transposase-accessible chromatin with sequencing) in vascular smooth muscle cells, which revealed that the recruitment of UHRF1 to the promoter of miR-26b led to DNA hypermethylation accompanied by relatively closed chromatin states, and caused downregulation of miR-26b expression in AAA. Regarding clinical significance, we found that underexpression of miR-26b-3p correlated with high risk in patients with AAA. Maintaining miR-26b-3p expression prevented AAA progression and alleviated the overall pathological process. CONCLUSIONS: Our study reveals a pivotal role of the LXRα/UHRF1/miR-26b-3p axis in AAA and provides potential biomarkers and therapeutic targets for AAA.

Allele-Specific Suppression of Variant MHC With High-Precision RNA Nuclease CRISPR-Cas13d Prevents Hypertrophic Cardiomyopathy.

BACKGROUND: Familial hypertrophic cardiomyopathy has severe clinical complications of heart failure, arrhythmia, and sudden cardiac death. Heterozygous single nucleotide variants (SNVs) of sarcomere genes such as MYH7 are the leading cause of this type of disease. CRISPR-Cas13 (clustered regularly interspaced short palindromic repeats and their associated protein 13) is an emerging gene therapy approach for treating genetic disorders, but its therapeutic potential in genetic cardiomyopathy remains unexplored. METHODS: We developed a sensitive allelic point mutation reporter system to screen the mutagenic variants of Cas13d. On the basis of Cas13d homology structure, we rationally designed a series of Cas13d variants and obtained a high-precision Cas13d variant (hpCas13d) that specifically cleaves the MYH7 variant RNAs containing 1 allelic SNV. We validated the high precision and low collateral cleavage activity of hpCas13d through various in vitro assays. We generated 2 HCM mouse models bearing distinct MYH7 SNVs and used adenovirus-associated virus serotype 9 to deliver hpCas13d specifically to the cardiomyocytes. We performed a large-scale library screening to assess the potency of hpCas13d in resolving 45 human MYH7 allelic pathogenic SNVs. RESULTS: Wild-type Cas13d cannot distinguish and specifically cleave the heterozygous MYH7 allele with SNV. hpCas13d, with 3 amino acid substitutions, had minimized collateral RNase activity and was able to resolve various human MYH7 pathological sequence variations that cause hypertrophic cardiomyopathy. In vivo application of hpCas13d to 2 hypertrophic cardiomyopathy models caused by distinct human MYH7 analogous sequence variations specifically suppressed the altered allele and prevented cardiac hypertrophy. CONCLUSIONS: Our study unveils the great potential of CRISPR-Cas nucleases with high precision in treating inheritable cardiomyopathy and opens a new avenue for therapeutic management of inherited cardiac diseases.

A phase 2 study of pembrolizumab after autologous stem cell transplantation in patients with T-cell non-Hodgkin lymphoma.

Autologous stem cell transplantation (ASCT) is often used as consolidation for several subtypes of peripheral T-cell lymphoma (PTCL) in first remission. However, many patients relapse after ASCT and have a very poor prognosis. There are no approved treatment options for posttransplantation maintenance or consolidation in PTCL. PD-1 blockade has demonstrated some efficacy for patients with PTCL. We, therefore, conducted a phase 2 multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab after ASCT in patients with PTCL in first remission. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles within 21 days from post-ASCT discharge (and within 60 days of stem cell infusion). The primary end point was progression-free survival (PFS) at 18 months after ASCT. Twenty-one patients were treated in this study and 67% (n = 14) completed 8 cycles of treatment. Among all patients who were evaluable, 13 of 21 were alive and achieved PFS at 18 months after ASCT, meeting the study's primary end point. The estimated 18-month PFS was 83.6% (95% confidence interval [CI], 68-100), and overall survival 94.4% (95% CI, 84-100). The toxicity profile was consistent with the known toxicity profile of pembrolizumab, with no grade 5 toxicities. In conclusion, PD-1 blockade after ASCT with pembrolizumab is feasible with a favorable safety profile and promising activity, supporting further confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02362997.

Five-year follow-up of KEYNOTE-087: pembrolizumab monotherapy for relapsed/refractory classical Hodgkin lymphoma.

Previous analyses of the phase 2 KEYNOTE-087 (NCT02453594) trial of pembrolizumab monotherapy demonstrated effective antitumor activity with acceptable safety in patients with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL). However, long-term response durability and outcome of patients who receive a second course after treatment discontinuation after complete response (CR) remain of clinical interest. We present KEYNOTE-087 data after >5 years of median follow-up. Patients with R/R cHL and progressive disease (PD) after autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV; cohort 1), salvage chemotherapy and BV without ASCT (cohort 2), or ASCT without subsequent BV (cohort 3), received pembrolizumab for ≤2 years. Patients in CR who discontinued treatment and subsequently experienced PD were eligible for second-course pembrolizumab. Primary end points were the objective response rate (ORR) using blinded central review and safety. The median follow-up was 63.7 months. ORR was 71.4% (95% confidence interval [CI], 64.8-77.4; CR, 27.6%; partial response, 43.8%). Median duration of response (DOR) was 16.6 months; median progression-free survival was 13.7 months. A quarter of responders, including half of complete responders, maintained a response for ≥4 years. Median overall survival was not achieved. Among 20 patients receiving second-course pembrolizumab, ORR for 19 evaluable patients was 73.7% (95% CI, 48.8-90.8); median DOR was 15.2 months. Any-grade treatment-related adverse events occurred in 72.9% of patients and grade 3 or 4 adverse events occurred in 12.9% of patients; no treatment-related deaths occurred. Single-agent pembrolizumab can induce durable responses, particularly in patients achieving CR. Second-course pembrolizumab frequently reinduced sustained responses after relapse from initial CR.

Pembrolizumab plus vorinostat induces responses in patients with Hodgkin lymphoma refractory to prior PD-1 blockade.

This phase 1 study evaluated the addition of vorinostat to pembrolizumab in patients with relapsed/refractory (RR) classical Hodgkin lymphoma (cHL), diffuse large B-cell lymphoma, and follicular lymphoma. We report the results in cases of cHL. Adult patients with RR cHL who had received ≥1 prior lines of therapy and were ineligible for transplantation were treated in a dose-escalation cohort with 2 dose levels (DLs) and then on an expansion cohort at the recommended phase 2 dose (RP2D) in 21-day cycles. Vorinostat 100 mg twice a day (DL1) and 200 mg twice a day (DL2) was administered orally from days 1 to 5 and 8 to 12; all patients received pembrolizumab 200 mg IV every 3 weeks. The primary end point was safety and determination of RP2D. In total, 32 patients with cHL were enrolled, including 30 at DL2 (RP2D); 78% had received prior anti-programmed cell death 1 (anti-PD-1) therapy, and 56% were PD-1 refractory. Grade ≥3 adverse events (AEs) included hypertension (9%), neutropenia (9%), hypophosphatemia (9%), thrombocytopenia (6%), and lymphopenia (6%). Immune-related AEs included grade 1 or 2 thyroiditis (13%), grade 1 rash (6%), and grade 3 esophagitis/duodenitis (3%). The overall response rate (ORR) was 72% and complete response (CR) rate was 34%. Patients refractory to prior PD-1 blockade (n = 18) had ORR and CR rates of 56% and 11%, respectively. Pembrolizumab and vorinostat was well tolerated with a high ORR rate in RR cHL including in anti-PD-1-refractory disease. This trial was registered at www.clinicaltrials.gov as #NCT03150329.

Five-year follow-up of ZUMA-1 supports the curative potential of axicabtagene ciloleucel in refractory large B-cell lymphoma.

In phase 2 of ZUMA-1, a single-arm, multicenter, registrational trial, axicabtagene ciloleucel (axi-cel) autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy demonstrated durable responses at 2 years in patients with refractory large B-cell lymphoma (LBCL). Here, we assessed outcomes in ZUMA-1 after 5 years of follow-up. Eligible adults received lymphodepleting chemotherapy followed by axi-cel (2 × 106 cells per kg). Investigator-assessed response, survival, safety, and pharmacokinetics were assessed in patients who had received treatment. The objective response rate in these 101 patients was 83% (58% complete response rate); with a median follow-up of 63.1 months, responses were ongoing in 31% of patients at data cutoff. Median overall survival (OS) was 25.8 months, and the estimated 5-year OS rate was 42.6%. Disease-specific survival (excluding deaths unrelated to disease progression) estimated at 5 years was 51.0%. No new serious adverse events or deaths related to axi-cel were observed after additional follow-up. Peripheral blood B cells were detectable in all evaluable patients at 3 years with polyclonal B-cell recovery in 91% of patients. Ongoing responses at 60 months were associated with early CAR T-cell expansion. In conclusion, this 5-year follow-up analysis of ZUMA-1 demonstrates sustained overall and disease-specific survival, with no new safety signals in patients with refractory LBCL. Protracted B-cell aplasia was not required for durable responses. These findings support the curative potential of axi-cel in a subset of patients with aggressive B-cell lymphomas. This trial was registered at ClinicalTrials.gov, as #NCT02348216.

Identification and experimental validation of PYCARD as a crucial PANoptosis-related gene for immune response and inflammation in COPD.

Chronic inflammatory and immune responses play key roles in the development and progression of chronic obstructive pulmonary disease (COPD). PANoptosis, as a unique inflammatory cell death modality, is involved in the pathogenesis of many inflammatory diseases. We aim to identify critical PANoptosis-related biomarkers and explore their potential effects on respiratory tract diseases and immune infiltration landscapes in COPD. Total microarray data consisting of peripheral blood and lung tissue datasets associated with COPD were obtained from the GEO database. PANoptosis-associated genes in COPD were identified by intersecting differentially expressed genes (DEGs) with genes involved in pyroptosis, apoptosis, and necroptosis after normalizing and removing the batch effect. Furthermore, GO, KEGG, PPI network, WGCNA, LASSO-COX, and ROC curves analysis were conducted to screen and verify hub genes, and the correlation between PYCARD and infiltrated immune cells was analyzed. The effect of PYCARD on respiratory tract diseases and the potential small-molecule agents for the treatment of COPD were identified. PYCARD expression was verified in the lung tissue of CS/LPS-induced COPD mice. PYCARD was a critical PANoptosis-related gene in all COPD patients. PYCARD was positively related to NOD-like receptor signaling pathway and promoted immune cell infiltration. Moreover, PYCARD was significantly activated in COPD mice mainly by targeting PANoptosis. PANoptosis-related gene PYCARD is a potential biomarker for COPD diagnosis and treatment.

Non-neutralizing antibodies targeting the immunogenic regions of HIV-1 envelope reduce mucosal infection and virus burden in humanized mice.

Antibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy was 31% and the sole primary correlate of reduced risk was shown to be vigorous antibody response targeting the V1V2 region of HIV-1 envelope. Antibodies against V3 also were inversely correlated with infection risk in subsets of vaccinees. Antibodies recognizing these regions, however, do not exhibit potent neutralizing activity. Therefore, we examined the antiviral potential of poorly neutralizing monoclonal antibodies (mAbs) against immunodominant V1V2 and V3 sites by passive administration of human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells, followed by mucosal challenge with an HIV-1 infectious molecular clone expressing the envelope of a tier 2 resistant HIV-1 strain. Treatment with anti-V1V2 mAb 2158 or anti-V3 mAb 2219 did not prevent infection, but V3 mAb 2219 displayed a superior potency compared to V1V2 mAb 2158 in reducing virus burden. While these mAbs had no or weak neutralizing activity and elicited undetectable levels of antibody-dependent cellular cytotoxicity (ADCC), V3 mAb 2219 displayed a greater capacity to bind virus- and cell-associated HIV-1 envelope and to mediate antibody-dependent cellular phagocytosis (ADCP) and C1q complement binding as compared to V1V2 mAb 2158. Mutations in the Fc region of 2219 diminished these effector activities in vitro and lessened virus control in humanized mice. These results demonstrate the importance of Fc functions other than ADCC for antibodies without potent neutralizing activity.

Diagnostic delay in monogenic disease: A scoping review.

PURPOSE: Diagnostic delay in monogenic disease is reportedly common. We conducted a scoping review investigating variability in study design, results, and conclusions. METHODS: We searched the academic literature on January 17, 2023, for original peer reviewed journals and conference articles that quantified diagnostic delay in monogenic disease. We abstracted the reported diagnostic delay, relevant study design features, and definitions. RESULTS: Our search identified 259 articles quantifying diagnostic delay in 111 distinct monogenetic diseases. Median reported diagnostic delay for all studies collectively in monogenetic diseases was 5.0 years (IQR 2-10). There was major variation in the reported delay within individual monogenetic diseases. Shorter delay was associated with disorders of childhood metabolism, immunity, and development. The majority (67.6%) of articles that studied delay reported an improvement with calendar time. Study design and definitions of delay were highly heterogenous. Three gaps were identified: (1) no studies were conducted in the least developed countries, (2) delay has not been studied for the majority of known, or (3) most prevalent genetic diseases. CONCLUSION: Heterogenous study design and definitions of diagnostic delay inhibit comparison across studies. Future efforts should focus on standardizing delay measurements, while expanding the research to low-income countries.

Cost-effectiveness of second-line axicabtagene ciloleucel in relapsed refractory diffuse large B-cell lymphoma.

The ZUMA-7 (Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma) study showed that axicabtagene ciloleucel (axi-cel) improved event-free survival (EFS) compared with standard of care (SOC) salvage chemoimmunotherapy followed by autologous stem cell transplant in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL); this led to its recent US Food and Drug Administration approval in this setting. We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapsed DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of second-line axi-cel compared with SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year EFS of 35% with second-line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of $150 000 per QALY ($93 547 per QALY). axi-cel was no longer cost-effective if its 5-year EFS was ≤26.4% or if it cost more than $972 061 at a WTP of $150 000. Second-line axi-cel was the cost-effective strategy in 73% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in EFS is maintained over time, second-line axi-cel for aggressive relapsed/refractory DLBCL is cost-effective compared with SOC at a WTP of $150 000 per QALY. However, its cost-effectiveness is highly dependent on long-term outcomes. Routine use of second-line chimeric antigen receptor T-cell therapy would add significantly to health care expenditures in the United States (more than $1 billion each year), even when used in a high-risk subpopulation. Further reductions in the cost of chimeric antigen receptor T-cell therapy are needed to be affordable in many regions of the world.

Cost-effectiveness of polatuzumab vedotin combined with chemoimmunotherapy in untreated diffuse large B-cell lymphoma.

In patients with treatment-naive diffuse large B-cell lymphoma (DLBCL), the POLARIX study (A Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone [R-CHP] Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R-CHOP] in Participants With Diffuse Large B-Cell Lymphoma) reported a 6.5% improvement in the 2-year progression-free survival (PFS), with no difference in overall survival (OS) or safety using polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We evaluated the cost-effectiveness of pola-R-CHP for DLBCL. We modeled a hypothetical cohort of US adults (mean age, 65 years) with treatment-naive DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of pola-R-CHP and R-CHOP using a range of plausible long-term outcomes. Progression rates and OS were estimated from POLARIX. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year PFS of 69.6% with pola-R-CHP and 62.7% with R-CHOP, pola-R-CHP was cost-effective at a WTP of $150 000 (incremental cost-effectiveness ratio, $84 308/QALY). pola-R-CHP was no longer cost-effective if its 5-year PFS was 66.1% or lower. One-way sensitivity analysis revealed that pola-R-CHP is cost-effective up to a cost of $276 312 at a WTP of $150 000. pola-R-CHP was the cost-effective strategy in 56.6% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in PFS is maintained over time, pola-R-CHP is cost-effective compared with R-CHOP at a WTP of $150 000/QALY. However, its cost-effectiveness is highly dependent on its long-term outcomes and costs of chimeric antigen receptor T-cell therapy. Routine usage of pola-R-CHP would add significantly to health care expenditures. Price reductions or identification of subgroups that have maximal benefit would improve cost-effectiveness.

Response-adapted anti-PD-1-based salvage therapy for Hodgkin lymphoma with nivolumab alone or in combination with ICE.

This phase 2 trial evaluated PET-adapted nivolumab alone or in combination with ifosfamide, carboplatin, and etoposide (NICE) as first salvage therapy and bridge to autologous hematopoietic cell transplantation (AHCT) in relapsed/refractory (RR) classical Hodgkin lymphoma (cHL). Patients with RR cHL received 240 mg nivolumab every 2 weeks for up to 6 cycles (C). Patients in complete response (CR) after C6 proceeded to AHCT, whereas patients with progressive disease at any point or not in CR after C6 received NICE for 2 cycles. The primary endpoint was CR rate per the 2014 Lugano classification at completion of protocol therapy. Forty-three patients were evaluable for toxicity; 42 were evaluable for response. Thirty-four patients received nivolumab alone, and 9 patients received nivolumab+NICE. No unexpected toxicities were observed after nivolumab or NICE. After nivolumab, the overall response rate (ORR) was 81%, and the CR rate was 71%. Among 9 patients who received NICE, all responded, with 8 (89%) achieving CR. At the end of protocol therapy, the ORR and CR rates were 93% and 91%. Thirty-three patients were bridged directly to AHCT, including 26 after Nivo alone. The 2-year progression-free survival (PFS) and overall survival in all treated patients (n = 43) were 72% and 95%, respectively. Among 33 patients who bridged directly to AHCT, the 2-year PFS was 94% (95% CI: 78-98). PET-adapted sequential salvage therapy with nivolumab/nivolumab+NICE was well tolerated and effective, resulting in a high CR rate and bridging most patients to AHCT without chemotherapy. This trial was registered at www.clinicaltrials.gov #NCT03016871.

Autologous transplant vs chimeric antigen receptor T-cell therapy for relapsed DLBCL in partial remission.

The relative efficacy of autologous hematopoietic cell transplant (auto-HCT) vs chimeric antigen receptor T-cell (CAR-T) therapy in patients with diffuse large B-cell lymphoma (DLBCL) who achieve a partial remission (PR) after salvage chemotherapy is not known. Using the Center for International Blood & Marrow Transplant Research registry database, we identified adult patients with DLBCL who received either an auto-HCT (2013-2019) or CAR-T treatment with axicabtagene ciloleucel (2018-2019) while in a PR by computed tomography or positron emission tomography scan. We compared the clinical outcomes between the 2 cohorts using univariable and multivariable regression models after adjustment for relevant baseline and clinical factors. In the univariable analysis, the 2-year progression-free survival (52% vs 42%; P = .1) and the rate of 100-day nonrelapse mortality (4% vs 2%; P = .3) were not different between the 2 cohorts, but consolidation with auto-HCT was associated with a lower rate of relapse/progression (40% vs 53%; P = .05) and a superior overall survival (OS) (69% vs 47%; P = .004) at 2 years. In the multivariable regression analysis, treatment with auto-HCT was associated with a significantly lower risk of relapse/progression rate (hazard ratio = 1.49; P = .01) and a superior OS (hazard ratio = 1.63; P = .008). In patients with DLBCL in a PR after salvage therapy, treatment with auto-HCT was associated with a lower incidence of relapse and a superior OS compared with CAR-T. These data support the role of auto-HCT as the standard of care in transplant-eligible patients with relapsed DLBCL in PR after salvage therapy.

Polatuzumab vedotin plus bendamustine and rituximab or obinutuzumab in relapsed/refractory follicular lymphoma: a phase Ib/II study.

Follicular lymphoma (FL) is the most common type of indolent non-Hodgkin lymphoma. Despite treatment advances that have improved outcomes for patients with relapsed or refractory (R/R) FL, many patients still die from progressive disease or treatment-related toxicities. In the phase Ib/II GO29365 study (clinicaltrials.gov 02257567), the safety and efficacy of polatuzumab vedotin plus bendamustine and rituximab (Pola-BR) versus bendamustine and rituximab (BR) alone, and polatuzumab vedotin plus bendamustine and obinutuzumab (Pola-BG) as a single-arm cohort were evaluated in patients with R/R FL. Following the phase Ib safety run-in, patients were randomized 1:1 to receive Pola-BR or BR alone in the phase II stage; a separate non-randomized Pola-BG cohort was examined in the phase Ib/II expansion stage. Primary endpoints included safety and tolerability (phase Ib) and positron emission tomography complete response (PET-CR) rate by independent review committee (phase II). Overall, 112 patients were enrolled (phase Ib safety run-in: Pola-BR, N=6; phase II randomized cohort: Pola-BR, N=39; BR, N=41; phase Ib/II expansion cohort: Pola-BG, N=26). PET-CR rates were 66.7% (phase Ib safety run-in, Pola-BR); 69.2% (phase II randomized, Pola-BR); 63.4% (phase II randomized, BR); and 65.4% (phase Ib/II expansion Pola-BG). There was a higher occurrence of cytopenias with Pola-BR and Pola-BG than with BR; serious adverse events were more frequent with Pola-BR (61.4%) and Pola-BG (46.2%) than with BR (29.3%). Overall, this analysis does not demonstrate a benefit of adding Pola to BR or BG regimens for patients with R/R FL.

Results from a phase I trial of pembrolizumab plus vorinostat in relapsed/refractory B-cell non-Hodgkin lymphoma.

Outcomes after programmed death-1 (PD-1) blockade in B-cell lymphomas are disappointing with few durable responses. Histone deacetylase inhibitors exhibit favorable immunomodulatory effects and demonstrate synergistic anti-tumor immune responses with anti-PD-1 therapy in preclinical models. We, therefore, developed a phase I study to evaluate the safety and preliminary efficacy of pembrolizumab with vorinostat in relapsed/refractory B-cell lymphomas. Patients were treated in a dose-escalation cohort using a Rolling 6 design followed by an expansion cohort at the recommended phase II dose (R2PD). Fifty-two patients were enrolled (32 Hodgkin and 20 non-Hodgkin lymphoma [NHL]). Here, we report safety data from the dose escalation cohort, and the toxicity and efficacy within NHL patients. Vorinostat was administered twice daily on days 1-5 and 8-12 (dose-level [DL]1: 100 mg; DL2: 200 mg) and pembrolizumab (200 mg) was administered on day 1 of each 3-week cycle. Of six patients treated at DL1, one had a dose-limiting toxicity (DLT) (Stevens-Johnson syndrome [SJS]), and one of six had a DLT at DL2 (thromboembolism); therefore, DL2 was the RP2D. The patient developing SJS was treated with corticosteroids, infliximab, and cyclosporine but ultimately died of invasive fungal infection from the extensive immunosuppression used to treat the SJS. The most common adverse events were hypertension, diarrhea, and cytopenias. Of 20 NHL patients, nine had follicular lymphoma (FL) and 11 had diffuse large B-cell lymphoma (DLBCL). Five DLBCL patients had primary mediastinal B-cell lymphoma (PMBL). The complete and overall response rates (CR and ORR) were 11% and 22% for FL and 45% and 55% for all DLBCL. Amongst DLBCL, the CR and ORR was 80% and 80% for PMBL and 17% and 33% for non-PMBL. In conclusion, pembrolizumab with vorinostat was tolerable and produced responses in relapsed/refractory B-cell NHL, with particularly notable efficacy in PMBL (clinicaltrials gov. Identifier: NCT03150329).