Francesco Onida

Academic CAR T-cell manufacturing is rapidly expanding across Europe, but cryopreservation practices remain heterogeneous, raising concerns about product comparability. While cryopreservation is essential for later infusion, storage of surplus cells, or treatment postponement, no specific harmonized guidelines exist for CAR T-cell products. An EBMT survey (52 academic centers) revealed wide variability in freezing timing, cryomedium composition, device choice, storage temperatures, and post-thaw quality control. To address these gaps, EBMT organized a workshop using its harmonisation methodology. A panel of experts reviewed survey data, literature, and professional experience to draft consensus recommendations. Key recommendations include: performing cryopreservation as soon as possible after manufacturing (preferably ≤48 h), initiating freezing within 30 min of cryomedium addition, and using controlled-rate freezing to at least -80 °C, with long-term storage below -120 °C whenever feasible. Retention samples, post-thaw viability, identity testing, and validated transportation procedures are considered mandatory. Liquid nitrogen and Peltier-based controlled-rate freezing systems were regarded as technically equivalent, while -80 °C passive freezing has been used successfully and may serve as a back-up method, local confirmation of suitability in a formal method validation provided. These consensus-based recommendations seek to establish technical recommendations for CAR-T cryopreservation for groups currently establishing academic manufacturing of CAR-T products.

Advanced mycosis fungoides (MF) and Sézary syndrome (SS) are the most aggressive forms of cutaneous T‐cell lymphoma and remain associated with a poor prognosis and heterogeneous therapeutic approaches. Recent advances, including targeted therapies and improved transplant strategies, have substantially expanded treatment options, highlighting the need for updated international guidance integrating dermatologic, hematologic, and transplant perspectives. An international multidisciplinary panel convened by the European Hematology Association (EHA), the EORTC Cutaneous Lymphoma Tumours Group (EORTC‐CLTG), the International Society for Cutaneous Lymphoma (ISCL), and the EBMT Lymphoma Working Party reviewed the available evidence and developed consensus recommendations for the management of advanced MF and SS. Thirty international experts participated in the process. Recommendations address diagnostic work‐up, systemic therapies, treatment sequencing, combination strategies, and indications for allogeneic hematopoietic cell transplantation (allo‐HCT). The consensus supports a stage‐adapted and compartment‐oriented therapeutic approach. Immunomodulatory strategies remain central in advanced CTCL: extracorporeal photopheresis is commonly used as first‐line therapy in SS and in patients with significant blood involvement, while interferon‐α and retinoids are widely used in MF, often in combination with skin‐directed therapies. Mogamulizumab and brentuximab vedotin represent key options after prior systemic therapy, with differential activity across skin, blood, and nodal compartments. Combination approaches integrating systemic and skin‐directed treatments may improve response depth and durability. Practical treatment algorithms for advanced MF and SS are proposed to support therapeutic sequencing and multidisciplinary management. Allo‐HCT remains the only potentially curative treatment and should be considered early in selected patients with high‐risk disease features.

Lower-risk myelodysplastic neoplasms (MDS) with isolated del(5q) are particularly sensitive to lenalidomide, although most patients eventually lose their response and may experience disease progression. Hypomethylating agents (HMAs) are commonly used as salvage therapy after lenalidomide failure, but treatment options following subsequent HMA failure remain limited. Evidence regarding lenalidomide rechallenge after intervening HMA therapy is scarce. We report the long-term clinical course of a woman with MDS with del(5q) and multilineage dysplasia, diagnosed after prior cytotoxic therapy for colon adenocarcinoma. Lenalidomide was started for transfusion-dependent anemia (IPSS Intermediate-1; IPSS-R Intermediate) and resulted in transfusion independence and a complete cytogenetic response after four cycles. Hematologic remission was maintained for more than three years, but lenalidomide was discontinued after 41 cycles because of progressive cytopenias and cytogenetic evolution. The patient subsequently received 36 cycles of azacitidine, achieving transient hematologic improvement before disease progression with an increase in bone marrow blasts. Because the del(5q) clone persisted and no established salvage option was available, lenalidomide was reintroduced at the original starting dose and produced a rapid erythroid response together with a reduction in bone marrow blasts, without a cytogenetic response. Hematologic benefit was sustained for approximately seven years using an individualized treatment schedule. Molecular analyses performed late during the second lenalidomide course identified two pathogenic TP53 variants, at low variant allele frequency, together with a SETBP1 mutation, corresponding to a Molecular International Prognostic Scoring System (IPSS-M) High-risk category. The response was eventually lost, and transformation to acute myeloid leukemia occurred after lenalidomide discontinuation. This case illustrates that lenalidomide rechallenge may provide prolonged clinical benefit in selected patients with persistent del(5q) after progression during HMA therapy. Further studies are required to determine the frequency and biological basis of renewed lenalidomide sensitivity in this setting.

Myelodysplastic neoplasms (MDS) relapsing after allogeneic stem cell transplantation (alloSCT) have a poor prognosis. A second alloSCT (alloSCT2) can offer durable remission, however, earlier studies reported <20% long-term survival. Here we summarize contemporary outcome and risk factors after alloSCT2 (2012-2023), particularly focusing on donor change (DoC). We included 313 adults undergoing alloSCT2 for MDS relapse. Donors for alloSCT2 were matched- related/unrelated/haploidentical in 19%/62%/19%, with DoC reported in 71%. Two-year overall-/progression-free survival (OS/PFS), cumulative relapse incidence (RI) and non-relapse mortality (NRM) from alloSCT2 were 45%/33%/37%/30%. Outcome improved over time (2y-OS/PFS: 51%/39% in years 2018-2023). In multivariable analyses, DoC was associated with lower risk of relapse (HR=0.56, 95%-CI: 0.36-0.89), a finding never observed after alloSCT2 for acute leukemia. Additionally, adverse cytogenetics were correlated with relapse risk (HR=1.93, 95%-CI: 1.18-3.17). Risk of NRM decreased in more recent years (HR=0.88, per year later) and in patients with Karnofsky performance score (KPS) ≥90 at alloSCT2 (HR=0.59). Concerning survival, remission after alloSCT1 ≥12 months (HR=0.62/0.67) and KPS ≥90 (HR=0.68/0.69) were associated with better OS/PFS. In summary, we report improved outcomes of alloSCT2 in MDS in more recent years and demonstrate superior disease control by DoC, although a trend toward increased NRM precluded a significant survival benefit.

Myelodysplastic syndromes (MDS) in young adults are uncommon and underrepresented in transplant cohorts. We evaluated 697 patients aged 18–40 years who underwent first allogeneic hematopoietic cell transplantation (allo-HCT) reported to the EBMT between 2016 and 2021. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), cumulative incidence of relapse (CIR), non-relapse mortality (NRM), and graft-versus-host disease (GVHD). With a median follow-up of 2.8 years, 3-year OS and PFS were 69% (95% CI, 65–73) and 62% (58–66), respectively. At 3 years, CIR and NRM were 20% (16–23) and 18% (15–21). Grade II–IV acute GVHD occurred in 28% (25–32) by day +100, while chronic GVHD and extensive chronic GVHD occurred in 38% (34–42) and 18% (14–21) at 3 years. In multivariable analysis, very-poor cytogenetic risk was associated with inferior OS (HR 2.81, 95% CI 1.77–4.45). Haploidentical donors and reduced-intensity conditioning were also associated with inferior survival. Patients younger than 30 years had superior PFS, whereas outcomes with matched sibling and matched unrelated donors were comparable. These findings support the feasibility of allo-HCT in young adults with MDS and may help inform risk-adapted transplant approaches.

The history of chronic myeloid leukemia (CML) is one of the clearest demonstrations of how biological insight, therapeutic innovation, and disciplined clinical observation can transform the natural history of a malignant disease

Background: Conventional response endpoints do not adequately capture durable clinical benefit in mycosis fungoides (MF) and Sézary syndrome (SS). Overall response lasting ≥ 4 months (ORR4) has been proposed as a clinically meaningful endpoint in clinical trials, but its prognostic value in real-world mogamulizumab-treated patients remains unknown. Objectives: To evaluate the effectiveness and safety of mogamulizumab in routine clinical practice and investigate the prognostic relevance of ORR4 in patients with MF/SS. Methods: FIL-MOGA was a nationwide, multicenter, retrospective study including 98 patients with MF/SS treated with mogamulizumab between January 2021 and December 2023 across 18 centers of the Italian Lymphoma Foundation (FIL). The primary endpoint was ORR4. Survival outcomes were assessed using Kaplan–Meier estimates, 4-month landmark analyses, and Cox proportional hazards models treating ORR4 as a time-varying covariate (TVC). Results: After a median follow-up of 35 months, ORR4 was achieved in 44 of 93 (47.3%) evaluable patients. Best overall response increased from 29.4% at 1 month to 38.0% at 4 months and 58.1% during follow-up. ORR4 varied significantly according to baseline disease stage (p=0.022), ranging from 10.0% in stage IIB to 70.8% in stage IVA1 disease. In landmark analyses, ORR4 was associated with improved 24-month OS (76% vs 60%; p=0.006), PFS (58% vs 35%; p=0.001), and TTNT (76% vs 47%; p=0.002). These findings were confirmed in time-dependent analyses (OS HR 2.53, p=0.008; PFS HR 2.70, p=0.001; TTNT HR 3.04, p=0.003). In multivariable models, lack of ORR4 remained independently associated with worse OS (HR 3.18, p=0.002), PFS (HR 2.67, p=0.002), and earlier initiation of subsequent systemic therapy (HR 4.27, p=0.001). Skin adverse events were associated with higher ORR4 rates (70% vs 40%, p=0.017) but not independently with survival outcomes. Thirteen patients (13%) underwent allogeneic hematopoietic stem cell transplantation after mogamulizumab. Conclusions: This large real-world study confirms the effectiveness of mogamulizumab and identifies ORR4 as a robust on-treatment prognostic marker independently associated with OS, PFS and TTNT. These findings support the incorporation of ORR4 as a clinically meaningful endpoint in real-world studies and routine management of MF/SS.