[Posted 27/Aug/2025]

AUDIENCE: Hematology, Oncology, Pathology

KEY FINDINGS: The combination of tamibarotene and azacitidine did not improve the complete remission rate in HR-MDS patients with RARA gene overexpression compared to azacitidine alone. The study highlights the challenges of conducting blinded trials and the difficulty of translating promising early-phase results into successful large-scale, global studies. Further research is needed to better understand the role of RARA gene overexpression as a predictive biomarker in MDS.

BACKGROUND: Myelodysplastic Syndromes (MDS) are a group of blood cancers where the bone marrow doesn't produce enough healthy blood cells. Higher-risk MDS (HR-MDS) can progress to acute myeloid leukemia (AML) and has a poor prognosis. A new approach to treatment involves targeting specific genetic markers. This phase 3 clinical trial, SELECT-MDS-1, investigated a combination therapy of tamibarotene and azacitidine for newly diagnosed HR-MDS patients with overexpression of the RARA gene.

DETAILS: The SELECT-MDS-1 study was a pivotal phase 3 trial designed to compare the efficacy of a combination of tamibarotene (a selective retinoic acid receptor-α agonist) and azacitidine against azacitidine monotherapy. The study focused on a specific subgroup of HR-MDS patients whose tumors showed overexpression of the RARA gene. The primary goal was to see if the combined therapy could improve the complete remission (CR) rate. The trial found that the complete remission rate was similar in both the combination therapy arm and the azacitidine monotherapy arm. The study did not demonstrate a clear improvement in efficacy with the addition of tamibarotene. The authors noted that unblinding of the study due to distinctive side effects of tamibarotene (like hypertriglyceridemia and bony aches) and challenges in replicating earlier phase 2 data in a larger, global setting may have influenced the results. The paper also mentioned the lack of overall survival (OS) data and the use of older response criteria as limitations.

Copyright © The American Society of Hematology. All rights reserved.

Source: DeZern, A. E., Thepot, S., de Botton, S., et al. (2024). Pivotal Results of SELECT-MDS-1 Phase 3 Study of Tamibarotene with Azacitidine in Newly Diagnosed Higher-Risk MDS. Blood Adv.. 2025; 9(16): 4090-4099. Published: August 26, 2025. DOI: 10.1182/bloodadvances.2025016229.

A Randomised, Open-Label, Multicentre, Phase 3 Trial

[Posted 28/Aug/2025]

AUDIENCE: Hematology, Oncology

KEY FINDINGS: With the limitation of a smaller sample size than planned due to the trial's early interruption, these results, to authors' knowledge, showed for the first-time high rates of MRD negativity with weekly carfilzomib added to lenalidomide-dexamethasone in patients with transplantation-ineligible newly diagnosed multiple myeloma. In the carfilzomib-lenalidomide-dexamethasone group, higher MRD negativity rates were associated with a progression-free survival advantage over lenalidomide-dexamethasone. Toxicities were predictable and generally manageable.

BACKGROUND: Before the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment for patients with newly diagnosed transplant-ineligible multiple myeloma, lenalidomide-dexamethasone was a standard of care. Authors aimed to explore whether addition of the second-generation proteasome inhibitor carfilzomib to lenalidomide-dexamethasone improved the rates of measurable residual disease (MRD) negativity and progression-free survival.

DETAILS: EMN20 is a randomised, open-label, multicentre, phase 3 trial comparing weekly carfilzomib-lenalidomide-dexamethasone versus lenalidomide-dexamethasone in patients with newly diagnosed transplant-ineligible multiple myeloma, conducted in 27 centres in Italy. Key inclusion criteria included fit or intermediate-fit status according to the International Myeloma Working Group (IMWG) frailty score, measurable disease according to IMWG criteria, and Eastern Cooperative Oncology Group performance status lower than 3. Patients randomly assigned to the carfilzomib-lenalidomide-dexamethasone group received 28-day carfilzomib-lenalidomide-dexamethasone cycles (carfilzomib 20 mg/m² intravenously on day 1 for cycle 1, followed by 56 mg/m² intravenously on days 8 and 15 for cycle 1, then 56 mg/m² intravenously on days 1, 8, and 15 for cycles 2-12, and 56 mg/m² intravenously on days 1 and 15 from cycle 13 until 5 years after randomisation; lenalidomide 25 mg orally on days 1-21 until disease progression or intolerance; dexamethasone 40 mg orally on days 1, 8, 15, and 22 until disease progression or intolerance). Patients assigned to the lenalidomide-dexamethasone group received 28-day cycles with lenalidomide-dexamethasone (same dosing and schedule used in the carfilzomib-lenalidomide-dexamethasone group). Primary endpoints were MRD negativity by next-generation sequencing (sensitivity 10-5) after 2 years of treatment and progression-free survival; and were assessed in the intention-to-treat (ITT) population (all patients who were eligible to receive treatment and who were randomly assigned to one of the treatment groups). On Nov 23, 2021, after enrolling 30% of planned patients (101/340), the trial was prematurely stopped due to the introduction of daratumumab-lenalidomide-dexamethasone as a first-line treatment in Italy, which caused the lenalidomide-dexamethasone control group to no longer be considered a standard treatment. This trial is registered with ClinicalTrials.gov, NCT04096066, and study recruitment is complete. Between Nov 14, 2019, and Nov 23, 2021, 82 of 101 enrolled patients were assessed for eligibility and were randomised to receive carfilzomib-lenalidomide-dexamethasone (n=42) or lenalidomide-dexamethasone (n=40). In the ITT population, 35 (43%) of 82 patients were female and 47 (57%) were male. At data cutoff (March 29, 2024), the median follow-up was 35.2 months (IQR 30.3-38.7). The 2-year MRD negativity rates were 25 (60% 95% CI 43-74) of 42 patients with carfilzomib-lenalidomide-dexamethasone versus 0 (0%; 0-9) of 40 patients with lenalidomide-dexamethasone (p<0.0001). Median progression-free survival was not reached (not reached-not reached) with carfilzomib-lenalidomide-dexamethasone versus 20.9 months (15.7-not reached) with lenalidomide-dexamethasone (hazard ratio 0.24 [95% CI 0.11-0.56], p=0.00084). One patient was excluded from the safety analysis because they died before starting treatment. The most frequent grade 3 or worse adverse events were neutropenia (nine [22%] of 41 patients), thrombocytopenia (four [10%]), diarrhoea (four [10%]), cardiac events (three [7%]), infections (three [7%]), and arterial hypertension (two [5%]) with carfilzomib-lenalidomide-dexamethasone, and neutropenia (six [15%] of 40) and skin rash (four [10%]) with lenalidomide-dexamethasone. The most common serious adverse event was SARS-CoV-2-related pneumonia in both the carfilzomib-lenalidomide-dexamethasone group (two [5%] of 41 patients) and lenalidomide-dexamethasone group (three [7%] of 40 patients). Treatment-emergent adverse events leading to death were observed in two patients in the carfilzomib-lenalidomide-dexamethasone (two SARS-CoV-2 infections) and four patients in the lenalidomide-dexamethasone group (one acute myocardial infraction, one heart failure, one septic shock, and one SARS-CoV-2 infection).

Copyright © Elsevier Ltd. All rights reserved.

Source: Bringhen, S., Cani, L., Antonioli, E., et al. (2024). Carfilzomib-Lenalidomide-Dexamethasone Versus Lenalidomide-Dexamethasone in Patients With Newly Diagnosed Myeloma Ineligible for Autologous Stem-Cell Transplantation (EMN20): A Randomised, Open-Label, Multicentre, Phase 3 Trial. The Lancet Haematology. 2025; 12(8): e621-e634. Published: August, 2025. DOI: 10.1016/S2352-3026(25)00162-0.

[Posted 28/Aug/2025]

AUDIENCE: Neurology, Pediatric, Neurosurgery

KEY FINDINGS: Infants up to 6 weeks of age with genetically diagnosed SMA who were treated with risdiplam before the development of clinical signs or symptoms appeared to have better functional and survival outcomes at 12 and 24 months than untreated infants in natural history studies. Larger, controlled studies with longer follow-up are needed to further understand the relative efficacy and safety of presymptomatic treatment of SMA with risdiplam.

BACKGROUND: Risdiplam, an oral pre–messenger RNA splicing modifier, is an efficacious treatment for persons with symptomatic spinal muscular atrophy (SMA). The safety and efficacy of risdiplam in presymptomatic disease are unclear.

DETAILS: Authors conducted an open-label study of daily oral risdiplam (with the dose adjusted to 0.2 mg per kilogram of body weight) in infants 1 day (birth) to 42 days of age with genetically diagnosed SMA but without strongly suggestive clinical signs or symptoms. The primary outcome, assessed in infants with two SMN2 copies and a baseline ulnar compound muscle action potential (CMAP) amplitude of at least 1.5 mV, was the ability to sit without support at month 12. Natural history studies have shown that the majority of infants with two SMN2 copies who are untreated would have a severe SMA phenotype (type 1), would never sit independently, would receive permanent ventilation and feeding support, or would die by 13 months of age. Secondary outcomes that were assessed over a period of 24 months included survival, ventilatory support, motor milestones, the development of clinically manifested SMA, feeding, and growth. A total of 26 infants with two, three, or four or more copies of SMN2 were enrolled. After 12 months of treatment, 21 infants (81%) could sit unsupported for 30 seconds, 14 (54%) could stand alone, and 11 (42%) could walk alone. A total of 4 of 5 infants (80%; 95% confidence interval, 28 to 100) with two SMN2 copies and a baseline ulnar CMAP amplitude of at least 1.5 mV were able to sit without support for at least 5 seconds. Three infants were withdrawn from the study by a parent or caregiver after the month 12 visit. Of 23 infants who completed 24 months of treatment, all were alive without the use of permanent ventilation or feeding support. Over a period of 24 months, nine treatment-related adverse events were reported in 7 infants; none of these events were serious.

Copyright © Massachusetts Medical Society. All rights reserved.

Source: Finkel, R. S., Servais, L., Vlodavets, D., et al. (2024). Risdiplam in Presymptomatic Spinal Muscular Atrophy. N Engl J Med. 2025; 393(7): 671-682. Published: August 13, 2025. DOI: 10.1056/NEJMoa2410120.

[Posted 22/Aug/2025]

AUDIENCE: All Healthcare Professionals

KEY FINDINGS:

BACKGROUND: Recurrent Respiratory Papillomatosis (RRP) is a rare and chronic condition caused by human papillomavirus (HPV) types 6 and 11. The disease leads to the formation of benign tumors in the respiratory tract, most often in the larynx, which can cause significant symptoms like voice changes and difficulty breathing. Historically, the primary treatment for RRP has been repeated surgical removal of the tumors, as there have been no approved medical therapies to address the underlying cause.

DETAILS: The U.S. Food and Drug Administration (FDA) has approved Papzimeos (zopapogene imadenovec-drba), a groundbreaking immunotherapy, for the treatment of adult patients with RRP. This therapy is a non-replicating adenoviral vector that works by stimulating a targeted immune response against the HPV-infected cells. It is administered via a subcutaneous injection and represents the first non-surgical therapeutic option for this rare disease, offering a new approach beyond traditional surgical management.

The approval of Papzimeos was based on data from a single-arm, open-label trial. The study demonstrated that 51.4% of patients who received the treatment achieved a complete response, defined as not needing any further surgical intervention for 12 months following the treatment. The clinical benefits were shown to be durable for most patients over a two-year period and correlated with the development of specific T-cells targeting HPV 6 and 11. The therapy had a favorable safety profile with no serious treatment-related adverse events.

Key information:

• First-of-its-kind Approval: Papzimeos is the first approved medical therapy for RRP.
• Novel Mechanism: It is an immunotherapy that targets the root cause of the disease, HPV-infected cells.
• Approval Pathway: The product received Orphan Drug and Breakthrough Therapy designations and was approved under Priority Review, reflecting the significant unmet medical need for RRP patients.

Source: FDA Approves First Immunotherapy for Recurrent Respiratory Papillomatosis. FDA. 2025; Published: August 14, 2025.

[Posted 8/Jul/2025]

AUDIENCE: Emergency Nursing

KEY FINDINGS: The findings support evidence-based guidelines to manage vaso-occlusive episodes in emergency departments. Patient-specific protocols can be implemented by partnering with local sickle cell disease providers to make protocols available in the emergency department.

BACKGROUND: National guidelines for the acute management of sickle cell disease vaso-occlusive episodes recommend the use of a patient-specific or a weight-based protocol. The authors compared patient satisfaction with pain management between those randomized to receive either a patient-specific or weight-based pain protocol in the COMPARE-VOE randomized control trial.

DETAILS: Participants with sickle cell disease were pre-enrolled and patient satisfaction with pain management was assessed at the time of discharge from the 6 participating emergency departments. Patients were randomized to receive a patient-specific or weight-based pain protocol. The authors compared continuous variables between the patient-specific and weight-based protocols with the 2-sample t test and categorical variables by the chi-square test. The authors enrolled 104 participants. Compared with satisfaction with pain management on previous ED visits, more participants in the patient-specific protocol group than the weight-based group (57.1% vs 31.8%; P = .02) were satisfied with pain management. Most who were discharged home (91.2%) felt their pain was sufficiently relieved to be discharged home.

Copyright © Elsevier Inc. Published by Elsevier Inc. All rights reserved.

Source: Ibemere, S. O., Barnhart, H., Myers, J., et al. Impact of Individualized Versus Weight-Based Pain Protocols on Patient Satisfaction for Patients With Sickle Cell Disease Experiencing a Vaso-Occlusive Episode. Journal of Emergency Nursing. 2025; 51(4): 626-635. Published: July, 2025. DOI: 10.1016/j.jen.2024.12.014.

Fluoropyrimidine Chemotherapy: Mortality and Cardiovascular Risk in Gastrointestinal Cancer

[Posted 4/Jul/2025]

AUDIENCE: Oncologists, Cardiologists, Cardio-Oncologists, and Researchers involved in the treatment of gastrointestinal cancers.

KEY FINDINGS:

• Fluoropyrimidine-based chemotherapy significantly reduced the absolute risk of all-cause mortality at 1 year (RD: -7.7%; 95% CI: -8.7% to -6.7%).
• There was a small increased risk of acute cardiovascular events (RD: 0.9%; 95% CI: 0.0% to 1.9%), primarily due to arrhythmias (RD: 0.8%; 95% CI: 0.1% to 1.6%) and cardiac arrest (RD: 0.3%; 95% CI: 0.1% to 0.5%).
• No increased risk of acute coronary syndromes was observed, even in patients with pre-existing coronary artery disease.
• The substantial survival benefit of fluoropyrimidines in GI cancer patients outweighs the small risk of cardiac arrhythmia and arrest.

BACKGROUND: Fluoropyrimidine chemotherapy is a primary first-line treatment for many gastrointestinal cancers. However, concerns regarding its cardiotoxicity often lead to the use of alternative treatments in patients with pre-existing cardiovascular disease. This study aimed to quantitatively assess the risks of all-cause mortality and acute cardiovascular events associated with fluoropyrimidine treatment to inform clinical decision-making.

DETAILS: This observational cohort study utilized a target trial emulation framework with linked national cancer, cardiac, and hospitalization registry data from the Virtual Cardio-Oncology Research Initiative. The study included 103,110 adult patients (mean age 69.7 years, 59% male) diagnosed with tumors eligible for first-line fluoropyrimidine-based chemotherapy. Researchers compared all-cause mortality and a composite of hospitalization for acute cardiovascular events (including acute coronary syndrome, heart failure, cardiac arrhythmia, cardiac intervention, cardiac arrest, and cardiac death) between patients receiving fluoropyrimidine-based chemotherapy and those undergoing alternative management. The findings indicate that the improved overall survival with fluoropyrimidines in patients with gastrointestinal cancer is a significant benefit that should encourage oncologists to avoid undue clinical conservatism, particularly when treating patients with co-existing cardiovascular disease.

Copyright © Authors. All rights reserved.

Source: Abiodun, A. T., Ju, C., Welch, C. A., et al. Fluoropyrimidine Chemotherapy and the Risk of Death and Cardiovascular Events in Patients With Gastrointestinal Cancer. J Am Coll Cardiol CardioOnc.. 2025; 7(4): 345-356. Published: June, 2025. DOI: 10.1016/j.jaccao.2025.01.019.