•The number of approved immune effector cell IEC cellular therapies for cancer has grown rapidly.•Duplicative onboarding, auditing, and logistical requirements impede scalability.•Clinical, society, ...and industry stakeholders have identified issues and solutions.•Standards are needed for patient care, provider education, and outcomes reporting.•Processes for apheresis/cell processing, labeling, and ordering need streamlining.
As the number and type of regulatory authority-approved cellular therapies grow, clinical treatment centers face a heavy burden of duplicative documentation around initial qualification, ongoing auditing, and reporting, with overlapping requirements from each manufacturer to ensure safe use of their specific product, which in the United States are stipulated under individual Food and Drug Administration (FDA) Biologic License Applications. The American Society for Transplantation and Cellular Therapy (ASTCT) convened the 80/20 Task Force to consider challenges and potential solutions to these issues. The Task Force proposed that 80% of manufacturers’ requirements for onboarding and ongoing operations of commercially available products could be standardized and streamlined. Task Force members interviewed dozens of stakeholders, including clinicians at large academic medical centers already using commercial and investigational immune effector cell (IEC) products, regulators, members of accrediting bodies and professional cellular therapy societies, and manufacturers of IEC therapies for oncologic indications. In November 2021, the Task Force organized and led virtual discussions in a public forum and at a private ASTCT 80/20 Workshop at the online AcCELLerate Forum, a cellular-therapy stakeholders’ meeting organized by the ASTCT, National Marrow Donor Program (NMDP), and Center for International Blood and Marrow Transplant Research (CIBMTR). At the workshop, approximately 60 stakeholders worked to identify and prioritize common challenges in onboarding and maintenance of operations at clinical sites for commercial FDA-approved and future IEC therapies and ways to streamline the process. It was agreed that standardization would improve efficiency of onboarding, allowing more cost-effective, sustainable growth of approved IEC therapies at treatment centers, and facilitate wider access while maintaining safety and clinical success. This early but extensive survey of stakeholders resulted in 5 overarching suggestions for both established and emerging treatment centers: (1) eliminate duplication in accreditation and auditing of clinical sites; (2) define expectations for the education about and management of CAR-T therapy toxicities to potentially replace product-specific REMS programs; (3) streamline current REMS education, testing, and data reporting; (4) standardize information technology (IT) platforms supporting enrollment, clinical site-manufacturer communication, and logistics of maintaining chain of identity/chain of custody across multiple transportation steps; and (5) encourage the use of universal nomenclature by cell therapy manufacturers. Future discussions need to engage a broader range of stakeholders, including administrators, pharmacists, nurses, data coordinators, surgeons, pathologists, and those developing promising cellular therapies for solid tumors, as well as teams from smaller academic or community cancer center settings. Continued collaboration with stakeholders outside of clinical sites will include accrediting bodies/auditors, established and emerging cell therapy companies, software developers, professional societies, and the patients who receive these therapies. Active dialog with government regulators remains essential. Such joint efforts are critical as the number of IEC therapies for myriad oncologic and nononcologic indications grows.
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CPX-351 and venetoclax and azacitidine (ven/aza) are both indicated as initial therapy for acute myeloid leukemia (AML) in older adults. In the absence of prospective randomized comparisons of these ...regimens, we used retrospective observational data to evaluate various outcomes for patients with newly diagnosed AML receiving either CPX-351 (n=217) or ven/aza (n=439). This study used both a nationwide electronic health record (EHR)-derived de-identified database and the University of Pennsylvania EHR. Our study includes 217 patients who received CPX-351 and 439 who received venetoclax/azacitidine. Ven/aza patients were older, more likely to be treated in the community, and more likely to have a diagnosis of de novo AML. Other baseline covariates were not statistically significantly different between the groups. Median overall survival (OS) for all patients was 12 months and did not differ based upon therapy (13 months for CPX-351 versus 11 months for ven/aza, HR 0.88, 95% CI 0.71-1.08, p = 0.22). Overall survival was similar across multiple sensitivity analyses. Regarding safety outcomes, early mortality was similar (10% vs. 13% at 60 days). However, documented infections were higher with CPX-351 as were rates of febrile neutropenia. Hospital length of stay, including any admission prior to next cycle of therapy, was more than twice as long for CPX-351. In this large multi-center real word dataset, there was no statistically significant difference in OS. Prospective randomized studies with careful attention to side effects, quality of life, and impact on transplant outcomes are needed in these populations.
Idiopathic acquired aplastic anemia (AA) is a rare lymphocyte-mediated bone marrow aplasia. No specific mechanisms or triggers of AA have been identified. We recently observed several patients who ...developed AA after Hodgkin lymphoma (HL). We hypothesized that the co-occurrence of HL and AA is not random and may be etiologically significant. To test this hypothesis, we determined the incidence of AA in HL patients at our institution. We identified four patients with co-occurring HL and AA, with the incidence of AA in HL patients >20-fold higher compared to the general population. We identified 12 additional patients with AA and HL through a systematic literature review. Of the 16 total patients,15 (93.8%) developed AA after or concurrent with a HL diagnosis. None of the patients had marrow involvement by HL. Five of 15 patients were in complete remission from HL at the time of AA diagnosis, and six had a concurrent presentation with no prior cytotoxic therapy, with diagnostic timeframe information unavailable for four patients. The median interval between HL diagnosis and AA onset was 16 months, ranging from concurrent to 14 years after a HL diagnosis. The median survival after AA diagnosis was 14 months (range: 1 month to 20 years). Our results show that patients with HL have a higher incidence of AA compared to the general population and suggest that HL-related immune dysregulation may be a risk factor for AA. Better recognition and management of AA in HL patients is needed to improve outcomes in this population.
Intensive chemotherapy with cytarabine and anthracycline (7&3) remains the standard therapy for patients medically fit for induction, but the assessment of fitness remains controversial. Venetoclax ...and hypomethylating agent (ven/HMA) combination therapy has improved outcomes in unfit patients but no prospective study has assessed ven/HMA versus 7&3 as initial therapy in older, fit patients. Given no studies and expectation of ven/HMA use in patients outside of trial criteria, we evaluated retrospective outcomes among newly diagnosed patients. A nationwide electronic health record (EHR)‐derived database and the University of Pennsylvania EHR identified 312 patients receiving 7&3 and 488 receiving ven/HMA who were 60–75 years old without history of organ failure. Ven/HMA patients were older and more likely to have secondary AML, adverse cytogenetics, and adverse mutations. Median overall survival (OS) for patients receiving intensive chemotherapy was 22 versus 10 months for ven/HMA (HR 0.53, 95% CI 0.40–0.60). Controlling for measured baseline characteristic imbalances reduced survival advantage by half (HR 0.71, 95% CI 0.53–0.94). A sub‐group of patients with equipoise, likelihood at least 30%–70% of receiving either treatment, had similar OS outcomes (HR 1.10, 95% CI 0.75–1.6). Regarding safety outcomes, 60‐day mortality was higher for ven/HMA (15% vs. 6% at 60 days) despite higher documented infections and febrile neutropenia for 7&3. In this multicenter real‐word dataset, patients selected for intensive chemotherapy had superior OS but a large group had similar outcomes with ven/HMA. Prospective randomized studies, controlling for both measured and unmeasured confounders, must confirm this outcome.
To characterize the impact of graft T-cell composition on outcomes of reduced-intensity conditioned (RIC) allogeneic hematopoietic stem-cell transplantation (alloHSCT) in adults with hematologic ...malignancies.
We evaluated associations between graft T-cell doses and outcomes in 200 patients who underwent RIC alloHSCT with a peripheral blood stem-cell graft. We then studied 21 alloHSCT donors to identify predictors of optimal graft T-cell content.
Higher CD8 cell doses were associated with a lower risk for relapse (adjusted hazard ratio aHR, 0.43; P = .009) and improved relapse-free survival (aHR, 0.50; P = .006) and overall survival (aHR, 0.57; P = .04) without a significant increase in graft-versus-host disease or nonrelapse mortality. A cutoff level of 0.72 × 10(8) CD8 cells per kilogram optimally segregated patients receiving CD8(hi) and CD8(lo) grafts with differing overall survival (P = .007). Donor age inversely correlated with graft CD8 dose. Consequently, older donors were unlikely to provide a CD8(hi) graft, whereas approximately half of younger donors provided CD8(hi) grafts. Compared with recipients of older sibling donor grafts (consistently containing CD8(lo) doses), survival was significantly better for recipients of younger unrelated donor grafts with CD8(hi) doses (P = .03), but not for recipients of younger unrelated donor CD8(lo) grafts (P = .28). In addition, graft CD8 content could be predicted by measuring the proportion of CD8 cells in a screening blood sample from stem-cell donors.
Higher graft CD8 dose, which was restricted to young donors, predicted better survival in patients undergoing RIC alloHSCT.
Invasive fungal infections (IFI) are a significant source of morbidity and mortality for patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Given the heterogeneity of the ...population receiving hypomethylating agents (HMA), it is difficult for clinicians to accurately assess their patients' risk of infection. Literature on the incidence of IFI following HMA is limited to several studies of azacitidine. The primary objective of this retrospective study was to establish the incidence of IFI in HMA treated AML/MDS patients at a large U.S. comprehensive cancer center. Secondary objectives included comparing incidence of IFI among pre‐specified subgroups to identify potential risk factors for IFI. Two hundred three patients with AML, intermediate to very high risk MDS or chronic myelomonocytic leukemia who received at least two cycles of HMA were included. The incidence of IFI, as defined by the European Organization for Research and Treatment of Cancer / Invasive Fungal Infections Cooperative Group criteria, was 9.6%, with 20 IFI diagnosed following HMA (three proven, four probable, 13 possible). Among the proven cases of IFI, molds included Scedosporium and Fusarium spp. Eleven patients who developed IFIs were neutropenic upon initiating HMA. The majority (17/20) of infections occurred during the first four cycles. Given this incidence, mold‐active prophylaxis can be considered in patients who are neutropenic at the start of therapy.
Introduction
Granulocyte colony-stimulating factor (G-CSF) hastens neutrophil engraftment and reduces infections after allogeneic hematopoietic cell transplant (alloHCT), yet the optimal start date ...is unknown. Additionally, concurrent G-CSF and methotrexate for graft-vs-host disease (GVHD) prophylaxis may potentiate myelosuppression, and prolonged G-CSF is costly. Our institution changed from day + 4 to day + 12 G-CSF initiation following reduced intensity (RIC) alloHCT with methotrexate GVHD prophylaxis.
Methods
We retrospectively compared day + 4 and day + 12 G-CSF initiation after RIC alloHCT from 2017–2021. The primary endpoint was the time to neutrophil engraftment. Secondary endpoints included length of stay (LOS) and the time to platelet engraftment as well as the incidence of infectious events, acute GVHD (aGVHD), and mucositis.
Results
Thirty-two patients were included in each group with similar baseline characteristics. We observed faster neutrophil engraftment (median 12 vs. 15 days, p = 0.01) and platelet engraftment (median 13 vs. 15 days, p = 0.026) with day + 4 vs. day + 12 G-CSF initiation. Median LOS was 23 days (range, 19–32) with day + 4 initiation vs. 24 days (21–30) with day + 12 (p = 0.046). The incidence of culture-negative febrile neutropenia (p = 0.12), any grade aGVHD (p = 0.58), and grade 2-4 mucositis (p = 0.8) were similar between groups.
Conclusion
Compared to day + 4, day + 12 G-CSF initiation following RIC alloHCT had a longer time to neutrophil and platelet engraftment. Day + 12 initiation also resulted in longer LOS, which while statistically significant, was potentially of limited clinical significance. These findings are hypothesis generating.
Previous retrospective studies have shown that chimeric antigen receptor T (CAR-T) cell therapy may be associated with major adverse cardiovascular events (MACE), especially in the context of ...cytokine-release syndrome (CRS) events.
The aim of this prospective observational study was to define the occurrence of MACE in adults undergoing treatment with CAR-T cell therapy and identify associated risk factors.
Vital signs, blood samples, and an echocardiogram were collected prior to and 2 days, 1 week, 1 month, and 6 months after CAR-T cell infusion, and charts were consulted at 12 months. In the event of CRS, echocardiography was repeated within 72 hours. MACE were defined as cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and de novo cardiac arrhythmia.
A total of 44 patients were enrolled (mean age 58 ± 11 years, 77% men). The median follow-up duration was 487 days (Q1-Q3: 258-622 days). There were 24 episodes of CRS in 23 patients (52%) (13 grade 1, 10 grade 2, and 1 grade 3), with a median time to CRS of 4 days. Two patients had MACE (heart failure with preserved ejection fraction and atrial fibrillation) within 1 year and 6 and 7 days after CAR-T cell infusion. There was no change in left ventricular ejection fraction, but a modest decrease in global longitudinal strain was noted.
There were few cardiac effects associated with contemporary CAR-T cell therapy. As MACE occurred after CRS episodes, aggressive treatment and close follow-up during CRS events are essential.
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