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ABSTRACT: Despite the high prevalence of kidney involvement in patients with light chain (AL) amyloidosis, a significant knowledge gap exists in understanding how immunoglobulin light chains drive kidney injury. The chief reason is the lack of molecular data from high-quality kidney tissue samples from this patient population. The RAIN trial (NCT03168906) was a phase 2b randomized placebo-controlled, clinical trial that evaluated the efficacy of NEOD001, a monoclonal antibody targeting amyloid fibrils, versus placebo in patients with AL nephropathy. Before drug administration, renal biopsies were taken and analyzed. OBJECTIVE: Identifying amyloid-specific molecular signatures in kidney biopsy tissue. MATERIALS & METHODS: Renal biopsies were collected on all RAIN participants before randomization to NEOD001 or placebo. Clinical data was collected and correlated to histologic and molecular findings. Histologic assessment included a composite scarring injury score (CSIC) as determined by the degree of glomerular and tubulointerstitial scarring, and a novel amyloid score (AS), as quantified by the extent and distribution of amyloid deposition. Glomerular (G) and tubulointerstitial (TI) compartments were micro-dissected and sequenced separately. To identify enriched pathways in AL nephropathy, the expression data was compared to the glomerular and tubular expression profiles of healthy living donor (LD) from the Nephrotic Syndrome Study Network (NEPTUNE) study. Differentially expressed genes (DEGs) were determined . RESULTS: Ten patients were enrolled, randomized and treated in the RAIN trial (5 NEOD001 and five placeboes) before trial closure in April 2018. Kidney tissue was available in nine of the ten patients. Cluster analysis revealed two distinct patient clusters (G1 and G2) within the glomerular and TI compartments ( See Figure 1). Key clinical data pertaining to kidney function and biopsy morphology by compartment and cluster type were documented. Despite similar eGFR and degree of proteinuria, there was a significantly higher AS score in the TI compartment (6.5 vs. 4.5; p=0.0290) of G2 which was driven most entirely by an increase in mesangial and capillary wall amyloid deposition. Pathway Enrichment in G2 versus G1: Glomeruli showed activation of fibrotic pathways accompanied by a reduction in metabolic processes including gluconeogenesis, lipid transport and xenobiotics. There was an increase in canonical signaling of LPS/IL-1 that drives increased IL1 and TNF release from macrophages. Transcriptomic evidence of TNF activation was also noted in the TI compartment. Other enriched ingenuity canonical pathways to note in the TI included ‘coagulation system’, ‘GADD45 signaling’, ‘Wnt/Ca+ pathway’, ‘intrinsic prothrombin activation pathway’ among others. Of note, genes like BRCA and CDKN1A were enriched between G1 and G2, both of which have been associated with molecular mechanisms that underly certain neoplasms ( See Figure 2). Pathway enrichment in Amyloid kidney disease versus LD: IPA analysis identified unique activation signatures in the glomeruli and tubules. In the glomeruli, there was increased signaling of TNF, NFKB, IL33, IL-8 and IL15, consistent with an important inflammatory response. There was also an enrichment in pathways related to migration, adhesion and integrin signaling. PI3K/Akt signaling was also noted. Tubules showed increased activation of transcriptional regulators TP53, TP73 and PI3K/AKT signaling. Some gene regulators of cellular proliferation such as ABL1, BCL2 and AKT1 were found to be enriched in the amyloid group. CONCLUSIONS: While the RAIN trial closed prematurely and NEOD001 cannot be evaluated, the molecular data revealed the presence of two distinct molecular subtypes of AL nephropathy. Whether these distinct molecular subtypes reflect different stages of the disease along a continuous spectrum or are of unique prognostic entities in of themselves remains unclear. Detailed studies, of a larger cohort of patients including investigating diseased tissue at a single cell resolution can help identify the response of individual kidney cell types. Understanding the cellular responses of key cell types to injury from amyloid deposits could provide novel therapeutic targets to mitigate renal injury and improve patient outcomes. Based on this early work, targeting the PI3K/Akt pathway may be a worthy pursuit in this disease.

Background: Event-free survival at 24 months (EFS24) after frontline immunochemotherapy (IC) is an important endpoint in diffuse large B-cell lymphoma and follicular lymphoma, and patients who achieve EFS24 have similar survival compared to age- and sex-matched general population. The role of EFS24 in predicting subsequent survival has not been established in mantle cell lymphoma (MCL), possibly due to perceived poor survival historically. In the last decade, the outcomes of MCL are improving in the evolving treatment landscape. In this international multicenter study, we investigated conditional survival and cause of death in patients with MCL who achieved EFS24 after frontline IC in the older and more recent eras. Methods: Outcomes after frontline IC were evaluated in 5 independent cohorts that included over 3000 patients in total: Mayo/Iowa MER prospective cohort, BC Cancer retrospective population-based cohort, US 12-center retrospective cohort, Swedish Lymphoma Registry, and Danish National Lymphoma Registry. For each cohort, 2 treatment eras were defined based on cohort-specific shifts in treatment patterns (Table 1). Overall survival (OS) after diagnosis and after achieving EFS24 were compared to the background age- and sex-matched general population using a standardized mortality ratio (SMR). Cumulative incidences of cause-specific deaths were analyzed using a competing risk model. Results: In the MER cohort, patients treated in Era M1 (2002-2009; n=147) and Era M2 (2010-2015; n=153) both had inferior OS compared to the general US population. A lower SMR in Era M2 vs M1 (2.25 vs 3.46) suggests a narrower gap in OS compared to the general US population. Lymphoma was the leading cause of death in both eras. In Era M1, patients who achieved EFS24 still had inferior OS compared to the general US population (SMR=2.40, 95% CI 1.76-3.19), and lymphoma remained the leading cause of death. For patients in Era M2 who achieved EFS24, the difference in OS compared to the general US population was not statistically significant with current follow-up (SMR=1.43, 95% CI 0.93-2.09), and lymphoma was no longer the leading cause of death (Table 2). In the BC cohort, patients treated in Era B2 (6/2013-2019; n=188) vs Era B1 (2003-5/2013; n=250) had a narrower gap in OS compared to the general British Columbia population (SMR 4.53 vs 6.69). Lymphoma was the leading cause of death in both eras. For patients achieving EFS24, the gap in OS was narrower in Era B2 vs B1 (SMR 3.56 vs 4.99). After achieving EFS24, lymphoma was the single leading cause of death for patients in Era B1 but not in Era B2 (Table 2). In the US 12-center cohort, patients treated in Era U1 (2002-2011; n=312) and Era U2 (2012-2016; n=417) both had inferior OS compared to the general US population (SMR 2.68 and 2.92, respectively). In patients who achieved EFS24, with current follow up, the difference in OS compared to the general US population was statistically significant in Era U1 (SMR=2.01, 95% CI 1.50-2.64) but not in Era U2 (SMR=1.44, 95% CI 0.82-2.34). Lymphoma was not the leading cause of death after achieving EFS24 (Table 2). In the Swedish cohort, the gap in OS compared to the general Swedish population was narrower in Era S2 (2013-2018; n=439) vs S1 (2006-2012; n=442), both after frontline IC (SMR 4.8 vs 5.4) and after achieving EFS24 (SMR 2.6 vs 3.4). After achieving EFS24, lymphoma was the leading cause of death for patients in Era S1 but not in Era S2 (Table 2). In the Danish cohort, patients treated in Era D2 (2014-2020; n=370) vs Era D1 (2004-2013; n=461) had a slightly narrower gap in OS compared to the general Danish population (SMR 1.90 vs 2.10). For patients who achieved EFS24, those in Era D1 still had inferior OS compared to the general Danish population (SMR=1.44, 95% CI 1.22-1.68), but the OS difference compared to the general Danish population in Era D2 was not statistically significant (SMR=1.27, 95% CI 0.92-1.72) with current follow-up (Table 2). Cause of death data were not available in this cohort. Conclusion: Survival in patients with MCL who achieved EFS24 after frontline IC improved in the more recent treatment era and moved closer to the background expected survival. After achieving EFS24, lymphoma-related mortality was no longer the leading cause of death in the more recent era. EFS24 following frontline treatment may become a critical endpoint for predicting subsequent outcomes in patients with MCL in the modern era.

Background: Bendamustine and rituximab (BR) is a standard-of-care first-line (1L) therapy for older or unfit patients with mantle cell lymphoma (MCL). The SHINE trial compared BR with rituximab maintenance plus ibrutinib vs placebo in patients ≥65 years old and showed that the ibrutinib arm had significantly improved progression-free survival (PFS; median 80.6 vs 52.9 months) but similar overall survival (OS; 57% vs 55% at 7 years) compared to the placebo arm. Whether sequential treatment with BR in 1L and a Bruton's tyrosine kinase inhibitor (BTKi) in second-line (2L) can result in a similar cumulative PFS compared to 1L BR plus BTKi combination therapy is unknown. To provide insight to this question, we modeled observational data to evaluate MCL outcomes after 1L BR and 2L BTKi therapy in the BTKi era. Methods: Patients with MCL who received 1L BR with or without rituximab maintenance in 2014-2020 at one of the 27 participating centers were included. Exclusion criteria included participation in the SHINE or ECHO trials, any additional 1L therapy other than BR (with or without rituximab maintenance), and stem cell transplant consolidation after 1L BR. Baseline characteristics, treatment, and follow-up data were abstracted by chart review. Event-free survival (EFS) was defined as time from index line treatment start to the first event (progression, relapse, retreatment, or death). OS was defined as time from index line treatment start to death. Using an intention-to-treat (ITT) framework, EFS2 was defined as time from 1L BR start to progression, relapse, or retreatment following 2L BTKi treatment or death. Patients who received a non-BTKi treatment at 2L were censored for EFS2 at 2L treatment start; living patients without an event following 1L BR or 2L BTKi were censored for EFS2 at last follow-up. Results: A total of 618 patients with MCL who received 1L BR in 2014-2020 were included. The median age was 71 (IQR 65-76) years, and 447 (72%) were male. 59 (11%) patients had an ECOG PS ≥2, 566 (93%) had stage III-IV disease, and simplified MIPI was low in 105 (21%), intermediate in 200 (39%), and high in 202 (40%) patients. The median follow-up following 1L BR start was 57.4 (95% CI 53.8-63.2) months. Response data were available in 580 patients, and the best ORR was 92% (79% complete response [CR] and 13% partial response [PR]). 258 (42%) patients received rituximab maintenance. As of last follow-up, 255 patients were alive and in remission after 1L BR, 92 patients died without 2L therapy, and 271 patients received a 2L therapy. The median EFS was 34.1 (95% CI 31.0-40.0) months. The median OS was 97.8 (95% CI 81.2-NA) months, the 5-year OS rate was 58.6% (95% CI 54.4-63.2), and the 7-year OS rate was 56.7% (95% CI 52.4-61.5) (Fig 1). Among the 271 patients who started a 2L treatment, 203 (75%) received a BTKi at 2L - 101 (50%) ibrutinib, 76 (37%) acalabrutinib, and 26 (13%) zanubrutinib. The median follow-up following 2L BTKi start was 38.5 (95% CI 31.3-45.1) months. Response data were available in 171 patients, and the best ORR was 64% (36% CR, 28% PR). The median EFS was 10.7 (95% CI 7.7-14.0) months, and the median OS was 24.8 (95% CI 17.3-33.1) months with 2L BTKi therapy (Fig 2). By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 72.1 (95% CI 56.7-97.8) months (Fig 1). A subset analysis of patients aged ≥65 years (n=471; 198 [42%] received rituximab maintenance) showed similar results. The median EFS with 1L BR was 32.7 (95% CI 29.1-36.3) months. The median OS was 81.5 (95% CI 65.0-NA) months, and the 7-year OS rate was 53.3% (95% CI 48.3-58.7). 208 patients received a 2L therapy, 163 (79%) with a BTKi. The median EFS was 11.5 (95% CI 7.6-15.8) months, and the median OS was 21.0 (95% CI 14.0-29.6) months with 2L BTKi therapy. By ITT analysis, the median EFS2 following 1L BR and 2L BTKi was 58.0 (95% CI 50.2-77.0) months. Conclusion: In this multicenter retrospective study, initiation of 1L BR (with or without rituximab maintenance) resulted in a 7-year OS of 57%. Median EFS2 for sequential 1L BR and 2L BTKi was 72.1 months. In context, the SHINE study reported a median PFS of 80.6 months in the BR (with rituximab maintenance) plus ibrutinib arm and a 7-year OS of 57% in the ibrutinib arm and 55% in the placebo arm, where 39% of patients received a BTKi in 2L. Within the constraints of observational data, our results provide support for sequential use of BR in 1L and BTKi in 2L for patients with MCL.

Background: Daratumumab-based combination with proteasome inhibitors (PI) and immunomodulatory drugs (IMiDs) have revolutionized the treatment outcomes of relapsed/refractory multiple myeloma (RRMM). Several daratumumab-based triplet combinations have been approved for the management of RRMM, but outcomes of daratumumab-based triplets in patients with high-risk cytogenetics RRMM (HC-RRMM) are not well described in the literature. This study aimed to evaluate the clinical outcome of daratumumab-based regimens in patients with HC-RRMM who are daratumumab-naïve. Methods: A retrospective review of 110 patients with HC-RRMM who received daratumumab-containing regimens from 6/2016 through 2/2023 at the University of Kansas Medical Center, in collaboration with the U.S Myeloma Innovations Research Collaborative (USMIRC) was conducted. Daratumumab was combined with bortezomib/dexamethasone (DVd), carfilzomib/dexamethasone (DKd), and pomalidomide/dexamethasone (DPd) for treatment of RRMM. HC-RRMM was defined as patients with one or more cytogenetic abnormalities (on FISH panel) including -17/del(17p), t(4;14), t(14;16), t(14;20), or amplification of 1q. Responses to therapy including overall response rate (ORR), complete response or better (≥CR), and very good partial response (VGPR) were evaluated using the International Myeloma Working Group (IMWG) criteria. Descriptive statistics were used to summarize patient and disease characteristics, along with efficacy outcomes. Progression-free survival (PFS) and overall survival (OS) were calculated by Kaplan-Meier methods. Results: Of the 110 patients with HC-RRMM, the median age was 66 years (range 43-84), 83 (75%) were Caucasian, 60 (54%) had IgG isotype, 41 (37%) had revised international staging system (R-ISS) stage III disease, 35 (32%) had extramedullary disease (EMD), 57 (52%) patients had one high-risk cytogenetic (HC) abnormality, 49 (44%) had 2 HC abnormalities, while four (4%) had 3 HC abnormalities. The median number of previous lines of therapy was 2 (1-4). Eighty-eight patients (80%) were lenalidomide refractory, while 53 patients (48%) had double refractory disease to both a PI and IMiD treatment. A total of 19 (17%), 27 (25%), and 64 (58%) patients received DVd, DKd, and DPd, respectively. The overall response rate (ORR) for the entire patient population was 73%, 45% had VGPR or better, and 35% achieved ≥CR. Median follow-up was 28 months (12.07-53.57), the median OS was 28 months (95% CI 23.2 - 43.9) and PFS was 8.03 months (95% CI 5.8 - 12.2) for all treatment groups. The median PFS for 1 HC vs ³ 2 HC was 14.8 vs 4.57 months (HR 1.72, 95%CI 1.17-2.72 p = 0.006), respectively. Similarly, median OS for 1 HC vs ³ 2 HC was 43.93 vs 22.47 months (HR 1.87, 95%CI 1.15-3.05, p = 0.011), respectively. (Figure 1). On multivariate analysis, R-ISS stage III, -17/del(17p), and the presence of more than one HC abnormality were associated with poor OS. The most common cause for treatment discontinuation was progressive disease, accounting for 73% of patients in the whole cohort. As for each daratumumab-based triplet, discontinuation due progression occurred in 78%, 48%, and 83% in DVd, DKd, and DPd, respectively. Other causes of discontinuation included > grade 3 neuropathy, which occurred in 16% of patients receiving DVd, and cardiac events, which occurred in 11% of patients receiving DKd. Treatment-related mortality occurred in 2% of patients in the whole cohort. At the time of evaluation, 14 patients remain on treatment. Conclusion: Advanced stage R-ISS disease at diagnosis, presence of -17/del(17p), and 2 or more HC abnormalities were associated with poor prognosis reflected by worse PFS and OS in HC-RRMM treated with daratumumab-based therapies. A larger cohort or a prospective study in patients with HC-RRMM is needed to compare long-term outcomes between daratumumab-based therapies (DKd, DVd, and DPd).

Introduction: Novel B cell maturation antigen (BCMA) directed therapies including chimeric antigen receptor- T (CART) such as idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel) have been approved since 2021. More recently in 2022, the first BCMA-directed T-cell-engager (TCE), teclistamab (tec), was also approved for the treatment of relapsed/ refractory multiple myeloma (RRMM). Unfortunately, limited access to these therapies worldwide appears to be a major challenge. This study aims to gain insight into the variation in access to these therapies, and barriers to access. Methods: This study was an electronic survey of 176 hematologists/oncologists in centers across the globe outside the USA who treat MM and was conducted in collaboration with US Myeloma Innovations Research Collaborative (USMIRC). The survey was distributed from June 18 th 2023, to July 15 th 2023. Sections included demographics of respondents, availability of drugs in the country, and barriers to access. The respondents categorized each medication as “easily accessible”, “moderately accessible,” “not readily accessible” or “no access”. To categorize a country/region as having “adequate access”, the cut-off was 60% of responders affirming easy/moderately easy access. We investigated whether higher healthcare spending in a country is associated with better drug accessibility. Health expenditure (HE) of a country's Gross domestic product (GDP) from the World Bank was utilized to categorize countries into two groups: “High healthcare investing nations” (HHIN), which included countries spending >10% of their GDP on healthcare, while “Low healthcare investing nations” (LHIN) included countries spending <10% on healthcare. An interim analysis is reported. Results: There were 95 (54%) completed responses from 33 countries. Most (51%) were university-based academic centers and only 17% were centers with a dedicated focus in plasma cell disorders. Only 17% reported adequate access to ide-cel and 16% to cilta-cel, while a limited, yet higher number of respondents had adequate access to tec (23%). Refer to Table 1 Access to CART (ide-cel and cilta-cel): Globally, only 3 of the 33 (9%) countries had access to ide-cel, cilta-cel or both (France, Morocco, Saudi-Arabia). All other countries had limited access. When grouped by continent, none of the continents had adequate access to CART. Both HHIN and LHIN countries had limited access to CART. Access to TCE (tec): Seven of the 33 (21%) countries had adequate access to tec (Switzerland, Netherlands, France, Portugal, Czech Republic, Morrocco, Saudi Arabia). All other countries had limited access. When grouped by continent, although Europe had the most access, none of the continents had adequate access to TEC. Both HHIN and LHIN countries had limited access to TCE, although relatively, TEC was more accessible compared to CART. Figure 1 summarizes access to CART and TCE Barriers to access: Other than Europe, the most common barrier for ide-cel, cilta-cel and tec was cited as financial burden for patients. Financial burden for patients as a top barrier for each of the products by continent was as follows: Asia (83%), South America (64%), Africa (71%) Australia (100%), and North America (100%). In Europe, for CART, financial burden remained a top barrier (50%) along with local agency approval (50% for ide-cel, 44% for cilta-cel). In Europe, the most cited barrier for TCE was the financial burden for patients (44%), while (33%) of oncologists reported no barrier to TCE. Reimbursement for CART and TCE in Europe requires phase 3 randomized controlled trial data, which is just emerging since 2022 for CART and relatively increased access may be due to the presence of compassionate use programs. Conclusion : The survey is the first attempt to highlight the significantly limited global access to novel therapies (ide-cel, cilta-cel, and tec) for the treatment of RRMM. All continents including HHIN had limited access to CART and TCE. Noticeably, CART is less accessible than TCE, even though approved earlier. The main barrier to both CART and TCE is reported as financial burden for patients. USMIRC in collaboration with oncologists worldwide, global agencies, governments, regulatory agencies, policymakers and industry partners, is planning to further explore restrictions to access to CART and TCE and strategies to overcome these barriers.

Background: BMT CTN 1703 was a Phase 3 trial comparing Tac/MTX (n = 217) to post-transplant cyclophosphamide (PT-Cy)/Tac/MMF (n = 214) GVHD prophylaxis after reduced intensity conditioning unrelated donor hematopoietic cell transplant (HCT). PT-Cy significantly improved GVHD-free Relapse-Free Survival (Bolanos-Meade et al NEJM 2023). However overall survival was not significantly different and the # of Grade 2 infections was higher with PT-Cy. To investigate its biologic underpinnings 1703 was linked to a mechanistic study, BMT CTN 1801, which co-enrolled 324 pts (159 CNI/MTX 165 PT-Cy). The resulting dataset enabled an analysis of post-HCT T cell reconstitution at an unprecedented level of detail. Methods: Samples were collected from the HCT infusion and on D+7, 14, 28, 63, 98, 180, 270, 1- and 2-yr. We extracted DNA (2,225 samples) and performed Adaptive Biotech β-strand T Cell Receptor (TCR) Immunosequencing (TCR-Seq). We profiled 44,077 (median) TCRs/sample resulting in 215,155,719 T cells analyzed. We evaluated multiple TCR diversity measures longitudinally and before/after cGVHD and infections. Each measure evaluates a specific aspect of TCR diversity, including Simpsons Clonality (focuses on the most expanded clones) Diversity Slope (mid-range clones) Richness (both mid-range and less-expanded clones) and Singletons (the TCR-Seq equivalent of naïve T cells). This analysis was robust to the full range (1000-50,000) of down-sampled TCRs sequenced. Results: We identified major differences in TCR reconstitution in Tac/MTX vs PT-Cy that begin early and persist through 2 yr post-HCT. These resulted in a significantly less diverse TCR repertoire with PT-Cy with substantial implications for its efficacy and toxicity. The most salient differences are: (1) PT-Cy caused significant in-vivo T cell depletion early post-HCT (% T cells/total WBC at D+28: 8.2% (Tac/MTX) vs 2.2% (PT-Cy) p=2.2x10 -23). (2) The remaining donor T cells in PT-Cy undergo substantial clonal expansion ( Fig 1) resulting in significantly constrained TCR diversity measured by Clonality, Slope, Richness, Singletons (not shown) and Singletons/Richness ( Fig 2) which began early (D+14) and persisted for 2 yr. (3) Linked T cell depletion and clonal expansion resulted in a TCR diversity bottleneck after PT-Cy ( Fig 1). Due to the bottleneck, while the fraction of T cells originating from the transplant infusion at =/> 1 yr was similar between arms (18% vs 24%, p=0.7) there were significantly fewer Singleton TCRs in PT-Cy, suggesting a reduction in naïve T cells ( Fig 2), an outcome that has critical consequences for both cGVHD and infection. Thus while cGVHD onset with Tac/MTX was linked to a significant drop in TCR diversity due to singleton clonal expansion (median log-2 fold change in singletons with Tac/MTX = -0.25 p = 0.01) this drop was not observed with PT-Cy (log-2 fold change = -0.05, p = 0.1). Along with the significantly decreased # singletons at all time-points in PT-Cy ( Fig 2) this suggests that while cGVHD after Tac/MTX is linked to substantial naïve T cell expansion, the same is not true with PT-Cy, identifying a novel mechanism for cGVHD control with PT-Cy. The substantially fewer singletons in PT-Cy vs Tac/MTX may also increase the risk of Grade 2+ infections. T cell responses to new infections rely on antigen recognition/effector maturation of naïve (singleton TCR) T cells. After infection, the TCR repertoire became less diverse for both Tac/MTX and PT-Cy (log-2-fold singleton change -0.17 and -1.2 p = 0.0006 and 0.01) indicating that singletons in both cohorts were capable of expanding to pathogens. However the markedly decreased # singletons in PT-Cy at all timepoints was associated with significantly fewer singletons prior to infection (mean 3979 at 5K read-depth for Tac/MTX vs 2820 for PT-Cy p<0.001). This singleton deficit would place PT-Cy patients at higher risk of missing the critical mass of TCRs required to respond effectively to infections, consistent with their increased rate of Gr 2 infections. Conclusions: We performed longitudinal TCR-Seq on >200 million T cells from 324 HCT patients, representing the largest post-HCT TCR-Seq analysis in the history of the field, and enabling novel insights into TCR dynamics. These data identify a previously unappreciated global TCR diversity bottleneck with PT-Cy that simultaneously protects patients from cGVHD and places them at higher risk of infectious complications.

Introduction The Ki-67 index has been previously shown to be prognostic, wherein the cut-off of 30% was associated with inferior survival outcomes (Determann O et al, Blood 2008) in newly diagnosed MCL patients (pts). However, this cut-off determination was made in pts treated with CHOP/R-CHOP as the first-line treatment, controlled only for MIPI, and predates the advent of novel agents. Short diagnosis to treatment interval (DTI ≤ 14 days) was recently shown to be prognostic in newly diagnosed MCL but its association with Ki-67 is unknown. We sought to determine the optimal Ki-67 cut-off in MCL and its prognostic relevance in the modern era. Methods This is a pooled analysis of 2 large datasets, one prospective (CALGB 50403) and one retrospective (MCL real world study [MCL-RWS]). CALGB is now part of the Alliance for Clinical Trials in Oncology. CALGB 50403 is a phase II randomized study wherein newly diagnosed MCL pts received intensive induction chemoimmunotherapy (IIC) followed by autologous transplant, and posttransplant rituximab. The MCL-RWS included adult pts (≥18 years [yrs]) with MCL treated from 2000 to 2017 at 12 participating US sites. Pts from sites in the MCL-RWS that enrolled on CALGB 50403 were excluded. Ki-67 was scored by central review in 10% increments in the CALGB 50403 and per institutional standard in the MCL-RWS. We assessed Ki-67 as a continuous variable and used a restricted quadratic spline fit to find an optimal cut-off. We looked at the associations between Ki-67 and other known/ established MCL prognostic markers including MIPI and DTI. The outcome parameters were PFS and OS. Time-to-event endpoints were evaluated by Kaplan-Meier and Cox proportional hazard methods. Results Among the 793 pts (n=666, MCL-RWS and n=127, CALGB 50403) in the pooled analysis, Ki-67 was available in 385 pts (311 from MCL-RWS and 74 from CALGB 50403). The median OS (mOS) and PFS (mPFS) in the entire cohort (n=793) was 11.8 years and 4.7 years, respectively. The two groups (gps), those with and without Ki-67 data, were well balanced including MIPI and DTI. The median age was 62 yrs (range, 32-88), 81% males, 94% with ECOG performance status (PS) 0-1 and 84% with stage 4. We found a Ki-67 cut-off of 50% to be optimal as the relative hazard of death rises after 50%. Pts in the Ki-67 >50% gp had significantly higher proportion with short DTI (36% vs 17%, p<0.001), ECOG PS ≥2 (12% vs 5%, p=0.02), elevated LDH (58% vs 39%, p=0.005), and MIPI ≥6.2 (38% vs 20%, p=0.007) compared to Ki-67 of ≤50%. Ki-67 >50% was associated with significantly inferior PFS with a hazard ratio (HR) of 2.10 (95%CI 1.50-2.92) compared to Ki-67 ≤50% with a mPFS of 2.1 vs 5.3 yrs, respectively, regardless of the age (young [≤65 yrs], 2.6 vs 5.3 yrs or old [>65 yrs], 1.1 vs 5.4 yrs) or receipt of IIC (2.2 vs 5.9 yrs). Figure 1 shows the statistically significant difference in PFS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% remained prognostic for PFS in multivariable analysis (MVA) after adjusting for significant variables in univariable analysis (UVA) including short DTI, ECOG PS ≥2, stage 4, elevated LDH, and MIPI ≥6.2 with adjusted HR (aHR) 2.19, 95%CI 1.38-3.48, p <0.001. Ki-67 >50% was associated with significantly inferior OS with a HR of 2.10 (95%CI 1.33-3.32) compared to Ki-67 ≤50% with a mOS of 9.4 yrs vs not reached (NR), respectively, regardless of the age or receipt of IIC. Figure 2 shows the statistically significant difference in OS between the Ki-67 gps of ≤10%, >10% to <30%, ≥30 to ≤50%, and >50%. Ki-67 >50% was not prognostic for OS in MVA after adjusting for significant variables in the UVA (MIPI and sex), aHR 1.79, 95% CI 0.92-3.49, p=0.08. Similar findings were seen in multivariable analysis with Ki-67 >30%, which showed no prognostic significance (aHR 1.46, 95%CI 0.82-2.58, p=0.19). Because of disparate datasets, we performed sensitivity analysis looking at the prognostic relevance of in individual datasets (CALGB 50403 and MCL-RWS) and found Ki67 >50% was prognostic for PFS and OS in both of the datasets consistent with the primary analysis. Conclusions This study evaluating the optimal Ki-67 cut off for pts with newly diagnosed MCL in the modern era found that Ki-67 > 50% was prognostic for PFS but not OS in MVA. A potential reason for the lack of prognostic relevance for OS in this more recent dataset is the availability of effective options at relapse. We also found that short DTI was associated with high Ki-67 gp which is a novel finding.

ABSTRACT Early COVID-19 convalescent plasma (CCP) transfusion to outpatients with COVID-19 decreases progression to hospitalization, but the mechanism of how CCP reduces severity is unknown. Among 882 COVID-19 participants transfused with CCP or control plasma in a randomized controlled trial, 21 cytokines and chemokines were measured using electrochemiluminescence assays. Wilcoxon rank sum tests were used to evaluate the difference between early (transfused within 5 days of symptom onset) CCP vs early control plasma and late (transfused 6–9 days after symptom onset) CCP vs late control plasma at each visit. Linear mixed-effect models were used to assess the difference in the slope of cytokine change. Median cytokine and chemokine levels were similar between the early CCP and early control groups pre-transfusion. At the day 14 visit, only the median IL-6 ( P = 0.014) and IL-16 ( P = 0.036) levels were lower in the early CCP group compared to the early control group, but these differences were not statistically significant after correcting for multiple comparisons (requiring P < 0.0024). IL-6 levels decreased significantly faster in the early CCP group from screening to the day 14 visit compared to the early control group ( P < 0.001). No difference was observed in the slope of cytokine change from screening to day 90 between early CCP and early control groups. Late control and late CCP arms showed similar cytokine and chemokine levels through study follow-up. One mechanism by which early CCP transfusion reduces hospitalization may be by decreasing IL-6 levels, as the reduction is associated with better recovery from COVID-19. IMPORTANCE This study examined the role that cytokines may have played in the beneficial outcomes found when outpatient individuals infected with SARS-CoV-2 were transfused with COVID-19 convalescent plasma (CCP) early in their infection. We found that the pro-inflammatory cytokine IL-6 decreased significantly faster in patients treated early with CCP. Participants with COVID-19 treated with CCP later in the infection did not have the same effect. This decrease in IL-6 levels after early CCP treatment suggests a possible role of inflammation in COVID-19 progression. The evidence of IL-6 involvement brings insight into the possible mechanisms involved in CCP treatment mitigating SARS-CoV-2 severity.

Abstract Background Post-COVID conditions (PCC) are common, and risk factors include older age and female sex. While high interleukin (IL)-6 and C-reactive protein are associated with more severe disease, it is unclear whether other cytokines are associated with PCC. This study was performed to identify factors associated with PCC development. Methods The Convalescent Plasma to Limit SARS-CoV-2 Associated Complications (CSSC-004) trial was a double-blind, multi-center, randomized, controlled trial comparing the use of COVID-19 convalescent plasma (CCP) to control plasma for the prevention of hospitalization among COVID-19 outpatients. Among 882 individuals participating in the trial with available biospecimens and symptom data, the association between early COVID-19 treatment, cytokine levels and PCC was evaluated. Cytokine and chemokine levels were assessed at baseline, day 14 and day 90 using a multiplexed sandwich immuosassay. Presence of any PCC symptom was assessed at day 90. Associations between COVID-19 treatment, cytokine levels and PCC were examined using multivariate logistic regression models. Results Baseline characteristics were similar by trial treatment group (Figure 1). At day 90, 292 (33.1%) participants had PCC. The most common symptoms were fatigue (14.5%), anosmia (14.5%), and ageusia (10.0%). Levels of most cytokines decreased over time (Figure 2). Six pro-inflammatory cytokines especially IL-6 were elevated at baseline among those with PCC (Figure 3). In multivariable analysis, female sex (adjusted odds ratio [AOR]=2.70[1.93-3.81]), age 50 or greater (AOR=1.32[1.17-1.50]), and elevated baseline IL-6 (AOR=1.59[1.02-2.47]) were associated with development of PCC, whereas race, obesity, vaccine status and diabetes were not. Those who received early CCP treatment (&lt;5 days after symptom onset) compared to late CCP treatment had statistically significant lower odds of PCC (AOR=0.60 [0.38-0.95]). Conclusion This study showed high prevalence of PCC symptoms at day 90, particularly among those with higher baseline levels of IL-6 or who did not receive early CCP treatment. The potential utility of IL-6 modulation as a therapeutic intervention among individuals as higher risk for PCC should be studied. Disclosures Kelly Gebo, MD, MPH, Pfizer: Advisor/Consultant|Spark HealthCare: Advisor/Consultant Sonya L. Heath, MD, Pfizer: Data Monitoring Committee/DSMB Shmuel Shoham, MD, adagio: Advisor/Consultant|Adamis: Advisor/Consultant|ansun: Grant/Research Support|Avir Pharma: Honoraria|cidara: Grant/Research Support|F2G: Grant/Research Support|Immunome: Advisor/Consultant|Karius: Honoraria|Scynexis: Advisor/Consultant|zeteo: Grant/Research Support Judith S. Currier, M.D., MSc, Merck and Company: Advisor/Consultant|Merck and Company: Honoraria Moises A. Huaman, MD, MSc, AN2 Therapeutics Inc: Grant/Research Support|Gilead Sciences Inc: Grant/Research Support|Insmed Inc: Grant/Research Support Jay S. Raval, MD, Sanofi Genzyme: Advisor/Consultant Arturo Casadevall, MD, PhD, Ortho Diagnostics: Speakers Bureau|Sabtherapeutics: Advisor/Consultant

AbstractBackgroundRecurrent/metastatic adenoid cystic carcinoma (ACC) is a rare, incurable disease. MYB is a putative oncogenic driver in ACC that is often overexpressed through an MYB‐NFIB rearrangement. The authors hypothesized that AKT inhibition with the allosteric inhibitor MK‐2206 could decrease MYB expression and induce tumor regression in patients with incurable ACC (ClinicalTrials.gov identifier NCT01604772).MethodsPatients with progressive, incurable ACC were enrolled and received MK‐2206 150 mg weekly; escalation to 200 mg was allowed. The primary end point was confirmed response. Secondary end points were progression‐free survival, overall survival, and safety. An exploratory analysis evaluating the effect of MK‐2206 on MYB expression was conducted in a subset of patients.ResultsSixteen patients were enrolled, and 14 were evaluable for efficacy. No confirmed responses were observed. Thirteen patients had stable disease, and one had disease progression as their best response. The median progression‐free survival was 9.7 months (95% CI, 3.8–11.8 months), and the median overall survival was 18.0 months (95% CI, 11.8–29.9 months). Nine of 16 patients (56%) had at least one grade 3 treatment‐related adverse event, and the most common were rash (38%), fatigue (19%), decreased lymphocyte count (13%), and hyperglycemia (13%). Twelve of 14 tumors (86%) had detectable MYB expression by immunohistochemistry, and seven of 14 tumors (50%) had an MYB‐NFIB gene rearrangement. Serial biopsies revealed decreased MYB levels with MK‐2206 in four of five patients.ConclusionsMK‐2206 failed to induce clinical responses in patients with incurable ACC. AKT inhibition may diminish MYB protein levels, although the effect was highly variable among patients. Novel approaches to target MYB in ACC are needed.