Outcome of patients with mantle cell lymphoma after autologous stem cell transplantation in the pre-CAR T-cell era.

Mantle cell lymphoma (MCL) patients can be treated with intensive induction therapy, followed by high dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) for consolidation and subsequent anti-CD20 maintenance. For patients relapsing after bruton tyrosine kinase (BTK) inhibitors, CAR T-cell therapy became available in late 2020 fueling the interest in outcomes of relapsing MCL patients. We retrospectively analyzed the outcome of MCL patients receiving HDCT/ASCT at our center between 2000 and 2021, thus, before availability of CAR-T cells. We identified 97 MCL patients undergoing HDCT/ASCT in this period with a median follow-up of 52 months. 43 (44%) patients ultimately relapsed, and 29 (30%) have died. The median progression-free survival (PFS) for the entire cohort was 48 months and overall survival (OS) was 202 months. Relapsing patients had a median PFS of only 28 months and median OS of 105 months. The OS of relapsing patients receiving BTK inhibitors was 148 versus 78 months in patients who never received BTK inhibitors (p = 0.1175). Even after HDCT/ASCT, a substantial proportion of MCL patients will relapse and ultimately die of the disease, emphasizing the need for new therapeutic options including CAR T-cell treatment for this lymphoma subtype.

Prophylactic corticosteroid use prevents engraftment syndrome in patients after autologous stem cell transplantation.

Engraftment syndrome (ES) following autologous stem cell transplantation (ASCT) at the time of neutrophil recovery may comprise fever, rash, pulmonary edema, or diarrhea. Usually, ES is easily manageable using corticosteroids but may prolong hospitalization. In two consecutive cohorts of subsequent patients with myeloma, lymphomas, and testicular/germ cell cancer, we assessed the benefit of corticosteroid use to prevent incidence and severity of ES following ASCT. Whereas Cohort A (82 patients) received no prophylactic corticosteroids, corticosteroids (4 mg dexamethasone oral daily) were started in Cohort B (60 patients) at day +9 until day +13 following ASCT. Steroid prophylaxis significantly reduced the incidence of ES (6/60; 10% vs. 33/82; 40%; p < 0.001). Hospitalization duration was longer in patients with ES than in patients without ES within both cohorts (in Cohort A: p = 0.007; and B: p = 0.011), but did not differ significantly between cohorts A and B. Finally, in Cohort A, there was a trend to an inferior 2-year overall survival rate in patients without ES compared to patients with ES (p = 0.067), but definite conclusions are not yet allowed. Our results suggest that corticosteroid prophylaxis from days +9 to +13 following ASCT significantly reduces the risk of ES and shortens hospitalization duration.

Reduced survival after autologous stem cell transplantation in myeloma and lymphoma patients with low vitamin D serum levels.

High-dose chemotherapy (HDCT) with autologous stem cell transplantation (ASCT) is applied for consolidation in myeloma and relapsing lymphoma patients. Vitamin D (VitD) exerts effects during hematopoietic stem cell proliferation, differentiation and interactions with the immune system. VitD deficiency is frequent in patients with hematological malignancies, but its prognostic relevance after ASCT remains unclear. We investigated the effect of VitD serum levels in patients with lymphomas and myeloma at ASCT on progression-free (PFS) and overall survival (OS). The cohort (n = 183) was divided into two groups: 81 (44%) had VitD levels >52 nmol/L and 102 (56%) ≤52 nmol/L at ASCT. VitD levels >52 nmol/L were associated with better PFS (P = 0.0194) and OS (P = 0.011). Similarly, when evaluating myeloma patients alone, patients with lower VitD levels (≤52 nmol/L) had inferior PFS (P = 0.0412) and OS (P = 0.049). Finally, the multivariate analysis was consistent that varying VitD levels were significantly associated with OS (P = 0.0167), also when stratifying patients in groups with VitD levels > versus ≤52 nmol/L (P = 0.0421). Our data suggest that reduced serum VitD levels in myeloma and lymphoma patients undergoing HDCT/ASCT are associated with inferior outcome. Optimizing VitD levels before ASCT may be warranted.

Recommendations for Therapeutic Apheresis by the Section "Preparative and Therapeutic Hemapheresis" of the German Society for Transfusion Medicine and Immunohematology.

The section "Preparative and Therapeutic Hemapheresis" of the German Society for Transfusion Medicine and Immunohematology (DGTI) has reviewed the actual literature and updated techniques and indications for evidence-based use of therapeutic apheresis in human disease. The recommendations are mostly in line with the "Guidelines on the Use of Therapeutic Apheresis in Clinical Practice" published by the Writing Committee of the American Society for Apheresis (ASFA) and have been conducted by experts from the DACH (Germany, Austria, Switzerland) region.

Visual Outcomes of Plasma Exchange Treatment of Steroid-Refractory Optic Neuritis: A Retrospective Monocentric Analysis.

INTRODUCTION: In acute inflammatory optic neuritis (ON) as a typical onset of multiple sclerosis (MS), only few studies have investigated plasma exchange (PLEX) as a sequential treatment after insufficient response to high-dose intravenous glucocorticosteroids. Therefore, we aimed to investigate treatment outcome on visual acuity (VA) with PLEX in patients with steroid-refractory ON. METHODS: In our retrospective monocentric study, medical records were screened for patients with acute ON as their first relapse with sequential MS diagnosis or with an established MS diagnosis from the Bern University Hospital (Switzerland) that were treated with PLEX between 2016 and 2018 due to lacking steroid response. VA prior to steroid administration, and before and after PLEX were assessed and compared using the Friedman multiple comparison test. RESULTS: In total, 18 patients were included in the analysis. Interval from symptom onset to PLEX was 20.3 days (mean, 95% CI 14.8-25.9). Relevant functional improvement (VA of ≥0.5, after a mean of 15.9 (13.3-18.5) days after start of PLEX) was detected in 16/18 (88.9%) with a significant amelioration as compared to VA before glucocorticosteroids and before PLEX (p < 0.0001). VA improvement at a later time point (38.1 weeks, 25.2-51.0) was present in 15/16 (93.8%) patients. No serious adverse events were detected. PLEX could be performed via peripheral access in 13/18 patients (72.2%). CONCLUSION: Our study demonstrates significant improvements of VA with PLEX in a cohort of MS patients with steroid-refractory ON. High response rates may be due to the timely treatment initiation. Despite the small sample size, our data support the early use of PLEX in steroid-refractory ON with a favorable safety profile.

Dose-intensified bendamustine and melphalan (BenMel) conditioning before second autologous transplantation in myeloma patients.

Consolidation in myeloma patients with high-dose melphalan chemotherapy (Mel HDCT) and autologous transplantation (ASCT) is standard of care since more than 2 decades. However, definite cure remains exceptional despite intensive treatment, and improving effectiveness of HDCT remains an unmet clinical need. Combining intensified bendamustine with melphalan may represent an option. We analyzed safety and efficacy of combining dose-intensified bendamustine (200 mg/m2 on days -4/-3) with high-dose melphalan (100 mg/m2 on days -2/-1) before a second (tandem) ASCT in adverse risk myeloma patients after Mel HDCT/ASCT1. Twelve patients received BenMel conditioning before ASCT2 because of high-risk cytogenetics and/or failure to achieve complete remission (CR) after Mel HDCT/ASCT1. Comparing Mel HDCT/ASCT1 and BenMel HDCT/ASCT2, we observed no differences in hematologic recovery and tolerance. Acute renal injury after BenMel conditioning occurred in 3 (25%) patients, but was reversible in all patients, and there were no treatment related deaths. Complete remission rates were increasing from 42% after Mel/ASCT1 to 75% after BenMel/ASCT2. PFS 1 year after ASCT2 was 67%, and OS was 83%. These data suggest that dose-intensified bendamustine with melphalan conditioning is safe and warrants a prospective randomized comparison to standard melphalan HDCT in myeloma patients.

Prolonged survival after second autologous transplantation and lenalidomide maintenance for salvage treatment of myeloma patients at first relapse after prior autograft.

Autologous stem cell transplantation (ASCT) as part of the primary therapy in multiple myeloma (MM) is standard practice. In contrast, the role of a second ASCT (ASCT2) and subsequent lenalidomide maintenance for relapsed disease remains unclear. In this study, we analysed 86 consecutive MM patients with a first relapse after prior ASCT receiving either a second ASCT or conventional chemotherapy. After a median follow-up of 37.7 months since first relapse, 54 (62.8%) patients were still alive and 29 (33.7%) without progression. Sixty-one (71.0%) patients received ASCT2 and had better progression-free survival (PFS) (30.2 versus 13.0 mo; P = .0262) and overall survival (OS) rates (129.6 versus 33.5 mo; P = .0003) compared with 25 (29.0%) patients with conventional treatment. Patients relapsing later than 12 months after ASCT1 benefitted from a second ASCT with better PFS2 (P = .0179) and OS2 (P = .0009). Finally, lenalidomide maintenance after ASCT2 was associated with longer PFS (41.0 vs 21.6 mo; P = .0034) and better OS (not yet reached vs 129.6 mo; P = .0434) compared with patients without maintenance. Our data suggest that a second ASCT and lenalidomide maintenance given at first relapse in MM after prior ASCT are associated with better survival rates.

Iron overload is correlated with impaired autologous stem cell mobilization and survival in acute myeloid leukemia.

BACKGROUND: Patients with acute myeloid leukemia (AML) undergoing consolidation with autologous stem cell transplantation (ASCT) depend on the successful mobilization of peripheral blood stem cells. However, the factors affecting the mobilization potential in AML patients and, in particular, the effect of transfusion-related iron overload on peripheral blood stem cell mobilization are largely unknown. STUDY DESIGN AND METHODS: We investigated the association of varying levels of iron overload and stem cell mobilization efficacy in consecutive AML patients after two induction cycles. RESULTS: A total of 113 AML patients in early first complete remission underwent the mobilization procedure. While 84 (74.3%) patients had serum ferritin levels exceeding 1000 µg/L, 26 (23.0%) patients had levels even higher than 2000 µg/L. Iron overload correlated with the number of preceding red blood cell transfusions and inversely correlated with circulating CD34+ cell levels (p = 0.04) at apheresis. Finally, the median progression-free and overall survival rates of patients with ferritin levels of higher than 2000 µg/L were shorter with 332 days versus 2156 days (p = 0.04) and 852 days versus 2235 days (p = 0.04), respectively. CONCLUSION: Our data suggest that transfusion-related iron overload is suppressing the mobilization potential and is associated with inferior outcome in AML.

Nationwide Implementation of Pathogen Inactivation for All Platelet Concentrates in Switzerland.

INTRODUCTION: Bacterial contamination of platelet concentrates (PCs) has been identified as the most prevalent transfusion-associated infectious risk. To prevent PC-related septic transfusion reactions, the Intercept® pathogen inactivation procedure was introduced for all PCs in Switzerland in 2011. METHODS: Based on numbers of transfused units and mandatorily reported adverse events with high imputability, we compare the risks associated with transfusion of conventional PCs (cPCs) and pathogen-inactivated PCs (PI-PCs). RESULTS: From 2005 to 2011, a total of 158,502 cPCs have been issued in Switzerland, and 16 transfusion-transmitted bacterial infections (including 3 fatalities) were reported. This corresponds to a morbidity and mortality rate of ca. 1:9,900 and 1:52,800, respectively. From 2011 to 2016, a total of 205,574 PI-PCs have been issued, and no transfusion-transmitted bacterial infection was reported. Despite continuously increasing transfusion reaction rates per 1,000 RBC and plasma issued between 2008 and 2016, we observed reductions of 66% for life-threatening and fatal reactions and of 26% for all high-imputability transfusion reactions related to PI-PCs as compared to cPCs. No increased rates of bleeding or clinical observations of ineffectiveness of PI-PCs have been reported. After implementation of PI-PCs, the annual increase in platelet usage per 1,000 inhabitants decelerated. DISCUSSION: Swiss hemovigilance data confirm a favorable safety profile of the nationwide introduced Intercept pathogen inactivation procedure and its reliable prevention of septic transfusion reactions and fatalities due to bacterially contaminated PCs.

Platelet Transfusion Induces Alloimmunization to D and Non-D Rhesus Antigens.

BACKGROUND: Platelet concentrates (PC) contain residual contaminating red blood cells (RBC), being higher in pooled buffy coat PC (BC-PC) than in apheresis units (AP-PC). Data about PC-induced alloimmunization against non-D Rhesus (Rh) antigens are limited. METHODS: For all newly detected RhD and non-D alloantibodies between August 2015 and September /2017 we prospectively evaluated if they were triggered through PC by analyzing for incompatible RBC and/or PC transfusions. RESULTS: We found 5,799 positive results in 89,190 antibody screening tests. We identified 13 newly detectable Rh antibodies through incompatible PCs in 11 patients: 6× anti-D, 4× anti-E, 2× anti-c, 1× anti-f. They received a total of 156 PC (83 BC-PC; 73 AP-PC): 5 patients received incompatible BC-PC only, 1 patient received incompatible AP-PC only, 5 patients received incompatible BC-PC and AP-PC. Quality control showed a mean (range) of 0.304 (0.152-1.662) and 0.014 (0.003-0.080) × 109 RBC/l for BC-PC and AP-PC, respectively. Ten of the 11 patients received RBC transfusions, all of them being antigen-negative for the alloantibodies identified. CONCLUSIONS: PC transfusions may not only induce RhD alloimmunization, but also immunization against further Rh antigens such as c, E, and f. The risk seems higher for BC-PC than for AP-PC. The results may have impact on future recommendations of PC transfusion with respect to Rh compatibility and upper limits of RBC contamination.

Donor Safety in Haemapheresis: Development of an Internet-Based Registry for Comprehensive Assessment of Adverse Events from Healthy Donors.

BACKGROUND: Currently, there is an extensive but highly inconsistent body of literature regarding donor adverse events (AEs) in haemapheresis. As the reports diverge with respect to types and grading of AEs, apheresis procedures and machines, the range of haemapheresis-related AEs varies widely from about 0.03% to 6.6%. METHODS: The German Society for Transfusion Medicine and Immunohaematology (DGTI) formed a 'Haemapheresis Vigilance Working Party' (Arbeitsgemeinschaft Hämapheresevigilanz; AGHV) to create an on-line registry for comprehensive and comparable AE assessment with all available apheresis devices in all types of preparative haemapheresis: plasmapheresis (PLS), plateletpheresis (PLT), red blood cell apheresis, all kind of leukaphereses (autologous/allogeneic blood stem cell apheresis, granulocyte apheresis, lymphocyte/monocyte apheresis) and all possible types of multi-component apheresis. To ensure the comparability of the data, the AGHV adopted the 'Standard for Surveillance of Complications Related to Blood Donation' from the International Society for Blood Transfusion in cooperation with the International Haemovigilance Network (IHN) and the American Association of Blood Banks for AE acquisition and automated evaluation. The registry is embedded in a prospective observational multi-centre study with a study period of 7 years. RESULTS: A preliminary evaluation encompassed the time period from January, 2012 to December, 2015. During this time, the system proved to be safe and stable. Out of approximately 345,000 haemaphereses 16,477 AEs were reported (4.9%) from 20 participating centres. The majority of AEs occurred in PLSs (63%), followed by PLT (34.5%) and SC (2.2%). Blood access injuries (BAI) accounted for about 55% of the supplied AEs, whereas citrate toxicity symptoms, vasovagal reactions and technical events (e.g. disposable leakages, software failures) rather equally affected haemaphereses at 8-15%. Out of 12,348 finalized AEs, 8,759 (70.1%) were associated with a procedure-related break-off, with BAI being the prevailing cause (5,463/8,759; 62.4%). An automated centre- and procedure-specific AE evaluation according to the latest IHN standard and AGHV pre-settings is available within a few minutes. CONCLUSIONS: An on-line electronic platform for comprehensive assessment and centre-specific automated evaluation of AEs in haemaphereses has been developed and proved to be stable and safe over a period of 4 years.

Too Many Blood Donors - Response Bias in the Swiss Health Survey 2012.

BACKGROUND: Data on blood donor status obtained from general surveys and health interview surveys have been widely used. However, the integrity of data on self-reported blood donor status from surveys may be threatened by sampling and non-sampling error. Our study aimed to compare self-reported blood donors (including one-time as well as regular donors) from the Swiss Health Survey 2012 (SHS) with register-based blood donors recorded by blood establishments and evaluate the direction and magnitude of bias in the SHS. METHODS: We compared population-weighted SHS point estimates of the number of blood donors with their corresponding 95% confidence intervals to the respective figures from blood donor registries (birth cohorts 1978-1993) and estimates of donors based on period donor tables derived from blood donor registries (birth cohorts 1920-1993). RESULTS: In the birth cohorts 1978-1993, the SHS-predicted number of donors was 1.8 times higher than the respective number of donors based on registry data. Adjusting for foreign and naturalized Swiss nationals that immigrated after their 18th birthday, the SHS overall predicted number of donors was 1.6 times higher. Similarly, SHS estimates for the 1920-1993 birth cohorts were 2.4 and 2.1 times higher as compared to register-based estimates. Generally, the differences between SHS and register-based donors were more pronounced in men than in women. CONCLUSION: Self-reported blood donor status in the SHS is biased. Estimates of blood donors are substantially higher than respective estimates based on blood donor registries.

Delayed Haematological recovery after autologous stem cell transplantation is associated with favourable outcome in acute myeloid leukaemia.

Autologous stem cell transplantation (ASCT) is applied to consolidate first remission in patients with acute myeloid leukaemia (AML). However, outcome after ASCT widely varies among AML patients. We analyzed the prognostic significance of haematological recovery for neutrophils [absolute neutrophil count (ANC) >1·0 × 10(9) /l] and platelets (platelet count >20·0 × 10(9) /l), stratifying at day 20 after ASCT in 88 consecutive and homogeneously treated AML patients in first remission. We observed that patients with delayed recovery had better overall survival (OS; ANC: P < 0·0001 and platelets: P = 0·0062) and time to progression (TTP; ANC: P = 0·0003 and platelets: P = 0·0125). Delayed recovery was an independent marker for better OS and TTP in a multivariate analysis including age, gender, number of transfused CD34+ cells, cytogenetics, FLT3-internal tandem duplication and NPM1 mutation. Our results suggest that delayed neutrophil and platelet recovery is associated with longer OS and TTP in AML patients consolidated with ASCT in first remission.

Comparison of Melphalan Combined with Treosulfan or Busulfan as High-Dose Chemotherapy before Autologous Stem Cell Transplantation in AML.

(1) Background: High-dose chemotherapy (HDCT) before autologous stem cell transplantation (ASCT) in acute myeloid leukemia (AML) patients predominantly combines busulfan with cyclophosphamide or melphalan. Treosulfan compares favorably regarding lower inter-individual bioavailability and neurotoxicity, but so far, had not been studied before ASCT in AML. (2) Methods: This single-center study investigated AML patients undergoing ASCT in CR1 between November 2017 and September 2020. The first 16 patients received busulfan 16 mg/kg b.w. (days -5 to -2) and melphalan 140 mg/m2 (day -1) (BuMel). In a subsequent (TreoMel) cohort, 20 patients received treosulfan 14 g/m2 (days -4 to -2) and melphalan. Plasma concentrations of busulfan and treosulfan were determined by mass spectrometry. (3) Results: Neutrophil engraftment and platelet recovery were similar, and PFS and OS were comparable. In only the BuMel cohort, patients reported central nervous toxicities, including seizures (6%) and encephalopathy (12%). The mean AUC for busulfan was 1471.32 µM*min, and for treosulfan it was 836.79 mg/L*h, with ranges of 804.1-2082 µM*min and 454.2-1402 mg/L*h. The peak values for busulfan ranged between 880.19-1734 µg/L and for treosulfan between 194.3-489.25 mg/L. (4) Conclusions: TreoMel appears to be safe and effective for pre-ASCT treatment in AML patients. Due to considerable interindividual biovariability, pharmacologic monitoring may also be warranted for the use of treosulfan.

Platelet Transfusion-Insights from Current Practice to Future Development.

Since the late sixties, therapeutic or prophylactic platelet transfusion has been used to relieve hemorrhagic complications of patients with, e.g., thrombocytopenia, platelet dysfunction, and injuries, and is an essential part of the supportive care in high dose chemotherapy. Current and upcoming advances will significantly affect present standards. We focus on specific issues, including the comparison of buffy-coat (BPC) and apheresis platelet concentrates (APC); plasma additive solutions (PAS); further measures for improvement of platelet storage quality; pathogen inactivation; and cold storage of platelets. The objective of this article is to give insights from current practice to future development on platelet transfusion, focusing on these selected issues, which have a potentially major impact on forthcoming guidelines.

Immunoadsorption for the Treatment of Acquired Hemophilia: New Observational Data, Systematic Review, and Meta-Analysis.

The treatment of patients with acquired hemophilia is challenging due to life-threatening hemorrhages, delayed response, and adverse effects to immunosuppressive agents. Even though immunoadsorption (IA) rapidly removes autoantibodies against factor VIII, this intervention's effectiveness is still a matter of debate. We aimed to study important outcomes of IA as adjunctive treatment in patients with acquired hemophilia. We performed comprehensive literature searches in MEDLINE and EMBASE databases. Clinical and laboratory data of all patients treated in our institution were additionally included. Literature searching yielded 498 records, of which 10 studies describing 106 patients were finally included. The number of patients varied from 1 to 65, and patients' ages ranged between 14 and 89. Treatment criteria in most patients were (1) failed response to immunosuppressive treatment alone, and/or (2) uncontrollable bleeding episodes, and/or (3) high inhibitor titer. Methodological quality was moderate. The number of IA sessions varied from 1 to 24. Within our institution, 12 patients have been treated since 2002; median age was 76 years (range 34-86); median titer of factor VIII inhibitor was 20 Bethesda units (range 3-214). Pooled estimates, modeling a random-effect binominal distribution incorporating the Freeman-Tukey double arcsine transformation, were 86% in case of factor VIII recovery (95% confidence interval 76%-94%), 95% for reduction of factor VIII inhibitor (83%, 100%), and 7% in case of death (0%, 18%). Our data suggest that IA might be a beneficial adjunctive treatment in patients with high-risk acquired hemophilia, but future studies shall confirm this observation.