Shah, Gunjan L.

Abstract Use of brentuximab vedotin (BV) and PD-1 monoclonal antibodies (mAbs) before autologous stem cell transplantation (ASCT) could impact the benefit of post-ASCT BV maintenance in relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL). We identified 1091 patients with R/R cHL who underwent ASCT between 2010-2022. In total, 244 (22%) received a PD-1 mAb and 443 (41%) received BV before ASCT, while 305 (28%) received BV maintenance. We performed 1:1 propensity score matching to assess the efficacy of BV maintenance in different patient subgroups. Among 608 matched patients, the 3-year progression-free survival (PFS) and overall survival were 73% (95% confidence interval [CI], 70-78) and 95% (95%CI, 93-97), respectively. BV maintenance was associated with improved PFS for patients with no exposure to novel agents, especially those with 2+ modified AETHERA risk factors (0-1 factors: hazard ratio (HR), 0.51; 95%CI, 0.24-1.09; P =.083; 2+ factors: HR, 0.40; 95%CI, 0.25-0.65; P< .001). In contrast, BV maintenance was not associated with a significant PFS benefit for any patient subgroup who received novel agents before ASCT (BV-treated, 0-1: HR, 1.43; 95%CI, 0.53-3.81; P =.48; 2+: HR, 0.79; 95%CI, 0.34-1.82; P =.58; PD-1-treated, 0-1 [P>.99], 2+: HR, 0.25; 95%CI, 0.03-2.14; P =.21). In particular, we observed excellent outcomes for patients undergoing ASCT in a complete response after one line of PD-1-based salvage treatment with no significant benefit for BV maintenance observed (2-year PFS 100% vs 95%; P>.99). The benefit of BV maintenance appears to be attenuated for patients receiving novel agents with salvage therapy. Omission of BV maintenance should be considered for patients anticipated to have excellent outcomes.

Abstract Combination therapy incorporating programmed cell death protein 1 (PD-1) blockade results in unprecedented response rates in both frontline and relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL). Previous retrospective studies have suggested benefit for PD-1 blockade before autologous stem cell transplant (ASCT) but included few patients receiving PD-1 blockade with cytotoxic chemotherapy. To explore the impact of anti–PD-1 based salvage on outcomes for patients with R/R cHL, we retrospectively reviewed 1280 patients with R/R cHL who underwent ASCT from 2010 to 2022 at 6 transplant centers, none of whom received PD-1 blockade as part of frontline therapy. Overall, 25% received a PD-1 inhibitor at any point before ASCT (10% in conjunction with chemotherapy), 28% received salvage brentuximab vedotin (BV) without PD-1 blockade, and the rest received salvage chemotherapy alone. Patients who received PD-1 inhibitors at any point before ASCT had a significantly higher 2-year progression-free survival than those who received BV without PD-1 inhibitors or patients receiving chemotherapy alone (88.2%, 70.2%, and 67.4%, respectively; P< .0001). When restricted to patients in complete response before ASCT, the benefit of PD-1 blockade remained significant. PD-1 blockade before ASCT is independently associated with superior post-ASCT outcomes and patients proceeding to ASCT should be treated with PD-1–based salvage.

Abstract Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

Introduction Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated. Methods We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq). We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry. Results The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients. Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet. Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells. Conclusion This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.

Abstract Artificial intelligence (AI)–enabled interpretation of electrocardiogram (ECG) images (AI-ECGs) can identify patterns predictive of future adverse cardiac events. We hypothesized that such an approach would provide prognostic information for the risk of cardiac complications and mortality in patients undergoing hematopoietic cell transplantation (HCT). We retrospectively subjected ECGs obtained before HCT to an externally trained, deep-learning model designed to predict the risk of atrial fibrillation (AF). Included were 1377 patients (849 autologous [auto] HCT and 528 allogeneic [allo] HCT recipients). The median follow-up was 2.9 years. The 3-year cumulative incidence of AF was 9% (95% confidence interval [CI], 7-12) in patients who underwent auto HCT and 13% (10%-16%) in patients who underwent allo HCT. In the entire cohort, pre-HCT AI-ECG estimate of AF risk correlated highly with the development of clinical AF (hazard ratio [HR], 7.37; 95% CI, 3.53-15.4; P < .001), inferior survival (HR, 2.4; 95% CI, 1.3-4.5; P = .004), and greater risk of nonrelapse mortality (NRM; HR, 95% CI, 3.36; 1.39-8.13; P = .007), without increased risk of relapse. Association with mortality was only noted in allo HCT recipients, where the risk of NRM was greater. The use of cyclophosphamide after transplantation resulted in greater 90-day incidence of AF (13% vs 5%; P = .01) compared to calcineurin inhibitor–based graft-versus-host disease prophylaxis, corresponding to temporal changes in AI-ECG AF prediction after HCT. In summary, AI-ECG can inform risk of posttransplant cardiac outcomes and survival in HCT patients and represents a novel strategy for personalized risk assessment.

High dose chemotherapy followed by autologous hematopoietic cell transplantation (auto HCT) is a standard therapy for patients with plasma cell disorders (PCD). A barrier to improving candidate selection for auto HCT is appraisal of risk for transplant related complications. Electrocardiography (ECG) is a standard pre-HCT test to evaluate the potential for arrhythmia and structural heart disease. We hypothesized that an artificial intelligence (AI) based interpretation of ECG waveform data (AI-ECG) could enhance risk prediction for cardiac-specific and other outcomes following auto HCT for patients with PCD. To test this hypothesis, we used several AI-ECG tools developed using a deep-learning based approach that were trained to predict comorbidity (Attia et al, Lancet 2019 & Grogan et al, Mayo Clin Proc 2021). Model outputs include a scaled prediction value indicating increasing risk for atrial fibrillation/flutter (AF), reduced ejection fraction (EF), or cardiac amyloidosis. We evaluated this tool in 9,225 ECGs obtained from 849 patients (median 6 ECGs/patient, inter-quartile range: 3-12) who underwent first or subsequent auto HCT at Memorial Sloan Kettering Cancer Center between 2016-2022 and who had a diagnosis of multiple myeloma (N = 810), amyloidosis (N = 37), or other PCD (N = 2). The endpoints were to determine whether baseline AI-ECG prediction of AF risk correlated with peri-transplant AF events, and to explore whether model outputs correlated with survival and other cardiac clinical outcomes. The mean age of patients was 61.0 years (range 23.7 - 81.2) and median follow up was 2.7 years post auto HCT. Contributing cardiovascular risk factors included a prior history of AF (N = 101, 11.9%), coronary or cerebrovascular disease (N = 95, 11.2%), and diabetes mellitus (N = 98, 11.5%). Reduced dose melphalan (< 200 mg/m 2) was administered in 26%. The HCT-comorbidity index (HCT-CI) was high risk (≥3) in 52.7%. The one-year overall survival and progression-free survival in the whole cohort was 94% (95% confidence interval (95% CI): 92 - 95%) and 86% (84 - 89%), respectively. Among patients not in AF at pre HCT evaluation, the 90-day cumulative incidence of AF was 5.6% (4.2 - 7.3%). In univariable competing risk regression, baseline pre HCT AI-ECG appraisal of AF risk was strongly correlated with incidence AF in patients who were in sinus rhythm before HCT (hazard ratio (HR): 25.1, 95% CI: 11.7 - 53.7, p < 0.001). In a multivariable model adjusting for patient age and HCT-CI, AI-ECG AF predicted risk remained associated with incidence of post HCT AF (HR: 13.4, 95% CI: 5.9 - 30.4, p < 0.001). Considering a decision threshold identified during original model training, AI-ECG predicted AF events with an accuracy of 75% (Mcnemar's p < 2 x 10 -16). The precision, recall, and F1-score were 0.94, 0.77, and 0.85, respectively. AI-ECG predicted age correlated highly with actual patient age (Spearman rho = 0.59, p < 2 x 10 -16). Amyloid risk scores were highly correlated with a known clinical history of amyloidosis (median 0.45 versus 0.05, Wilcoxon rank-sum p < 0.001). Patients with EF < 50% had greater prediction scores for cardiomyopathy compared to patients with normal EF (median 0.23 versus 0.01, Wilcoxon rank-sum p <0.001). In univariable analysis, increasing AI-ECG predicted age (HR 1.02, CI: 1.003 - 1.04, p = 0.02) and predicted AF risk score (HR: 3.2, CI: 1.4 - 7.2, p = 0.006) were associated with risk for death, whereas predicted amyloid score and predicted low EF were not associated with decreased survival. In multivariable analysis of all patients that considered patient age, hematopoietic comorbidity index, and remission status at HCT, increasing predicted AF score trended towards association with increased risk for death (HR: 2.3, 95%CI: 1.0 - 5.5, p = 0.059). Predicted AF score correlated highly with the HCT-CI and patient age. Finally, we examined whether risk prediction for low EF correlated with peri-HCT fluid overload (FO) defined by absolute weight gain. The incidence of ≥ 10% weight gain (grade 2 FO) and ≥ 20% weight gain (grade 3 FO) at 180 days post HCT was 7.4% (95% CI: 5.8%, 9.3%) and 1.0% (95% CI: 0.5%, 1.8%), respectively. Predicted low EF was not associated with development of either grade 2 or grade 3 FO in this population. In summary, AI-ECG predicts episodes of AF in patients undergoing auto HCT for PCD and may augment transplant risk appraisal when considered in conjunction with other measures of comorbidity.

Background: Maintenance therapy with brentuximab vedotin (BV) after autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) among high-risk patients (pts) with relapsed or refractory (R/R) classical Hodgkin lymphoma (cHL) in the phase III AETHERA trial. However, cHL treatment has changed significantly since that trial with frequent incorporation of BV and PD-1 inhibitors into earlier lines of therapy. The efficacy of BV maintenance may be different among pts who receive novel agents before ASCT. Methods: Pts with a diagnosis of R/R cHL who underwent ASCT between 2010 and 2022 were identified at 5 US transplant centers. Pts receiving no systemic post-ASCT maintenance or BV maintenance were included, while pts receiving investigational maintenance treatments were excluded. Medical records were reviewed to identify clinical variables. Results: 921 pts were identified. Median age was 32 yrs (IQR 24-44). 641 pts (70%) had primary refractory disease or relapsed within 12 months of frontline therapy, 326 (35%) had extranodal disease at relapse, and 173 (19%) had B symptoms at relapse. Pts received a median of 2 (1-9) lines of therapy before ASCT, including 295 (32%) who received ≥3 lines. 425 (46%) pts received BV before ASCT (including 24 pts as part of frontline treatment). 70 pts (8%) were BV-refractory (defined as failure to achieve an objective response to any BV-based treatment). 169 (18%) received a PD-1 agent with salvage treatment. 638 pts (69%) had a complete response on pre-ASCT positron emission tomography (PET). BEAM (71%) or CBV (21%) conditioning were used for most pts and 236 pts (26%) received peri-ASCT radiation. 224 pts (24%) received post-ASCT BV maintenance (including 37% of pts undergoing ASCT from 2015-2022). Compared to pts receiving no maintenance, pts receiving BV maintenance were more likely to have primary refractory/early relapsed disease (79% vs 67%, p<0.001), have received only 1 salvage regimen (79% vs 65%, p=0.001), and received BEAM conditioning (83% vs 67%, p<0.001). BV maintenance pts were less likely to receive peri-ASCT radiation (20% vs 28%, p=0.022). The median number of BV maintenance cycles was 10 (1-18) and the most common reason for discontinuation was neuropathy. Median post-ASCT follow-up was 4.9 yrs. 5-yr PFS and OS after ASCT were 70% (95% CI 67-74%) and 85% (83-88%), respectively. Because BV-refractory pts were much less likely to receive BV maintenance (p=0.0044) and had inferior PFS (HR 2.2, p<0.001) (and therefore would serve as a confounder), we excluded BV-refractory pts from additional analyses. Use of BV maintenance was associated with improved PFS (5-yr 81% vs 67%, HR 0.47 [0.33-0.69], p<0.001) and OS (5-yr 92% vs 83%, HR 0.38 [0.20-0.73], p=0.004). The benefit of BV maintenance depended upon pre-ASCT therapy. BV maintenance was associated with a significant improvement in PFS for pts who received no novel agents before ASCT (HR 0.41 [0.25-0.65], p<0.001), but not for BV-treated (HR 0.69 [0.38-1.25], p=0.22) or PD-1-treated pts (HR 0.63 [0.13-3.03], p=0.56) ( Figure). Among pts with 0-1 modified AETHERA risk factors, BV maintenance was not associated with a significant PFS benefit in any treatment subgroup (no novel agents, HR 0.50, p=0.087; BV-treated, HR 1.28, p=0.67; PD-1-treated, HR 2.97, p=0.44). For pts with 2+ modified AETHERA risk factors, BV maintenance significantly improved PFS in the no novel agent group (HR 0.35, p<0.001) but not in the BV-treated (HR 0.55, p=0.099) or PD-1 treated groups (HR 0.24, p=0.19). In multivariable analyses that included key variables (age, year of ASCT, conditioning regimen, peri-ASCT radiation, early relapse/primary refractory disease, B symptoms, extranodal sites, pre-ASCT PET, lines of therapy), BV maintenance was associated with a significant PFS benefit among pts who received no novel agents before ASCT (HR 0.27 [0.12-0.65], p<0.001), but not for pts treated with BV (HR 0.56 [0.28-1.10], p=0.091) or PD-1 blockade (HR 1.10 [0.22-5.56], p=0.91) before ASCT. Conclusions: In this large cohort, BV maintenance was associated with the clearest benefit among pts who received only chemotherapy before ASCT. We were unable to identify a significant improvement in PFS for pts receiving novel agents before ASCT (which could be due to insufficient power to detect a small benefit in this population), suggesting that if these pts benefit from BV maintenance, its impact is likely more limited.

Introduction: Single arm studies incorporating PD-1 blockade and/or brentuximab vedotin (BV) to salvage regimen have produced encouraging results in transplant-eligible relapsed/refractory classic Hodgkin lymphoma (R/R cHL) and are increasingly used in practice. As prospective randomized studies comparing PD1 based salvage to other salvage regimens are lacking, we conducted a retrospective study comparing post-transplant outcomes of R/R cHL patients who received PD1-based regimen and other novel and conventional regimen. Methods: Consecutive adult patients with R/R cHL who received salvage therapy and underwent autologous stem cell transplant (ASCT) between 2010 and 2021 at 5 United States academic institutions were included. Demographics and clinical variables were recorded at relapse by electronic health records review. Study Objectives were post-ASCT progression free survival (PFS) and overall survival (OS). Results: 981 pts of R/R cHL were identified. At relapse, median age was 31 (IQR: 21-43) years, 504 (52%) were male, 323 (49%) had advanced stage, 353 (41%) had extranodal disease (END), 185 (22%) had B symptoms, 345 (45%) were refractory to frontline therapy and 317 (32%) relapsed within a year of frontline therapy.308 (31%) received >1 line of salvage before ASCT. Patients were divided into 3 groups based on salvage therapy received: 1) 195 (20%) patients received a PD-1 agent with or without BV at any point before ASCT (PD-1 group), 2) 312 (32%) patients received BV at any point before ASCT without PD-1 (BV group), and 3) 474 (48%) patients received no novel agent before ASCT (chemo group). PFS was significantly higher in PD1 group (2-yr PFS 93.1 (CI 95: 89.4-96.9)%); compared to BV (2 yr PFS 73.9 (CI 95: 69.1-79.1)% , p <0.0001) or chemo groups (2 yr PFS 71.6 (CI 95: 67.6-75.9)% , p<0.0001). PFS was not different between the BV and chemo groups (p=0.88) (Figure 1). OS was not significantly different between PD-1 group (2 yr OS 96.2 % (CI 95: 93.2-99.2), p=0.06), BV group (2 yr OS 94.3% (CI 95: 91.7-97.0), p=0.2) and chemo group (2 yr OS 91.8% (CI 95: 89.3-94.4)). Amongst pts who were transplanted in complete metabolic response (CMR), we assessed post-ASCT PFS and OS based on salvage therapy received immediately before ASCT. Pts who received PD-1 as last salvage therapy had improved PFS compared to chemo (HR: 0.15 (CI 95: 0.07-0.3), p= <0.0001) and BV (HR: 0.2 (CI 95: 0.08-0.5), p= <0.001). Pts receiving PD-1 immediately before ASCT also had higher OS compared to those receiving chemo (HR: 0.2 (CI 95: 0.05-0.8), p= 0.02) but not BV (HR: 0.8 (CI 95: 0.4-1.3), p=0.1). There was no difference between BV and chemo group in regards to PFS and OS. In multivariable analysis that included time to relapse, B symptoms, END, pre-ASCT response, number of salvage therapy lines before ASCT, year of transplant and BV consolidation, PD-1 salvage therapy had significantly higher PFS compared to chemotherapy (HR: 0.3 (CI 95: 0.2-0.5), p= <0.001). BV group had significantly lower PFS (HR: 3.34 (CI 95: 1.8-6.0), group=0.002) compared to PD1 group. PFS was not different between BV and chemo group (p= 0.7). OS was similar between all 3 groups. Similar PFS and OS were seen among patients receiving PD-1 + BV (n=83) and PD-1 with or without chemo (n =112) (p=0.96 for PFS; p= 0.72 for OS); as well as for patients receiving PD-1 as part of their first salvage therapy (n=151) or later salvage treatments (n=44) (p=0.45 for PFS, p= 0.3 for OS). Patients who received PD1 based regimen as last salvage therapy pre-ASCT had significantly better PFS (HR: 6.8 (CI 95: 2.4-19.2), p= <0.0001) and OS (HR: 10.6 (CI 95: 2.5-44.8), p= 0.0001) compared to patients who received PD1 prior to their last line of salvage therapy per-ASCT. Conclusion: Receipt of PD-1 based salvage therapy at any point before ASCT is associated with significantly improved PFS compared to either BV or chemotherapy-based salvage treatments. In the subgroup of patients transplanted in CMR, PD1 based last salvage regimen were associated with higher PFS compared to chemotherapy and BV and higher OS compared to chemotherapy. PD1 based last salvage therapy pre-ASCT was associated with better survival compared to PD1 prior to last salvage therapy. Results of this study strongly support the use of PD-1 based salvage therapy for patients with R/R cHL. S.D., R.M., H.S contributed equally. R.S., M.M. contributed equally.

5017 Background: HDCT/ASCT represents a curative salvage treatment for patients with GCT but is rarely used for other solid tumors. Patients undergoing HDCT/ASCT for hematologic neoplasms require revaccination for their childhood immunizations. Whether this is necessary in patients with GCT is unknown. Methods: In this prospective longitudinal study, patients with GCT undergoing HDCT-ASCT from 11/2010 to 5/2018 had serologies for Measles, Mumps, Rubella, Diphtheria, Tetanus, Polio, and Varicella Zoster measured before HDCT and at 3, 6, and in a subset, 12+ months after the last HDCT with results at these timepoints compared using descriptive statistics. In addition, titer levels at ≥6 months post-transplant were matched 1:1 for age and gender with HL patients who underwent HDCT/ASCT during the same time period. Immunity was compared between cohorts using the Cochran-Mantel-Haenszel test. Results: Of 80 patients with GCT (median age 30, 84% nonseminoma), 91% received 3 sequential transplants and 68 had repeat titers at ≥6 months. Immunity at baseline was >95% for Diphtheria, Tetanus and Polio and 89% for Varicella Zoster but lower for Measles (74%), Mumps (85%), and Rubella (83%) (Table). Compared to baseline, proportional immunity for all infections was similar at 3, 6, and 12 months post-transplant in the GCT population (≥6 months shown in Table). Matching resulted in 58 GCT-HL pairs. One-year immunity was numerically lower for most infections in the HL vs. GCT patients and significantly decreased for Measles and Rubella (Table). Conclusions: To our knowledge, this is the first study to assess vaccine titers following HDCT/ASCT for GCT. We demonstrate that HDCT/ASCT does not result in loss of immunity to childhood vaccines and that GCT patients retain protective titers more frequently than those with HL. However, 15-31% of GCT patients lack MMR immunity at baseline and at 1-year post-ASCT. Therefore, we recommend checking MMR titers at 1-year post-ASCT with revaccination of those lacking immunity. Titer evaluation and revaccination is not necessary for other childhood immunizations.[Table: see text]