The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency met on 7–10 April 2026 and adopted important safety recommendations for two medicinal products: the CAR-T cell therapy axicabtagene ciloleucel (Yescarta) and the tyrosine kinase inhibitor ponatinib (Iclusig). This article provides a detailed medical analysis of these signals, including the clinical presentation, pathophysiology, epidemiological evidence, and implications for healthcare professionals.
The first signal relates to an increased risk of cerebral oedema in patients with primary mediastinal large B‑cell lymphoma (PMBCL) treated with axicabtagene ciloleucel, with a reported event rate of 1.6% in this indication compared to 0.7% in other lymphomas. The second signal describes cases of congenital megacolon (Hirschsprung’s disease) in children born to women exposed to ponatinib during the first trimester of pregnancy, a previously unreported adverse reaction. Both signals resulted in updates to the product information (Summary of Product Characteristics and Package Leaflet).
1. Introduction: The Role of PRAC in Medication Safety
The Pharmacovigilance Risk Assessment Committee (PRAC) is the European Medicines Agency’s committee responsible for evaluating safety signals for human medicines. At its meeting of 7–10 April 2026, PRAC adopted recommendations for two safety signals requiring updates to product information for centrally authorised products (CAPs). These signals highlight the importance of post-marketing surveillance in identifying rare but serious adverse events, particularly in specialised patient populations and during pregnancy.
2. Signal 1: Axicabtagene Ciloleucel (Yescarta) – Increased Risk of Cerebral Oedema in PMBCL Patients
2.1 Background: CAR-T Cell Therapy and Axicabtagene Ciloleucel
Axicabtagene ciloleucel (Yescarta) is a CD19-directed genetically modified autologous chimeric antigen receptor (CAR) T‑cell therapy. It is indicated for the treatment of adult patients with:
- Relapsed or refractory diffuse large B‑cell lymphoma (DLBCL) after two or more lines of systemic therapy
- Primary mediastinal large B‑cell lymphoma (PMBCL) after two or more lines of systemic therapy
- High-grade B‑cell lymphoma after two or more lines of systemic therapy
CAR‑T cell therapy has revolutionised the treatment of aggressive B‑cell malignancies, but it is associated with unique and potentially life‑threatening toxicities, including cytokine release syndrome (CRS) and immune effector cell‑associated neurotoxicity syndrome (ICANS). Cerebral oedema is a rare but severe neurological complication that has been reported with CAR‑T therapies.
2.2 The Signal: Increased Risk of Cerebral Oedema in PMBCL Patients
PRAC identified a signal that the risk of cerebral oedema may be higher in patients with primary mediastinal large B‑cell lymphoma (PMBCL) treated with axicabtagene ciloleucel compared to other lymphoma indications.
2.2.1 What is Cerebral Oedema?
Cerebral oedema is the accumulation of excess fluid in the intracellular or extracellular spaces of the brain, leading to increased intracranial pressure. It can be focal or generalised and, if severe, may cause brain herniation, irreversible neurological damage, and death.
| Type of Cerebral Oedema | Mechanism | Clinical Features |
|---|---|---|
| Vasogenic | Disruption of blood‑brain barrier; fluid leaks into extracellular space | Most common in tumours, abscesses, inflammation |
| Cytotoxic | Cellular swelling due to energy failure (e.g., hypoxia, ischaemia) | Seen in stroke, metabolic disorders |
| Interstitial | Flow of CSF into brain parenchyma (e.g., obstructive hydrocephalus) | Often post‑surgical or tumour‑related |
| Osmotic | Water shifts due to plasma hypo‑osmolarity | Improper fluid management; SIADH |
In the context of CAR‑T therapy, cerebral oedema is thought to be related to severe ICANS and excessive inflammatory cytokine production.
2.2.2 Epidemiological Data from the Signal
The PRAC recommendation cites registry data showing:
| Indication | Cerebral Oedema Event Rate | Number of Cases / Exposed Patients |
|---|---|---|
| Primary mediastinal large B‑cell lymphoma (PMBCL) | 1.6% | 2 cases in 129 exposed |
| Diffuse large B‑cell lymphoma (DLBCL) and other lymphomas | 0.7% | 28 cases in 3,876 exposed |
The rate in PMBCL patients is more than double that observed in other indications. Most cases of cerebral oedema occurred in patients who had experienced ICANS.
2.2.3 Pathophysiological Considerations
PMBCL is a distinct subtype of aggressive B‑cell lymphoma that typically affects younger patients (median age 30–40 years) and presents with a large mediastinal mass. It shares biological features with Hodgkin lymphoma, including expression of CD30 and PD‑L1/PD‑L2. The higher risk of cerebral oedema in PMBCL patients may be related to:
- Differences in tumour biology and inflammatory milieu
- Higher baseline levels of circulating cytokines
- Greater disease burden at the time of CAR‑T infusion
- Potential interactions between CAR‑T cells and the mediastinal tumour microenvironment
However, the exact mechanism remains unknown and requires further investigation.
2.3 Regulatory Action
PRAC recommended that the Marketing Authorisation Holder (MAH) of Yescarta update the product information as follows:
Summary of Product Characteristics (SmPC)
Section 4.4 – Special warnings and precautions for use (Neurologic adverse reactions):
“Fatal and serious cases of cerebral oedema have been reported in patients treated with Yescarta, with most cases occurring in patients with ICANS. The risk for cerebral oedema may be higher in PMBCL patients (see section 4.8).”
Section 4.8 – Undesirable effects (Table 1 – Adverse drug reactions):
Nervous system disorders: Cerebral oedema – frequency “Uncommon” (with footnote: “Most cases of cerebral oedema occurred in patients with ICANS”)
Section 4.8 – Description of selected adverse reactions (Neurologic adverse reactions):
“In registries, the cerebral oedema event rate in the PMBCL indication was 1.6% overall (2 cases in 129 exposed) compared with 0.7% overall in DLBCL and other lymphoma indications (28 cases in 3876 exposed).”
Package Leaflet (Section 4 – Possible side effects, Serious side effects, Uncommon):
“Swelling of the brain (cerebral oedema).”
2.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Risk stratification | Recognise that patients with PMBCL may have a higher baseline risk of cerebral oedema following axicabtagene ciloleucel therapy. |
| Monitoring | For PMBCL patients receiving CAR‑T therapy, intensify neurological monitoring, especially in those who develop signs of ICANS. |
| Early intervention | Cerebral oedema can be rapidly progressive. Prompt recognition (headache, altered mental status, focal deficits, seizures) and immediate management (high‑dose corticosteroids, mannitol, hyperventilation, neurosurgical consultation) are critical. |
| Patient and caregiver education | Inform patients and families about the signs and symptoms of cerebral oedema and the importance of seeking immediate medical attention. |
| Reporting | Report any confirmed or suspected cases of cerebral oedema following axicabtagene ciloleucel to the national pharmacovigilance centre, regardless of indication. |
3. Signal 2: Ponatinib (Iclusig) – Congenital Megacolon (Hirschsprung’s Disease) Following First‑Trimester Exposure
3.1 Background: Ponatinib
Ponatinib (Iclusig) is a third‑generation BCR‑ABL tyrosine kinase inhibitor (TKI). It is indicated for:
- Chronic myeloid leukaemia (CML) in patients resistant or intolerant to prior TKIs, or with the T315I mutation
- Philadelphia chromosome‑positive acute lymphoblastic leukaemia (Ph+ ALL) in patients resistant or intolerant to prior TKIs, or with the T315I mutation
Ponatinib is known to be teratogenic in animal studies (reproductive toxicity, see section 5.3 of the SmPC) but human data on pregnancy outcomes have been limited. The product information previously stated that there are no adequate data from the use of ponatinib in pregnant women and that the potential risk for humans is unknown, recommending that it should only be used during pregnancy if clearly necessary.
3.2 The Signal: Congenital Megacolon (Hirschsprung’s Disease)
PRAC identified a signal of congenital megacolon (Hirschsprung’s disease) in children born to women exposed to ponatinib during the first trimester of pregnancy. This represents a new adverse reaction not previously listed in the product information.
3.2.1 What is Congenital Megacolon (Hirschsprung’s Disease)?
Hirschsprung’s disease (congenital megacolon) is a developmental disorder of the enteric nervous system characterised by the absence of ganglion cells (aganglionosis) in the distal colon, resulting in functional intestinal obstruction.
| Feature | Description |
|---|---|
| Incidence | Approximately 1 in 5,000 live births |
| Sex ratio | Male predominance (4:1) |
| Genetics | Associated with mutations in the RET proto‑oncogene; also other genes (EDNRB, SOX10, etc.) |
| Clinical presentation | Failure to pass meconium within 48 hours of birth, abdominal distension, vomiting, constipation, enterocolitis |
| Diagnosis | Rectal suction biopsy showing absence of ganglion cells; anorectal manometry; contrast enema |
| Treatment | Surgical resection of aganglionic segment (pull‑through procedure); staged procedures may be required |
| Prognosis | Excellent with early diagnosis and surgery; risk of Hirschsprung‑associated enterocolitis (HAEC) persists |
3.2.2 Signal Characteristics
The PRAC recommendation states that:
“Based on limited human data (less than 50 known pregnancy outcomes), cases of congenital megacolon (Hirschsprung’s disease) have been reported in children born to women exposed to ponatinib during the first trimester.”
Key points:
- Small number of exposed pregnancies (<50 known outcomes) – the absolute number of cases is not explicitly given, but the signal has been confirmed based on observed cases exceeding the expected background rate.
- First‑trimester exposure – the critical period for enteric nervous system development is during early embryogenesis (weeks 4–10), when neural crest cells migrate to form the myenteric and submucosal plexuses.
- Previously unreported – this adverse reaction was not listed in the product information; the signal represents a new important identified risk.
3.2.3 Pathophysiological Plausibility
Enteric nervous system development depends on the migration, proliferation, differentiation, and survival of neural crest cells. Receptor tyrosine kinases, particularly RET, play a central role in this process. Ponatinib is a potent multi‑targeted TKI that inhibits not only BCR‑ABL but also other kinases including members of the RET family, vascular endothelial growth factor receptors (VEGFRs), fibroblast growth factor receptors (FGFRs), and platelet‑derived growth factor receptors (PDGFRs). Inhibition of RET signalling during critical developmental windows could theoretically disrupt neural crest cell colonisation of the gut, leading to aganglionosis (Hirschsprung’s disease).
This biological plausibility strengthens the causal interpretation of the signal.
3.3 Regulatory Action
PRAC recommended that the MAH of Iclusig update the product information as follows:
Summary of Product Characteristics (SmPC)
Section 4.6 – Fertility, pregnancy and lactation (Pregnancy):
“Based on limited human data (less than 50 known pregnancy outcomes), cases of congenital megacolon (Hirschsprung’s disease) have been reported in children born to women exposed to ponatinib during the first trimester. There are no adequate data from the use of Iclusig in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Iclusig should not be used during pregnancy unless the clinical condition of the woman requires treatment with ponatinib. Iclusig should be used during pregnancy only when clearly necessary.”
Package Leaflet (Section 2 – What you need to know before you take Iclusig)
No specific new text quoted in the extract, but the updated SmPC information will be reflected in the leaflet.
3.4 Clinical Implications for Healthcare Professionals
| Implication | Action |
|---|---|
| Pre‑conception counselling | For women of childbearing potential taking ponatinib, discuss effective contraception before, during, and after treatment. Advise against becoming pregnant while on therapy. |
| Pregnancy testing | Perform a pregnancy test before starting ponatinib in women of childbearing potential. |
| Accidental exposure in first trimester | If a woman becomes pregnant while taking ponatinib, refer for specialist obstetric and genetic counselling. Arrange detailed fetal ultrasound, including assessment of the colon (although Hirschsprung’s disease may not be detectable prenatally in all cases). |
| Neonatal assessment | Newborns exposed to ponatinib in utero should be monitored for delayed passage of meconium, abdominal distension, vomiting, and signs of intestinal obstruction. |
| Reporting | Report all pregnancy exposures (with or without adverse outcomes) to the national pharmacovigilance centre and to the MAH’s pregnancy registry if available. Report any suspected cases of congenital megacolon or other congenital anomalies. |
| Risk communication | Update patient information leaflets to include the risk of congenital megacolon and emphasise the importance of pregnancy prevention. |
4. Comparative Overview of the Two Signals
| Parameter | Signal 1 | Signal 2 |
|---|---|---|
| Drug | Axicabtagene ciloleucel (Yescarta) | Ponatinib (Iclusig) |
| Therapeutic area | CAR‑T cell therapy for lymphoma | Tyrosine kinase inhibitor for leukaemia |
| Adverse event | Cerebral oedema | Congenital megacolon (Hirschsprung’s disease) |
| Population at risk | PMBCL patients (higher risk than DLBCL) | Foetuses exposed in first trimester |
| Event rate | 1.6% in PMBCL vs. 0.7% in other indications | Unknown; based on <50 known pregnancy outcomes with several reported cases |
| Regulatory action | Update SmPC (warnings, undesirable effects, registry data) | Update SmPC (pregnancy section – new congenital anomaly) |
| Clinical urgency | High (fatal/serious cases reported) | High (congenital malformation requiring surgery) |
5. The Pharmacovigilance Perspective
5.1 Limitations of Pre‑authorisation Data
Both signals illustrate the limitations of pre‑approval clinical trials:
- Axicabtagene ciloleucel was studied in hundreds of patients, but the PMBCL subgroup was relatively small (129 patients in registries). Rare events such as cerebral oedema may not be detected until larger post‑marketing datasets are available.
- Ponatinib pregnancy outcomes are inevitably limited because clinical trials exclude pregnant women, and post‑marketing exposure data accumulate slowly. Fewer than 50 known pregnancy outcomes are available, yet even this modest dataset allowed detection of a signal for a rare congenital anomaly (baseline incidence ~1 in 5,000 births).
5.2 The Role of Pregnancy Registries
The ponatinib signal highlights the critical importance of pregnancy exposure registries and systematic collection of pregnancy outcomes for teratogenic risk assessment. Marketing authorisation holders should establish or participate in pregnancy registries for drugs with potential teratogenicity.
5.3 Benefit‑Risk Balance
Neither signal changes the overall positive benefit‑risk balance of these life‑saving cancer therapies. Axicabtagene ciloleucel offers durable remissions in patients with relapsed/refractory aggressive lymphomas. Ponatinib is uniquely effective against T315I‑mutant CML/ALL. The regulatory actions are intended to inform clinical decision‑making and enhance patient safety through better risk communication, monitoring, and risk mitigation.
6. Practical Recommendations for Healthcare Professionals
6.1 For Axicabtagene Ciloleucel
| Action | Details |
|---|---|
| Pre‑infusion risk assessment | Identify PMBCL patients and discuss the increased risk of cerebral oedema |
| Neurological monitoring | Use standardised ICANS grading; perform frequent neurological assessments, especially during the peak neurotoxicity window (days 5–10 post‑infusion) |
| Emergency preparedness | Ensure availability of high‑dose corticosteroids, mannitol, and neurosurgical consultation |
| Multidisciplinary team | Involve neuro‑intensivists early in patients with severe ICANS or suspected cerebral oedema |
| Reporting | Report all cases of cerebral oedema, regardless of outcome, to the national PV centre and to the MAH |
6.2 For Ponatinib
| Action | Details |
|---|---|
| Contraception | Advise women of childbearing potential to use effective contraception during treatment and for an appropriate period after the last dose (refer to local label) |
| Pregnancy testing | Perform a pregnancy test within 7 days before initiating ponatinib |
| Accidental pregnancy | If pregnancy occurs, discuss the potential risk to the foetus, including congenital megacolon; refer for genetic counselling and high‑risk obstetric care |
| Neonatal follow‑up | Exposed newborns should be examined for signs of intestinal obstruction; prompt evaluation if meconium passage is delayed >24–48 hours |
| Reporting | Report all pregnancy exposures (and pregnancy outcomes) to the national PV centre and to the MAH’s pregnancy registry |
7. Conclusion
The April 2026 PRAC recommendations highlight the dynamic nature of pharmacovigilance and the ongoing need for post‑marketing safety surveillance, even for innovative therapies. The signals discussed in this article demonstrate:
- Advanced therapies such as CAR‑T cells can have indication‑specific safety profiles (higher risk of cerebral oedema in PMBCL).
- Pregnancy exposure data, even from small numbers, can reveal previously unknown teratogenic risks (congenital megacolon with ponatinib).
- Product information updates are essential to inform healthcare professionals and patients, enabling better risk minimisation and monitoring.
For clinicians, these updates serve as reminders to:
- Stay current with safety communications from regulatory agencies.
- Counsel patients appropriately about new risks.
- Monitor and report suspected adverse reactions promptly.
Every report contributes to the global knowledge of drug safety and helps protect future patients.
