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.

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.

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.

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.

Insights from the Hereditary Thrombotic Thrombocytopenic Purpura Registry: Discussion of Key Findings Based on Individual Cases from Switzerland.

The Hereditary TTP Registry is an international cohort study for patients with a confirmed or suspected diagnosis of hereditary thrombotic thrombocytopenic purpura (hTTP) and their family members. Hereditary TTP is an ultra-rare blood disorder (prevalence of ∼1-2 cases per million), the result of autosomal-recessively inherited congenital ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) deficiency (ADAMTS13 activity <10% of the normal), and associated with yet many unanswered questions. Until December 2017, the Hereditary TTP Registry had enrolled 123 confirmed hTTP patients. Their median age at disease onset was 4.5 years (range: 0-70) and at clinical diagnosis 16.7 years (range: 0-69), a difference that highlights the existing awareness gap in recognizing hTTP. The systematic collection of clinical data of individual patients revealed their substantial baseline comorbidities, as a consequence of recurring TTP episodes in the past. Most notable was the high proportion of patients having suffered from premature arterial thrombotic events, mainly transient ischemic attacks, ischemic strokes, and to a lesser extent myocardial infarctions. At 40 to 50 years of age and above, more than 50% of patients had suffered from at least one such event, and many had experienced arterial thrombotic events despite regular plasma infusions every 2 to 3 weeks that supplements the missing plasma ADAMTS13. The article by van Dorland et al. (Haematologica 2019;104(10):2107-2115) and the ongoing Hereditary TTP Registry cohort study were recognized with the Günter Landbeck Excellence Award at the 50th Hemophilia Symposium in Hamburg in November 2019, the reason to present the Hereditary TTP Registry in more detail here.

Analysis of IL-6 serum levels and CAR T cell-specific digital PCR in the context of cytokine release syndrome.

INTRODUCTION: Chimeric antigen receptor T-cell (CAR-T) therapies are increasingly used to treat relapsed B-cell lymphomas and acute lymphoblastic leukemia. Considering the frequency of cytokine release syndrome and CAR-T-related encephalopathy syndrome (CRS/CRES) after CAR-T administration, strategies enabling timely prediction of impending CRS/CRES are a clinical need. METHODS: We evaluated the dynamics of serum interleukin (IL)-6 levels and CAR-T transgene copy numbers by digital droplet polymerase chain reaction in the peripheral blood of 11 consecutive patients with aggressive B-cell malignancies. RESULTS: Four of 11 patients developed CRS, and 3 patients had CRES (33%), 2 of them had previous CRS. IL-6 levels increased on the day of clinical manifestation of CRS. All CRS patients had increased IL-6 peak levels (median IL-6 peak 606 pg/mL in CRS patients vs. 22 pg/mL in non-CRS patients, p = 0.0061). Different patterns emerged from the dynamics of CAR-T/µg genomic DNA: "rapid increase and rapid decrease with complete disappearance," "rapid increase and slow decrease with higher persistence," "rapid increase and rapid decrease with lower persistence," and "slow increase and rapid decrease with almost disappearance." Patients with the pattern "rapid increase and slow decrease with higher persistence" of CAR-T/µg genomic DNA concentration seemed to be at higher risk of developing CRS/CRES. CONCLUSION: Thus, the dynamics of CAR-T transgene copy numbers merits further evaluation for a possible association with manifestation of CRS. Increased IL-6 serum levels at CRS manifestation may contribute to the interpretation of symptoms.

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.

Peripheral blood progenitor cell collection in pediatric patients optimized by high pre-apheresis count of circulating CD34+ cells and high blood flow.

Collection of peripheral blood progenitor cells by leukapheresis is the preferred method to obtain grafts for autologous transplantation. Optimizing this procedure is important to warrant sufficient cell yield and reduce associated risks. To obtain sufficient to optimal yields of ≥ 2 to ≥ 5 × 106 CD34+ cells/kg body weight with a single leukapheresis procedure, success rates between 83 and 92% have been reported in children. In this retrospective study, we describe an improved protocol for autologous stem cell collection with an extraordinarily high success rate applied in 122 consecutive pediatric patients treated at the University Hospital Bern between 2004 and 2017. By comparing our data with previous studies, we identify two main optimizing factors: higher pre-apheresis CD34+ cell counts with a median of 130/µl and higher blood flow rates of 42-100 ml/min. Consequently, blood volumes processed were increased, duration of leukapheresis was shorter and CD34+ cell yields with a median of 19.0 × 106/kg body weight were higher than previously described. Safety in our study was comparable to previous studies. Based on our data, we present an innovative algorithm for determination of the necessary blood volume and time of pediatric leukapheresis procedure.

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.