A hub-and-spoke model to deliver effective access to chimeric antigen receptor T-cell therapy in a public health network: the Catalan Blood and Tissue Bank experience.

BACKGROUND AIMS: To describe and analyze whether a hub-and-spoke organizational model could efficiently provide access to chimeric antigen receptor (CAR) T-cell therapy within a network of academic hospitals and address the growing demands of this complex and specialized activity. METHODS: The authors performed a retrospective evaluation of activity within the Catalan Blood and Tissue Bank network, which was established for hematopoietic stem cell transplantation to serve six CAR T-cell programs in academic hospitals of the Catalan Health Service. Procedures at six hospitals were followed from 2016 to 2021. Collection shipments of starting materials, CAR T-cell returns for storage and infusions for either clinical trials or commercial use were evaluated. RESULTS: A total of 348 leukocytapheresis procedures were performed, 39% of which were delivered fresh and 61% of which were cryopreserved. The network was linked to seven advanced therapy medicinal product manufacturers. After production, 313 CAR T-cell products were shipped back to the central cryogenic medicine warehouse located in the hub. Of the units received, 90% were eventually administered to patients. A total of 281 patients were treated during this period, 45% in clinical trials and the rest with commercially available CAR T-cell therapies. CONCLUSIONS: A hub-and-spoke organizational model based on an existing hematopoietic stem cell transplantation program is efficient in incorporating CAR T-cell therapy into a public health hospital network. Rapid access and support of growing activity enabled 281 patients to receive CAR T cells during the study period.

Age, CD34+ cell dose, conditioning and pre-transplant cytopenias can help predict transfusion support in lymphoma patients undergoing autologous stem cell transplantation.

BACKGROUND AND OBJECTIVES: Autologous stem cell transplant (ASCT) is a widely used therapy for lymphoma patients and can nowadays be performed on an outpatient basis. This study aimed to describe transfusion support in lymphoma patients undergoing ASCT and identify increased or prolonged transfusion requirement predictors. MATERIALS AND METHODS: A retrospective study of all consecutive lymphoma patients undergoing ASCT between 2010 and 2020. RESULTS: Out of 226 patients, 145 (64%) received red blood cell (RBC) transfusions, whereas all 226 (100%) required platelet transfusion (PT). Transfusions between Day +1 and +30 were higher in patients over 60 (2 [1-4] vs. 2 [0-2] RBC; p = 0.001 and 4 [2-8] vs. 3 [2-4] PT; p < 0.001); patients with pre-transplant anaemia (4 [2.5-6] vs. 2 [0-2] RBC; p < 0.001 and 5 [3-9] vs. 3 [2-4] PT; p = 0.001); pre-transplant thrombocytopenia (2 [1-4] vs. 2 [0-2] RBC; p < 0.001 and 4 [3-8.5] vs. 2 [1-3] PT; p < 0.001) or CD34+ cell dose <4 × 106 /kg (2 [0-4] vs. 2 [0-2] RBC; p = 0.024 and 4 [2-6] vs. 2 [1-3.5] PT; p < 0.001). RBC transfusion independence was reached later in patients receiving carmustine, cytarabine, etoposide and melphalan (BEAM) (hazard ratio [HR] 1.6; confidence interval [CI] 1.1-2.3) and those requiring RBC before infusion and/or with pre-transplant anaemia (HR 2.2; CI 1.4-3.4). Age above 60 (HR 1.4; CI 1.0-1.9), BEAM conditioning (HR 1.4; CI 1.0-2.0) and pre-transplant thrombocytopenia and/or requiring PT before infusion (HR 1.8; CI 1.4-2.5) entailed longer time until PT independence. CONCLUSION: These four factors (age ≥60 years; BEAM conditioning, CD34+ dose <4 × 106 /kg and pre-transplant cytopenia and/or Day -10 to 0 transfusion) allowed dividing patients into three groups with significant differences between them regarding the time until transfusion independence.

Development of an in-house bone marrow collection kit: The Catalan bone marrow transplantation group experience.

BACKGROUND AND OBJECTIVES: Bone marrow (BM) harvesting is one of the essential sources of stem cells for haematopoietic stem cell transplantation. In 2019, commercial BM collection kits became unavailable in Europe. Consequently, we created an in-house BM collection kit as an alternative. MATERIALS AND METHODS: We compared two groups of BM collections. The first collections were taken using an in-house kit from June 2022 through February 2023 and the second with a commercial kit from February 2021 through May 2022. These all took place at seven collection centres (CC). We analysed the harvest quality (cell blood count, CD34+ cells, viability, potency and sterility), the incidents occurring with each kit and the time to neutrophil and platelet engraftment in recipients. RESULTS: A total of 23 donors underwent BM harvesting with the in-house kit and 23 with the commercial one. Both cohorts were comparable regarding donor characteristics, CC and time to procedure. No statistical differences were found in harvest quality between the in-house and commercial kits. A new transfusion set was required in three BM harvests (13%) with the in-house kit because of filter clogging. The median time to neutrophil and platelet engraftment was 21 days for both cohorts and 29 days (in-house) and 33 days (commercial), p = 0.284, respectively. CONCLUSION: The in-house BM collection kit offers a real approach to solve the diminished supply of commercial kits. A higher risk of filter clogging was observed compared with commercial kits due to the lack of 850 and 500 µm filters.

Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations.

Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.

How donor selection criteria can be evaluated with limited scientific evidence: lessons learned from the TRANSPOSE project.

BACKGROUND AND OBJECTIVE: Donor selection criteria (DSC) are a vital link in the chain of supply of Substances of Human Origin (SoHO) but are also subject to controversy and differences of opinion. Traditionally, DSC have been based on application of the precautionary principle. MATERIALS AND METHODS: From 2017 to 2020, TRANSPOSE (TRANSfusion and transplantation PrOtection and SElection of donors), a European research project, aimed to identify discrepancies between current DSC by proposing a standardized risk assessment method for all SoHO (solid organs excluded) and all levels of evidence. RESULTS: The current DSC were assessed using a modified risk assessment method based on the Alliance of Blood Operators' Risk-based decision-making framework for blood safety. It was found that with limited or diverging scientific evidence, it was difficult to reach consensus and an international standardized method for decision-making was lacking. Furthermore, participants found it hard to disregard their local guidelines when providing expert opinion, which resulted in substantial influence on the consensus-based decision-making process. CONCLUSIONS: While the field of donation-safety research is expanding rapidly, there is an urgent need to formalize the decision-making process regarding DSC. This includes the need for standardized methods to increase transparency in the international decision-making process and to ensure that this is performed consistently. Our framework provides an easy-to-implement approach for standardizing risk assessments, especially in the context of limited scientific evidence.

Putting the spotlight on donation-related risks and donor safety - are we succeeding in protecting donors?

BACKGROUND AND OBJECTIVE: The European consortium project TRANSPOSE (TRANSfusion and transplantation: PrOtection and SElection of donors) aimed to assess and evaluate the risks to donors of Substances of Human Origin (SoHO), and to identify gaps between current donor vigilance systems and perceived risks. MATERIALS AND METHODS: National and local data from participating organizations on serious and non-serious adverse reactions in donors were collected from 2014 to 2017. Following this, a survey was performed among participants to identify risks not included in the data sets. Finally, participants rated the risks according to severity, level of evidence and prevalence. RESULTS: Significant discrepancies between anticipated donor risks and the collected data were found. Furthermore, many participants reported that national data on adverse reactions in donors of stem cells, gametes, embryos and tissues were not routinely collected and/or available. CONCLUSIONS: These findings indicate that there is a need to further develop and standardize donor vigilance in Europe and to include long-term risks to donors, which are currently underreported, ensuring donor health and securing the future supply of SoHO.

Incidence, diagnosis, and outcome of immune-mediated thrombotic thrombocytopenic purpura: A nationwide survey by the Spanish registry of thrombotic thrombocytopenic purpura.

BACKGROUND: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare disease characterized by the presence of anti-ADAMTS13 autoantibodies. Achieving accurate information on incidence and customary disease management is important to provide appropriate diagnostic and therapeutic resources. The aim of this study was to determine the incidence and outcomes of iTTP in Spain. STUDY DESIGN AND METHODS: A cross-sectional survey was carried out among Spanish hospitals, focused on iTTP patients ≥16 years old attended between 2015 and 2017, and those at follow-up before that interval. Incidence, prevalence, mortality, refractoriness, exacerbations, treatment complications, relapses, and sequelae were estimated. RESULTS: Forty-two hospitals covering roughly 20 million inhabitants answered the survey and reported 203 episodes (138 newly-diagnosed and 65 relapses), of which 193 (95.1%) were treated. Incidence was 2.67 (95% CI 1.90-3.45) patients per million inhabitants per year and prevalence 21.44 (95% CI% 19.10-23.73) patients per million inhabitants. At diagnosis, ADAMTS13 activity and anti-ADAMTS13 autoantibody were measured in 97% and 84.3% of reported episodes, respectively. Fifteen patients (7.4%) died as a direct consequence of iTTP, 6 of them before receiving any iTTP-specific treatment. Thirty-one (16.1%) of the 193 treated episodes were refractory to plasma exchange and corticosteroids, and 51 (26.4%) suffered at least one exacerbation. CONCLUSION: iTTP incidence and prevalence were somewhat higher than those documented in neighboring countries. Together with data on treatments and outcomes, this information will allow us to better estimate what is needed to improve diagnosis and prognosis of iTTP patients in Spain.

Leukocytapheresis variables and transit time for allogeneic cryopreserved hpc: better safe than sorry.

Cryopreservation was recommended to ensure continuity in allogeneic hematopoietic progenitor cells (HPC) transplantation during the COVID-19 pandemic. Several groups have shown no impact on clinical outcomes for patients who underwent HPC transplantation with cryopreserved products during the first months of this pandemic. However, concerns about quality control attributes after cryopreservation have been raised. We investigated, in 155 allogeneic peripheral blood cryopreserved HPC, leukocytapheresis characteristics influencing viable CD34+ and CD3+ cells, and CFU-GM recoveries after thawing. Collection characteristics such as volume, nucleated cells (NC)/mL and hematocrit correlated with viable CD34+ and CD3+ cells recoveries after thawing in univariate analysis but only CD3+ cells remained statistically significant in multivariate analysis (r2 = 0.376; P = < 0.001). Additionally, transit time also showed correlation with viable CD34+ (r2 = 0.186), CD3+ (r2 = 0.376) and CFU-GM recoveries (r2 = 0.212) in multivariate analysis. Thus, diluting leukocytapheresis below 200 × 106 NC/mL, avoiding red cells contamination above 2%, cryopreserving below 250 × 106 NC/mL and minimizing transit time below 36 h, prevented poor viable CD34+ and CD3+ cells, and CFU-GM recoveries. In summary, optimizing leukocytapheresis practices and minimizing transportation time may better preserve the quality attributes of HPC when cryopreservation is indicated.

Cryopreservation of unrelated donor hematopoietic stem cells: the right answer for transplantations during the COVID-19 pandemic?

Cryopreservation was recommended to ensure continuity of unrelated donor (UD) hematopoietic stem cell transplantation (HSCT) during COVID-19 pandemic. However, its impact on clinical outcomes and feasibility was not well known. We compared 32 patients who underwent UD HSCT using cryopreserved peripheral blood stem cells (PBSC) during the COVID-19 pandemic with 32 patients who underwent UD HSCT using fresh PBSC in the previous period. Median neutrophil engraftment was 17.5 and 17.0 days with cryopreserved and fresh grafts, respectively. Non-significant delays were found in platelet recovery days (25.5 versus 19.0; P = 0.192) and full donor chimerism days (35.0 and 31.5; P = 0.872) using cryopreserved PBSC. The rate of acute graft-versus-host disease at 100 days was 41% (95% CI [21-55%]) in cryopreserved group versus 31% (95% CI [13-46%]) in fresh group (P = 0.380). One-hundred days progression-relapse free survival and overall survival did not differ significantly. During COVID-19 pandemic, six frozen UD donations were not transfused and logistical and clinical issues regarding cryopreservation procedure, packaging, and transporting appeared. In summary, UD HSCT with cryopreserved PBSC was safe during this challenging time. More efforts are needed to ensure that all frozen grafts are transplanted and cryopreservation requirements are harmonized.

[Comparative study on the usefulness of antibacterial prophylaxis with levofloxacin in patients submitted to hematopoietic stem cell transplantation]. / Estudio comparativo sobre la utilidad de la profilaxis antibacteriana con levofloxacino en pacientes receptores de un trasplante de progenitores hematopoyéticos.

BACKGROUND: Bacterial infection remains a frequent complication in patients receiving a hematopoietic stem cell transplantation (HSCT). However, the impact of the antibacterial prophylaxis mortality in these patients is controversial. PATIENTS AND METHODS: Retrospective comparison of 2 consecutive groups of patients undergoing HSCT receiving (n=132) or not (n=107) antibacterial prophylaxis with levofloxacin. RESULTS: 41% of patients receiving prophylaxis with levofloxacin had microbiologically documented infection (MDI) with bacteremia, compared with 40% of those not receiving levofloxacin. The frequency of gram-negative bacteremia was 11 and 38%, the resistance to levofloxacin was 39 and 14%, and the mortality was 8 and 7%, respectively. CONCLUSIONS: In our experience, the use of levofloxacin as prophylaxis in HSCT was associated with a lower frequency of gram-negative bacteremia but was not associated with a decreased rate of MDI and did not influence their outcome. In contrast, there was an increase in quinolone resistance in patients treated with levofloxacin.