Complete Responders Research Articles

Predictors of Response to Venetoclax Plus Hypomethylating Agent Therapy and Survival in Blast-Phase Myeloproliferative Neoplasm

Introduction Myeloproliferative neoplasms (MPN) with blast phase (BP) transformation (MPN-BP) are associated with shortened survival since most patients are elderly and unfit for intensive chemotherapy. Venetoclax (Ven) plus hypomethylating agent (HMA) is FDA approved for elderly/unfit acute myeloid leukemia, however MPN-BP patients were excluded from Ven+HMA clinical trials. Accordingly, in the current study, our main objective was to examine Ven+HMA treatment outcomes including the impact of karyotype and mutations on response and survival in MPN-BP. Methods Patients with MPN-BP that received Ven+HMA outside clinical trials at the Mayo Clinic between July 2018 and May 2022 were retrospectively recruited after institutional review board approval. Diagnosis of MPN-BP required the presence of ≥20% blasts in either the peripheral blood or bone marrow. Cytogenetic and molecular studies were performed by conventional karyotype, and next-generation sequencing, respectively. All patients received at least one cycle of Ven+HMA which included either azacitidine 75 mg/m2 days 1-7 or decitabine 20 mg/m2 days 1-5. Response was assessed according to the 2017 European Leukemia Net (ELN) criteria. ResultsPatient characteristics 47 patients with MPN-BP (median age 71 years, range 46-84; 60% males) received Ven+HMA either upfront (n=32) or following relapse (n=15). Antecedent MPN included ET/post-ET MF in 18 (38%), PV/post-PV MF in 16 (34%), and PMF in 13 (28%) patients. Driver mutation profile included JAK2 in 76% of the patients and CALR in 18%; other mutations included TP53 in 17 patients (39%), TET2 in 10 (23%), ASXL1 in 15 (34%), IDH1/2 in 12 (27%), EZH2 in 6 (14%), RUNX1 in 6 (14%), N/KRAS,SRSF2 and U2AF1 in 5 (11%) each. ELN cytogenetic risk was favorable (2%), intermediate (34%) or adverse (64%); among the latter, 55% were classified as complex. Response Thirty-one (66%) patients received decitabine and the remainder azacitidine with median Ven dose of 200 mg for a median of 3 cycles (range, 1-9 cycles). 21 (45%) patients experienced cycle delays/interruptions and treatment was complicated by neutropenic fever in 22 (47%) cases. CR or CRi was documented in 20 (43%) patients; 12 (26%) patients with CR and 8 (17%) with CRi, and residual morphological features of MPN were present in 10 patients. Among complete responders, median time to response was 1.7 months (range; 1-7 months), with median response duration of 5 months (range, 0.4-35 months). Relapse was documented in 9 (45%) of responding patients. Importantly, 7 of 13 (54%) transplant-eligible patients in CR/CRi, were bridged to transplant. CR/CRi rates were similar with upfront therapy or in the relapsed setting (47% vs 33%; p=0.38), azacitidine or decitabine (50% vs 39%; p=0.46), presence or absence of TP53 (41% vs 44%; p=0.83), ASXL1 (47% vs 41%, p=0.74), IDH1/2 (50% vs 41%; p=0.58), and K/NRAS mutations (20% vs 46%; p=0.25). CR/CRi was superior without vs with antecedent PV (55% vs 19%, p=0.01), presence vs absence of TET2 mutation (70% vs 35%, p=0.05), and absence of complex karyotype (60%, vs 29%, p=0.04). Multivariable analysis confirmed the favorable impact of TET2 mutation (p=0.02), and absence of antecedent PV (p=0.009) on CR/CRi. Moreover, CR/CRi was significantly higher in TET2 mutated vs unmutated patients without antecedent PV (83% vs 48%) and with antecedent PV (50% vs 9%) (p=0.01). Survival After a median follow up of 6 months (range, 1-37 months) from initiation of Ven+HMA, 31 (66%) patients have died. Median overall survival was 7 months (range; 1-37 months) and longer in transplanted patients (11 vs 6 months; p=0.04) (Figure). On univariate analysis, survival was superior in the absence of complex karyotype (10 vs 5 months, p=0.003), N/KRAS mutations (8 vs 4 months; p=0.02), with achievement of CR/CRi (10 vs 6 months; p=0.02), and transplant (11 vs 6 months, p=0.04). Multivariable analysis confirmed the favorable prognostic impact of absence of complex karyotype and N/KRAS mutations (p=0.003 and 0.03) (Figure). Conclusions The current study identifies MPN-BP patients with a higher likelihood of response (TET2 mutated without antecedent PV) and prolonged survival (absence of complex karyotype and N/RAS mutations) following treatment with Ven+HMA. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Identification of Molecular Mechanisms Governing CAR-T Cell Response in MM Patients Using Single Cell Transcriptomics

Background: CAR-T therapies have revolutionized cancer immunotherapy, especially for hematological malignancies, representing a promising advanced therapy for relapsed/refractory (R/R) multiple myeloma (MM) patients. Nevertheless, despite the high remission rates observed with BCMA CAR-T cells, not every patient achieves a complete response, and a significant number of patients still relapse. Application of single-cell technologies to study CAR-T cells has helped to shed light on important aspects of their expansion and evolution after administration. Methodology: CAR-T cells were FACS-isolated from infusion products (IP) as well as from bone marrow (BM) and peripheral blood (PB) from three MM patients (HCB08, IBS08 and HVA02), enrolled in the academic clinical trial CARTBCMA-HCB-01 (NCT04309981) assessing ARI0002h, an autologous CAR T-cell product targeting BCMA1, at different times after cell infusion (1 and 3 months). Single-cell analysis was performed using the Chromium Single-Cell Immune Profiling solution from 10X Genomics that allows simultaneous analysis of gene expression and paired T-cell receptors. Gene Regulatory Network (GRN) analysis was performed using SimiC, a novel computational method developed by our group, that infers regulatory dissimilarities2. Phenotypic analyses were performed by multidimensional flow cytometry. Results: scRNAseq analysis revealed that although CAR-T cells from IP presented similar phenotype, with CD4+ and CD8+ memory cells, and a high number of proliferative cells, CAR-T cells remaining after cell infusion were mainly resting CD8+ cells, with an effector/effector-memory phenotype. In addition, cell type distribution varied among patients, with a population of terminally differentiated effector cells in HCB08 patient, that presented a partial response and an early relapse, that increased from month 1 to 3 and presented a more exhausted phenotype. In contrast, IBS08 and HVA02 (complete responders) presented CD8+ cells in transition to central memory phenotype and a relatively constant pool of effector memory CD8+ CAR-T cells, respectively. Interestingly, CAR-T cells infiltrating BM presented increased expression of cytotoxic (GZMA, PRF1) and exhaustion (LAG3, HAVCR2, TIGIT) markers, compared to their PB counterparts. Functional characterization showed enrichment of T cell activation and cell-cell adhesion pathways in CAR-T cells from BM. GRN analysis at single-cell level with SimiC showed several regulons, such as IRF3 and PRDM1, presenting increased activity in BM. IRF3, a key transcriptional regulator of type I interferon response, was associated to DUSP2, IL32 and CCL5, genes associated to lymphocyte activation and inflammation. PRDM1, with crucial role in maintaining effector T cells homeostasis, was correlated with CST7, PRF1, MAP4K1 and CYTOR, genes associated with effector function and proliferation. All these data suggest that these regulons would be modulating the increased activation and inflammatory response of CAR-T cells observed in the BM. Further analysis using single-cell TCRseq allowed the identification of a hyperexpanded CAR-T cell clone in the BM of HCB08 patient (with an early relapse). Deeper characterization showed that this clone had higher expression of cytotoxicity (PRF1, GZMB) and activation markers (HLA-DRA, TNFRSF9). Strikingly, we also found increased expression of IL10, an immunosuppressor cytokine. Further analysis of this clone with SimiC showed increased activity of regulons from TFs related to exhausted CD8+ T cells (CREM, BHLHE40), meanwhile regulons from TFs associated to naïve and memory T cells (FOXP1, KLF2) had reduced activity. Interestingly, PRDM1, that is implicated in IL10 production in Treg, also presented increased activity in this clone. These data would suggest mechanistic insights regulating the phenotype of this hyperexpanded clone, that could represent a mechanism of therapeutic failure and/or early relapse. Conclusions: Overall, our data show that multiomic analysis are useful tools to characterize CAR-T cells and their dynamics after infusion, that presented different characteristics regarding their location (PB vs BM) and a heterogeneous behavior within the patients. Moreover, GRN analysis at single cell level offers an important tool to understand mechanisms modulating CAR-T cell response and to identify possible mechanisms of relapse. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Venetoclax in Combination with Hypomethylating Agents or Low-Dose Cytarabine for Relapsed/Refractory Acute Myeloid Leukemia: A Retrospective Single-Centre Experience

Background. Relapsed/refractory (R/R) acute myeloid leukemia (AML) is a largely unmet medical condition with an overall dismal outcome owing to the lack of standardized, effective treatment approaches. The only curative option for R/R AML patients (pts) is allogeneic hematopoietic stem cell transplantation (HSCT), that can be exploited in a minority of otherwise eligible pts due to poor efficacy and high toxicity of salvage regimens used to induce leukemia remission as bridge-to-transplant. Recently, a number of targeted agents with relatively favorable toxicity profiles have been explored in clinical trials for R/R AML pts. Since its first accelerated approval by the Food and Drugs Administration in 2018, the Bcl-2 inhibitor venetoclax (VEN), in combination with hypomethylating agents (HMA) or low dose cytarabine (LDAC), has steadily become the standard therapeutic approach for newly diagnosed AML in elderly or unfit pts, while its role in R/R disease is not well defined yet. Aim. To gain insights into the potential effectiveness of VEN-based regimens in patients with R/R AML. Patients. We retrospectively analyzed the clinical outcomes of 67 R/R AML pts treated at our Institution with venetoclax-based regimens on an off-label basis, between March 2018 and April 2022. Fifty-eight pts (87%) carried a de-novo AML diagnosis, 6 pts (9%) had AML secondary to myelodysplastic syndrome and 3 pts (4%) had therapy-related AML. Median age was 58y (33-74y); 30 pts (45%) were aged >60, while 7 pts (10%) were aged >70y at VEN initiation. Thirty-eight pts (56%) were treated for first (n=32) or second relapse (n=6); last complete remission (CR) duration was <6 mo in 18 pts, 6-12 mo in 16 pts and >12 m (12-56) o in 4 patients; 11 pts (16%) had relapsed after HSCT; remaining 18 pts (27%) were treated for primary refractory disease. All pts received conventional immunophenotypic and cytogenetic characterization and at least NPM1, FLT3, CBFB/MYH11 and RUNX1/RUNX1T1 mutation/rearrangement detection. Next-generation sequencing (NGS) data were available for 56 pts (83%); specifically, 40 pts (primary refractory, n=18; relapsed, n=22) had NGS analysis carried out on bone marrow samples shortly before VEN initiation, while in 16 pts NGS was carried out on baseline diagnostic specimens. VEN partner drug was azacitidine in 45 pts (68%), LDAC in 15 (22%) and decitabine in 7 (10%). Thirty-nine pts (58%) were treated with an intention-to-transplant (ITT). Median follow-up duration was 11.8 mts (1.1 - 44). Results. Overall, we report a composite complete response (CCR) rate of 55% (n=37); 10 of complete responders (27%) had incomplete peripheral counts recovery. Minimal residual disease (MRD) negativity was achieved in 21/37 pts (56%). All CR invariably occurred during the first 8 weeks of treatment. Although it did not reach significance level (p=0.065), there was considerable variation in CCR rate among treatment settings: relapsed pts, 66%; primary refractory, 50%; post-HSCT relapse, 27%. Conventional risk stratification parameters (age, leukocyte counts, ELN 2017 risk category, NPM1/FLT3 mutational status, secondary disease, last CR duration) were poorly predictive of CR probability. A positive trend towards higher CCR rate, although not statistically significant, was found for NPM1 (CCR rate: 57%) and IDH1/2 mutation (66%) while FLT3/Ras pathway mutations were detrimental (23%). Median overall survival (OS) but not event-free survival (EFS), differed significantly among settings: relapsed pts, 11.9 mo; refractory, 8.6 mo; post-HSCT, 6.7 mo. (p=0.030). Stratifying pts based on NPM1 and FLT3-ITD status resulted in markedly different EFS: NPM1mut/FLT3-ITDneg, not reached; NPM1wt/FLT3any, 6.2 mo; NPM1mut, FLT3-ITDpos, 3.4 mo (p=0.031); as well as different OS: NPM1mut/FLT3-ITDneg, not reached; NPM1wt/FLT3any, 10.5 mo; NPM1mut, FLT3-ITDpos, 5.6 mo (p=0.003). Among the ITT population, HSCT actualization rate was 66%. Four pts are currently long-term survivors with follow-up exceeding 24 mo without receiving HSCT; notably, they all carried a NPM1mut/FLT3-ITDneg/Ras pathwayneg genotype. Conclusions: Overall, these findings suggest a role for venetoclax-based regimens in R/R AML patients and support the design of prospective studies. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epcoritamab Monotherapy Provides Deep and Durable Responses Including Minimal Residual Disease (MRD) Negativity: Novel Subgroup Analyses in Patients with Relapsed/Refractory (R/R) Large B-Cell Lymphoma (LBCL)

Background: Epcoritamab, a subcutaneously administered (SC) bispecific CD3xCD20 antibody, has shown potent antitumor activity as a single agent and in combination. Results of the EPCORE NHL-1 LBCL expansion cohort demonstrated clinically meaningful and compelling efficacy across a highly refractory population and a manageable safety profile, consistent with prior findings (Thieblemont et al, EHA 2022). Here, we present additional subgroup data on the efficacy and safety of epcoritamab in the LBCL expansion cohort of the EPCORE NHL-1 phase 2 trial (NCT03625037). Methods: Adults with R/R CD20+ LBCL were treated with 1-mL SC priming and intermediate doses, followed by full doses of epcoritamab in 28-d cycles (QW: cycles 1-3; Q2W: cycles 4-9; Q4W: cycles ≥10). Step-up dosing and corticosteroid prophylaxis were administered in cycle 1 to mitigate CRS. Prespecified and exploratory subanalyses were performed; response was assessed by independent review committee. Results: As of Jan 31, 2022, 157 patients (pts) with LBCL, including double/triple-hit (DH/TH) lymphoma, were treated. Per protocol there was no minimum life expectancy requirement. Median age was 64 y (range, 20-83), median number of prior lines of therapy was 3 (range, 2-11), and median time from initial diagnosis was 1.6 y. Overall, 39% of pts had received prior CAR T, 20% had prior autologous stem cell transplantation, and 61% had primary refractory disease; 14% of pts with diffuse LBCL (DLBCL; 12/88 tested) were confirmed DH/TH by central FISH. At a median follow-up of 10.7 mo, the overall response rate (ORR) for the total population was 63%, with a complete response (CR) rate of 39%. The median duration of response (mDOR) was 12.0 mo (95% CI, 6.6-not reached [NR]) overall. In subgroup analyses, mDOR was NR (95% CI, 2.8-NR) for primary refractory pts, 9.7 mo (95% CI, 5.4-NR) for pts with prior CAR T, 12.0 mo (95% CI, 5.6-NR) for CAR T-naive pts, and 12.0 mo (95% CI, 1.1-NR) for DH/TH pts. Responses occurred early, with a median time to response of 1.4 mo. The mDOR in pts who achieved a CR was 12 mo for DH/TH pts and not reached in other subgroups. MRD negativity was assessed by a ctDNA NGS assay in this LBCL population with 52 of 112 evaluable pts (46.4%) being MRD negative at any time point on treatment. MRD negativity was reached early (median of 8 wk for complete responders), and high MRD negativity rates were observed across all subpopulations: 50% in pts with prior CAR T, 44% in CAR T-naive pts, 33% in DH/TH pts, and 49% in non-DH/TH pts. MRD-negative responses were durable (Table) and correlated with PFS. Durability of CR was also demonstrated in a cohort of pts with DLBCL from the dose-escalation portion of this trial with extended follow-up (median, 21.1 mo; longest follow-up, 26.7 mo), of which 6 pts (at ≥12 mg) remain on Q4W treatment and in CR, with median duration of CR not reached. Overall, epcoritamab was well tolerated. Incidence of AEs declined after wk 12, and only 1 pt experienced any related serious treatment-emergent AE after wk 12 (CRS grade 1/2). CRS was reported in 78 pts (49.7%), and all but 1 event resolved. Events were primarily low grade (31.8% grade 1, 15.3% grade 2, and 2.5% grade 3), and timing was predictable, with 5.7% of pts experiencing CRS after the priming dose, 11.8% after the intermediate dose, 42.9% after the first full dose, 4.9% after the second full dose, and 2.9% after the third full dose or later doses. Median time to CRS onset after the first full dose was 20.0 h (range, 12-126). Ten pts had ICANS events; 9 events were grade 1 or 2, and there was 1 grade 5 event (the only treatment-related death, pt with multiple confounding factors). All but 1 ICANS event occurred in cycle 1. There were 8 pts (5%) who experienced both CRS and ICANS. Grade 3 or 4 neutropenia occurred in 33 pts (21.0%; 10.8% grade 3, 10.2% grade 4). Grade 3 anemia was reported in 16 pts (10.2%). Few pts discontinued epcoritamab treatment due to AEs (n=11). Notably, there were no treatment discontinuations due to neutropenia or anemia. Conclusions: SC epcoritamab is a convenient, off-the-shelf therapy that has demonstrated deep and durable responses including high MRD negativity rates as a single agent. The safety profile was favorable, and CRS events were mostly low grade and transient, with most events occurring after the first full dose. These subgroup analyses demonstrate consistent, clinically meaningful activity of epcoritamab across subgroups of pts with R/R LBCL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Immune-based biomarker accurately predicts response to imiquimod immunotherapy in cervical high-grade squamous intraepithelial lesions

BackgroundThe complete response rate of cervical high-grade squamous intraepithelial lesion (cHSIL) patients to imiquimod immunotherapy is approximately 60%. Consequently, many patients are exposed to unnecessary adverse effects of imiquimod. On...

462P Limited duration of treatment with checkpoint inhibitors in complete responders, yet prolonged survival: A real-world study from India

Immune checkpoint inhibitors have revolutionised the treatment of malignancies particularly in metastatic setting with increased response rates and improved survival rates . Studies have shown that those with complete response tend to have a prolonged duration of response. However there is data lacking particularly in the Indian setting with regard to the duration of treatment in those who achieve a complete response (CR).

GSOR18 Presentation Time: 11:55 AM: Obesity and Skin D2cc Predict for Radiation Necrosis After Interstitial Brachytherapy Boost in Locally Advanced Vulvar Cancer

<h3>Background</h3> Interstitial brachytherapy (ISBT) has been increasingly utilized in treating locally advanced as well as locally recurrent vulvar cancer. However, the risk of BT-associated grade 3 or 4 skin necrosis is largely underreported, owing to the rarity of the disease. The purpose of this investigation was to evaluate therapeutic benefit of BT boost and risk of necrosis in a relatively large subset of patients with locally advanced vulvar cancer. <h3>Methods</h3> Patients with vulvar cancer treated with radiation therapy at Upstate Medical University between January 1, 2014 and July 1, 2021 were retrospectively analyzed. Demographics, oncologic history, external beam and BT dosimetry details, clinical outcomes, and CTCAE graded skin toxicities were evaluated and compared across individuals receiving external beam radiation (EBRT) only versus EBRT+brachytherapy (EBRT+BT). <h3>Results</h3> Of the 33 patients with vulvar cancer included, the median age of the cohort was 65.5 years; 97% were non-Hispanic Caucasian. Median follow-up was 31.1 months (2 patients were lost to follow-up and 11 patients were deceased at the time of analysis). The majority of patients had FIGO stage III and IV disease (24/33, 73%); however, stage IV was more frequent among patients treated with EBRT+BT (9/15, 60%; p=0.03). A total of 6 patients were being treated for recurrent disease and 27 with definitive intent. In this cohort, 15 patients received only EBRT and 18 received EBRT+BT. There was a greater proportion of patients with history of smoking in the EBRT+BT group (87% vs. 56%, p=0.05); and the percentage of active smokers was numerically greater in the EBRT+BT group (54% vs. 20%, p=0.09). The median dose of EBRT alone was 6120 cGy (4500-7000 cGy) and the median dose of EBRT for patients receiving BT was 5040 cGy (4500-6750 cGy). Median BT prescription was 2500 cGy over 5 fractions twice daily (1600-3000 cGy). Overall (n=31), there were 6 cases of grade 3 (19%) and 7 of grade 4 (23%) radiation-related skin toxicity including ulceration and/or necrosis. Grade 4 toxicities were exclusively cited among patients treated with BT (7/7, 100%, p=0.014). There were 10 (33%) cases of necrosis: 3 in the EBRT group and 7 in the EBRT+BT group (50%, p=0.07). The odds of developing necrosis were greater among women treated with BT, OR=4.3, CI (0.85-22.23). Obese patients (BMI ≥ 30 kg/m2) had 15 times the odds of developing necrosis from BT as compared to non-obese patients, OR=15.0, 95% CI (1.03-218.3). The risk of BT-related necrosis was even greater in obese smokers, OR=20.0, (1.4-282.5). Patients with grade 4 skin necrosis had a mean skin D2cc of 139%, whereas those with grade 1 or 2 toxicity had a mean D2cc of 79.8% (p=0.001). Overall response to treatment, either partial or complete, appeared to be greater in the BT group (92% vs. 81%, p=0.14). Clinically, a greater proportion of patients receiving BT achieved complete response (77% vs. 65%, p=0.312). Complete responders had a significantly lower BMI (30.3 kg/m²) than non-responders (36.2 kg/m²) and partial responders (37.2 kg/m²) (p=0.05). <h3>Conclusion</h3> ISBT for locally advanced vulvar cancer appears to provide an improvement in overall response to therapy. Toxicity appears greatest in obese patients who are active smokers. Additionally, skin D2cc greater than 130% of prescribed dose appears to correlate with increased risk of grade 4 skin necrosis. These clinical and dosimetric factors should be taken into account when utilizing ISBT for vulvar cancer.

TIME TO CLINICALLY MEANINGFUL RESPONSE TO OMALIZUMAB IN PATIENTS WITH CHRONIC SPONTANEOUS URTICARIA

<h3>Introduction</h3> Chronic spontaneous urticaria (CSU) is a debilitating skin disorder associated with decreased quality of life and psychological comorbidities. Omalizumab is currently the only biologic approved for the treatment of CSU, however data is lacking describing the pattern of response to omalizumab, including the time to a clinically meaningful response. <h3>Methods</h3> Post-hoc analysis examined pooled data from ASTERIA-I (N=319; NCT01287117) and ASTERIA-II (N=323; NCT01292473; for both studies - injections every 4 weeks of omalizumab 150mg, 300mg, or placebo). Time to minimally important difference (MID) (reduction from baseline ≥11) analyses were performed via Kaplan-Meier curves, and percent responders/complete responders to 12 weeks (weekly). Responders were defined as Urticaria Activity Score (UAS; range 0 [no symptoms] to 42)7≤6; complete responders defined as UAS7=0. <h3>Results</h3> Time to MID analyses revealed statistical superiority of omalizumab compared with placebo (P<0.0001 for both doses); median time to MID, 5 weeks for placebo and 2 weeks for 150mg/300 mg omalizumab (Figure). The percent of responders/complete responders to omalizumab increased dose-dependently over time. At Week 1, percent of responders was greater for omalizumab (150mg 6.2%, 300mg 6.3%) than placebo (1.9%). By Week 12, percent of both responders and complete responders was greater for omalizumab (150mg 41.4%/18.5%, 300mg 58.8%/40.0%) than placebo (15.1%/6.9%). Overall safety results are available (Saini JID 2015;135;67-75; Maurer NEJM 2013;368:924-935). <h3>Conclusions</h3> Patients with moderator-severe CSU on omalizumab had a significantly superior time to clinically meaningful response compared with placebo, and improvements in urticaria symptoms were observed as early as 1 week after omalizumab initiation.

COVID-19 vaccination in autoimmune diseases (COVAD) study: vaccine safety and tolerance in rheumatoid arthritis.

The COVID-19 vaccination in autoimmune diseases (COVAD) study aimed to assess short-term COVID-19 vaccination-related adverse events (AEs) in RA patients. An online self-reported questionnaire (March-December 2021) was used to capture data related to COVID-19 vaccination-related AEs in RA, other autoimmune rheumatic diseases (AIRDs) (excluding RA and inflammatory myositis), non-rheumatic autoimmune diseases (nrAIDs) and healthy controls (HCs). Descriptive and multivariable regression analyses were performed. Of the 9462 complete respondents, 14.2% (n = 1347) had been diagnosed with RA; they had a mean (s.d.) age of 50.7 (13.7) years, 74.2% were women and 49.3% were Caucasian. In total, 76.9% and 4.2% of patients with RA reported minor and major AEs, respectively. Patients with active and inactive RA had similar AE and hospitalization frequencies. Overall, AEs were reported more frequently by BNT162b2 and mRNA-1273 recipients and less frequently by BBV152 recipients compared with the rest. Major AE and hospitalization frequencies were similar across recipients of different vaccines. Patients receiving methotrexate and hydroxychloroquine reported fewer minor AEs than those patients not on them. Compared with HCs and patients with other AIRDs, patients with RA reported similar total AEs, overall minor AEs, and hospitalizations. Compared with nrAIDs, patients with RA reported lower frequencies of overall AEs, minor AEs (both odds ratio [OR] = 0.7; 95% CI: 0.5, 0.9), and injection site pain (OR = 0.6; 95% CI: 0.5, 0.8) with similar major AE and hospitalization frequencies. Despite the differences in AE frequency across different COVID-19 vaccines, all were well tolerated in patients with RA and were comparable to HCs, providing reassurance as to the safety of COVID-19 vaccination.

Multiple Imputation to Salvage Partial Respondents: Analysis of the Forgotten Joint Score-12 After Total Hip Arthroplasty.

Missing responses are common when Asian patients complete the Forgotten Joint Score-12 (FJS-12), which is widely used to evaluate total hip arthroplasty (THA). We aimed to provide orthopaedic researchers with a solution for handling missing values in such patient-reported outcome measures (PROMs). Patients who had undergone primary THA between 1998 and 2016 (n = 1,021) were investigated in 2020. The FJS-12 and 9 other PROMs, including questions related to Asian lifestyle activities, were administered. Risk factors for missing FJS-12 items were investigated. Partial respondents were matched with complete respondents; then, in each pair, the items not completed by the partial respondent were deleted from the responses of the complete respondent. Predictive mean matching (PMM) was performed in an attempt to recover the deleted items, using 65 sets of imputation models. After the missing values had been imputed, we explored patient characteristics that affected the FJS-12, using data from all complete and partial respondents. A total of 652 patients responded to the survey (393 complete and 193 partial respondents). Partial respondents were older, more often female, and less active. Older respondents were more likely to skip items involving the bed, while those who reported a better ability to sit in the seiza style (traditional Japanese floor sitting) were more likely to skip items about chair sitting. The imputed FJS-12 value exhibited excellent reliability (intraclass correlation coefficient for agreement with the true scores, 0.985). FJS-12 values of complete respondents were significantly higher than those of respondents with 4 to 11 missing items (51.6 versus 32.8, p < 0.001). Older age was associated with higher FJS-12 values, which was revealed only via analysis of the multiply imputed data sets (p < 0.001). Analysis of only complete FJS-12 responses after THA resulted in a nonresponse bias, preferentially excluding older, female, and less active individuals and those with a traditional floor living style. Multiple imputation could provide a solution to scoring and analyzing PROMs with missing responses by permitting the inclusion of partial respondents. Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Dual Oxidase 2 (DUOX2) as a Proteomic Biomarker for Predicting Treatment Response to Chemoradiation Therapy for Locally Advanced Rectal Cancer: Using High-Throughput Proteomic Analysis and Machine Learning Algorithm.

High-throughput mass-spectrometry-based quantitative proteomic analysis was performed using formalin-fixed, paraffin-embedded (FFPE) biopsy samples obtained before treatment from 13 patients with locally advanced rectal cancer (LARC), who were treated with concurrent chemoradiation therapy (CCRT) followed by surgery. Patients were divided into complete responder (CR) and non-complete responder (nCR) groups. Immunohistochemical (IHC) staining of 79 independent FFPE tissue samples was performed to validate the predictive ability of proteomic biomarker candidates. A total of 3637 proteins were identified, and the expression of 498 proteins was confirmed at significantly different levels (differentially expressed proteins-DEPs) between two groups. In Gene Ontology enrichment analyses, DEPs enriched in biological processes in the CR group included proteins linked to cytoskeletal organization, immune response processes, and vesicle-associated protein transport processes, whereas DEPs in the nCR group were associated with biosynthesis, transcription, and translation processes. Dual oxidase 2 (DUOX2) was selected as the most predictive biomarker in machine learning algorithm analysis. Further IHC validation ultimately confirmed DUOX2 as a potential biomarker for predicting the response of nCR to CCRT. In conclusion, this study suggests that the treatment response to RT may be affected by the pre-treatment tumor microenvironment. DUOX2 is a potential biomarker for the early prediction of nCR after CCRT.

Long-Term Follow-Up Evaluation of Efficacy in Alpha-Emitting Radiation Therapy on Recurrent and Locally Advanced Squamous Cell Carcinomas in Multi-Center Clinical Study

<h3>Purpose/Objective(s)</h3> Diffusing Alpha-emitter Radiation Therapy (DaRT) represents a novel method to deliver alpha particles intratumorally via the decay of Radium-224. Early results demonstrated the feasibility, safety, and efficacy of DaRT with an associated 100% overall response rate at six weeks and a favorable toxicity profile. The purpose of the study was to report the long-term tumor control outcomes of DaRT for the treatment of locally advanced and recurrent squamous cancers (SCC) of the skin and head and neck. <h3>Materials/Methods</h3> This retrospective study evaluated the outcomes of patients with histologically-confirmed SCC of the skin and head and neck who either previously failed or were medically unfit for definitive therapy. For this study, 28 lesions in 23 patients were eligible and treated per protocol. Treatment was delivered via a percutaneous interstitial technique with placement of the radioactive DaRT to encompass the tumor volume with margin. Tumor control was assessed using serial radiographic imaging or clinical assessments. The median follow-up time was 28 months following treatment. <h3>Results</h3> Complete response to the Ra-224 DaRT treatment was observed in 22 lesions (22/28; 79%); 6 lesions (6/28, 21%) manifested a partial response. Among the 22 lesions with a CR, 9 (41%) developed a subsequent local relapse at the site of DaRT implantation at a median time of 6.2 months (range: 2.8-35.4 months). The 2-year local progression-free survival (PFS) probability at the implanted site was 50% (95% Confidence Interval, CI: 28-68%) for complete responders. The 2-year overall survival rates post-DaRT implantation was 65% (95% CI: 42%-81%) among all patients and was 77% (95% CI: 50%-91%) among complete responders. <h3>Conclusion</h3> Despite prior therapy among these recurrent, locally advanced tumors, Ra-224 DaRT treatment was well tolerated and associated with excellent 2-year tumor control outcomes. A pivotal US trial for marketing approval is already underway.

Development of a Reactive Stroma Gene Signature (RSGS) Score to Characterize the Longitudinal Cellular and Molecular Alterations in the Tissue Microenvironment of Locally Advanced Cervical Cancer in Response to Radiotherapy at Single-Cell Resolution

<h3>Purpose/Objective(s)</h3> Understanding how the tumor-associated tissue microenvironment impacts and reflects the response and effectiveness of chemoradiotherapy in cervical and vaginal cancer will open avenues for future clinical interventions and appropriate selection of radiation dose delivered via brachytherapy. <h3>Materials/Methods</h3> Biopsies of tumor and adjacent normal tissue from 7 cervical and vaginal cancer patients were collected longitudinally at baseline and after 45 Gy of ionizing radiation (IR) and analyzed by single-cell RNA sequencing to better understand the tumor, immune, and stromal determinants of response and resistance. Five of the 7 patients had biopsies available at 3 months and were included in this analysis. The single-cell transcriptomes of 4 cervical cancer patients (adenocarcinomas N=3, squamous cell carcinoma N=1) and one patient diagnosed with vaginal cancer (squamous cell carcinoma) were characterized. <h3>Results</h3> Of 5 patients evaluated at 3 months following high-dose-rate brachytherapy, 3 had a complete response, one had persistent disease and one had distant relapse in the peritoneum. Collectively, over 70,000 cells were analyzed in this study. We compared the single-cell transcriptomes of 2 poor responders versus 3 patients with a complete clinical response. The tumor tissue of poor responders had a molecular and cellular signature indicative of a reactive stroma (VCAM1+ fibroblasts, CXCR4+ endothelial cells, and elevated expression of select collagens), with infiltration of immunosuppressive lymphoid and myeloid cells. We developed a reactive stroma gene signature (RSGS) score, which was enriched in cells from irradiated tumor biopsies collected from subjects with poor outcomes. In contrast, the RSGS score was consistently low in normal biopsies at both baseline and post-IR across all subjects, with one exception. The subject with distant relapse showed RSGS score enrichment in the normal post-IR biopsy. When evaluating the cell proportions of immune cell populations, we observed that the abundance of mast cells was consistently lower (< 0.05%) in normal biopsies at both baseline and post-IR. Likewise, the proportion of mast cells in post-IR biopsies was also low in subjects with complete responses. However, in subjects with poor outcomes, the mast cell abundance increased at least three-fold compared to matched baseline tumor biopsies. <h3>Conclusion</h3> Importantly, the findings stemming from this study suggest that treatment-refractory disease upregulated tumor-promoting stromal and immune responses after initiating radiotherapy that was not observed in the tumor microenvironments of complete clinical responders; thus nominating molecular factors that can potentially be therapeutically exploited to improve the efficacy of radiation-based therapies in patients diagnosed with cervical and vaginal cancer. Future studies with larger cohorts enabled by more scalable in situ approaches will be necessary to assess the generalizability of these findings.

Convolutional Neural Network Classification of Pretreatment Biopsies of Rectal Adenocarcinoma Predicts Complete Clinical Response to Short-Course Radiation and Consolidation Chemotherapy

<h3>Purpose/Objective(s)</h3> Nonoperative treatment of rectal cancer (RCa) with short course radiation (SCRT) (25 Gy in 5 fractions) followed by chemotherapy results in high treatment efficacy while maintaining rectal function. Identifying patients likely to experience a complete response to nonoperative management could prevent overtreatment with chemotherapy and reduce the risk of metastatic progression for incomplete responders. We constructed a convolutional neural network (CNN) classifier of pre-treatment histopathological images to identify patients who will experience a complete response to SCRT and consolidation chemotherapy. <h3>Materials/Methods</h3> Image files of hematoxylin and eosin-stained pre-treatment rectal adenocarcinoma biopsies (n=15) were acquired using the Zeiss microscopy software suite. Files were segmented using grid tools in the ZEN software package. Grid images comprised largely of whitespace were manually removed. Grid images were exported to .jpeg format, preserving micron scale pixel resolution. This analysis utilized 32 .jpeg images belonging to complete responders and 37 .jpeg images belonging to partial responders as the basis for data augmentation to generate a more robust training cohort. We employed the architecture and weights of the well-known VGG16 model with fine tuning of the later layers of the model during training. Regularization, dropout, and early stopping were implemented to prevent overfitting. <h3>Results</h3> Utilizing the VGG16 model with frozen nodal weights resulted in poor classification accuracy and failure to improve via monitoring loss function (training accuracy: 0.3152, validation accuracy: 0.33). Unfreezing, or pruning, after the 7th layer of the VGG16 model and allowing fine tuning of the transferred architecture improved this approach. Later network architectural layers are hypothesized to represent the most sophisticated image features. When nodal weights in VGG16's later layers were allowed to be updated based on training from histopathological slide images the classifiers accuracy improved (training accuracy: 0.9457, validation accuracy: 0.944). Further, loss function was reliably minimized (Epoch 10 validation set binary cross-entropy loss: 0.610, Epoch 50 validation set binary cross-entropy loss: 0.0648). <h3>Conclusion</h3> This is the first study to utilize imaging features extracted by a CNN to predict biological behavior or responsiveness to therapy in rectal cancer. We demonstrated that a transfer learning and layer pruning approach outperforms classical transfer learning utilizing previously deeply trained architectures. While future studies to refine and validate this CNN classifier are warranted, deep learning methods can play a role in preventing overtreatment vs metastatic progression in patients receiving SCRT for RCa.

Long-term efficacy and safety of osilodrostat in Cushing’s disease: final results from a Phase II study with an optional extension phase (LINC 2)

BackgroundMany patients with Cushing’s disease (CD) require long-term medical therapy to control their hypercortisolism. In the core phase of a Phase II study (LINC 2; NCT01331239), osilodrostat normalized mean urinary free cortisol (mUFC) in 78.9% of patients with CD. Here, we report long-term efficacy and safety data for osilodrostat following completion of an optional extension to LINC 2.MethodsAdult patients with CD were enrolled in a 22-week prospective Phase II study. Patients with mUFC ≤ upper limit of normal (ULN) or receiving clinical benefit at week 22 could enter the optional extension. The proportion of complete (mUFC ≤ ULN) or partial (mUFC > ULN but ≥ 50% decrease from baseline) mUFC responders was assessed over time.ResultsSixteen of 19 enrolled patients entered the extension. Median (range) osilodrostat exposure from baseline to study end was 5.4 years (0.04–6.7); median (range) average dose was 10.6 mg/day (1.1–47.9). Overall response rate (complete and partial mUFC responders) was consistently ≥ 50%. Sustained control of most cardiovascular-related parameters was observed during the extension. The long-term safety profile was consistent with that reported during the core phase. Testosterone levels (females) decreased towards baseline levels during long-term follow-up, with no new or worsening cases of hirsutism during the extension.ConclusionsIn the longest prospective study of a steroidogenesis inhibitor to date, osilodrostat provided sustained reductions in mUFC for up to 6.7 years of treatment, with no new safety signals emerging during the extension. These findings support osilodrostat as an effective long-term treatment for patients with CD.

Endoscopy and MRI for restaging early rectal cancer after neoadjuvant treatment.

Chemoradiotherapy (CRT) has great potential to downstage rectal cancer. Response assessment has been investigated in locally advanced rectal cancer but not in early stage rectal cancer. The aim is to characterize the diagnostic accuracy of endoscopy performed by surgical endoscopists compared to (diffusion-weighted, DWI) MRI only and a multimodal approach combining (DWI-)MRI and endoscopic information both analysed by an abdominal radiologist for response assessment in early rectal cancer after neoadjuvant CRT. Patients treated with neoadjuvant CRT for early distal rectal cancer (cT1-3N0) followed by transanal endoscopic microsurgery were included. Three separate reassessment groups were analysed for response assessment using endoscopic evaluation alone versus (DWI-)MRI alone versus the combination of endoscopy with (DWI-)MRI with a focus on sensitivity and specificity and analysis using receiver operating characteristic curves. Three cohorts (N= 36, N= 25 and N= 25, respectively) were analysed for response assessment. Of the endoscopy cohort, 16 of the 36 patients had a complete response. Area under the curve was 0.69 (0.66-0.74; pooled sensitivity 55.3%, pooled specificity 80.0%). Agreement for scoring separate endoscopic features was poor to moderate. Of the (DWI-)MRI cohort, 11 of the 25 patients had a complete response. Area under the curve for (DWI-)MRI alone was 0.55 (sensitivity 72.7%, specificity 42.9%). The areas under the receiver operating characteristic curve improved to 0.68 (sensitivity 90.9%, specificity 75.0%) when (DWI-)MRI was combined with endoscopic information, with 11 out of 25 patients with a complete response. The most accurate response assessment was made by combining endoscopy and (DWI-)MRI with a high negative predictive value (90.9%). Good and complete responders after chemoradiation of early stage rectal cancer can be best assessed using a multimodality approach combining endoscopy and (DWI-)MRI.

ABCL-422 Subcutaneous Epcoritamab in Patients With Relapsed or Refractory Large B-Cell Lymphoma (EPCORE NHL-1): Pivotal Results from a Phase 2 Study

Treatment options that are more tolerable, readily available, and capable of inducing deep and durable responses are needed in patients with relapsed or refractory (R/R) large B-cell lymphoma (LBCL). Epcoritamab is a novel, subcutaneous (SC) CD3xCD20 bispecific antibody with preliminary potent antitumor activity. Report primary results from the LBCL expansion cohort in the phase 2 study of SC epcoritamab in patients with R/R B-cell NHL (EPCORE NHL-1; NCT03625037). Adults with R/R CD20+ LBCL were included. Patients had DLBCL (including double/triple-hit and transformed), high-grade B-cell lymphoma (HGBCL), primary mediastinal LBCL (PMBCL), or follicular lymphoma (FL) grade (G) 3B. As of January 31, 2022, 157 patients were treated. Patients received epcoritamab (priming and intermediate doses followed by 48 mg) as 1-mL SC injections (QW, cycle [C] 1-3; Q2W, C4-9; Q4W, C≥10) until disease progression or unacceptable toxicity. The 157 patients had a median of 3 (range, 2-11) prior lines of therapy (LOT), 61 (38.9%) received prior CAR T, 61% had primary refractory disease, and 83% were refractory to the last LOT. With a median follow-up of 10.7 mo, the overall response rate (ORR) by IRC (Lugano/PET-CT) was 63% with 39% complete response (CR). ORR/CR rates were 69%/42% for CAR T-naive patients and 54%/34% for CAR T-exposed patients. Median duration of response was 12 mo overall and not reached among complete responders. ORR was similar across prespecified subgroups of age, prior LOT, and de novo or transformed disease. The most common treatment-emergent AEs were CRS (49.7%; 31.8% G1, 15.3% G2, 2.5% G3), pyrexia (23.6%), fatigue (22.9%), neutropenia (21.7%), and diarrhea (20.4%). Ten patients (6.4%) experienced ICANS; all but one event was G1-2, and the G5 ICANS was the only treatment-related death. Epcoritamab is a convenient, SC, off-the-shelf therapy that demonstrated clinically meaningful, compelling efficacy including deep and durable responses in a challenging-to-treat, highly refractory LBCL population. Efficacy was observed in both CAR T-exposed and CAR T-naive patients. The safety profile was manageable and consistent with previous findings. This study was funded by Genmab A/S and AbbVie.

IBCL-249 Mosunetuzumab Monotherapy Is an Effective and Well-Tolerated Treatment Option for Patients With Relapsed/Refractory (R/R) Follicular Lymphoma (FL) Who Have Received ≥2 Prior Lines of Therapy: Pivotal Results From a Phase I/II Study

In a Phase I/II study (NCT02500407), escalating doses of the CD20xCD3 bispecific antibody mosunetuzumab were active and well-tolerated in patients with R/R FL and ≥2 prior therapies. Report pivotal Phase II expansion results. All patients had R/R FL (Grade 1-3a) and ≥2 prior therapies, including an anti (a)-CD20 therapy and alkylating agent, and an ECOG PS of ≤1. Mosunetuzumab was given intravenously in 21-day cycles with C1 step-up dosing for CRS mitigation (C1D1: 1mg; C1D8: 2mg; C1D15 and C2D1: 60mg; D1 of C3+: 30mg). Hospitalization was not mandatory. Mosunetuzumab was continued for 8 (CR by C8) or 17 cycles (PR/SD by C8). The primary endpoint was CR rate (best response) by Independent Review. As of March 15, 2021, 90 patients had been enrolled (median age: 60 years; median number of prior therapies: 3); 68.9% were refractory to their last therapy, 78.9% to any prior aCD20 therapy, and 53.3% to any prior aCD20 therapy and alkylating agent (double refractory). 52.2% had POD24. Median follow-up was 12.9 months. ORR (CR/PR) and CR rates in all patients were 78.9% and 57.8%, respectively. Rates were comparable in POD24 (83% and 55%, respectively) and double-refractory patients (69% and 48%). At cut-off, 12-month event-free rates after first response were 65.4% in responders and 80.1% in complete responders. Median PFS was 17.9 months. CRS (44.4% by ASTCT 2019 criteria) occurred primarily in C1 and was predominantly Grade 1-2 (42.2%). Grade 3-4 CRS occurred in 2 patients. No Grade 5 (fatal) CRS events occurred. All CRS events resolved. Other AEs (≥20%) were fatigue (36.7%), headache (31.1%), neutropenia and pyrexia (28.9% each), hypophosphatemia (22.2%), and pruritus (21.1%). Grade 3-4 AEs (≥5%) were neutropenia (26.6%), hypophosphatemia (13.3%), hyperglycemia and anemia (7.8% each), and elevated ALT (5.6%). Grade 5 AEs were malignant neoplasm progression and unexplained death (both events mosunetuzumab unrelated). AEs leading to mosunetuzumab discontinuation occurred in 4 patients (4.4%). Mosunetuzumab induces high CR rates and durable remissions in patients with R/R FL and ≥2 prior therapies. Mosunetuzumab has favorable safety, allowing administration without mandatory hospitalization.

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (<pT2pN0) and pathologic complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders (<ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P< .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years, and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences were infrequent. Median progression-free survival (PFS) and OS for M1 disease were 6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients. Loss of ERCC2 function was significantly enriched among those with pathologic complete response to NAC (mutations present in 50% of pathologic complete responders vs. 15% nonresponders, P = .045). M0 SCCB is chemo-sensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC.

Effectiveness of Low-Dose Mepolizumab in the Treatment of Eosinophilic Granulomatosis with Polyangiitis (EGPA): A Real-Life Experience

Introduction: Data showing effectiveness of mepolizumab in patients with eosinophilic granulomatosis with polyangiitis (EGPA) are limited. Methods: This is a single-center retrospective chart review of patients with EGPA treated with mepolizumab. Clinical, laboratory, functional parameters and asthma, rhinitis control, and quality of life scores (Asthma Control Test [ACT], Asthma Quality of Life Questionnaire [AQLQ], Rhinoconjunctivitis Quality of Life Questionnaire [RQLQ], and SinoNasal Outcome Test [SNOT]-22) were evaluated at the baseline, 6th month, and 12th month. Complete response was defined as the absence of asthma and/or ear, nasal symptoms and exacerbations with a prednisone of ≤7.5 mg/day, partial response if it was achieved with a prednisone of >7.5 mg/day. Results: Overall, 25 patients (18 F/7 M) with a median age of 47 years (23–76) were enrolled. Mepolizumab 100 mg/month was administered (dose increased to 300 mg/month in 3 patients). Mepolizumab significantly decreased daily dose of oral corticosteroid (OCS) from 11.04 mg to 3.65 mg together with a significant improvement in ACT, AQLQ, RQLQ, and SNOT-22 scores and a significant reduction in asthma exacerbations and blood eosinophil count at the 6th and 12th month (all p values <0.05). The mean forced expiratory volume in 1 s increased (at baseline: 1.88 L to 2.46 L at the 12th month [p = 0.037]). Seventy-six percent of patients responded completely at the 6th month and 81.25% at the 12th month. The complete responders at the 6th and 12th month were older than partial responders and nonresponders (p = 0.030 and p = 0.057, respectively). Patients with complete response at the 6th month were on lower doses of OCS than partial responders and nonresponders (p = 0.029). Conclusions: Low-dose mepolizumab was effective in EGPA patients by improving sinonasal and asthma outcomes, while reducing the need for OCS.