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PURPOSE Brexucabtagene autoleucel (brexu-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory mantle cell lymphoma (MCL). This therapy was approved on the basis of the single-arm phase II ZUMA-2 trial, which showed best overall and complete response rates of 91% and 68%, respectively. We report clinical outcomes with brexu-cel in the standard-of-care setting for the approved indication. PATIENTS AND METHODS Patients who underwent leukapheresis between August 1, 2020 and December 31, 2021, at 16 US institutions, with an intent to manufacture commercial brexu-cel for relapsed/refractory MCL, were included. Patient data were collected for analyses of responses, outcomes, and toxicities as per standard guidelines. RESULTS Of 189 patients who underwent leukapheresis, 168 (89%) received brexu-cel infusion. Of leukapheresed patients, 79% would not have met ZUMA-2 eligibility criteria. Best overall and complete response rates were 90% and 82%, respectively. At a median follow-up of 14.3 months after infusion, the estimates for 6- and 12-month progression-free survival (PFS) were 69% (95% CI, 61 to 75) and 59% (95% CI, 51 to 66), respectively. The nonrelapse mortality was 9.1% at 1 year, primarily because of infections. Grade 3 or higher cytokine release syndrome and neurotoxicity occurred in 8% and 32%, respectively. In univariable analysis, high-risk simplified MCL international prognostic index, high Ki-67, TP53 aberration, complex karyotype, and blastoid/pleomorphic variant were associated with shorter PFS after brexu-cel infusion. Patients with recent bendamustine exposure (within 24 months before leukapheresis) had shorter PFS and overall survival after leukapheresis in intention-to-treat univariable analysis. CONCLUSION In the standard-of-care setting, the efficacy and toxicity of brexu-cel were consistent with those reported in the ZUMA-2 trial. Tumor-intrinsic features of MCL, and possibly recent bendamustine exposure, may be associated with inferior efficacy outcomes.

The majority of patients with large B-cell lymphoma treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, develop cytokine release syndrome (CRS). Whether the lack of development of CRS with axi-cel is associated with inferior lymphoma outcomes is unknown. Additionally, relationship between CRS grade and lymphoma outcome is not well established.The US Lymphoma CAR T Consortium includes seventeen US academic centers that contribute data independently of manufacturers. We analyzed the modified intent-to-treat population of 275 patients receiving axi-cel in two different ways: 1) Two group analysis comparing no CRS with any grade CRS; 2) Three group analysis comparing grade 0 CRS with grade 1 to 2 CRS, and grade 3-5 CRS.In this large multi-center observational cohort of 275 patients receiving axi-cel, 9% (n = 24) did not develop CRS, 84% (n = 232) developed grade 1-2 CRS, and 7% (n = 19) developed grade 3 to 5 CRS. Patients without CRS, compared with those having any grade CRS, had similar overall response rates (ORR), lower complete response (CR) rates and inferior progression free survival (PFS) with no statistically significant difference in overall survival (OS). Patients experiencing grade 1 to 2 CRS had superior CR rate and PFS, as compared to those without CRS or with grade 3 to 5 CRS. Grade 3 to 5 CRS was associated with a worse OS.Overall, durable responses were seen in patients that did not develop CRS, however grade 1 to 2 CRS was associated with better outcomes while those with grade 3 to 5 experienced the worse outcomes.

Cleaning procedures for manufacturing equipment have been shown to prevent product contamination through the cleaning validation process. This review aims to understand how the cleaning validation plays a critical role in managing contamination or cross-contamination issues during good manufacturing practices (GMP). Emphasis on the quantity of cleaning required for the machinery, the elimination of contamination during manufacturing procedures are discussed here. The article describes various cleaning agents as well as sampling methods for cleaning equipment. Focus is laid on the elements of cleaning validation, objectives of the cleaning validation, regulatory significance of requirements for cleaning validation, etc. Also, it provides information on the different cleaning standards to meet regulatory requirements by the pharmaceutical industry.

Patients receiving CD19 CAR T-cell therapy for relapsed/refractory lymphoma experience prolonged and profound B-cell aplasia and hypogammaglobulinemia, placing them at a higher risk for severe COVID-19. Independently, Oh et al and Atanackovic et al demonstrate that despite attenuated humoral response to mRNA-based vaccines, patients demonstrate normal or heightened functional T-cell responses, including antiviral T-cell activity against SARS-CoV-2 variants including Omicron. Collectively, these data reinforce the importance of COVID-19 vaccination following CD19 CAR T-cell therapy, despite long-term B-cell aplasia.

Abstract: Bridged peptide macrobicycles (BPMs) from natural resources belong to types of compounds that are not investigated fully in terms of their formation, pharmacological potential, and stereo- chemical properties. This division of biologically active congeners with multiple circular rings has merits over other varieties of peptide molecules. BPMs form one of the most hopeful grounds for the establishment of drugs because of their close resemblance and biocompatibility with proteins, and these bio-actives are debated as feasible, realistic tools in diverse biomedical applications. Despite huge potential, poor metabolic stability and cell permeability limit the therapeutic success of macrocyclic peptides. In this review, we have comprehensively explored major bicyclic peptides sourced from plants and mushrooms, including βs-leucyl-tryptophano-histidine bridged and tryptophanocysteine bridged peptide macrobicycles. The unique structural features, structure-activity relationship, synthetic routes, bioproperties, and therapeutic potential of the natural BPMs are also discussed.

Diffuse large B cell lymphoma (DLBCL) is an aggressive malignancy that has been traditionally treated with anthracycline-based chemotherapy, but approximately one-third of patients relapse after first-line therapy or have primary refractoriness. In this focused review, we discuss the seven novel Food & Drug Administration (FDA)-approved medications for relapsed/refractory (R/R) DLBCL. We describe five CD19-targeted therapies, three of which are chimeric antigen receptor (CAR)-T cell therapies. We also highlight novel non-cell-based targeted therapies and discuss optimal sequencing considerations based on the goal of treatment, with an emphasis on CAR-T cell therapy as curative intent. We consider the limited tolerability of certain novel agents, prospects for elderly patients, and financial aspects of these approaches. We discuss advantages and limitations of these targeted therapies based on seminal clinical trials. Finally, we summarize ongoing trials involving promising agents making their way in the pharmacologic pipeline, including allogeneic CAR-T treatments and multi-antigen targeting therapies such as the CD19/CD22 CAR-T and the CD3/CD20 bispecific antibodies mosunetuzumab and odronextamab. We summarize our approach based on the best available evidence as we enter 2022.

We examined the meaning of metabolically active lesions on 1 month restaging nuclear imaging of patients with relapsed/refractory (R/R) large B-cell lymphoma (LBCL) receiving axicabtagene ciloleucel (axi-cel) by assessing the relationship between total metabolic tumor volume (MTV) on positron emission tomography (PET) scans and circulating tumor DNA (ctDNA) in the plasma. In this prospective multicenter sample collection study, MTV was retrospectively calculated via commercial software at baseline, 1 and 3 months post chimeric antigen receptor (CAR) T-cell therapy; ctDNA was available pre and post axi-cel. Spearman correlation coefficient (rs) was used to study the relationship between the variables and a mathematical model was constructed to describe tumor dynamics 1 month post CAR T-cell therapy. The median time between baseline scan and axi-cel infusion was 33 (range, 1-137) days for all 57 patients. For 41 of the patients with imaging within 33 days of axi-cel or imaging before that time but no bridging therapy, the correlation at baseline became stronger (rs 0.61, P< 0.0001) compared to all patients (rs 0.38, P= 0.004). Excluding patients in complete remission with no measurable residual disease, ctDNA and MTV at 1 month did not correlate (rs 0.28, P= 0.11), but did correlate at 3 months (rs 0.79, P= 0.0007). Modeling of tumor dynamics, which incorporated ctDNA and inflammation as part of MTV, recapitulated outcomes of patients with positive radiologic 1-month scans. Our results suggested that non-progressing hypermetabolic lesions on 1 month PET represent ongoing treatment response and their composition may be elucidated by concurrent ctDNA.

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disorder. Use of chimeric antigen receptor T-cell therapy (CAR-T) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and secondary HLH. However, application of HLH scoring systems (H-score, HLH-2004 criteria) are not validated in this setting. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify patients with possible HLH post-CAR-T for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Only two of four patients with post CAR-T HLH met five or more of the diagnostic criteria for HLH by HLH 2004 criteria. In contrast all four post CAR-T HLH patients had a high H-score (169); however, an additional ten patients that did not have HLH also had a high H-score. Thus, in this patient population, both scoring systems were demonstrated to have low prognostic significance in differentiating between high grade CRS and HLH.

PURPOSE Although the majority of patients with relapsed or refractory large B-cell lymphoma respond to axicabtagene ciloleucel (axi-cel), only a minority of patients have durable remissions. This prospective multicenter study explored the prognostic value of circulating tumor DNA (ctDNA) before and after standard-of-care axi-cel for predicting patient outcomes. METHODS Lymphoma-specific variable, diversity, and joining gene segments (VDJ) clonotype ctDNA sequences were frequently monitored via next-generation sequencing from the time of starting lymphodepleting chemotherapy until progression or 1 year after axi-cel infusion. We assessed the prognostic value of ctDNA to predict outcomes and axi-cel–related toxicity. RESULTS A tumor clonotype was successfully detected in 69 of 72 (96%) enrolled patients. Higher pretreatment ctDNA concentrations were associated with progression after axi-cel infusion and developing cytokine release syndrome and/or immune effector cell–associated neurotoxicity syndrome. Twenty-three of 33 (70%) durably responding patients versus 4 of 31 (13%) progressing patients demonstrated nondetectable ctDNA 1 week after axi-cel infusion ( P < .0001). At day 28, patients with detectable ctDNA compared with those with undetectable ctDNA had a median progression-free survival and OS of 3 months versus not reached ( P < .0001) and 19 months versus not reached ( P = .0080), respectively. In patients with a radiographic partial response or stable disease on day 28, 1 of 10 patients with concurrently undetectable ctDNA relapsed; by contrast, 15 of 17 patients with concurrently detectable ctDNA relapsed ( P = .0001). ctDNA was detected at or before radiographic relapse in 29 of 30 (94%) patients. All durably responding patients had undetectable ctDNA at or before 3 months after axi-cel infusion. CONCLUSION Noninvasive ctDNA assessments can risk stratify and predict outcomes of patients undergoing axi-cel for the treatment of large B-cell lymphoma. These results provide a rationale for designing ctDNA-based risk-adaptive chimeric antigen receptor T-cell clinical trials.

Here, we report the first comparative analysis of patient-reported outcomes (PROs) with chimeric antigen receptor T-cell therapy vs standard-of-care (SOC) therapy in second-line relapsed/refractory large B-cell lymphoma (R/R LBCL) from the pivotal randomized phase 3 ZUMA-7 study of axicabtagene ciloleucel (axi-cel) vs SOC. PRO instruments were administered at baseline, day 50, day 100, day 150, month 9, and every 3 months from randomization until 24 months or an event-free survival event. The quality of life (QoL) analysis set comprised patients with a baseline and ≥1 follow-up PRO completion. Prespecified hypotheses for Quality of Life Questionnaire-Core 30 (QLQ-C30) physical functioning, global health status/QoL, and EQ-5D-5L visual analog scale (VAS) were tested using mixed-effects models with repeated measures. Clinically meaningful changes were defined as 10 points for QLQ-C30 and 7 for EQ-5D-5L VAS. Among 359 patients, 296 (165 axi-cel, 131 SOC) met inclusion criteria for QoL analysis. At day 100, statistically significant and clinically meaningful differences in mean change of scores from baseline were observed favoring axi-cel over SOC for QLQ-C30 global health status/QoL (estimated difference 18.1 [95% confidence interval (CI), 12.3-23.9]), physical functioning (13.1 [95% CI, 8.0-18.2]), and EQ-5D-5L VAS (13.7 [95% CI, 8.5-18.8]; P < .0001 for all). At day 150, scores significantly favored axi-cel vs SOC for global health status/QoL (9.8 [95% CI, 2.6-17.0]; P = .0124) and EQ-5D-5L VAS (11.3 [95% CI, 5.4-17.1]; P = .0004). Axi-cel showed clinically meaningful improvements in QoL over SOC. Superior clinical outcomes and favorable patient experience with axi-cel should help inform treatment choices in second-line R/R LBCL. This trial was registered at www.clinicaltrials.gov as #NCT03391466.

Use of granulocyte colony-stimulating factor (G-CSF) has been associated with side effects including reports of acute glomerulonephritis (GN), almost all of which have been immune complex associated. There is one prior report of pauci-immune GN in a child, but was negative for ANCA (anti-neutrophilic cytoplasmic antibodies). We describe the first case of ANCA-positive pauci-immune GN exacerbated by the use of G-CSF for peripheral blood stem cell (PBSC) donation in a patient with no prior history of vasculitis. Given the use of G-CSF in PBSC donation and neutropenias associated with various conditions, it is important that both the nephrologist and the hematologist are aware of the renal risks associated with its use.

PURPOSE Axicabtagene ciloleucel (axi-cel) is an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory large B-cell lymphoma (LBCL) on the basis of the single-arm phase II ZUMA-1 trial, which showed best overall and complete response rates in infused patients of 83% and 58%, respectively. We report clinical outcomes with axi-cel in the standard-of-care (SOC) setting for the approved indication. PATIENTS AND METHODS Data were collected retrospectively from all patients with relapsed/refractory LBCL who underwent leukapheresis as of September 30, 2018, at 17 US institutions with the intent to receive SOC axi-cel. Toxicities were graded and managed according to each institution’s guidelines. Responses were assessed as per Lugano 2014 classification. RESULTS Of 298 patients who underwent leukapheresis, 275 (92%) received axi-cel therapy. Compared with the registrational ZUMA-1 trial, 129 patients (43%) in this SOC study would not have met ZUMA-1 eligibility criteria because of comorbidities at the time of leukapheresis. Among the axi-cel–treated patients, grade ≥ 3 cytokine release syndrome and neurotoxicity occurred in 7% and 31%, respectively. Nonrelapse mortality was 4.4%. Best overall and complete response rates in infused patients were 82% (95% CI, 77% to 86%) and 64% (95% CI, 58% to 69%), respectively. At a median follow-up of 12.9 months from the time of CAR T-cell infusion, median progression-free survival was 8.3 months (95% CI, 6.0 to15.1 months), and median overall survival was not reached. Patients with poor Eastern Cooperative Oncology Group performance status of 2-4 and elevated lactate dehydrogenase had shorter progression-free and overall survival on univariable and multivariable analysis. CONCLUSION The safety and efficacy of axi-cel in the SOC setting in patients with relapsed/refractory LBCL was comparable to the registrational ZUMA-1 trial.

Background CD19-directed chimeric antigen receptor (CAR) T-cell therapy (CAR-T) has emerged as effective for relapsed/refractory large B-cell lymphoma (R/R LBCL). The neurologic toxicity seen with CAR-T, referred to as immune effector cell–associated neurotoxicity syndrome (ICANS), is poorly understood. To better elucidate the clinical characteristics, treatment outcomes, and correlative biomarkers of ICANS, we review here a single-center analysis of ICANS after CAR T-cell therapy in R/R LBCL. Methods Patients (n = 45) with R/R LBCL treated with axicabtagene ciloleucel (axi-cel) were identified. Data regarding treatment course, clinical outcomes, and correlative studies were collected. Patients were monitored and graded for ICANS via CARTOX-10 scoring and Common Terminology Criteria for Adverse Events (CTCAE) v4.03 criteria, respectively. Results Twenty-five (56%) patients developed ICANS, 18 (72%) of whom had severe (CTCAE grades 3–4) ICANS. Median time to development of ICANS was 5 days (range, 3–11). Elevated pre-infusion (day 0 [D0]) fibrinogen (517 vs 403 mg/dL, upper limit of normal [ULN] 438 mg/dL, P = 0.01) and D0 lactate dehydrogenase (618 vs 506 units/L, ULN 618 units/L, P = 0.04) were associated with ICANS. A larger drop in fibrinogen was associated with ICANS (393 vs 200, P < 0.01). Development of ICANS of any grade had no effect on complete remission (CR), progression-free survival (PFS), or overall survival (OS). Duration and total dose of steroid treatment administered for ICANS did not influence CR, PFS, or OS. Conclusions ICANS after CAR-T with axi-cel for R/R LBCL was seen in about half of patients, the majority of which were high grade. Contrary to previous reports, neither development of ICANS nor its treatment were associated with inferior CR, PFS, or OS. The novel finding of high D0 fibrinogen level can identify patients at higher risk for ICANS.

Summary Background Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness. Methods In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing. Findings Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57–76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53–2·21), male sex (1·63, 1·07–2·48), smoking status (former smoker vs never smoked: 1·60, 1·03–2·47), number of comorbidities (two vs none: 4·50, 1·33–15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11–7·18), active cancer (progressing vs remission: 5·20, 2·77–9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79–4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07–0·84) or the US-Midwest (0·50, 0·28–0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality. Interpretation Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments. Funding American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

BackgroundSolid organ transplant recipients (SOTR), who typically receive post-transplant immunosuppression, show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines in SOTR can overcome the reduced immune responsiveness against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants.MethodsWe performed a prospective cohort study of 53 SOTR receiving SARS-CoV-2 vaccination into a prospective cohort study performing detailed immunoprofiling of humoral immune responses against SARS-CoV-2 and its variants.ResultsPrior to the additional vaccine dose, 60.3% of SOTR showed no measurable neutralization and only 18.9% demonstrated neutralizing activity of >90% following two vaccine doses. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titers against microbial recall antigens were in fact higher. In contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titers against SARS-CoV-2 and its delta variants. Vaccinated SOTR showed a markedly fewer linear B cell epitopes, indicating reduced B cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titers and neutralizing activity across alpha, beta and delta variants. However, we observed a significant decrease in anti-spike antibody titers with the omicron variant.ConclusionsOnly a small subgroup of SOTR generated functionally relevant antibodies after completing the initial vaccine series based on dysfunctional priming of immune responses against novel antigens. An additional dose of the vaccine results in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron.

Background/aimsChimeric antigen receptor T-cell (CAR T) therapy has been shown to improve the remission rate and survival for patients with refractory haematological malignancies. The aim of this study is to describe ocular adverse effects associated with CAR T therapy in patients with haematological malignancies.MethodsThis is a retrospective, single-institution, case series. Patients aged 18 years or older who received standard of care CAR T therapy for relapsed/refractory large B-cell lymphoma with a documented ophthalmic evaluation were included. The primary outcome was clinician ophthalmic examination findings.ResultsA total of 66 patients received CAR T-cell therapy from February 2018 to October 2019 with 11 receiving an ophthalmic examination. Eleven patients (n=22 eyes) who received CAR T-cell therapy were included in review. The median time from CAR T-cell infusion date to ocular examination was 57.5 days. The median patient age at the time of examination was 60.5 years. Ten patients had subjective symptoms prompting ophthalmic examination. Two patients reported floaters and photopsias. One patient had worsening ocular graft-versus-host disease. Two patients were identified with possible reactivation of viral infections, including herpes zoster ophthalmicus and regressing acute retinal necrosis.ConclusionsThe increasing use of CAR T therapy for malignancies underscores the importance of ophthalmologists and oncologists understanding the potential toxicities associated with its use, particularly ocular toxicities and when to refer for an ophthalmic examination.

Bridged peptide macrobicycles (BPMs) from natural resources belong to types of compounds that are not investigated fully in terms of their formation, pharmacological potential, and stereo- chemical properties. This division of biologically active congeners with multiple circular rings has merits over other varieties of peptide molecules. BPMs form one of the most hopeful grounds for the establishment of drugs because of their close resemblance and biocompatibility with proteins, and these bio-actives are debated as feasible, realistic tools in diverse biomedical applications. Despite huge potential, poor metabolic stability and cell permeability limit the therapeutic success of macrocyclic peptides. In this review, we have comprehensively explored major bicyclic peptides sourced from plants and mushrooms, including β

Patients after autologous (autoSCT) and allogeneic stem cell transplantation (alloSCT) are at an increased risk of COVID-19-related morbidity and mortality, compounded by an immune system weakened by the underlying malignancy and prior treatments. Allogeneic transplantation, including stem cell and solid organ transplants, requires intensive immunosuppressive prophylaxis, which may further undermine the development of a protective vaccine-induced anti-viral immunity. Herein, we report on short- and long-term antiviral immune responses in two peri-stem cell transplant recipients and a third patient who received a COVID-19 vaccination after kidney transplantation. Our data indicate that: (1) patients post-alloSCT may be able to mount an anti-COVID-19 immune response; however, a sufficient time interval between transplant and exposure may be of critical importance; (2) alloSCT recipients with preexisting anti-SARS-CoV-2 immunity are at risk for losing protective humoral immunity following transplantation, particularly if the stem-cell donor lacks antiviral immunity, e.g., vaccine-derived immunity; and (3) some post-transplant patients are completely unable to build an immune response to a COVID-19 vaccine, perhaps based on the prophylactic suppression of T cell immunity.

PURPOSE OF REVIEW: The treatment landscape for older patients with acute myeloid leukemia (AML) is evolving. Many treatments have comparable efficacy making their impact on quality of life (QoL) an important differentiating factor. In this review, we discuss QoL in older adults with AML, focusing on therapeutic and observational trials that have incorporated QoL assessments. FINDINGS: Health-related quality of life (HRQoL) is a multi-dimensional concept incorporating physical, mental, emotional, and social functioning domains. HRQoL components overlap with components of geriatric assessment, a multidisciplinary diagnostic process that identifies underlying vulnerabilities of older adults and guides subsequent management strategies. HRQoL questionnaires may be general, cancer-specific, leukemia-specific, or symptom-focused. Therapeutic and observational cohort studies suggest HRQoL improves, or at least remains stable, during intensive and lower intensity therapies. Nonetheless, HRQoL is not routinely incorporated in AML therapeutic trials. SUMMARY: HRQoL assessments can inform both decision-making and management for older adults with AML.

Anti-SARS-CoV-2 antibodies are crucial for protection from future COVID-19 infections, limiting disease severity, and control of viral transmission. While patients with the most common type of hematologic malignancy, B cell lymphoma, often develop insufficient antibody responses to messenger RNA (mRNA) vaccines, vaccine-induced T cells would have the potential to ‘rescue’ protective immunity in patients with B cell lymphoma. Here we report the case of a patient with B cell lymphoma with profound B cell depletion after initial chemoimmunotherapy who received a total of six doses of a COVID-19 mRNA vaccine. The patient developed vaccine-induced anti-SARS-CoV-2 antibodies only after the fifth and sixth doses of the vaccine once his B cells had started to recover. Remarkably, even in the context of severe treatment-induced suppression of the humoral immune system, the patient was able to mount virus-specific CD4+ and CD8+ responses that were much stronger than what would be expected in healthy subjects after two to three doses of a COVID-19 mRNA vaccine and which were even able to target the Omicron ‘immune escape’ variant of the SARS-CoV-2 virus. These findings not only have important implications for anti-COVID-19 vaccination strategies but also for future antitumor vaccines in patients with cancer with profound treatment-induced immunosuppression.

Introduction: Patients with hematologic malignancies are at an increased risk of morbid/mortality from COVID-19. Our prospective clinical study evaluated immune responses to COVID-19 mRNA vaccines in patients with B-cell lymphoma who had received CD19-directed chimeric antigen receptor (CAR) T cell therapy. Methods: We measured SARS-CoV-2 neutralizing activity of plasma from 18 patients and 4 healthy controls (HC) and antibody titers against viral spike proteins (S1, S2, RBD) including their “delta” variants using an enzyme-linked immunoassay (ELISA). We measured B cell subpopulations in the patients’ blood using flow cytometry. Results: We found that the peripheral blood plasma from 3/4 HCs showed substantial SARS-CoV-2 neutralizing activity already at 4 weeks after the first dose of COVID-19 mRNA vaccine while none of the CD19 CART patients evidenced any antibody-mediated neutralizing activity at the same point in time. At 4 weeks after receiving the second dose of the vaccine, all 4 HCs showed complete neutralizing activity. In marked contrast, only 1 of 14 CART patients evidenced any relevant antibody-mediated SARS-CoV-2 neutralizing activity. Assessing whether a globally insufficient antibody-mediated immunity was the underlying cause of the lack of a response to the COVID-19 vaccine in our CART patients, we found that IgG antibody levels against common microbial and viral antigens like influenza, Epstein-Barr virus (EBV), Cytomegalovirus (CMV), and tetanus toxoid, were comparable to those observed in HCs. However, while at 4 weeks post second dose of the vaccine the HCs showed high levels of vaccine-induced IgG antibody titers against all the viral spike proteins (S1, S2, RBD), including the “delta” variants of the S1 and RBD proteins, the vast majority of our CART patients did not evidence any SARS-CoV-2-specific antibodies. Importantly, a third “booster” vaccination did not lead to an improvement in the antiviral immunity in the 4 CART patients analyzed. When we assessed B cell subpopulations in the blood of patients and HCs, we found that prior treatments had completely eradicated all CD19+/CD20+ B cells in the patients while numbers of long-lived memory plasma cells were comparable to those of HCs. Conclusions: In this study, 17 of 18 patients with lymphoma who received CD19 CART therapy had very poor immunoreactivity to 1-3 doses of mRNA-based COVID-19 vaccines. Importantly, antibody responses to common recall antigens were preserved, suggesting impaired immune response primarily against novel antigens like SARS-COV-2. This lack of immunoreactivity against novel antigens was probably based on the eradication of earlier-stage B cell subpopulations after treatment with anti-CD19 and anti-CD20 immunotherapies. Citation Format: Thierry Iraguha, Saurabh Dahiya, Stephanie Avila, Aaron Rapoport, Tim Luetkens, Djordje Atanackovic. Immune response to COVID-19 vaccination in patients with B-cell malignancies after CD19 CART cell therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3586.

TPS7579 Background: One mechanism by which B-cell tumors can resist the effects of CD19-targeted CAR T-cell therapy is through CD19 antigen escape (Neelapu et al. ASH 2019). Recent analyses in large B-cell lymphoma (LBCL) demonstrated that approximately one-third to two-thirds of relapses after infusion of CAR T-cell therapy were CD19 negative (Plaks et al. Blood. 2021; Spiegel, Dahiya et al. Blood. 2021; Spiegel et al. Nat Med. 2021). KITE-363 is an autologous CAR T cell transduced with a bicistronic vector with resultant expression of a CD19 CAR with a CD28 costimulatory domain and a CD20 CAR with a 41BB costimulatory domain. In preclinical studies, KITE-363 recognized and eliminated tumor cells expressing CD19 and/or CD20. KITE-363 CAR T-cell therapy has the potential to rescue CD19-negative relapsing patients with BCL as well as prevent CD19 antigen escape by minimizing selective pressure through upfront therapeutic dual targeting. This Phase 1, first-in-human, open-label, multicenter study (NCT04989803) will evaluate the safety and preliminary efficacy of KITE-363 in patients with R/R BCL. Methods: The Phase 1 design includes a 3+3 dose-escalation portion (1A), with 5 planned CAR T-cell levels, and a dose expansion portion (1B). Patients may receive optional corticosteroid bridging therapy following leukapheresis. Patients will then receive conditioning chemotherapy (cyclophosphamide and fludarabine) on Day ‒5 to Day ‒3 followed by KITE-363 infusion on Day 0. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per Lugano criteria (Cheson et al. J Clin Oncol. 2014). Secondary endpoints include complete response rate, time to next treatment, duration of response, progression-free survival, overall survival, safety, and levels of CAR T cells in blood and cytokines in serum. Eligible adult patients have histologically confirmed BCL, including LBCL, indolent non-Hodgkin lymphoma, nodular lymphocyte-predominant Hodgkin lymphoma (HL), and BCL, unclassifiable (with features intermediate between diffuse LBCL and classical HL), that is R/R after ≥2 lines of therapy (patients with LBCL may have primary refractory disease). Other key inclusion criteria are adequate bone marrow and organ function and ECOG performance status 0‒1. Key exclusion criteria are central nervous system (CNS) involvement from lymphoma, active infection including hepatitis B and C, and clinically significant CNS disorder. This study is currently open and accruing patients. Clinical trial information: NCT04989803.