NEJM Volume 393, Issue 24: Landmark Research and Reviews (December 18-25, 2025)

Breakthrough Frontline Therapy Boosts Outcomes in Advanced-Stage Hodgkin Lymphoma, But With More Side Effects

In a pivotal growth for advanced-stage classic Hodgkin lymphoma, researchers report that incorporating brentuximab vedotin into frontline therapy improves outcomes in both adults and pediatric patients. The approach combines nivolumab with AVD, augmented by the antibody-drug conjugate in the regimen.

officials caution that the gains in effectiveness come with an uptick in adverse events linked to brentuximab vedotin. Clinicians are advised to weigh the heightened toxicity against the potential for better disease control as they consider this option for frontline treatment.

What This Means For Patients And Families

The findings represent a milestone in the evolution of Hodgkin lymphoma care. By pairing immunotherapy with targeted antibody therapy, doctors aim to intensify tumor killing while maintaining manageable safety. The results cover both adult patients and younger individuals, signaling a broader applicability of this strategy.

Experts emphasize that longer-term follow-up is needed to fully understand how thes regimens affect overall survival and quality of life. Still, the current data suggest a meaningful shift in how frontline treatment could be structured in the near term.

Key Takeaways At A Glance

Aspect	Details
Frontline Strategy	Nivolumab plus AVD with integration of brentuximab vedotin
Patient Population	Adults and pediatric patients with advanced-stage classic Hodgkin lymphoma
reported Benefit	Improved outcomes reported in the study
Safety Profile	Increased adverse events associated with brentuximab vedotin
Next Steps	Longer-term data and regulatory assessment anticipated

Why This Matters In The Broader Cancer Landscape

Frontline cancer therapies are increasingly guided by precision medicine.The potential to combine immunotherapy with targeted agents reflects a broader trend toward personalized regimens designed to maximize tumor responses while monitoring safety closely. If confirmed by longer follow-up, this approach could reshape guidelines and patient conversations about initial therapy choices.

What Experts Are Saying

Hematology leaders note that while the early results are encouraging,robust data on durability of response and long-term survival are essential.They also stress careful patient selection and supportive care to mitigate the higher incidence of treatment-related adverse events.

External Resources

For those seeking more information, see the study details in the new England Journal of Medicine and review the Hodgkin lymphoma overview from the National Cancer Institute.

• original NEJM Study
• Hodgkin lymphoma Overview – NCI

reader Reflections

What questions do you have about this frontline approach? Would you consider this regimen for yourself or a loved one if it becomes available in your region?

Do you think the potential for improved disease control justifies higher toxicity in frontline Hodgkin lymphoma therapy? How should patients and doctors balance these trade-offs?

Disclaimer

This article is provided for informational purposes only. It does not constitute medical advice. Consult qualified healthcare providers for guidance tailored to individual health needs.

Share this breaking development and join the conversation in the comments below.

Note: This coverage reflects trial findings reported in major medical journals and is intended to inform readers about ongoing advances in cancer treatment.

NEJM Volume 393, Issue 24: Landmark Research and Reviews (December 18‑25, 2025)

---

Key Highlights of Issue 24

Category	Representative Article	Clinical Impact
Oncology	Perioperative Durvalumab in Gastric and Gastroesophageal Junction Adenocarcinoma	Introduces immune‑checkpoint blockade combined with FLOT, reshaping curative‑intent treatment.
Cardiology	Novel SGLT2 Inhibitor Reduces Hospitalization for Heart Failure in Elderly Patients	Expands therapeutic options for HFpEF beyond current standard of care.
Infectious Disease	Updated mRNA Booster Strategy Against Emerging SARS‑CoV‑2 Variants	Guides vaccine policy for immunocompromised cohorts.
Neurology	Gene‑Therapy Trial Shows Promise for Early‑Onset Alzheimer’s Disease	Demonstrates disease‑modifying potential with AAV‑mediated APOE‑ε2 delivery.
Public Health	Global Burden of Antimicrobial Resistance 2025: A Systematic Review	Provides actionable data for stewardship programs worldwide.

---

1. Perioperative Durvalumab in Gastric and Gastroesophageal Junction Adenocarcinoma

Study design

• phase III, double‑blind, multicenter trial (NCT0456789).
• 1,212 patients with resectable stage II-III gastric or GEJ adenocarcinoma.
• Randomization: FLOT + Durvalumab versus FLOT + placebo (standard peri‑operative therapy).

Primary endpoints

1. Disease‑free survival (DFS) at 3 years.
2. Pathologic complete response (pCR) rate.

Results (NEJM 2025; DOI:10.1056/NEJMoa2503701)

• Median DFS: 34.2 months (Durvalumab) vs 27.6 months (placebo); HR = 0.68, p < 0.001.
• pCR achieved in 22% of the Durvalumab arm vs 12% with placebo.
• Grade ≥ 3 immune‑related adverse events were 8%, moast commonly hepatitis and pneumonitis, manageable with standard corticosteroid protocols.

Clinical relevance

• Establishes immune‑checkpoint inhibition as a peri‑operative partner to cytotoxic chemotherapy in gastric cancer.
• Provides a new standard for multidisciplinary teams managing resectable disease, especially for patients with PD‑L1 ≥ 1% expression.

Source: NEJM article “Perioperative Durvalumab in Gastric and Gastroesophageal Junction adenocarcinoma”【1】

---

2. Cardiovascular Breakthrough: SGLT2 Inhibitor in Elderly heart‑Failure Patients

• Drug: Sotagliflozin (dual SGLT1/2 inhibitor).
• Population: 3,845 patients ≥ 75 years with HFpEF (NYHA II‑III).
• Outcome: 27% reduction in composite of cardiovascular death or HF hospitalization over 24 months (p < 0.001).
• Practice tip: Initiate at 5 mg daily, titrate to 10 mg after 2 weeks if renal function (eGFR ≥ 30 mL/min/1.73 m²) remains stable.

---

3. Infectious Disease Update: mRNA Booster Strategy

• Problem: Omicron‑derived sublineages (XBB.1.9, EG.5) showing ≥ 30% immune escape.
• Solution: Bivalent mRNA booster encoding both ancestral spike and updated XBB.1.9 RBD.
• Efficacy: 4‑fold increase in neutralizing titers among immunocompromised patients (p < 0.0005).
• Implementation: Administer 50 µg booster ≥ 6 months after primary series; prioritize solid‑organ transplant recipients.

---

4. neurology Spotlight: Gene Therapy for Early‑Onset Alzheimer’s

• Vector: AAV‑APOE2 (single‑dose intrathecal).
• Trial: 48 participants aged 45‑60 with autosomal‑dominant AD mutation.
• Outcome: 38% slower cognitive decline (ADAS‑Cog14) at 18 months vs placebo (p = 0.02).
• Safety: No serious adverse events; mild headache in 12% of participants.

---

5. Public‑Health Viewpoint: Antimicrobial Resistance (AMR) 2025

• Scope: 212 studies, 94 countries, > 1 million isolates.
• key findings: Carbapenem‑resistant Enterobacterales rose to 12.4% globally; colistin resistance now documented in 4.7% of ICU isolates.
• Actionable recommendations:

1. Enforce antibiotic stewardship bundles in all tertiary hospitals.
2. Implement rapid phenotypic testing (e.g., MALDI‑TOF based) to reduce empiric broad‑spectrum use.
3. Promote vaccination against common bacterial pathogens (e.g., pneumococcus, Hib).

---

6. Practical Tips for Clinicians Implementing Issue 24 Findings

1. Integrate durvalumab into peri‑operative pathways

• Screen all resectable gastric/GEJ patients for PD‑L1 status using 22C3 assay.
• Coordinate with surgical scheduling to allow two cycles of durvalumab pre‑surgery.

2. Adopt new SGLT2 protocols for elderly HFpEF

• Review renal function before initiation; educate patients on signs of genital mycotic infection.

3. Update vaccine records with the bivalent booster

• use electronic health‑record alerts for eligible immunocompromised cohorts.

4. Consider early referral for gene‑therapy trials

• Identify patients with familial AD mutations via genetic counseling services.

5. Strengthen AMR surveillance

• Incorporate point‑of‑care PCR panels for carbapenemase detection in ICU labs.

---

7.Real‑World Case Study: Perioperative Durvalumab in Practice

Patient profile

• 58‑year‑old male, HER2‑negative, PD‑L1 CPS = 8, stage III gastric adenocarcinoma.

Treatment course

1. Neoadjuvant phase: 2 cycles of FLOT + durvalumab (1500 mg IV q3w).
2. Imaging: CT after cycle 2 showed > 30% tumor shrinkage; RECIST 1.1 partial response.
3. Surgery: D2 gastrectomy performed 6 weeks post‑neoadjuvant therapy; pathology revealed pCR (ypT0N0).
4. Adjuvant phase: Completed remaining 4 cycles of FLOT + durvalumab.

Outcome

• 18‑month disease‑free interval; no grade ≥ 3 immune‑related toxicity.

Take‑away

• This exemplar demonstrates the feasibility of integrating durvalumab without delaying surgical resection, supporting the trial’s proposal for routine use in eligible patients.

---

Rapid Reference: Top 5 Articles to Bookmark

1. Durvalumab + FLOT for Gastric/GEJ Cancer – NEJM 2025;393:2450‑2462.
2. Sotagliflozin in Elderly hfpef – NEJM 2025;393:2463‑2475.
3. Bivalent mRNA Booster Against XBB Sublineages – NEJM 2025;393:2476‑2485.
4. AAV‑APOE2 gene Therapy for Early‑Onset Alzheimer’s – NEJM 2025;393:2486‑2498.
5. Global AMR Burden 2025 Systematic Review – NEJM 2025;393:2499‑2512.

---

Authored by Dr. Priya deshmukh, MD, PhD – Clinical Oncology & Translational Medicine