FDA Finalizes Move to Recommend Individual Risk Assessment to Determine Eligibility for Blood Donations
FDA finalized recommendations for assessing blood donor eligibility using a set of individual risk-based questions to reduce the risk of transfusion-transmitted HIV.
DETAILS: The U.S. Food and Drug Administration finalized recommendations for assessing blood donor eligibility using a set of individual risk-based questions to reduce the risk of transfusion-transmitted HIV. These questions will be the same for every donor, regardless of sexual orientation, sex or gender. Blood establishments may now implement these recommendations by revising their donor history questionnaires and procedures.
This updated policy is based on the best available scientific evidence and is in line with policies in place in countries like the United Kingdom and Canada. It will potentially expand the number of people eligible to donate blood, while also maintaining the appropriate safeguards to protect the safety of the blood supply.
These final recommendations are consistent with the policy initially proposed in January. The FDA worked diligently to review and consider all comments submitted to the agency to finalize these recommendations as quickly as possible. "The FDA has worked diligently to evaluate our policies and ensure we had the scientific evidence to support individual risk assessment for donor eligibility while maintaining appropriate safeguards to protect recipients of blood products. The implementation of these recommendations will represent a significant milestone for the agency and the LGBTQI+ community," said Peter Marks, M.D., PhD., director of the FDA’s Center for Biologics Evaluation and Research. "The FDA is committed to working closely with the blood collection industry to help ensure timely implementation of the new recommendations and we will continue to monitor the safety of the blood supply once this individual risk-based approach is in place."
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This policy eliminates time-based deferrals and screening questions specific to men who have sex with men (MSM) and women who have sex with MSM. Under the final guidance issued today, all prospective blood donors will answer a series of individual, risk-based questions to determine eligibility. All prospective donors who report having a new sexual partner, or more than one sexual partner in the past three months, and anal sex in the past three months, would be deferred to reduce the likelihood of donations by individuals with new or recent HIV infection who may be in the window period for detection of HIV by nucleic acid testing.
Additionally, under these final recommendations, those taking medications to treat or prevent HIV infection (e.g., antiretroviral therapy (ART), pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP)), will also be deferred. Though these antiretroviral drugs are safe, effective, and an important public health tool, the available data demonstrate that their use may delay detection of HIV by currently licensed screening tests for blood donations, which may potentially give false negative results. Although HIV is not transmitted sexually by individuals with undetectable viral levels, this does not apply to transfusion transmission of HIV because a blood transfusion is administered intravenously, and a transfusion involves a large volume of blood compared to exposure with sexual contact. As stated in the guidance, individuals should not stop taking their prescribed medications, including PrEP, or PEP, in order to donate blood. The FDA remains committed to evaluating additional data and new technological developments as they become available to inform our donor eligibility recommendations.
The FDA has been evaluating alternatives to time-based deferrals for MSM and helping to facilitate the generation of scientific evidence that would support an individual risk based- assessment blood donor questionnaire. This scientific information has given the agency a solid foundation to support this new policy. The FDA strongly believes the implementation of an individual risk-based approach will not adversely affect the safety or availability of the U.S. blood supply.
The FDA carefully reviewed numerous data sources, including data from countries with similar HIV epidemiology that have implemented an individual risk-based approach for assessing donor eligibility, surveillance information obtained from the Transfusion Transmissible Infections Monitoring System, performance characteristics of nucleic acid testing for HIV and the FDA-funded Assessing Donor Variability And New Concepts in Eligibility study. The ADVANCE study examined the rates of HIV risk factors, such as anal sex and rates of HIV infection, as well as the usage of medications to treat or prevent HIV infection, among MSM study participants.
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Source: FDA Finalizes Move to Recommend Individual Risk Assessment to Determine Eligibility for Blood Donations. FDA. Published: May 11, 2023.
Rapidly Evolving Pre- and Post-surgical Systemic Treatment of Melanoma
Melanoma therapeutics continues to advance with combination adjuvant approaches now investigating anti-PD1 with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies. How this progress will be integrated into the management of a unique patient to reduce recurrence, limit toxicity, and avoid over-treatment will dominate clinical research and patient care over the next decade.
KEY FINDINGS: Melanoma therapeutics continues to advance with combination adjuvant approaches now investigating anti-PD1 with lymphocyte activation gene 3 (LAG3), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), and individualized neoantigen therapies. How this progress will be integrated into the management of a unique patient to reduce recurrence, limit toxicity, and avoid over-treatment will dominate clinical research and patient care over the next decade.
BACKGROUND: With the development of effective BRAF-targeted and immune-checkpoint immunotherapies for metastatic melanoma, clinical trials are moving these treatments into earlier adjuvant and perioperative settings. BRAF-targeted therapy is a standard of care in resected stage III-IV melanoma, while anti-programmed death-1 (PD1) immunotherapy is now a standard of care option in resected stage IIB through IV disease.
DETAILS: With both modalities, recurrence-free survival and distant-metastasis-free survival are improved by a relative 35-50%, yet no improvement in overall survival has been demonstrated. Neoadjuvant anti-PD1 therapy improves event-free survival by approximately an absolute 23%, although improvements in overall survival have yet to be demonstrated. Understanding which patients are most likely to recur and which are most likely to benefit from treatment is now the highest priority question in the field. Biomarker analyses, such as gene expression profiling of the primary lesion and circulating DNA, are preliminarily exciting as potential biomarkers, though each has drawbacks. As in the setting of metastatic disease, markers that inform positive outcomes include interferon-γ gene expression, PD-L1, and high tumor mutational burden, while negative predictors of outcome include circulating factors such as lactate dehydrogenase, interleukin-8, and C-reactive protein. Integrating and validating these markers into clinically relevant models is thus a high priority.
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Source: Augustin, R. C. and Luke, J. J. (2024). Rapidly Evolving Pre- and Post-surgical Systemic Treatment of Melanoma. American Journal of Clinical Dermatology. Published: March, 2024. DOI: 10.1007/s40257-024-00852-5.
Single-Cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-Specific Metastasis
By using integrative scRNA-seq, spatial transcriptomic analysis and functional assays, authors have uncovered a stem-like cell cluster marked with PTPRO and ASCL2 as the metastatic culprit, whose subpopulations show further different liver or ovary organotropism.
KEY FINDINGS: By using integrative scRNA-seq, spatial transcriptomic analysis and functional assays, authors have uncovered a stem-like cell cluster marked with PTPRO and ASCL2 as the metastatic culprit, whose subpopulations show further different liver or ovary organotropism.
BACKGROUND: Metastasis is the major cause of cancer death. However, what types of heterogenous cancer cells in primary tumour and how they metastasise to the target organs remain largely undiscovered.
DETAILS: Authors performed single-cell RNA sequencing and spatial transcriptomic analysis in primary colorectal cancer (CRC) and metastases in the liver (lCRC) or ovary (oCRC). Authors also conducted immunofluorescence staining and functional experiments to examine the mechanism. Integrative analyses of epithelial cells reveal a stem-like cell cluster with high protein tyrosine phosphatase receptor type O (PTPRO) and achaete scute-like 2 (ASCL2) expression as the metastatic culprit. This cell cluster comprising distinct subpopulations shows distinct liver or ovary metastatic preference. Population 1 (P1) cells with high delta-like ligand 4 (DLL4) and MAF bZIP transcription factor A (MAFA) expression are enriched in primary CRC and oCRC, thus may be associated with ovarian metastasis. P3 cells having a similar expression pattern as cholangiocytes are found mainly in primary CRC and lCRC, presuming to be likely the culprits that specifically metastasise to the liver. Stem-like cells interacted with cancer-associated fibroblasts and endothelial cells via the DLL4-NOTCH signalling pathway to metastasise from primary CRC to the ovary. In the oCRC microenvironment, myofibroblasts provide cancer cells with glutamine and perform a metabolic reprogramming, which may be essential for cancer cells to localise and develop in the ovary.
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Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.
Source: Li, R., Liu, X., Huang, X., et al. (2024). Single-Cell Transcriptomic Analysis Deciphers Heterogenous Cancer Stem-Like Cells in Colorectal Cancer and Their Organ-Specific Metastasis. Gut. 2024; 73(3): 470-484 .Published: March, 2024. DOI: 10.1136/gutjnl-2023-330243.
Safety and Efficacy of Ibrutinib in Combination With Rituximab and Lenalidomide in Previously Untreated Follicular and Marginal Zone Lymphoma
IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash.
KEY FINDINGS: IRR is highly active as frontline therapy for FL and MZL. Compared to historical results with lenalidomide and rituximab, PFS is similar with higher grade 3-4 toxicity, particularly rash.
BACKGROUND: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL). Median survival for iNHL is approximately 20 years. Because standard treatments are not curative, patients often receive multiple lines of therapy with associated toxicity-rationally designed, combination therapies with curative potential are needed. The immunomodulatory drug lenalidomide was evaluated in combination with rituximab for the frontline treatment of FL in the phase 3 RELEVANCE study. Ibrutinib, an oral Bruton tyrosine kinase inhibitor, is active in NHL and was evaluated in combination with lenalidomide, rituximab, and ibrutinib (IRR) in a phase 1 study.
DETAILS: The authors conducted an open-label, phase 2 clinical trial of IRR for previously untreated FL and MZL. The primary end point was progression-free survival (PFS) at 24 months. This study included 48 participants with previously untreated FL grade 1-3a (N = 38), or MZL (N = 10). Participants received 12, 28-day cycles of lenalidomide (15 mg, days 1-21 cycle 1; 20 mg, cycles 2-12), rituximab (375 mg/m2 weekly in cycle 1; day 1 cycles 2-12), and ibrutinib 560 mg daily. With a median follow-up of 65.3 months, the estimated PFS at 24 months was 78.8% (95% confidence interval [CI], 68.0%-91.4%) and 60-month PFS was 59.7% (95% CI, 46.6%-76.4%). One death occurred unrelated to disease progression. Grade 3-4 adverse events were observed in 64.6%, including 50% with grade 3-4 rash.
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Copyright © John Wiley & Sons, Inc. All rights reserved.
Source: Gordon, M. J., Feng, L., Strati, P., et al. (2024). Safety and Efficacy of Ibrutinib in Combination With Rituximab and Lenalidomide in Previously Untreated Follicular and Marginal Zone Lymphoma: An Open Label, Phase 2 Study. Cancer, . 2024; 130(6): 876-885; Published: March 15, 2024. DOI: 10.1002/cncr.35114.
Increased Risk of Recurrence and Disease-Specific Death Following Delayed Postoperative Radiation for Merkel Cell Carcinoma
Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.
KEY FINDINGS: Delay of PORT was associated with increased LRR, usually beyond the radiation field. This is consistent with the tendency of MCC to spread quickly via lymphatics. Initiation of PORT within 8 weeks was associated with improved locoregional control and MCC-specific survival.
BACKGROUND: Merkel cell carcinoma (MCC) is often treated with surgery and postoperative radiation therapy (PORT). The optimal time to initiate PORT (Time-to-PORT [ttPORT]) is unknown. Purpose of this study was to assess if delays in ttPORT were associated with inferior outcomes.
DETAILS: Competing risk regression was used to evaluate associations between ttPORT and locoregional recurrence (LRR) for patients with stage I/II MCC in a prospective registry and adjust for covariates. Distant metastasis and death were competing risks. The cohort included 124 patients with median ttPORT of 41 days (range: 8-125 days). Median follow-up was 55 months. 17 (14%) patients experienced a LRR, 14 (82%) of which arose outside the radiation field. LRR at 5 years was increased for ttPORT >8 weeks vs less than or equal to 8 weeks, 28.0% vs 9.2%, P = .006. There was an increase in the cumulative incidence of MCC-specific death with increasing ttPORT (HR = 1.14 per 1-week increase, P = .016).
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Copyright © Elsevier Ltd. All rights reserved.
Source: Alexander, N. A., Schaub, S. K., Goff, P. H., et al. (2024). Increased Risk of Recurrence and Disease-Specific Death Following Delayed Postoperative Radiation for Merkel Cell Carcinoma. Journal of the American Academy of Dermatology. 2024; 90(2): 261-2678. Published: February, 2024. DOI: 10.1016/j.jaad.2023.07.1047.
Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis
In a contemporary analysis of patients with suspected ICI myocarditis, severe ICI myocarditis was associated with increased 1-year cardiovascular mortality, which was lower than previously reported. Patients with nonsevere ICI myocarditis had outcomes similar to negative cases. The optimal management strategies for nonsevere ICI myocarditis need to be re-evaluated.
KEY FINDINGS: In a contemporary analysis of patients with suspected ICI myocarditis, severe ICI myocarditis was associated with increased 1-year cardiovascular mortality, which was lower than previously reported. Patients with nonsevere ICI myocarditis had outcomes similar to negative cases. The optimal management strategies for nonsevere ICI myocarditis need to be re-evaluated.
BACKGROUND: The long-term contemporary outcomes of patients with immune checkpoint inhibitor (ICI) myocarditis, spanning the spectrum of clinical severity, are undetermined. Authors sought to investigate the characteristics and cardiovascular outcomes of patients with severe and nonsevere ICI myocarditis.
DETAILS: This was a retrospective cohort study of patients with suspected ICI myocarditis at Massachusetts General Brigham Health System conducted between 2015 and 2022. Cases were classified as severe, nonsevere, and negative based on the International Cardio-Oncology Society criteria. One-year cardiovascular mortality, all-cause mortality, and cardiovascular readmissions were evaluated. We also evaluated 1-year ICI resumption and left ventricular ejection fraction over a median follow-up of 18 (Q1-Q3: 8-67) weeks. The study included 160 patients: 28 severe, 96 nonsevere, and 36 negative cases. Patients with severe myocarditis had an increased risk of 1-year cardiovascular mortality, particularly in the early post-myocarditis period (29% vs 5%; HR: 6.52; 95% CI: 2.2-19.6; P < 0.001). Patients with nonsevere myocarditis had a cardiovascular mortality rate similar to negative cases (HR: 0.61; 95% CI: 0.14-2.54). One-year all-cause mortality did not differ between severe, nonsevere, and negative cases (P = 0.74). Rates of 1-year cardiovascular readmissions and long-term left ventricular ejection fraction were also similar among the 3 groups. ICI resumption was low, even in negative cases.
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Copyright © American College of Cardiology Foundation. All rights reserved.
Source: Zadok, O. I. B., Levi, A., Divakaran, S., et al. (2023). Severe vs Nonsevere Immune Checkpoint Inhibitor-Induced Myocarditis: Contemporary 1-Year Outcomes. J Am Coll Cardiol CardioOnc. 2023; 5(6): 732–744. Published: December, 2023. DOI: 10.1016/j.jaccao.2023.09.004.
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