Idecabtagene vicleucel (Ide-cel) chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory multiple myeloma (RRMM): Real-world experience

Background: Ide-cel, a BCMA directed CAR T-cell therapy, was FDA approved 3/26/2021 for the treatment of RRMM after 4 prior lines of therapy. We evaluated the real-world outcomes of patients treated with standard of care ide-cel under the commercial FDA label. Methods: Ten US academic centers contributed data to this effort independent of the manufacturer. As of 1/10/2022, 138 patients were leukapheresed with overall manufacturing failure in 6 (4%). 108 patients were infused ≥ 30 days prior to data-cut off and constitute the study population for this retrospective analysis. Results: Table describes the study population compared to the pivotal KarMMa-1 trial (Munshi et al, NEJM 2021). Patients in our study were less likely to have ECOG PS of 0/1 (77%) and more likely to be penta-refractory (41%). 67% of patients would not have met eligibility criteria for KarMMa. Common reasons for ineligibility (> 1 reason in 22% patients) were co-morbidities (28%), cytopenias (22%), prior therapy with alloSCT/ CAR-T/other BCMA therapy (19%), CNS myeloma/non-measurable disease/plasma cell leukemia (13%), and fitness (12%). 81% of patients received bridging therapy. Toxicity was comparable to that seen in KarMMa-1. Cytokine release syndrome (CRS) was seen in 82% (> grade 3: 4%) and immune effector cell-associated neurotoxicity syndrome (ICANS) in 15% (> grade 3: 5%) of patients, respectively. Tocilizumab and steroids were used in 72% and 25% of patients, respectively. Infections were seen in 34% of patients. Day 30 response was evaluable in 104 patients. Response rates were: ≥ partial response, 83%;≥ very good partial response, 64%;and ≥ complete response (CR), 34%. 11% of patients have died by data cut-off, 7 due to disease progression and 5 due to other causes (1 grade 5 CRS, 1 hemophagocytic lymphohistiocytosis, 1 progressive neurological weakness, 2 COVID-19). Conclusions: This multicenter retrospective study delineates the real-world outcomes of ide-cel CAR T-cell therapy for RRMM. Despite more patients being penta-refractory and less fit compared to the pivotal KarMMa trial, safety and 30-day responses in the real-world setting (overall response rate: 83%, CR: 34%) are comparable to the clinical trial population. Follow-up is ongoing and updated data will be presented.

Prospective voluntary SARS-CoV-2 virus and anti-COVID-19 antibody tests in asymptomatic medical and research staff who work in direct contact with cancer patients: A single center study

Background The SARS-CoV-2 pandemic has assaulted all aspects of daily life. Medical professionals in oncology face additional challenges with balancing prompt cancer diagnosis and urgent treatment against potential COVID-19 exposure risk in these high-risk patients. We designed this prospective freewill study to offer testing for SAR2-CoV-2 viral RNA and/or anti-COVID-19, respectively in asymptomatic medical and research staff who work in direct contact with cancer patients. The overall goal was to evaluate the prevalence of infection in this group of asymptomatic healthcare providers to reduce exposure of cancer patients to asymptomatic staff. Methods Asymptomatic medical and research staff who work in direct contact with cancer patients were asked to voluntarily be tested for either SARS-CoV-2 viral RNA or antibodies or both. Either NP swabs and/or blood samples (EDTA tube) were collected. Tests are performed at Sinochips Kansas LLC, Sinochips Diagnostics (CLIA number:17D2176068, CAP number: 8709463). The PCR test is performed with FDA authorized 2019-Novel Coronavirus (2019-nCoV) Real-Time RT-PCR Diagnostic Panel EUA. The Elecsys® Anti-SARS-CoV-2 (Roche Diagnostics) immunoassay was used to qualitative detection of antibodies to SARS-CoV-2 in human plasma. Results From 06/18/2020 to 12/18/2020, 861 participated in the study. 1095 tests were completed for SAR2-CoV-2 virus infection, and 918 were completed for antibody. Amount participants, 530 had both virus and antibody tested. 235 were tested more than once for viral infection and 166 were tested more than once for the antibody. Median age of participants was 39 years (IQR 32-51 years). Among these 84.7% were females, 84.4% white, 6.7% African American, 4.8% Asian and 84.7% non-Hispanic. The cumulative incidence of a positive test for the virus was 2.2% (16/712), and for the antibody test was 3.8% (26/679). 5 had both viral and antibody tests positive, with an average time of 4.1 weeks from viral testing positivity to detectable antibody among 3 cases and 2 cases with both viral infection and antibody detected at same time. There were 3 cases virus was detected more than once after turning positive. 2 remained positive at 16 and 22 days after initial test and one turned negative at 36 days as of last follow up. There were 7 cases where the antibody was tested more than once after turning positive and all 7 remained positive as of last follow up (range 7-103 days). Conclusion Prospective voluntary testing in asymptomatic medical and research staff who work in direct contact with cancer patients was feasible and resulted in identification of asymptomatic carriers who then placed in quarantine, thereby limiting exposure to cancer patients. Medical and research staff who work with cancer patients are general very cautious and the frequency of infections were significantly lower than general society. In addition, it seems that 1) virus and antibody may co-exist in the same person after exposure, and 2) the antibody may last for a relatively long time.

Immunogenicity of SARS-CoV-2 vaccination in subjects on active treatment for breast cancer

Background: Infection with SARS-CoV-2 has led to a global pandemic and has significantly impacted the care of cancer patients. Breast cancer patients receiving active systemic therapy need protection against COVID19 but the efficacy of vaccines in this population is unknown. Although specific biomarkers associated with protection from SARS-CoV-2 infection have yet to be identified, measurement of serum antibody activity is generally accepted as a surrogate of in vivo humoral response to vaccine. This study evaluates the efficiency and durability of binding antibodies to SARS-CoV-2 spike (S) protein in response to COVID19 vaccine in breast cancer patients receiving systemic treatment. Methods: Breast cancer patients, who were unvaccinated, partially or fully vaccinated with Pfizer-BioNTech BNT162b2 (PF), Moderna mRNA-1273 (Mod) or Johnson & Johnson AD26.COV2.S (J&J) were enrolled in this prospective longitudinal study. Eligible patients were on systemic treatment with cytotoxic chemotherapy, chemotherapy plus a checkpoint inhibitor (CPI), CPI alone or a CDK 4/6 inhibitor. Longitudinal blood samples are being collected at baseline, prior to vaccination in unvaccinated patients (T0), 2 weeks after the first vaccine dose and before Sthe second dose for the mRNA vaccines (T1), 1 month (T2), 3 months (T3), 6 months (T4) and 12 month post vaccination. For J&J, there was no T1 timepoint. Roche Elecsys® Anti-SARS-CoV-2 S receptor binding domain (RBD) antibody immunoassay was used to measure antibody titers (range 0.4 to 250 U/mL). Cut points of <0.8 U/mL = negative, ≥0.8 U/mL = seropositive, were based on validated product specifications. Results: Of the 84 breast cancer patients enrolled, 9 had documented COVID infection at baseline and were excluded from analysis. Mean age was 58 years;99% were female, 85% were Caucasian, 49% had early stage disease and 51% had metastatic breast cancer. 67% were receiving cytotoxic chemotherapy, 20% a CKD 4/6 inhibitor, 13% a CPI with or without chemotherapy. 61.2% were vaccinated with PF, 34.3% with Mod and 4.5% with J&J vaccines. Seropositivity rate for the entire group was 10% at T0, 78% at T1, 98% at T2 and 100% at T3. Seropositivity rates of all cohorts at different timepoints are shown in the table. Mean titers for all patients were 12.6 U/mL at T0, 102.3 U/mL at T1, 204.4 U/mL at T2 and 214.6 U/mL at T3 timepoints. Similar incremental increase in antibody levels was observed in all cohorts (Table). Conclusions: 78% of the patients with breast cancer on active systemic treatment were seropositive after the first dose of COVID19 vaccine and 98% after the second dose. The antibody response was maintained at 3 months, with 100% seropositivity rate. 6-month antibody response will be available at the time of presentation. Durability of antibody response at 6 and 12 months will help determine the timing of additional vaccine booster doses in this population. Importantly, this study has found that active treatment with chemotherapy, immunotherapy or CDK4/6 inhibitor therapy does not impact antibody response to SARS-CoV-2 vaccination in patients with breast cancer. Table: Seropositivity rate and mean Anti-S protein antibody levels by cohort at each time point. T0= baseline, T1=after first vaccine dose (mRNA vaccines), T2= 4 weeks after 2 doses of mRNA vaccine or after single dose of J&J vaccine, T3=3 months after the first dose of vaccine.

Long-term outcomes of patients with large B-cell lymphoma treated with standard-of-care axicabtagene ciloleucel: Results from the us lymphoma CAR-T cell consortium

Introduction: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 Chimeric Antigen Receptor (CAR) T-cell therapy that induces durable responses in patients with relapsed or refractory large B-cell lymphoma. At a median of 27.1 months follow-up on the ZUMA-1 trial, median overall survival (OS) was 25.8 months with 39% progression free survival (PFS) at 2 years post-infusion (Locke, Lancet Onc 2019). We previously reported outcomes of axi-cel patients treated with standard of care therapy at a median follow up of 12.9 months, including 42% who did not meet eligibility criteria for ZUMA-1 based on co-morbidities (Nastoupil, JCO 2020). Here we report results from this cohort at a median follow up of 32.4 months, as well as late outcomes of interest including cytopenias, infections and secondary malignancies. Methods and Results: The US Lymphoma CAR-T Consortium comprised of 17 US academic centers who contributed data independent of the manufacturer. Two hundred and ninety-eight patients underwent leukapheresis with intent to manufacture standard of care axi-cel as of September 30, 2018. In infused patients (n=275), OS and PFS were calculated from date of infusion. After median follow-up of 32.4 months (95% CI 31.1 - 34.3), median OS was not reached (95% CI 25.6 - not evaluable) (Figure 1A) with 1-, 2- and 3-year OS of 68.5% (95% CI 62.6-73.7), 56.4% (95% CI 50.1-62.2) and 52.2% (95% CI 45.7-58.2%), respectively. Median PFS was 9 months (95% CI 5.9-19.6) (Figure 1B);1-, 2- and 3-year PFS was 47.4% (95% CI 41.4-53.2), 41.6% (95% CI 35.6-47.5) and 37.3% (95% CI 31.3-43.2), respectively. Twenty-seven PFS events occurred at or after 1 year post infusion;19 events were progressive lymphoma, with the latest relapse observed 28 months after axi-cel infusion. Eight patients died while in remission from their lymphoma: 4 from secondary malignancy, 3 from infection, and 1 from unknown causes. Results of multivariable modeling were similar to our prior analysis: factors associated with both a shorter PFS and shorter OS included male sex, elevated pre-lymphodepletion LDH, and poor ECOG status. Complete blood count and B- and T-cell recovery data were collected at 1 and 2-years post-infusion, excluding patients who had relapsed or been treated for secondary malignancy at time of collection (Table 1). Rates of neutropenia (absolute neutrophil count ≤1000) at 1- and 2- years were 9.2% (10/109) and 11.2% (9/80) and rates of CD4 count ≤200/ul were 62% (23/37) and 27% (7/26). Recovery of B cells was seen in 54% (15/28) and 57% (13/23) at 1-and 2-years post infusion. Infections were reported in 31.2% (34/109) patients between 6- and 12-months post infusion, and 17% (18/109) were severe, requiring either hospitalization and/or IV antibiotics. Twenty-one patients (24%, 21/89) had an infection between 1- and 2- years, 11% of which were severe. Twenty percent (10/49) of patients between 2- and 3-years had an infection and 4 (8%) were severe. Neutropenia, low CD4 counts, and IgG levels were not associated with infection, though patients with infection between 6-12 months were more likely to have received IVIG (p<0.001). No patient in this cohort died of COVID-19. Twenty-two of 275 (8%) patients were diagnosed with subsequent malignancy after axi-cel treatment: 14/275 (5%) patients were diagnosed with myeloid malignancies (MDS (n=12), AML (n=1), CMML (n=1));other malignancies included squamous cell carcinoma of skin (n=3);sarcoma (n=1);endometrial (n=1);lung (n=1);mesothelioma (n=1) and AITL (n=1). Patients with myeloid malignancy had a median age of 62 at axi-cel apheresis (IQR 56-67), 64% were male and median lines of prior therapy was 4 (IQR 3-6), including 36% with a prior autologous stem cell transplant. Eleven patients were in remission from lymphoma at myeloid malignancy diagnosis, while 3 were diagnosed after progression and interval therapy. Conclusion: This multi-center retrospective study showed similar long-term results to the ZUMA-1 trial, despite including patients who did not meet ZUMA-1 eligibility criteria ba ed on comorbidities. Sixteen percent of PFS events were seen after 1 year, largely due to disease progression. Late infection was common but was not explained by persistent neutropenia or low CD4 counts. Subsequent malignancy, including MDS, occurred in 8% of patients and require further study to better identify patients at risk. (Figure Presented).

Neutralizing Antibody Responses Against Sars-Cov-2 in Patients with Plasma Cell Disorders Who Are on Active Treatment after Two Doses of mRNA Vaccination

Background Patients (Pts) with multiple myeloma (MM) experience prolonged immunosuppression due to the incurable nature of the disease and corresponding treatment modalities. Due to this many MM pts with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) require hospitalization, with an increased mortality rate over healthy adults. Two mRNA vaccines against (SARS-CoV-2): BNT162b2 & mRNA-1273 were approved under an emergency use authorization (EUA) by the Food and Drug Administration (FDA) due to the high efficacy in preventing SARS-CoV-2. The aim of this study was to analyze the antibody (Abs) response in all pts with plasma cell disorders (PCD) including MM, AL-Amyloidosis, and smoldering myeloma (SMM) who are on active treatment. Patients & Methods All pts (MM, AL-Amyloidosis, and SMM) on active treatment who received SARS-CoV-2 mRNA vaccine were identified at the University of Kansas Health System between January 2021 to July 2021and reviewed retrospectively. Descriptive analyses were performed on available data for patient characteristics. Abs against SARS-CoV-2 were measured using methodology approved by the FDA (enzyme-linked immunosorbent assay;cPass SARS-CoV-2 Neutralizing Antibody Detection Kit;GenScript, Piscataway, NJ). We stratified pts into clinically relevant responders (>250 IU/mL), partial responders (50-250 IU/mL), and non-responders (<50 IU/mL) Results A total of 118 pts were identified in our analysis and are described in Table 1. Of the total pts, 102 (86%) had MM, 13 (11%) pts had AL-Amyloidosis, and 3 (3%) pts had SMM. Median age was 69 years (45-95), 96 pts (81%) were Caucasian, and 57 (48%) were male. Median lines of prior treatment was 2 (1-13). Active PCD patients were treated with single-agent therapy in 60 pts (51%), doublet-based therapy in 5 pts (4%), and triplet-based therapy in 51 pts (43%). Daratumumab based therapy was utilized in 59 pts (50%). All pts included received two doses of either BNT162b2 or mRNA-1273. At the time of abs testing 82 patients (69%) were in a very good partial response (VGPR) or better, 29 pts (25%) were in partial response, while 7 pts (6%) had stable disease. Five pts (4%) had COVID-19 infection prior to the vaccine. The median time between thesecond dose of the vaccine and testing for Abs was 100 days (34-190). Only 46 pts (39%) developed an adequate response, 36 pts (30.5%) had a partial response, while 36 (30.5%) did not respond to the vaccine. Low Ab levels were seen in all PCD subtypes with the following mean levels: SMM :25.4 (5.4- 36.9) IU/mL, MM 148 (0- >250) IU/mL, and AL- Amyloidosis 92.35 (range 0- >250) IU/mL. Among the 5 pts with COVID-19 infection prior to the vaccination, full Abs response was observed in 4 pts, and 1 patient had no Abs response. Type of treatment did not affect the response to treatment in any clinically meaningful way. The odds ratio of achieving a clinically relevant Abs response was higher in pts with absolute lymphocyte counts>0.5 K/uL (p=0.01) and IgG levels> 400 mg/dL (p=0.04) and lower in pts receiving treatments with daratumumab combinations or anti-BCMA therapy (p<0.0001). Higher levels of anti-SARS-CoV-2 Abs were observed in pts with ≥ VGPR (mean≈147 IU/mL) compared to <VGPR (mean≈ 119 IU/mL). However, in this dataset, this difference was not statistically significant (p=0.17). Conclusion mRNA vaccine Ab response is lower in PCD pts getting active treatment compared with the general population. For PCD patients on active treatment, mRNA vaccine produced full antibody responses and partial responses in 39% and 30.5% of pts, respectively. anti-SARS-CoV-2 abs are especially low for patients on daratumumab combinations or anti-BCMA therapy, low lymphocytes, and low IgG levels at the time of vaccination. Some PCD may not develop anti-SARS-CoV-2 abs despite vaccination and/or previous COVID-19 infection. Therefore, checking anti-SARS-CoV-2 abs may be clinically useful in identifying patient's response. Further prospective studies should ascertain the value of a 3 rd vaccine dose in this population. [Fo mula presented] Disclosures: Mahmoudjafari: Omeros: Membership on an entity's Board of Directors or advisory committees;GSK: Membership on an entity's Board of Directors or advisory committees;Incyte: Membership on an entity's Board of Directors or advisory committees. McGuirk: Astelllas Pharma: Research Funding;Juno Therapeutics: Consultancy, Honoraria, Research Funding;EcoR1 Capital: Consultancy;Gamida Cell: Research Funding;Magenta Therapeutics: Consultancy, Honoraria, Research Funding;Fresenius Biotech: Research Funding;Bellicum Pharmaceuticals: Research Funding;Novartis: Research Funding;Pluristem Therapeutics: Research Funding;Allovir: Consultancy, Honoraria, Research Funding;Kite/ Gilead: Consultancy, Honoraria, Other: travel accommodations, expense, Kite a Gilead company, Research Funding, Speakers Bureau;Novartis: Research Funding. Atrash: Jansen: Research Funding, Speakers Bureau;AMGEN: Research Funding;GSK: Research Funding.

Outcomes with COVID-19 in patients with hematopoietic stem cell transplant and cellular therapy: A systemic review and meta-analysis

Background: Coronavirus Disease 2019 (COVID19) was declared a pandemic on March 11, 2020. COVID-19 has caused over 100 million infections and over 2 million deaths globally. Patients who have received a hematogenic stem cell transplant or cellular therapy (HCT) have a high risk of mortality and morbidity with COVID-19 due to severe immune dysregulation. We conducted a systematic review and metaanalysis aimed to evaluate the outcomes of COVID-19 in HCT patients. Methods: A literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines (PRISMA) guidelines was performed on 3 databases (PubMed, Cochrane, and Clinical trials.gov) from the date of inception to Jan 2021. MeSH terms included 'hematological malignancies', 'hematopoietic stem cell transplantation', 'SARS-CoV-2', and 'COVID 19'. We screened 99 articles and 6 studies (4 retrospective studies, 2 prospective) were included after excluding review, duplicate, and non-relevant articles. Quality evaluation was done using the NIH quality assessment tool. The Inter-study heterogeneity among the studies was assessed using the Q statistic proposed by Cochrane and the I2 index introduced by Higgins and Thompson. Pooled analysis was done using the 'metaXL', and the random effects model was used to estimate the pooled prevalence with 95% CI. Results: Of 1619 patients in 6studies, 646 HCT patients were analyzed (Table ). The median age of patients was 63 years and 59% were males. Median days since HCT for autologous (auto) HCT and allogeneic (allo) HCT patients were 690 and 450 days respectively. The average follow-up duration after COVID-19 was 24 days. COVID-19 mortality in HCT patients was 20% (95%CI 0.17 to 0.23, I2=0). Roedl et al (n=6) reported a mortality of 83% and was excluded from the pooled analysis. The mortality rate was 19% (95% CI 0.15 to 0.24, I2=0%) in auto HCT patients and 21% (95% CI 0.17 to 0.25, I2=0%) in allo HCT patients. Conclusions: The HCT patients are at significant risk of increased mortality and morbidity due to COVID-19. There is a need to prioritize HCT patients for COVID-19 vaccination, close surveillance, and aggressive management. (Table Presented).

Outcomes with COVID-19 in hematopoietic stem cell transplant and cellular therapy patients

Background: The Coronavirus Disease 2019 (COVID-19) has caused over 25 million infections in the US with over 0.4 million deaths. Hematogenic stem cell transplant (HCT) or cellular therapy (CT) recipients have a high risk of mortality with COVID-19 due to profound immune dysregulation. We aimed to assess the outcomes with COVID-19 in HCT/CT recipients. Methods: A single-center prospective study was conducted, including all (n=40) adult HCT/CT patients who were diagnosed with COVID-19 at the University of Kansas from Apr 2020 to Jan 2021. Baseline and disease-related characteristics were ascertained from medical records. Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were conducted. Results: The study included 40 COVID-19 patients (72.5% Oct 2020-Jan 2021), including allogeneic HCT (n=25), autologous HCT (n=13) and CAR-T CT (n=2) with median time since HCT/CT of 12.4 (1- 201.9), 37.2 (0.4-118.7), and 3.8 (2.8-4.8) months. Seventy percent were Caucasians and 17.5 were Hispanics. Primary hematologic malignancy was myeloid (37.5%), lymphoid (35%) or plasma cell disorder (27.5%). Myeloablative conditioning was performed in 65% of patients. Donors were autologous (37.5%), matched sibling (17.5%), matched unrelated (22.5%) and haploidentical (22.5%). COVID-19 was mild (42.5%), moderate (42.5%) or severe (15%). Clinical findings included pneumonia (62.5%), hypoxia (25%) and ICU admission (17.5%) while therapies included remdesivir (47.5%), convalescent plasma (40%), dexamethasone (25%) and monoclonal antibodies (17.5%). Concurrent cancer treatment, other infections and active GVHD were reported in 25% (all myeloma), 20% and 32.5% of patients. After a median follow-up of 74 days (7-269), the mortality rate was 12.5% in all patients and 20% in allo-HCT patients. Significant predictors of COVID-19 severity included allogeneic HCT, concurrent immune suppression and elevated inflammatory markers. (Table). Conclusions: Hematopoietic stem cell transplant recipients have an increased risk of mortality with COVID-19. Our findings confirm the need for vaccination prioritization, close monitoring, and aggressive treatment in HCT/CT patients.