May 12, 2026
Prepared by Dr Edwin Uriel Suárez

Reconstitution of alloreactive B cells contributes to the pathogenesis of chronic graft-versus-host disease (GVHD) through multiple mechanisms. CD19-directed chimeric antigen receptor (CAR) T-cell therapy has changed the treatment landscape for B-cell cancers and is also promising for the treatment of autoimmune diseases. In some autoimmune diseases, evidence of a return of B cells without disease recurrence suggests that CD19 CAR T cells may induce durable remissions. Thus far, studies evaluating CAR T cells as a treatment for alloimmune disorders, including chronic GVHD, have been lacking.

Here, the authors report treatment with a split infusion of autologous CD19 CAR T cells in a 32-year-old woman with relapsed B-cell acute lymphoblastic leukemia (ALL) and active chronic GVHD after a second allogeneic hematopoietic cell transplantation procedure. These data from a single patient show that CD19 CAR T cells can be safely given in the setting of B-cell ALL and active chronic GVHD and can reverse sclerodermatous chronic GVHD in the absence of additional immunosuppressive therapies.  

Recommendations:

●      Clinicians should be aware that administration of andexanet alfa is associated with a significantly increased risk of thromboembolic events, particularly ischaemic stroke (1A).

●      If administration of andexanet alfa is being considered, clinicians should be aware that thromboembolic risk may outweigh benefit (2A).

●      If andexanet alfa is to be given, clinicians should ensure that it is only administered within its licensed indication (1A). 

Highlights:

●      Venetoclax-based low-intensity regimens have improved the outcomes of older or unfit patients with acute myeloid leukemia  (AML).

●      In this study, the combination of cladribine plus low-dose cytarabine and venetoclax produced a high rate of remissions, translating into favorable outcomes for older patients with newly diagnosed AML.

This study investigated the combination of cladribine plus low-dose cytarabine and venetoclax alternating with azacitidine plus venetoclax for older or unfit patients with newly diagnosed AML. A total of 190 patients were included; the median age was 68 years (range, 47–84 years; 13% ≥ 75 years). By the European LeukemiaNet 2022 classification, 16%, 20%, and  64% were stratified as favorable, intermediate, and adverse risk, respectively. The rates of complete remission (CR)/CR with incomplete blood count recovery (CRi) and minimal residual disease (MRD) negative CR/CRi were 84% and 75% overall and 91%  and 77% among patients with TP53- wild type AML, respectively. Among responders, 44% proceeded to allogeneic hematopoietic stem cell transplantation. The median overall survival (OS) and  event free survival (EFS) were 52 and 50 months, respectively. The 2-  and 5- year OS rates were 60% and 45%, respectively. The  2- and 5- year EFS rates were 56% and 43%, respectively. Patients achieving MRD-negative CR had a median OS not reached  and a 2-year OS rate of 70%. Overall, the treatment was safe and most grade 3 and 4 adverse events were infectious complications. 

Highlights:

●      The standard treatment for patients with newly diagnosed, advanced-stage classic Hodgkin lymphoma (cHL) primarily consisted, until recently, of ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) or BEACOPPesc (escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone). Treatment selection was largely driven by local preferences and established practices, rather than tailored to the individual patient's characteristics and risk profile.

●      Brentuximab vedotin combined with doxorubicin, vinblastine, and dacarbazine (A-AVD) improves outcomes in advanced-stage cHL, but patients with a positive early interim positron-emission tomography (PET) have inferior prognosis.

●      The results of this study (EORTC-1537-COBRA) suggest that patients who do not reach an early complete metabolic response to A-AVD could overcome their relatively poor prognosis by switching to the more intensive brentuximab vedotin-containing chemotherapy (BrECADD [brentuximab vedotin, etoposide, cyclophosphamide, doxorubicin, dacarbazine, and dexamethasone]). This way, overall outcomes are optimised while most patients are spared the more intensive chemotherapy.

This single-arm, multicentre, phase 2 trial was conducted at 16 centres in seven European countries. Adults aged 18–60 years with previously untreated advanced-stage cHL, performance status 0–2, and adequate organ function received one cycle of A-AVD, followed by centrally reviewed ^[F]FDG-PET–CT (PET1). PET1-negative (Deauville score 1–3) patients received five additional A-AVD cycles; PET1-positive (Deauville score 4–5) patients switched to six cycles of BrECADD. The primary endpoint was 2-year modified progression-free survival (mPFS), defined as the proportion of patients alive and free of progression, relapse, or death from treatment start, with initiation of new systemic therapy for persistent disease counted as an event.

From 2019 to  2021, 150 patients were enrolled (81 males [54%] and 69 females [46%]; median age 32 years [interquartile range (IQR) 23–39]) who received one cycle of A-AVD, after which 90 (60%) of them had a negative PET1 and 60 (40%) a positive result. 86 and 59 patients, respectively (n=145) were evaluable for efficacy. The median follow-up at the clinical cutoff was 30.1 months (IQR 24.6-36.4). 16 (11%) patients experienced a modified progression-free survival (mPFS) event. The estimated 2-year mPFS was 89.5% (80% CI 85.7–92.4). The most common grade 3–4 adverse event was neutropenia (53 [35%] of 150, enrolled who began A-AVD treatment), followed by anemia (18 [12%]) and peripheral sensory neuropathy (nine [6%]). Serious adverse events occurred in 45 (30%) of 150 patients. No deaths occurred. 

The International Porphyria Network invited 34 acute porphyria specialists from 17 countries to form an expert panel. The invited group included clinicians from diverse specialities (internal medicine, hematology, endocrinology, gastroenterology, hepatology, neurology, and biochemistry) together with laboratory scientists and patient representatives. The panel met online (in 2023–25) to develop 15 evidence-based recommendations.

Key points:

●      Autosomal dominant acute porphyrias are rare inherited disorders of haem biosynthesis characterised by accumulation of potentially neurotoxic porphyrin precursors and attacks of severe abdominal pain with autonomic and neuropsychiatric features.

●      Disease severity ranges from asymptomatic individuals to those with recurrent, life-threatening attacks.

●      The panel recommends that all individuals with acute porphyria should be informed of the risk that some drugs could trigger an acute attack and instructed on how to check drug safety. (Strong recommendation based on very low certainty in the evidence).

●      The panel recommends the use of haemin (limits hepatic and/or marrow porphyrin synthesis by inhibiting synthesis of aminolaevulinic acid synthase, the enzyme that regulates the porphyrin/heme pathway) for the treatment of a severe acute attack. (Strong recommendation based on very low certainty in the evidence).

○      The main side-effect is phlebitis. The risk can be reduced by: reconstituting haemin in albumin; flushing vein with 0.9 % sodium chloride solution after haemin administration; and administering haemin through a central line or large peripheral vein.

○      The safety of haemin in pregnancy has not been formally studied, but clinical experience has shown no adverse effects to the fetus.

●      The panel suggests the use of haemin for the treatment of an acute attack without features that flag it as severe. (Conditional recommendation based on very low certainty in the evidence).

○      In patients with recurrent attacks, the panel suggests that haemin is administered prophylactically rather than only to treat acute attacks. (Conditional recommendation based on very low certainty in the evidence).

●      In patients with recurrent attacks, the panel suggests givosiran (causes degradation of aminolaevulinate synthase 1 [ALAS1] messenger RNA [mRNA] in hepatocytes through RNA interference, reducing the elevated levels of liver ALAS1 mRNA) in preference to other preventative treatments (See Figure in original paper). Conditional recommendation based on very low certainty in the evidence).

○      Givosiran is the preferred treatment for recurrent attacks when available and not contraindicated (eg, pregnancy).

●      In women with cyclic (pre-menstrual recurrent) attacks, the panel suggests considering gonadotropin releasing hormone analogues when givosiran is not available or not tolerated. (Conditional recommendation based

●      on very low certainty in the evidence).

●      The panel suggests surveillance for primary liver cancer in patients aged 50 years and older with active acute porphyria (recurrent or sporadic attacks), symptomatic high excreters, asymptomatic high excreters, and asymptomatic acute porphyria. (Conditional recommendation based on very low certainty in the evidence).

●      The panel recommends predictive DNA testing supported by counselling from a porphyria specialist in asymptomatic family members of all patients with symptomatic acute porphyria or high excreters. (Conditional recommendation based on very low certainty in the evidence).