News of the Week

Key points:

• TP53 loss-of-function (TP53-LoF) remains the single most important prognostic factor in chronic lymphocytic leukemia (CLL).
• Comprehensive assessment for TP53-LoF requires testing for both gene deletion and mutation.
• Historically, patients with TP53-LoF CLL have had poor outcomes and experienced short survival when treated with chemoimmunotherapy. Patients with del(17p) by fluorescent in-situ hybridization had a median overall survival of less than 3 years from diagnosis.
• In the novel agent era, multiple studies have demonstrated the effectiveness of continuous covalent BTK inhibitor (cBTKi) therapy, especially in the frontline setting, with a median progression-free survival (PFS) of approximately 7 years. Continuous cBTKi is therefore the de-facto standard for current management of TP53-LoF CLL.
• In contrast, fixed-duration regimens combining venetoclax with either obinutuzumab or cBTKi have shown slower response kinetics with longer time to undetectable minimal residual disease (uMRD) status, and reduced PFS, in patients with TP53-LoF CLL.
• Although early data from fixed-duration regimen studies indicate that most patients respond to retreatment, specific data for the TP53-LoF subset have not been reported. Therefore, the application of fixed-duration regimens for treatment of TP53-LoF CLL requires careful deliberation on the risks versus benefits of long-term cBTKi therapy.
  • It is reasonable to consider fixed-duration therapy as frontline treatment of TP53-LoF CLL in patients who express a strong preference for fixed-duration therapy and accept the uncertainty regarding retreatment efficacy, or in circumstances (eg. cardiovascular disease) where indefinite cBTKi therapy is undesirable.
• Multiple fixed-duration studies have shown that uMRD is a key endpoint in patients with TP53-LoF CLL. In this respect, clinical trials examining consolidation strategies in patients with detectable MRD, or in those with high-risk genomics, may be especially impactful in patients with TP53-LoF CLL.

This review provides an updated, clinically oriented framework for inherited microcytic anemias caused by defects in systemic iron homeostasis, cellular iron transport, mitochondrial iron utilization, and heme biosynthesis.

Key points:

• Microcytic anemia is among the most common hematological abnormalities in clinical practice and is usually attributable to iron deficiency, thalassemia traits, or anemia of inflammation.
• A small but clinically important subset of patients, however, has inherited disorders of iron metabolism or heme synthesis presenting with persistent, unexplained, familial, or iron‐refractory microcytosis.
• Early recognition enables accurate diagnosis, avoids inappropriate investigations and treatment, facilitates genetic counselling, and helps prevent irreversible organ damage, particularly in iron‐overload disorders.
• Persistent microcytic anemia (age-adjusted mean corpuscular volume [MCV]): exclude iron deficiency, thalassemia, inflammation, blood loss and, in children, lead exposure. See Figure 2 in original paper: A contemporary diagnostic approach to unexplained inherited microcytic anemia.
  • Assess pattern of iron indices (transferrin saturation [TSAT], ferritin, ceruloplasmin, hepcidin):
    • Very low TSAT (ferritin low or inappropriately normal): iron-refractory iron deficiency anemia (IRIDA; transmembrane serine protease 6 [TMPRSS6 mutation]) with low TSAT/hepcidin ratio; transferrin receptor 1 gene (TFRC) deficiency if immunodeficiency present.
    • High ferritin (TSAT low or normal): aceruloplasminemia (low/absent ceruloplasmin, neurological signs); ferroportin disease / type 4A (loss-of-function); heme oxygenase (HMOX1) deficiency (hyperinflammation, asplenia, hemolysis).
    • Increased TSAT (with or without hyperferritinemia): divalent metal transporter 1 (DMT1) deficiency; atransferrinemia (TSAT ≃100%); ferroportin disease/type 4B (gain-of-function); iron-loading sideroblastic anemias.
    • Separate route – normal iron indices: with suggestive syndrome features
      • Photosensitivity + raised erythrocyte protroporphyrin = erythropoietic porphyrias
      • Neurological signs = ATP-binding cassette subfamily B member 7 (ABCB7 [X-linked sideroblastic anemia] with ataxia)
      • Immunodeficiency + thrombocytopenia = TFRC
    • Two diagnostic pitfalls:
      • Age: Age-specific reference intervals are essential because: MCV, ferritin, and hemoglobin vary in infancy, when nutritional deficiency may both mimic and mask inherited disorders
      • Coexistence: inherited disease often coexists with thalassemia trait, inflammation, blood loss or nutritional deficiency. Disproportion, high red blood cell count or discordant hemoglobin analysis = coexistence.
    • See Table 3 in original paper for Summary of management strategies across inherited-microcytic anemias.

Key points:

• TP53 myeloid neoplasms are being increasingly encountered in clinical practice and have been recognised in 2022, as a unique entity in the setting of functional loss of the two copies of the gene.
• TP53 mutations are observed among the whole spectrum of myeloid neoplasms, from premalignant clonal haematopoiesis of indeterminate potential (CHIP) to acute myeloid leukaemia, and they vary in their frequency and allelic inactivation status.
  • TP53 mutations are most observed in therapy-related myeloid neoplasms (~30–40% of cases).
  • In patients with CHIP and clonal cytopenia of unknown significance, TP53 mutations are reported in 3–5% of the cases and more often among patients with cancer and individuals who later develop therapy-related myeloid neoplasms.
  • In myelodysplastic syndromes (MDS), TP53 has been reported in 5–10% of de novo MDS and increases up to 30–40% in therapy-related MDS.
  • Those mutations further increased to 70–80% in patients with complex karyotype, particularly individuals with chromosome 5 abnormalities.
  • TP53 mutations have also been observed frequently in patients with ring sideroblasts and more than 5% myeloblasts (>70%), particularly in presence of deletion 5q (91%).
  • These TP53 mutations are less frequent in myeloproliferative neoplasms or overlap myelodysplastic neoplasms or myeloproliferative neoplasms where their presence often indicates disease progression.
• The classification of myeloid neoplasm based on presence of biallelic (multi-hit) TP53 should precede morphological classification.
• The identification of biallelic (multi-hit) inactivation continues to evolve and is a matter of great debate balancing definitive biallelic identification via assays, pathology classifications, and clinical applicability.
• There is clear interplay between myeloblast percentage, TP53 allelic state, and cytogenetics as most TP53 cases encountered (~90%) are associated with poor outcomes driven by those variables and can be approached similarly.
• Only a small subset of individuals with monoallelic (single-hit) TP53 mutation status and no concomitant increased myeloblasts or complex cytogenetics have better outcomes and perhaps can be managed as non-TP53 cases.
• See Figure in original paper for Management of TP53 mutant myelodysplastic syndromes and acute myeloid leukemia:
  • Unfavorable TP53: Clinical trial.
    • Biallelic (multi-hit) or
    • Monoallelic (single-hit) and myeloblasts ≥5% or
    • Monoallelic (single-hit) and complex karyotype.

*If no clinical trial:

• Not allogeneic hematopoietic stem cell transplantation (HSCT) candidate: Hypomethylating agent (HMA; or observation for asymptomatic patients with adequate blood cell counts); in cases of biallelic TP53 with no increased blasts can manage as MDS with low blasts.
• Allogeneic HSCT candidate: HMA candidate = HMA alone or with venetoclax; post-allogeneic HSCT HMA maintenance
  • Favourable TP53:
    • Monoallelic (single-hit) plus myeloblasts <5% plus no complex karyotype:
  • MDS with low blasts: Lower-risk MDS management (erythropoiesis-stimulating agent or luspatercept for anaemia; HMA for pancytopenia).
  • Deletion 5q: Lenalidomide for anaemia.

In 2024, an international expert panel from the European Society for Blood and Marrow Transplantation (EBMT), the International Society for Cell and Gene Therapy (ISCT), and the Joint Accreditation Committee of ISCT and EBMT (JACIE) released the first best-practice recommendations on CAR T cells for autoimmune diseases. Using the same consensus methodology, these living recommendations were updated thereafter. The 2026 consensus reviews current evidence and expert practices on CAR T cells for rheumatic, neurological, haematological, other autoimmune diseases, and paediatric indications, providing updated, expert-based recommendations on patient selection, diagnostic investigation, clinical management, follow up, and immune monitoring for each disease group. Unmet needs and future research priorities are also highlighted.

Key points:

• See Table 1 in original paper for recommendations for CAR T-cell use in autoimmune rheumatic disease.
  • Systemic lupus erythematosus (SLE):
    • Age 16 years (y) or childhood SLE might be eligible. Anti-double-stranded DNA antibodies, ani-histone antibodies, anti-Smith antibodies, or anti-nucleosome antibody positive.
    • Lymphopenia might inhibit feasibility of CAR T-cell production; contraindication for CAR T-cell therapy: lymphopenia: lymphocyte cell count <100×10⁹/L for adults and CD³⁺ cells <200/uL in small children (15-20kg bodyweight).
  • Systemic sclerosis
    • Age: 16 y or juvenile systemic sclerosis <16 y might be eligible.
    • Disease duration ≤5 y with modified Rodnan skin score (mRSS)>20 and erythrocyte sedimentation rate (ESR) >25 mm or haemoglobin <11g/dL, or mRSS >15 and one or more major organ involvement.
  • Rheumatoid arthritis
    • Age 16 y or in specific cases patients with <16 y might be eligible.
    • Seropositivity for rheumatoid factor or anti-cyclic citrullinated peptide antibodies and presence of B cells signs synovial biopsies is recommended for CAR therapy targeting B cells.
    • Signs of active disease with a DAS28-CPR score >3.2 plus active synovitis shown clinically and via imaging signs of synovitis on Color Power ultrasound, magnetic resonance imaging, or PET-CT.
  • Autoimmune inflammatory myopathies:
    • Age 18 y or juvenile dermatomyositis in those <18 y might be eligible.
    • Presence of myositis-specific or myositis-associated antibodies.
    • Active disease: Myositis on MRI or biopsy, with or without interstial lung disease (ILD)
    • Consider ruling out concomitant cancer as a trigger of autoimmune inflammatory myopathies.
    • Challenge of rapidly progressive ILD (especially in MDA5 and autoimmune inflammatory myopathies)
  • Primary Sjögren´s disease:
    • Age 18 y
    • Persistent high activity defined by EULAR ESSDAI score >5
    • Presence of extra-glandular domains such as vasculitis, haematological, lung, kidney or neuronal involvement
    • Serological activity defined as hypocomplementemia (C3 or C4), or elevated inflammatory markers (ESR, C-reactive protein, immunoglobulin G, or rheumatoid factor concentration)
  • See Table 2 in original paper for Recommendations for CAR T-cell use in neurological autoimmune diseases: myasthenia gravis; neuromyelitis optica spectrum disorder; multiple sclerosis; chronic inflammatory demyelinating polyneuropathy; stiff person syndrome; autoimmune encephalitis.
  • See Table 3 in original paper for Recommendations on washout period before leukapheresis and before lymphodepleting conditioning for autoimmune diseases, and Table 4 for Recommendations on supportive care and management of short-term and medium-term complications and long-term follow-up in patients with automimmune disease after CAR T-cell therapy.