Atrial arrhythmias following CAR-chimeric antigen receptor T-cell therapy: Incidence, risk factors and biomarker profile.

Recent reports have raised concerns about the association of chimeric antigen receptor T cell (CAR-T) with non-negligible cardiotoxicity, particularly atrial arrhythmias. First, we conducted a pharmacovigilance study to assess the reporting of atrial arrhythmias following CD19-directed CAR-T. Subsequently, to determine the incidence, risk factors and outcomes of atrial arrhythmias post-CAR-T, we compiled a retrospective single-centre cohort of non-Hodgkin lymphoma patients. Only commercial CAR-T products were considered. Atrial arrhythmias were nearly fourfold more likely to be reported after CAR-T therapy compared to all other cancer patients in the FAERS (adjusted ROR = 3.76 [95% CI 2.67-5.29]). Of the 236 patients in our institutional cohort, 23 (10%) developed atrial arrhythmias post-CAR-T, including 12 de novo arrhythmias, with most (83%) requiring medical intervention. Atrial arrhythmias frequently co-occurred with cytokine release syndrome and were associated with higher post-CAR-T infusion peak levels of IL-10, TNF-alpha and LDH, and lower trough levels of fibrinogen. In a multivariable analysis, risk factors for atrial arrhythmia were history of atrial arrhythmia (OR = 6.80 [2.39-19.6]) and using CAR-T product with a CD28-costimulatory domain (OR = 5.17 [1.72-18.6]). Atrial arrhythmias following CD19-CAR-T therapy are prevalent and associated with elevated inflammatory biomarkers, a history of atrial arrhythmia and the use of a CAR-T product with a CD28 costimulatory domain.

Conventional and novel [18F]FDG PET/CT features as predictors of CAR-T cell therapy outcome in large B-cell lymphoma.

Relapse and toxicity limit the effectiveness of chimeric antigen receptor T-cell (CAR-T) therapy for large B-cell lymphoma (LBCL), yet biomarkers that predict outcomes and toxicity are lacking. We examined radiomic features extracted from pre-CAR-T 18F-fluorodeoxyglucose positron emission tomography/computed tomography ([18F]FDG PET/CT) scans (n = 341) of 180 patients (121 male; median age, 66 years). Three conventional (maximum standardized uptake value [SUVmax], metabolic tumor volume [MTV], total lesion glycolysis [TLG]) and 116 novel radiomic features were assessed, along with inflammatory markers, toxicities, and outcomes. At both pre-apheresis and pre-infusion time points, conventional PET features of disease correlated with elevated inflammatory markers. At pre-infusion, MTV was associated with grade ≥ 2 cytokine release syndrome (odds ratio [OR] for 100 mL increase: 1.08 [95% confidence interval (CI), 1.01-1.20], P = 0.031), and SUVmax was associated with failure to achieve complete response (CR) (OR 1.72 [95% CI, 1.24-2.43], P < 0.001). Higher pre-apheresis and pre-infusion MTV values were associated with shorter progression-free survival (PFS) (HR for 10-unit increase: 1.11 [95% CI, 1.05-1.17], P < 0.001; 1.04 [95% CI, 1.02-1.07], P < 0.001) and shorter overall survival (HR for 100-unit increase: 1.14 [95% CI, 1.07-1.21], P < 0.001; 1.04 [95% CI, 1.02-1.06], P < 0.001). A combined MTV and LDH measure stratified patients into high and low PFS risk groups. Multiple pre-infusion novel radiomic features were associated with CR. These quantitative conventional [18F]FDG PET/CT features obtained before CAR-T cell infusion, which were correlated with inflammation markers, may provide prognostic biomarkers for CAR-T therapy efficacy and toxicity. The use of conventional and novel radiomic features may thus help identify high-risk patients for earlier interventions.

Transplantation-Associated Altered Mentation and Encephalopathy: A New Classification for Acute Neurocognitive Changes Associated with Hematopoietic Cell Transplantation from the ASTCT Committee on Practice Guidelines.

Acute encephalopathy, manifesting clinically as delirium, is a common but often unrecognized complication of hematopoietic cell transplantation (HCT). Delirium can occur in patients of any age and is observed after autologous or allogeneic HCT. Although delirium has been studied primarily during initial HCT hospitalizations in recipients of myeloablative conditioning, recent investigations have identified delirium later post-transplantation and in recipients of reduced-intensity conditioning. Acute encephalopathy can be driven by infectious complications, medications, tissue damage, and/or organ dysfunction. Altered consciousness, either mild or profound, is often its only clinical manifestation. Identifying delirium is essential to overall HCT care, because patients who experience delirium have longer hospitalization and recovery times and are at risk for other poor post-HCT outcomes. Given the critical nature of this common complication and the ongoing expansion of HCT for more vulnerable populations, the American Society of Transplantation and Cellular Therapy (ASTCT) recommends intensifying research into post-HCT cognitive changes and establishing standardized definitions that encompass the full spectrum of altered consciousness for clinical care purposes and to provide benchmark endpoints for future research studies. To capture a range of acute neurocognitive changes specifically found in HCT patients (often referred to as acute encephalopathy), the ASTCT proposes a new diagnosis, transplantation-associated altered mentation and encephalopathy (TAME). The TAME diagnosis includes HCT patients who meet Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for delirium and those with acute neurocognitive changes who do not meet all the DSM-5 criteria for delirium (subsyndromal delirium). Early TAME is defined as occurring during conditioning or ≤100 days post-HCT, whereas late TAME occurs >100 days post-HCT in patients with additional HCT-related complications. This manuscript establishes clear diagnostic criteria and discusses factors that can potentially impact the development of TAME, as well as the workup and management of TAME.

Cellular therapies in older adults with hematological malignancies: A case-based, state-of-the-art review.

Cellular therapies, including autologous stem cell transplant (ASCT), allogeneic hematopoietic cell transplantation (alloHCT), and chimeric antigen receptor- (CAR-) T cell therapies are essential treatment modalities for many hematological malignancies. Although their use in older adults has substantially increased within the past decades, cellular therapies represent intensive treatment approaches that exclude a large percentage of older adults due to comorbidities and frailty. Under- and overtreatment in older adults with hematologic malignancy is a challenge and many treatment decisions are influenced by chronologic age. The advent of efficient and well-tolerated newer treatment approaches for multiple myeloma has challenged the role of ASCT. In the modern era, there are no randomized clinical trials of transplant versus non-transplant strategies for patients ≥65 years. Nonetheless, ASCT is feasible for selected older patients and does not result in long-term compromise in quality of life. AlloHCT is the only curative approach for acute myeloid leukemia of intermediate and unfavourable risk but carries a significant risk for non-relapse mortality depending on comorbidities, general fitness, and transplant-specific characteristics, such as intensity of conditioning and donor choice. However, alloHCT is feasible in appropriately-selected older adults. Early referral for evaluation is strongly encouraged as this is the most obvious barrier. CAR-T cell therapies have shown unprecedented clinical efficacy and durability in relapsed and refractory diffuse large B cell lymphoma. Its use is well tolerated in older adults, although evidence comes from limited case numbers. Whether patients who are deemed unfit for ASCT qualify for CAR-T cell therapy remains elusive, but the tolerability and efficacy of CAR-T cell therapy appears promising, especially for older patients. The evidence from randomized trials is strong in favor of using a comprehensive geriatric assessment (CGA) to reduce treatment-related toxicities and guide treatment intensity in the care for solid tumors; its use for evaluation of cellular therapies is less evidence-based. However, CGA can provide useful information on patients' fitness, resilient mechanisms, and reveal potential optimization strategies for compensating for vulnerabilities. In this narrative review, we will discuss key questions on cellular therapies in older adults based on illustrative patient cases.

Transplantation and Cellular Therapy for Older Adults-The MSK Approach.

PURPOSE OF REVIEW: Hematologic malignances more commonly affect older individuals and often present with advanced, higher risk disease than younger patients. Allogeneic and autologous hematopoietic cell transplantation is well-established treatment modalities with curative potential following either frontline treatments for these diseases or salvage therapy in the relapsed or refractory setting. More recently, novel cellular immunotherapy such as chimeric antigen receptor T-cell therapy has been shown to lead to high response rate and durable remission in many patients with advanced blood cancers. RECENT FINDINGS: Given unique characteristics of older patients, how best to deliver these higher-intensity and time sensitive treatment modalities for them remains challenging. Moreover, their short-term and potential long-term impact on their functional status, cognitive status, and quality of life may be significant considerations for many older patients. All these issues contributed to the lack of access and significant underutilization of these potential curative treatment strategies. In this review, we present up to date evidence to support potential benefits of transplantation and cellular therapy for older adults, their steady improving outcomes, and most importantly, highlight the use of geriatric assessment to help select appropriate older patients and optimize them prior to and following transplantation and cellular therapy. We specifically describe our approach at Memorial Sloan Kettering Cancer Center and encouraging early results from its implementation.

Prospective analysis to determine barriers to allogeneic hematopoietic cell transplantation in patients with acute leukemia.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for patients with acute leukemia. Despite this, studies have shown that only a minority of patients ultimately proceed to allo-HCT. The primary objective of this prospective, observational study was to identify the rate of allo-HCT in patients for whom it was recommended, and reasons why patients deemed appropriate and eligible for HCT did not subsequently undergo transplant. Between April 2016 and April 2021, adult patients with newly diagnosed or relapsed/refractory acute leukemia were enrolled at the time of induction/reinduction therapy. Initial transplantation workup and allo-HCT recommendations were made during the early phase of induction/reinduction. Of the 307 enrolled patients, allo-HCT was recommended to 85% (n = 259), of whom 66% (n = 170) underwent transplant. Donor sources comprised 54% human leukocyte antigen (HLA)-matched unrelated donors, 20% HLA-matched sibling donors and HLA-mismatched graft sources with 15% umbilical cord blood units, 8% HLA-mismatched unrelated donors, and 4% HLA-haploidentical donors. The most common reason for transplant disqualification in the 89 patients in whom it was initially recommended was persistent/relapsed disease (70%), followed by early patient death (10%). In this prospective study, we report a high allo-HCT rate, which may be due to early transplant referral and workup. The main allo-HCT barrier was disease control, followed by early patient death. With the increasing availability of HLA-mismatched graft sources, the lack of donor availability was not a transplant barrier. Further development of novel transplant strategies for patients not achieving remission and improvements in induction regimens could result in increased allo-HCT utilization.

The Simplified Comorbidity Index predicts non-relapse mortality in reduced-intensity conditioning allogeneic haematopoietic cell transplantation.

Comorbidity assessment before allogeneic haematopoietic cell transplantation (allo-HCT) is essential for estimating non-relapse mortality (NRM) risk. We previously developed the Simplified Comorbidity Index (SCI), which captures a small number of 'high-yield' comorbidities and older age. The SCI was predictive of NRM in myeloablative CD34-selected allo-HCT. Here, we evaluated the SCI in a single-centre cohort of 327 patients receiving reduced-intensity conditioning followed by unmanipulated allografts from HLA-matched donors. Among the SCI factors, age above 60, mild renal impairment, moderate pulmonary disease and cardiac disease were most frequent. SCI scores ranged from 0 to 8, with 39%, 20%, 20% and 21% having scores of 0-1, 2, 3 and ≥4 respectively. Corresponding cumulative incidences of 3-year NRM were 11%, 16%, 22% and 27%; p = 0.03. In multivariable models, higher SCI scores were associated with incremental risks of all-cause mortality and NRM. The SCI had an area under the receiver operating characteristic curve of 65.9%, 64.1% and 62.9% for predicting 1-, 2- and 3-year NRM versus 58.4%, 60.4% and 59.3% with the haematopoietic cell transplantation comorbidity index. These results demonstrate for the first time that the SCI is predictive of NRM in patients receiving allo-HCT from HLA-matched donors after reduced-intensity conditioning.

CD19 CAR T-cell therapy and prophylactic anakinra in relapsed or refractory lymphoma: phase 2 trial interim results.

In preclinical models, anakinra, an IL-1 receptor antagonist (IL-1Ra), reduced immune effector cell-associated neurotoxicity syndrome (ICANS) without compromising anti-CD19 chimeric antigen receptor (CAR) T-cell efficacy. We initiated a phase 2 clinical trial of anakinra in patients with relapsed/refractory large B-cell lymphoma and mantle cell lymphoma treated with commercial anti-CD19 CAR T-cell therapy. Here we report a non-prespecified interim analysis reporting the final results from cohort 1 in which patients received subcutaneous anakinra from day 2 until at least day 10 post-CAR T-cell infusion. The primary endpoint was the rate of severe (grade ≥3) ICANS. Key secondary endpoints included the rates of all-grade cytokine release syndrome (CRS) and ICANS and overall disease response. Among 31 treated patients, 74% received axicabtagene ciloleucel, 13% received brexucabtagene ciloleucel and 4% received tisagenlecleucel. All-grade ICANS occurred in 19%, and severe ICANS occurred in 9.7% of patients. There were no grade 4 or 5 ICANS events. All-grade CRS occurred in 74%, and severe CRS occurred in 6.4% of patients. The overall disease response rate was 77% with 65% complete response rate. These initial results show that prophylactic anakinra resulted in a low incidence of ICANS in patients with lymphoma receiving anti-CD19 CAR T-cell therapy and support further study of anakinra in immune-related neurotoxicity syndromes.

Older Adults With Newly Diagnosed AML: Hot Topics for the Practicing Clinician.

Over the past decade, our understanding of AML pathogenesis and pathophysiology has improved significantly with mutational profiling. This has led to translational advances in therapeutic options, as there have been 10 new US Food and Drug Administration (FDA) approvals for AML therapies since 2017, half of which target specific driver mutations in FLT3, IDH1, or IDH2. These new agents have expanded the therapeutic armamentarium for AML, particularly for patients who are considered ineligible for intensive chemotherapy with anthracycline- and cytarabine-containing regimens. These new treatment options are relevant because the median age at diagnosis is 68 years, and outcomes for patients older than 60 years have historically been dismal. However, the optimal approach to incorporating novel agents into frontline regimens remains a clinical challenge, particularly with regard to sequencing of therapies, considering the role of allogeneic hematopoietic stem cell transplantation and managing toxicities.

Characteristics of Distress and Support Group Participation in Caregivers of Older Allogeneic Hematopoietic Cell Transplantation Patients: A Single Institution Retrospective Review.

Older patients with hematologic malignancies are increasingly considered for allogeneic hematopoietic cell transplant (allo-HCT). However, older patients often have increased comorbidities and thus may require an increased level of post-transplant care. These factors can contribute to increased caregiver distress, which has been associated with worsened health outcomes for caregivers and patients. To examine predictors of caregiver distress and support group participation in caregivers of older allo-HCT patients, we retrospectively reviewed charts of 208 patients aged 60 and older who underwent their first allo-HCT at our institution from 2014 through 2016. We systematically characterized and identified the incidence of caregiver distress and attendance in a caregiver support group from the start of conditioning through 1 year post allo-HCT. Evidence of caregiver distress and support group participation was recorded by reviewing clinical and/or social work documentation. We found that 20 caregivers (10%) endorsed stress and 44 caregivers (21%) attended our support group at least once. A patient's prior history of psychiatric diagnosis (p = .046) or the use of potentially inappropriate medications for older adults (p = .046) was found to be associated with caregiver stress. Caregivers who were spouses or partners of patients (p = .048) or caregivers of married patients were more likely to attend the support group (p = .007). While limited by retrospective design and likely underreporting, this study reveals factors associated with caregiver distress in the older allo-HCT caregiver population. This information can help providers identify caregivers at risk for distress and improve caregiver resources, which may improve both caregiver and patient outcomes.

Open-label pilot study of romiplostim for thrombocytopenia after autologous hematopoietic cell transplantation.

There are no standard treatments to prevent or hasten the recovery from severe conditioning-regimen-induced thrombocytopenia occurring after autologous hematopoietic cell transplantation (auto-HCT). We conducted an open-label, single-arm pilot study of romiplostim, a thrombopoietin receptor agonist, to enhance platelet recovery in patients with multiple myeloma or lymphoma undergoing auto-HCT. All patients were treated weekly with romiplostim starting day +1 after auto-HCT until the platelet count was >50 × 109/L without transfusion. Compared with contemporary retrospective data from romiplostim-naïve patients (N = 853), romiplostim-treated patients (N = 59) had a similar median number of days of grade 4 thrombocytopenia or days requiring transfusions, time to platelet engraftment, and number of platelets transfusions during the auto-HCT. However, romiplostim-treated patients had enhanced platelet recovery to normal values beginning at approximately day +15. In matched cohort multivariable analyses, romiplostim treatment was associated with higher platelet counts by an average of 40 × 109/L (95% confidence interval (CI) (14, 67), P = .003) and 118 × 109/L (95% CI [84, 152], P<.001) at days +21 and +30, respectively, compared with those of no romiplostim. Only 1 adverse event was deemed possibly attributable to romiplostim: a low-risk pulmonary embolism in a patient with multiple myeloma. In conclusion, romiplostim showed promising activity and safety after auto-HCT, but the improvement in platelet counts occurred later than the goal of shortening the duration and depth of the platelet nadir. This trial was registered at www.clinicaltrials.gov (#NCT04478123).

Analysis of disparities in time to allogeneic transplantation in adults with acute myelogenous leukemia.

Although alternative donors extend transplant access, whether recipient ancestry affects the time to allogeneic transplant is not established. We analyzed the likelihood of clinically significant delays to allograft by patient ancestry in 313 adult patients with acute myelogenous leukemia (AML) who underwent transplantation. Non-European ancestry patients (n = 99) were more likely than Europeans (n = 214) to receive HLA-mismatched donor allografts (45% vs 24%). Overall, the median time from transplant indication to allograft was 127 days (range, 57-1683). In multivariable analysis, non-Europeans had an increased risk of prolonged indication to transplant time >180 days owing to significant delays in indication to consult >90 days and consult to transplant >120 days. Compared with recipients of HLA-matched unrelated donors (URDs), HLA-mismatched adult donor recipients were at an increased risk of delayed indication to transplant, whereas HLA-identical sibling and cord blood recipients were at a lower risk. Subanalysis showed more indication to transplant delays >180 days in non-European (44%) vs European (19%) 8/8 URD recipients. Finally, the pandemic further exacerbated delays for non-Europeans. In summary, although non-European patients with AML are less likely to receive 8/8 URDs as expected, if they do, their transplants are delayed. HLA-identical siblings and cord blood facilitate the fastest transplants regardless of patient ancestry, whereas other adult donor transplants are delayed. Strategies to mitigate referral barriers, hasten donor evaluation, and use all alternative donor sources are critical to ensure timely transplantation for patients with AML.

Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma.

Persistence or recurrence of large B-cell lymphoma after CD19-CAR-T is common, yet data guiding management are limited. We describe outcomes and features following CAR-T treatment failure. Of 305 adults who received CD19-CAR-T, 182 experienced disease recurrence or progression (1-year cumulative incidence 63% [95%CI: 57-69]). Of 52 post-CAR-T biopsies evaluated by flow cytometry, 49 (94%) expressed CD19. Subsequent anti-cancer treatment was administered in 135/182 (74%) patients with CAR-T treatment failure. Median OS from the first post-CAR-T treatment was 8 months (95%CI 5.6-11.0). Polatuzumab-, standard chemotherapy-, and lenalidomide-based treatments were the most common approaches after CAR-T. No complete responses (CRs) were observed with conventional chemotherapy, while CR rates exceeding 30% were seen following polatuzumab- or lenalidomide-based therapies. Factors associated with poor OS among patients treated post-CAR-T were pre-CAR-T bulky disease (HR 2.27 [1.10-4.72]), lack of response to CAR-T (2.33 [1.02-5.29]), age >65 years (HR 2.65 [1.49-4.73]) and elevated LDH at post-CAR-T treatment (HR 2.95 [1.61-5.38]). The presence of ≥2 of these factors was associated with inferior OS compared to ≤1 (56% vs. 19%). In this largest analysis to date of patients who progressed or relapsed after CD19-CAR-T, survival is poor, though novel agents such as polatuzumab and lenalidomide may have hold promise.

Vitamin D Insufficiency and Clinical Outcomes with Chimeric Antigen Receptor T-Cell Therapy in Large B-cell Lymphoma.

Vitamin D insufficiency is a potentially modifiable risk factor for poor outcomes in newly diagnosed large B-cell lymphoma (LBCL). However, the role of circulating vitamin D concentrations in relapsed/refractory LBCL treated with CD19-directed chimeric antigen receptor T-cell therapy (CAR-T) is currently unknown. This was a single-center, observational study that evaluated the association of pre-CAR-T 25-hydroxyvitamin D (25-OHD) status with 100-day complete response, progression-free survival, overall survival, and CAR-T-related toxicity in 111 adult relapsed/refractory LBCL patients. Vitamin D insufficiency was defined as ≤30 ng/mL in accordance with the Endocrine Society guidelines. The median pre-CAR-T 25-hydroxyvitamin D concentration was 24 ng/mL (interquarile range = 18-34). Vitamin D-insufficient patients (≤30 ng/mL; n = 73 [66%]) were significantly younger than their vitamin D-replete (>30 ng/mL; n = 38 [34%]) counterparts (P= .039). The vitamin D-insufficient cohort was enriched for de novo LBCL as the histological subtype (P= .026) and had a higher proportion of tisagenlecleucel as the CAR-T product (P= .049). There were no other significant differences in the baseline characteristics between the two groups. In vitamin D-insufficient compared to -replete patients, 100-day complete response was 55% versus 76% (P= .029), and 2-year overall survival was 41% versus 71% (P= .061), respectively. In multivariate analysis, vitamin D insufficiency remained significantly associated with 100-day complete response (odds ratio 2.58 [1.05-6.83]; P= .045) and overall survival (hazard ratio 2.24 [1.08-4.66], P= .030). In recipients of tisagenlecleucel, vitamin D insufficiency was associated with significantly lower cell viability of the infused CAR-T product (P= .015). Finally, pretreatment vitamin D insufficiency did not predict for subsequent CAR-T-related toxicity. This is the first report to demonstrate that vitamin D insufficiency is associated with inferior clinical outcomes in CAR-T recipients. Further study into the mechanistic insights of this finding, and the potential role of vitamin D supplementation to optimize CAR-T are warranted.