Disease burden at the time of BCMA-directed chimeric antigen receptor (CAR) T-cell infusion is a key determinant of outcome in relapsed or refractory multiple myeloma (RRMM). Bridging therapy is frequently administered between leukapheresis and infusion to prevent disease progression, yet its clinical impact remains unclear. We conducted a multicenter real-world cohort study of 399 patients with RRMM treated with BCMA-directed CAR T-cell therapy, including 348 (87%) who received bridging therapy. Bridging therapy recipients had more advanced and biologically adverse disease, including higher rates of high-risk cytogenetics and penta-class refractoriness. Bridging efficacy varied substantially by regimen (P.

BACKGROUND:Autologous haematopoietic stem cell transplantation (aHSCT) represents a treatment option for highly aggressive multiple sclerosis (MS). Here, we report outcome analyses from the two largest German centres performing aHSCT in MS. METHODS:In this retrospective analysis, people with (pw) MS who underwent aHSCT between 2007 and 2025 were included. Outcomes comprise no evidence of disease activity (NEDA-3), 3-month confirmed disability changes on the Expanded Disability Status Scale and transplantation-related mortality (TRM). Predictors of treatment response were evaluated according to the European Committee for Treatment and Research in Multiple Sclerosis and the European Society of Blood and Marrow Transplantation consensus criteria. RESULTS:A total of 109 pwMS were included: 55 (50.5%) with relapsing-remitting MS (RRMS), 23 (21.1%) with secondary progressive MS (SPMS) and 31 (28.4%) with primary progressive MS (PPMS). Median follow-up after aHSCT was 20.1 months. Overall, 82.8% (SE 4.9%) of pwMS maintained NEDA-3. PwRRMS had significantly higher NEDA-3 rates (Kaplan-Meier (KM) estimate 91%, SE 5%) than those with SPMS (KM 80.1%, SE 10.5%, p=0.018) or PPMS (KM 70.6%, SE 11.4%, p=0.035). Patients meeting core consensus criteria achieved NEDA-3 more often (KM 94.4%, SE 5.4%) than those meeting the extended criteria (KM 84.4%, SE 8.5%, p=0.199) or those outside the criteria (KM 73.7%, SE 8.8%, p=0.004). In progressive MS, a disease duration of <5 years indicated a potential prediction of NEDA-3 stability. TRM was 0.9% (n=1/109). CONCLUSIONS:In this heterogeneous cohort, comprising a substantial proportion of people with progressive MS, aHSCT provided sustained NEDA-3 stability and a marked reduction in inflammatory disease activity, particularly in RRMS, with a potential benefit in progressive MS.

Abstract Myelofibrosis in patients with myeloproliferative neoplasms (MPNs) is traditionally characterized by bone marrow fibrosis and osteosclerosis, with de novo bone formation commonly attributed to impaired osteoclast-mediated resorption. Here, we challenge this paradigm by demonstrating that a solitary clonal driver mutation simultaneously induces pathological bone formation and resorption, with osteosclerosis acting to conceal localized and active bone destruction rather than inhibiting it. Through population analysis; clinical imaging; patient-derived multi-tissue sequencing; murine models and organ-on-a-chip systems, we demonstrate that spatial and ontogeny-dependent remodeling in mesoderm- and neural crest–derived bones is mechanistically interconnected via a previously unidentified osteochondral stromal injury program. Neural crest–derived stromal cells suppress osteogenic programs and undergo injury-induced lineage plasticity with ectopic chondrogenesis, mirroring pathological remodeling in mesoderm-derived growth plate regions. This shared injury response promotes osteoclastogenesis and is mediated by a conserved Thrombospondin 1+ (THBS1+) stromal population that links fibrotic remodeling to bone loss. Combined pharmacological inhibition of THBS1 and JAK signaling reduces myeloproliferation, halts fibrosis progression, and restores two developmentally distinct bones, establishing THBS1 as a unifying therapeutic target in myelofibrosis.

Density plots for each covariate used for propensity score matching before and after matching.

Haematopoietic cell transplantation (HCT) with HLA-mismatched unrelated donors (MMUD) offers access to curative therapy for patients lacking well-matched donors. Accumulating evidence suggests that functional matching among allele-mismatched pairs can significantly influence patient outcomes. Therefore, real-world data on mismatch frequencies in MMUD-HCT could provide fundamental information for the assessment of patient risks and donor selection strategies. Here, we analysed HLA matching in 28,376 first unrelated transplants reported to the EBMT Registry with available 6-locus high-resolution typing. Mismatches at each locus were quantified and characterised at the allelic, antigenic and functional (antigen-recognition domain, peptide-binding motif) levels. 25% of the transplants were performed across one (9/10; n = 6053) or more (< 9/10; n = 1013) high-resolution mismatches at the five main HLA loci, a proportion that was markedly higher (43.9%) among transplants performed with post-transplantation cyclophosphamide (PTCy). Median time from diagnosis to transplant was longer for MMUD compared to 10/10 transplants, but this difference decreased over time (14.9 vs. 11.3 months pre-2011, p = 0.003; 8.1 vs. 7.4 months 2021-2022, p = 0.016). Across transplant eras, single class I mismatches were three times more common than class II mismatches. Conversely, matching for HLA-DPB1 increased from 15% pre-2011 to 31% in 2021-2022. The landscapes of allelic mismatches differed markedly between HLA loci. For class II, skewed distributions dominated by frequent combinations result in significantly higher frequencies of functional matching compared to class I in both PTCy and non-PTCy pairs. Our study constitutes the first large-scale characterisation of real-world HLA mismatch frequencies in contemporary unrelated HCT, bearing implications for future clinical outcome studies.

Philadelphia-negative myeloproliferative neoplasms (MPNs) can progress to blast phase (MPN-BP), a biologically distinct and highly lethal entity with a median survival typically under six months. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the only potentially curative approach, yet relapse and non-relapse mortality limit durable benefit. We retrospectively analyzed post-transplant outcomes in 51 consecutive adults undergoing 53 allo-HSCTs for MPN-BP. Median age was 62 years; most cases evolved from myelofibrosis, and JAK2 was the predominant driver mutation. Neutrophil engraftment occurred in all but two patients (median 12 days). At 1-year, cumulative incidences were 35.8% for grade II-IV acute GVHD, 7.5% for moderate-severe chronic GVHD, 44.3% for relapse, and 25.8% for non-relapse mortality. One-year overall survival (OS) and disease-free survival were 43.4% and 37.7%, respectively; relapse was the leading cause of death. In multivariable analysis, TP53 mutations and higher peripheral blast burden adversely affected OS, while CALR mutations appeared to be associated with improved OS, peripheral blasts also independently predicted relapse. These data underscore the cure rate of approximately one-third of MPN-BP and highlight peripheral blasts and TP53 as actionable risk markers for transplant strategies.

Allogeneic hematopoietic cell transplantation (allo-HCT) can cure acute leukemia, but relapse and non-relapse mortality restrict its success. Existing models focus on single prognostic areas and are not designed to predict leukemia-free survival (LFS), the outcome that best reflects allo-HCT's curative intent. In this large retrospective cohort of allografted AL patients (N = 24,317), we combined key pre-transplant patient, disease, and treatment factors into a practical holistic H-score to predict post-allo-HCT LFS. Component weights were derived from Cox-regression hazard ratios in a training cohort (N = 19,029). The model was validated in a geographically split testing cohort (N = 4760), with outcomes assessed using Kaplan-Meier analysis and multivariate Cox models. In the overall cohort (N = 24,317), 2-year overall survival and LFS were 64% and 56%, respectively. The H-score stratified patients into four risk groups, with 2-year LFS ranging from 66.2% in the low-risk group to 32.0% in the very high-risk group. The H-score was the strongest independent predictor of LFS (p < 0.0001), outperforming individual indices and offering more refined risk stratification. The H-score was also an independent predictor of overall survival, relapse, and non-relapse mortality. While individual prediction is limited, the H-score aids patient counseling and provides a useful baseline for comparing new transplant treatments.

Multivariate cox regression analysis of different treatments for OS adjusting for baseline characteristics (ZUMA-2: n = 64, alloHCT: n = 272)

The recently published ONKOPEDIA guideline on myelofibrosis, issued under the auspices of the German Society of Hematology and Oncology (DGHO), provides an updated, evidence-based framework for the diagnosis and management of this rare, chronic myeloproliferative neoplasm. Developed by a panel of experts (including Germany, Austria and Switzerland) nominated by the DGHO, the guideline reflects a structured and consensus-oriented process in which internationally recognized specialists in hematology critically reviewed the available evidence, revised the written draft, and engaged in multiple rounds of discussion to ensure consistency, clinical relevance, and scientific rigor. This update builds upon the foundation of the previously available ONKOPEDIA guideline (accessible at www.onkopedia.com), but extends and refines the recommendations in light of several important recent developments.

Overall survival (OS) and progression-free survival (PFS) in the unmatched alloHCT cohort based on response status before alloHCT.

Abstract Background Ciltacabtagene autoleucel (cilta-cel) is a BCMA-directed chimeric antigen receptor (CAR) T-cell therapy approved for relapsed or refractory multiple myeloma (RRMM). Following the CARTITUDE-1 results in heavily pretreated patients, the randomized phase 3 CARTITUDE-4 trial demonstrated superior progression-free survival (PFS) and overall survival for cilta-cel compared with standard of care in lenalidomide-refractory patients after one to three prior lines, leading to label expansion in 2024. However, real-world data characterizing outcomes in this earlier-line indication are lacking. Methods We analyzed all patients with RRMM receiving standard-of-care cilta-cel between 2022 and 2025 from the German Registry for Stem Cell Transplantation and Cellular Therapy. Patients were stratified by prior lines of therapy into an Early group (1–3 prior lines) and a Late group (> 3 prior lines). The primary endpoint was PFS. Secondary endpoints included overall response rate, response conversion, and safety outcomes including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome (ICANS), non-ICANS neurotoxicity, and non-relapse mortality. Prognostic associations were assessed using restricted cubic spline Cox regression and univariable Cox models. Results Of 606 patients, 177 (30%) were treated in the Early and 429 (70%) in the Late setting. The overall response rate was 91% and 88%, with complete response in 63% and 54%, respectively. The 12-month PFS was 79% for Early and 70% for Late cilta-cel. Depth of response was the strongest predictor of PFS in both cohorts, with patients maintaining complete response showing 100% PFS at 12 months irrespective of treatment line. Extramedullary disease was adversely prognostic in both groups, whereas high-risk cytogenetics were not associated with inferior PFS in the Early group. Non-ICANS neurotoxicity occurred less frequently in the Early group (3% versus 8%), while non-relapse mortality was comparable (6% versus 7%). Conclusions This analysis demonstrates that cilta-cel in earlier lines of therapy achieves deep responses and high PFS consistent with the CARTITUDE-4 trial. These results provide real-world evidence for the deployment of cilta-cel as early as first relapse and may be a benchmark outside prospective trials.

The selection of the best available donor is crucial for patients' outcome after allogeneic stem cell transplantation (allo-SCT). In the absence of fully Human leucocyte antigen (HLA) -matched donors, mismatched unrelated donor (9/10-MUD) or haploidentical donor (haplo) can be considered. No consensus has been reached on the best alternative and large real-world data are warranted to support decisional processes. We compared the outcome of 1413 patients with myeloid malignancies undergoing allo-SCT from 9/10-MUD with anti-thymocyte-globulin (ATG) (n = 1134) or haplo with post-transplant cyclophosphamide (PT-Cy, n = 279) between 2009 and 2020 in 48 German centres. Donor type with related graft versus host disease (GvHD) prophylaxis showed in multivariable analysis no significant impact on acute GvHD development, both grade II-IV (HR 0.90, 95% CI 0.69-1.19, p = 0.469) and severe (HR 1.22, 95% CI 0.82-1.81, p = 0.319), nor on moderate to severe chronic GvHD (HR 0.78, 95% CI 0.59-1.03, p = 0.077). Moreover, no influence from donor type was observed on GVHD-relapse-free survival (HR 1.12, 95% CI 0.92-1.36, p = 0.227), progression-free survival (HR 1.2, 95% CI 0.95-1.51, p = 0.121), non-relapse mortality (HR 1.1, 95% CI 0.81-1.51, p = 0.542) and overall survival (HR 1.16, 95% CI 0.91-1.48, p = 0.235). Our real-world data demonstrate that haplo allo-SCT with PT-Cy is not inferior to 9/10-MUD allo-SCT with ATG.

Comparison of ZUMA-2 and alloHCT population for Overall survival (OS), Progression-free survival (PFS), Non-relapse mortality (NRM) and incidence of relapse (IR) in unmatched cohorts.

We compared long-term outcomes in 78 patients with steroid-refractory acute graft-versus-host disease (SR-aGvHD) treated at the University Medical Center Hamburg, Germany, between December 2015 and August 2022 who received either ruxolitinib alone (Ruxo, N=29) or Ruxo plus extracorporeal photopheresis (Ruxo-ECP, N=49). Patients were well balanced between both arms except for SR-aGvHD grade IV which was higher in the Ruxo-ECP group (45% vs. 14%, P<0.001). In both cohorts, steroids were tapered rapidly, and median steroid treatment was 39 days in Ruxo and 35 days in Ruxo-ECP. The overall response rate including complete remissions (CR) of aGvHD at day 28 was 90% and 31% for Ruxo versus 86% and 0% (P<0.001, respectively) for Ruxo-ECP. At six months, partial remission (PR) and CR status of evaluable patients was 11% and 50% in Ruxo-ECP versus 10% and 40% after Ruxo alone, respectively (P=0.018). At 12 months, PR and CR status was 6% and 17% in the Ruxo group, but 82% and 64% (P<0.001) in the Ruxo-ECP cohort, and the cumulative incidence of chronic GvHD was significantly higher after Ruxo versus Ruxo-ECP at 49% (95% CI: 33-69%) versus 24% (95% CI: 15-38%) (P=0.01). Reconstitution of B cells occurred significantly earlier at one and three months in the Ruxo arm. No difference in 1-year non-relapse mortality, relapse, and 2-year overall survival was observed. Despite the limitations of this retrospective single- center study, the data suggest a better long-term control of aGvHD and less chronic GvHD at one year combining ruxolitinib with ECP compared to ruxolitinib alone in SR-aGvHD.

Acute and chronic Graft-versus-host-disease in the total alloHCT cohort based on full case analysis.

We explored single or consecutive chimeric antigen receptor (CAR) T and bispecific antibody (BsAb) treatment modalities as correlates of clinical outcomes, by complementary bias-correction analysis of a retrospective multicenter study of 640 patients with relapsed/refractory multiple myeloma. The sequential use of both modalities seemed to yield the most favorable survival trajectories. Initiating treatment with CAR T [idecabtagene vicleucel (ide-cel), ciltacabtagene autoleucel (cilta-cel), cesnicabtagene autoleucel (cesni-cel)] was associated with longer remission. However, mortality from early progression was similar regardless of initial modality, suggesting that resistance may negate initial efficacy difference. On the product level, the benefit of CAR T seemed to be driven by cilta-cel and cesni-cel, whereas BsAbs showed at least comparable outcomes with ide-cel. These exploratory findings highlight the critical importance of treatment sequencing in optimizing long-term outcomes and underscore the need for equitable and timely access to both modalities across healthcare systems. SIGNIFICANCE:In this real-world cohort, initiating treatment with CAR T was associated with longer remission, and sequential immunotherapy incorporating both modalities yielded the most favorable outcomes. However, early treatment failure negated initial efficacy differences between modalities. These findings provide a rationale for prospective sequencing trials and equitable access to both treatments. See related commentary by Banerjee, p. 650.