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Donor-specific anti-HLA antibodies (DSA) are an important cause of engraftment failure and may negatively impact survival outcomes of patients receiving allogeneic hematopoietic stem cell transplantation (HSCT) using an HLA-mismatched allograft. The incidence of DSA varies across studies, depending on individual factors, detection or identification methods and thresholds considered clinically relevant. Although DSA testing by multiplex bead arrays remains semiquantitative, it has been widely adopted as a standard test in most transplant centers. Additional testing to determine risk of allograft rejection may include assays with HLA antigens in natural conformation, such as flow cytometric crossmatch, and/or antibody binding assays, such as C1q testing. Patients with low level of DSA (<2,000 mean fluorescence intensity; MFI) may not require treatment, while others with very high level of DSA (>20,000 MFI) may be at very high-risk for engraftment failure despite current therapies. By contrast, in patients with moderate or high level of DSA, desensitization therapy can successfully mitigate DSA levels and improve donor cell engraftment rate, with comparable outcomes to patients without DSA. Treatment is largely empirical and multimodal, involving the removal, neutralization, and blocking of antibodies, as well as inhibition of antibody production to prevent activation of the complement cascade. Desensitization protocols are based on accumulated multicenter experience, while prospective multicenter studies remain lacking. Most patients require a full intensity protocol that includes plasma exchange, while protocols relying only on rituximab and intravenous immunoglobulin may be sufficient for patients with lower DSA levels and negative C1q and/or flow cytometric crossmatch. Monitoring DSA levels before and after HSCT could guide preemptive treatment when high levels persist after stem cell infusion. This paper aims to standardize current evidence-based practice and formulate future directions to improve upon current knowledge and advance treatment for this relatively rare, but potentially serious complication in allogeneic HSCT recipients., Competing Interests: Declaration of competing interest PK - none for this work; other COI - consulting for CareDx and reseach funding from Eurofins Viracor PV - none declared JZ - none declared SS - none declared BS - none declared RMS - none declared AV - none declared JM - none for this work; other COI - honoraria from Kite, AlloVir, Bristol Myers Squibb, Novartis, CRISPR, Nektar Therapeutics, Caribou Bio, Sana Technologies, Legend Biotech and Cargo Therapeutics. BRD - none declared SRM – none declared AED - none for this work; participated in advisory boards, and/or had a consultancy with and received honoraria from Celgene/BMS, Agios, Regeneron, Sobi, Novartis, Astellas, Gilead. AED served on clinical trial steering committees or DSMB for Novartis, Abbvie, Kura, Geron and Celgene/BMS. NB – none for this work; consulting, advisory role or research funding with Magenta Therapeutics, Medexus Pharmaceuticals, CTI BioPharma, CareDx Pharma, Orca Bio, Allovir and CRISPR Therapeutics. AB – none declared SF – none declared LC – none declared JM – none declared AR - none declared RB - none for this work; travel & accommodation: Pfizer, Jazz Pharmaceuticals, Gilead Sciences, Sanofi. Research Funding: Jazz Pharmaceuticals. Speaker: Pfizer, Gilead Sciences. TT – none declared XH - none declared CB – none declared FA – none declared KC – none declared PAC – none for this work; consulting or advisory roles and/or research funding with Incyte, AbbVie and Sanofi MH - none for this work; research support/funding from ADC Therapeutics; Spectrum, Pharmaceuticals; Astellas Pharma, consultancy for ADC Therapeutics, Omeros, BMS, Kite, Abbvie, Genmab, Allovir, CRISPR, Caribou, Autolus, Forte Biosciences, and speaker's bureau for ADC Therapeutics, AstraZeneca, Kite, Beigene MA – none for this work; director clinical services, Be The Match/National Marro Donor Program (NMDP), Minneapolis, MN MFV – none declared AG – none declared SOC – none for this work; reports participation is advisory board for Hansa Therapeutics, CardDx, Spetrum/Achrotech, Kiadis Pharma, Magenta, Allogene, Cellularity, MolMed, Pharmacyclics and received research funds from Miltenyi and Kiadis Pharma., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: Chronic graft-versus-host disease (cGVHD) is a cause of late morbidity and nonrelapse mortality (NRM) after allogenic hematopoietic stem cell transplantation (allo-HSCT). Although studies evaluating haploidentical allo-HSCT (haplo-HSCT) using posttransplant cyclophosphamide (PTCy) demonstrate lower cGVHD rates, comprehensive data describing the clinical profile, risk factors, or outcomes of cGVHD within this platform are scarce., Methods: We conducted a retrospective multicenter analysis of 389 consecutive patients who underwent haplo-HSCT PTCy in 7 transplant centers of the Spanish Group Grupo Español de Trasplante Hematopoyético y Terapia Celular (GETH-TC) between 2008 and 2020 describing incidence, clinical profile, risk factors, and cGVHD outcomes., Results: Ninety-five patients of 389 developed cGVHD. Our data revealed that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis and that the strongest predictor for cGVHD was previous acute GVHD ( P  = 0.031). Also, recipient age ≥60 y ( P  = 0.044) was protective against cGVHD. Moreover, patients with moderate cGVHD had longer event-free survival at 3 y than other patients ( P  = 0.016) and a lower relapse rate at 3 y ( P  = 0.036)., Conclusions: Our results support the fact that the incidence and severity of cGVHD are lower than those reported for HLA-identical transplantation with conventional prophylaxis. In this series, patients who develop moderate cGVHD after haplo-HSCT PTCy had a higher overall survival and event-free survival, and lower relapse, suggesting higher graft-versus-leukemia effect. Although this is the largest series focused on characterizing cGVHD in haplo-HSCT PTCy, further prospective studies are needed to confirm the findings., Competing Interests: The authors declare no funding or conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Invasive fungal infections (IFI) pose a significant complication after hematopoietic stem cell transplantation (HSCT). Isavuconazole (ISV) is a new generation azole with a favourable adverse effect and interaction profile approved for the treatment of invasive aspergillosis and mucormycosis. We analyzed the indications, effectiveness, adverse event profile and drug interaction management of ISV in the real-world setting in adults who received allogeneic-HSCT (allo-HSCT) within the Spanish Group of HSCT and Cell Therapy (GETH-TC). We conducted a multicenter retrospective study of all consecutive adult allo-HSCT recipients (≥18 years) who received ISV either for IFI treatment or prophylaxis, from December 2017 to August 2021, in 20 centers within the Spanish Group of Hematopoietic Stem Cell Transplantation and Cell Therapy (GETH-TC). A total of 166 adult allografted patients who received ISV from 2017 to 2021 were included. Median age was 48 years with 43% females. In 81 (49%) patients, ISV was used for treatment of IFI, and in 85 (51%) for prophylaxis. Median duration of ISV administration for IFI treatment was 57 days (range 31-126) and 86 days (range 33-196) for prophylaxis. Most frequent indication for treatment was invasive aspergillosis (78%), followed by mucormycosis (6%). Therapeutic success (45%) was the most frequent reason for ISV withdrawal. In the prophylaxis group, the resolution of IFI risk factors was the most frequent reason for withdrawal (62%). Six (7%) breakthrough IFI were reported. The majority of patients (80%) presented pharmacologic interactions. Twenty-one patients (13%) reported adverse events related to ISV, mainly liver biochemistry abnormalities, which led to ISV withdrawal in 7 patients (4%). ISV was effective and well tolerated for IFI treatment and prophylaxis, with a manageable interaction profile., (Copyright © 2024 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Background: The incidence, risk factors, and outcomes of venous thromboembolism (VTE) in patients with chronic lymphocytic leukemia (CLL) and monoclonal B-cell lymphocytosis (MBL) are not well described., Objectives: We aimed to determine the clinical characteristics, risk factors, and outcomes of incident VTE in patients with newly diagnosed MBL/CLL and compare the incidence to the age- and sex-matched general population., Methods: Using the Mayo Clinic CLL Database, we identified 946 patients with newly diagnosed MBL/CLL between 1998 and 2021. Incidence of VTE was identified by querying the electronic health record for VTE-specific International Classification of Diseases-9 and -10 codes and reviewing results of radiographic studies., Results: Eighty patients developed VTE. The incidence of VTE in patients with newly diagnosed MBL/CLL was ∼1% per year. In multivariable analyses, prior history of VTE (hazard ratio [HR]: 5.33; 95% CI: 1.93-14.68, P = .001) and high/very high-risk CLL-International Prognostic Index score (HR: 2.63; 95% CI: 1.31-5.26; P = .006) were associated with an increased risk of VTE; receipt of CLL treatment or occurrence of nonhematologic malignancy was not. Development of VTE was associated with shorter overall survival (HR: 1.82, 95% CI: 1.30-2.55) after adjusting for age, sex, prior history of VTE, and Rai stage. The age- and sex-adjusted VTE incidence rate for patients with MBL/CLL and no prior history of VTE (n = 904) was 1254 per 100 000 person-years compared with 204 per 100 000 person-years in the general population, reflecting a 5.9-fold increase., Conclusion: Our study demonstrates a 6-fold increased risk of VTE in patients with MBL/CLL compared with the age- and sex-matched general population., Competing Interests: Declaration of competing interests P.J.H.: None. T.H.: Consulting: BeiGene. Research funding to the institution from BeiGene. S.A.P.: Research funding has been provided to the institution from Janssen, AstraZeneca, Merck, and Genentech for clinical studies in which Sameer A. Parikh is a principal investigator. Honoraria has been provided to the institution from Pharmacyclics, Merck, AstraZeneca, Janssen, BeiGene, Genentech, Amgen, MingSight Pharmaceuticals, TG Therapeutics, Novalgen Limited, Kite Pharma, and AbbVie for Sameer A. Parikh’s participation in consulting activities/advisory board meetings. E.M.: Consultancy fee from Protego (fee paid to institution). A.B.K.: Consulting: AstraZeneca, Pharmacyclics, Bristol Meyer Squib, AbbVie (money to institution). NEK Advisory Board for AbbVie, AstraZeneca, Beigene, Behring, Boehringer Ingelheim Pharmaceuticals, Inc, Dava Oncology, Janssen, Juno Therapeutics, Pharmacyclics. Data Safety Monitoring Committee for Agios Pharm, AstraZeneca, BMS–Celgene, Dren Bio Janssen. Researchfundingreceived from AbbVie, Acerta Pharma, Bristol Meyer Squib, Celgene, Genentech, Pharmacyclics, Sunesis, Vincerx. No other conflicts of interest were reported by the authors., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background/Objectives: Immune effector cell-associated hematotoxicity (ICAHT) is a frequent adverse event after chimeric antigen receptor (CAR)-T cell therapy. Grade ≥ 3 thrombocytopenia occurs in around one-third of patients, and many of them become platelet transfusion-dependent. Eltrombopag is a thrombopoietin receptor agonist (TPO-RA) able to accelerate megakaryopoiesis, which has been used successfully in patients with bone marrow failure and immune thrombocytopenia (ITP). Its role in managing thrombocytopenia and other cytopenias in CAR-T cell-treated patients has been scarcely addressed. Our aim was to report the safety and efficacy of this approach in patients included in the Spanish Group for Hematopoietic Transplantation and Cellular Therapy (GETH-TC) registry. Methods: This is a retrospective, multicenter, observational study. Patients who developed platelet transfusion dependence subsequently to CAR-T cells and received eltrombopag to improve platelet counts were recruited in 10 Spanish hospitals. Results: Thirty-eight patients were enrolled and followed up for a median (interquartile range [IQR]) of 175 (99, 489) days since CAR-T cell infusion. At the moment eltrombopag was indicated, 18 patients had thrombocytopenia and another severe cytopenia, while 8 patients had severe pancytopenia. After 32 (14, 38) days on eltrombopag, 29 (76.3%) patients recovered platelet transfusion independence. The number of platelet units transfused correlated with the time needed to restore platelet counts higher than 20 × 10 9 /L (Rho = 0.639, p < 0.001). Non-responders to eltrombopag required more platelet units (58 [29, 69] vs. 12 [6, 26] in responders, p = 0.002). Nineteen out of twenty-three (82.6%) patients recovered from severe neutropenia after 22 (11, 31) days on eltrombopag. Twenty-nine out of thirty-five (82.9%) patients recovered red blood cell (RBC) transfusion independence after 29 (17, 44) days. Seven patients recovered all cell lineages while on treatment. No thromboembolic events were reported. Only two transient toxicities (cholestasis, hyperbilirubinemia) were reported during eltrombopag treatment, none of which compelled permanent drug withdrawal. Conclusions: Eltrombopag could be safely used to manage thrombocytopenia and accelerate transfusion independence in CAR-T cell-treated patients.

In the pre-chimeric antigen receptor T cell (CAR-T) therapy era, the SCHOLAR-1 study identified a group of patients with refractory aggressive B cell lymphoma (ABCL) with particularly poor prognoses. We recently published our real-world data from Spain, focused on this SCHOLAR-1 refractory group, and compared patients who underwent CAR-T therapy with the previous standard of care. In this study, we found that the efficacy of CAR-T therapy in refractory patients, in terms of progression-free survival (PFS) and overall survival (OS), was superior to that of the treatments available in the pre-CAR-T era. The main objective of these new analyses was to analyze treatment efficacy in terms of response rates and survival for patients with ABCL with or without the SCHOLAR-1 criteria. In addition, we analyzed the prognostic impact of each SCHOLAR-1 criterion independently. Our study aimed to assess the prognostic impact of SCHOLAR-1 criteria on ABCL patients treated with CAR-T therapy in Spain. This multicenter, retrospective, observational study. We included all adult patients treated with commercially available CAR-T cell products and diagnosed with ABCL different from primary mediastinal large B cell lymphoma between February 2019 and July 2022. Patients meeting any SCHOLAR-1 criteria (progressive disease as the best response to any line of therapy, stable disease as the best response to ≥4 cycles of first-line therapy or ≥2 cycles of later-line therapy, or relapse at <12 months after autologous stem cell transplantation [auto-SCT]) in the line of treatment before CAR-T therapy (SCHOLAR-1 group) were compared with those not meeting any of these criteria (non-SCHOLAR-1 group). To analyze the prognostic impact of individual SCHOLAR-1 criteria, all the patients who met any of the SCHOLAR-1 criteria at any time were included to assess whether these criteria have the same prognostic impact in the CAR-T era. In addition, patients were grouped according to whether they were refractory to the first line of treatment, refractory to the last line of treatment, or relapsed early after auto-SCT. The PFS and OS were calculated from the time of appearance of the SCHOLAR-1 refractoriness criteria. Of 329 patients treated with CAR-T (169 with axi-cel and 160 with tisa-cel), 52 were in the non-SCHOLAR-1 group and 277 were in the SCHOLAR-1 group. We found significantly better outcomes in the non-SCHOLAR-1 patients compared with the SCHOLAR-1 patients (median PFS of 12.2 and 3.3 months, respectively; P = .009). In addition, axi-cel showed better results in terms of efficacy than tisa-cel for both the non-SCHOLAR-1 group (hazard ratio [HR] for PFS, 2.7 [95% confidence interval (CI), 1.1 to 6.7; P = .028]; HR for OS, 7.1 [95% CI, 1.5 to 34.6; P = .015]) and SCHOLAR-1 group (HR for PFS, 1.8 [95% CI, 1.3 to 2.5; P < .001]; HR for OS, 1.8 [95% CI, 1.2 to 2.6; P = .002]), but also significantly more toxicity. Finally, separately analyzing the prognostic impact of each SCHOLAR-1 criterion revealed that refractoriness to the last line of treatment was the variable with the most significant impact on survival. In conclusion, SCHOLAR-1 refractoriness criteria notably influence the efficacy of CAR-T therapy. In our experience, axi-cel showed better efficacy than tisa-cel for both SCHOLAR-1 and non-SCHOLAR-1 patients. Refractoriness to the last line of treatment was the variable with the most significant impact on survival in the CAR-T therapy era., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)

Anti-CD19 chimeric antigen receptor T cells (CART) has rapidly been adopted as the standard third-line therapy to treat aggressive B-cell lymphomas (ABCL) after failure of second-line therapy despite the lack of direct comparisons with allogeneic hematopoietic cell transplantation (alloHCT)-based strategies. Using the Grupo Español de Trasplante y Terapia Celular (GETH-TC) registry, we selected patients with the following characteristics: CART or alloHCT performed between 2016 and 2021; ≥18 years old; ABCL diagnosis; ≥2 lines of therapy; and either anti-CD19 CART or alloHCT as therapy at relapse. The analysis included a total of 316 (CART = 215, alloHCT = 101) patients. Median follow-up was 15 and 36 months for the CART and alloHCT cohorts, respectively. In the multivariate analysis, CART was confirmed to be similar to alloHCT for the primary study endpoint (progression-free survival) (hazard ratio [HR] 0.92, CI95%:0.56-1.51, p = 0.75). Furthermore, when the analysis was limited to only patients with chemo-sensitive diseases (complete and partial response) at infusion (CART = 26, alloHCT=93), no differences were reported (progression-free survival at month +18: 65% versus 55%, p = 0.59). However, CART had lower non-relapse mortality (HR 0.34, 95% CI: 0.13-0.85, p = 0.02). Given the lower toxicity and similar survival outcomes, these results suggest the use of CART before alloHCT., (© 2023. The Author(s), under exclusive licence to Springer Nature Limited.)

Real-world evidence comparing the efficacy of chimeric antigen receptor (CAR) T-cell therapy against that of the previous standard of care (SOC) for refractory large B-cell lymphoma (LBCL) is scarce. We retrospectively collected data from patients with LBCL according to SCHOLAR-1 criteria treated with commercial CAR T-cell therapy in Spain (204 patients included and 192 treated, 101 with axicabtagene ciloleucel [axi-cel], and 91 with tisagenlecleucel [tisa-cel]) and compared the results with a historical refractory population of patients (n = 81) obtained from the GELTAMO-IPI study. We observed superior efficacy for CAR-T therapy (for both axi-cel and tisa-cel) over pSOC, with longer progression-free survival (PFS) (median of 5.6 vs. 4-6 months, p ≤ 0.001) and overall survival (OS) (median of 15 vs. 8 months, p < 0.001), independently of other prognostic factors (HR: 0.59 (95% CI: 0.44-0.80); p < 0.001] for PFS, and 0.45 [(95% CI: 0.31-0.64)] for OS). Within the CAR-T cohort, axi-cel showed longer PFS (median of 7.3 versus 2.8 months, respectively, p = 0.027) and OS (58% versus 42% at 12 months, respectively, p = 0.048) than tisa-cel. These differences were maintained in the multivariable analysis. On the other hand, axi-cel was independently associated with a higher risk of severe cytokine release syndrome and neurotoxicity. Our results suggest that the efficacy of CAR-T cell therapy is superior to pSOC in the real-world setting. Furthermore, axi-cel could be superior in efficacy to tisa-cel, although more toxic, in this group of refractory patients according to SCHOLAR-1 criteria., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Bastos-Oreiro, Gutierrez, Reguera, Iacoboni, López-Corral, Terol, Ortíz-Maldonado, Sanz, Guerra-Dominguez, Bailen, Mussetti, Abrisqueta, Hernani, Luzardo, Sancho, Delgado-Serrano, Salar, Grande, Bento, González de Villambrosía, García-Belmonte, Sureda, Pérez-Martínez, Barba, Kwon and Martín García-Sancho.)

Introduction: Acute graft-versus-host disease GVHD (aGVHD) is the main complication during the first months after bone transplantation. Steroid therapy is clearly the upfront established treatment for aGVHD. However, there are patients with partial response to steroid treatment and steroid-refractory cases. For those patients, a vast number of therapeutic options have emerged, although the evidence is scarce., Case Report: We report the use of tocilizumab as salvage treatment in a patient with corticosteroid refractory pulmonary aGVHD that was admitted to the critical care unit for respiratory support measures., Management & Outcome: We decided to use tocilizumab as rescue treatment, after failure of corticosteroid treatment, standard treatment with broad-spectrum antibiotics and etanercept. The patient showed a remarkable clinical improvement two days after first infusion and a total resolution of the symptomatology with normalization of the spirometry tests after 4 weeks of the administration of tocilizumab., Discussion: To the authors' knowledge, this is the first case that describes the effective and safe use of tocilizumab as a rescue treatment in a patient with steroid-refractory pulmonary aGVHD. It showed a rapid onset of action and a favorable safety profile, which could make it an interesting option for the treatment of this potentially fatal complication.

Autologous hematopoietic stem cell transplantation (ASCT) is a well-established treatment strategy in HIV-related lymphoma patients (HIV+ Ly). Nevertheless, current evidence is mainly based on reports from specialized centers, multicentre heterogeneous studies, noncomparative analyses, or registry data-based comparisons. Likewise, the risk of infections reported so far for this population, seems to be similar to that of HIV- patients, and it does not seem to impact on mortality. We report a single-center retrospective comparative analysis of AHCT procedural results, infectious complications and survival in HIV+ Ly matched with a non-HIV comparative cohort. Thirty-three HIV+ patients and 45 matched controls, who underwent ASCT between 2000 and 2016, were included. Transplant-related toxicity, event-free survival, relapse rate, and overall survival were similar in both groups. Engraftment was delayed in HIV+ Ly (neutrophils: 15 vs 12 days (p = 0.0001), and platelets 39 vs 16 days (p = 0.00001)). Bacterial infections during the pre-engraftment period were more frequent in HIV+ Ly (RR 2.24, p = 0.017), as well as viral infections in the postengraftment period (RR 3.22, p = 0.004). CMV reactivation was more frequent in HIV+ Ly (39% vs 15% p = 0.007). In conclusion, ASCT is viable and effective in HIV+ Ly, but it is associated with a higher risk of infection.

Background: Prognostic factors of poor outcome in patients with hematological malignancies and COVID-19 are poorly defined., Patients and Methods: This was a Spanish transplant group and cell therapy (GETH) multicenter retrospective observational study, which included a large cohort of blood cancer patients with laboratory-confirmed SARS-CoV-2 infection through PCR assays from March 1st 2020 to May 15th 2020., Results: We included 367 pediatric and adult patients with hematological malignancies, including recipients of autologous (ASCT) (n = 58) or allogeneic stem cell transplantation (allo-SCT) (n = 65) from 41 hospitals in Spain. Median age of patients was 64 years (range 1-93.8). Recipients of ASCT and allo-SCT showed lower mortality rates (17% and 18%, respectively) compared to non-SCT patients (31%) (p = 0.02). Prognostic factors identified for day 45 overall mortality (OM) by logistic regression multivariate analysis included age > 70 years [odds ratio (OR) 2.1, 95% confidence interval (CI) 1.2-3.8, p = 0.011]; uncontrolled hematological malignancy (OR 2.9, 95% CI 1.6-5.2, p < 0.0001); ECOG 3-4 (OR, 2.56, 95% CI 1.4-4.7, p = 0.003); neutropenia (< 0.5 × 10 9 /L) (OR 2.8, 95% CI 1.3-6.1, p = 0.01); and a C-reactive protein (CRP) > 20 mg/dL (OR 3.3, 95% CI 1.7-6.4, p < 0.0001). In multivariate analysis of 216 patients with very severe COVID-19, treatment with azithromycin or low dose corticosteroids was associated with lower OM (OR 0.42, 95% CI 0.2-0.89 and OR 0.31, 95% CI 0.11-0.87, respectively, p = 0.02) whereas the use of hidroxycloroquine did not show significant improvement in OM (OR 0.64, 95% CI 0.37-1.1, P = 0.1)., Conclusions: In most patients with hematological malignancies COVID-19 mortality was directly driven by older age, disease status, performance status, as well as by immune (neutropenia) parameters and level of inflammation (high CRP). Use of azithromycin and low dose corticosteroids may be of value in very severe COVID-19., Competing Interests: Competing interestsThe author(s) declare that they have no conflict of interests., (© The Author(s) 2020.)