High-dose chemotherapy and autologous haematopoietic stem-cell transplantation in older, fit patients with primary diffuse large B-cell CNS lymphoma (MARTA): a single-arm, phase 2 trial.

BACKGROUND: Available treatments for older patients with primary diffuse large B-cell CNS lymphoma (PCNSL) offer progression-free survival of up to 16 months. We aimed to investigate an intensified treatment of high-dose chemotherapy and autologous haematopoietic stem-cell transplantation (HSCT) in older patients with PCNSL. METHODS: MARTA was a prospective, single-arm, phase 2 study done at 15 research hospitals in Germany. Patients aged 65 years or older with newly diagnosed, untreated PCNSL were enrolled if they had an Eastern Cooperative Oncology Group performance status of 0-2 and were fit for high-dose chemotherapy and autologous HSCT. Induction treatment consisted of two 21-day cycles of high-dose intravenous methotrexate 3·5 g/m2 (day 1), intravenous cytarabine 2 g/m2 twice daily (days 2 and 3), and intravenous rituximab 375 mg/m2 (days 0 and 4) followed by high-dose chemotherapy with intravenous rituximab 375 mg/m2 (day -8), intravenous busulfan 3·2 mg/kg (days -7 and -6), and intravenous thiotepa 5 mg/kg (days -5 and -4) plus autologous HSCT. The primary endpoint was progression-free survival at 12 months in all patients who met eligibility criteria and started treatment. The study was registered with the German clinical trial registry, DRKS00011932, and recruitment is complete. FINDINGS: Between Nov 28, 2017, and Sept 16, 2020, 54 patients started induction treatment and 51 were included in the full analysis set. Median age was 71 years (IQR 68-75); 27 (53%) patients were female and 24 (47%) were male. At a median follow-up of 23·0 months (IQR 16·8-37·4), 23 (45%) of 51 patients progressed, relapsed, or died. 12-month progression-free survival was 58·8% (80% CI 48·9-68·2; 95% CI 44·1-70·9). During induction treatment, the most common grade 3-5 toxicities were thrombocytopenia and leukopenia (each in 52 [96%] of 54 patients). During high-dose chemotherapy and autologous HSCT, the most common grade 3-5 toxicity was leukopenia (37 [100%] of 37 patients). Treatment-related deaths were reported in three (6%) of 54 patients, all due to infectious complications. INTERPRETATION: Although the primary efficacy threshold was not met, short induction followed by high-dose chemotherapy and autologous HSCT is active in selected older patients with PCNSL and could serve as a benchmark for comparative trials. FUNDING: Else Kröner-Fresenius Foundation, Riemser Pharma, and Medical Center-University of Freiburg.

Cup positioning and its effect on polyethylene wear of vitamin E- and non-vitamin E-supplemented liners in total hip arthroplasty: radiographic outcome at 5-year follow-up.

BACKGROUND: Aseptic loosening remains a challenging problem after total hip arthroplasty. Accurate cup placement and supplementation of antioxidants in acetabular liners might reduce material failure rates. The aim of this study is to assess the effect of the cup position on the wear behaviour of UHMWPE-XE and UHMWPE-X liners in vivo using virtual radiographs. METHODS: We conducted a prospective, randomized, controlled, multicenter trial. Clinical data of 372 probands were analyzed. Anteroposterior pelvic X-rays of 324 patients immediately postoperatively and after 1 and 5 years were evaluated by the RayMatch® analysis software regarding cup position and wear behaviour. RESULTS: Mean cup anteversion was 20.3° (± 7.4) and inclination was 41.9° (± 7.0) postoperatively. 62.3% of all patients had an anteversion and inclination within the Lewinnek safe zone. Anterior and anterolateral approaches led to significantly higher cup anteversion compared to lateral approaches (27.3° ± 5.5; 20.9° ± 7.2; 17.5° ± 6.6; p < 0.001 and p = 0.001, respectively). Mean anteversion increased to 24.6° (± 8.0) after 1 year (p < 0.001). Only one revision occurred because of implant dislocation. Wear rates from UHMWPE-X and UHMWPE-XE did not differ significantly. Anteversion angles ≥ 25° correlated to increased polyethylene wear (23.7 µm/year ± 12.8 vs. 31.1 µm/year ± 22.8, p = 0.012) and this was amplified when inclination angles were ≥ 50° (23.6 µm/year ± 12.8 vs. 38.0 µm/year ± 22.7, p = 0.062). CONCLUSION: Anterior approaches lead to the highest inaccuracy of cup placement, but cup positioning outside the Lewinnek safe zone does not necessarily cause higher dislocation rates. Moreover, mean anteversion increased by approximately four degrees within the first year after operation, which is expected to be functional due to a regularization of pelvic tilt after intervention. Mid-term wear rates of UHMWPE-X and UHMWPE-XE liners are comparable, but steep cup positions lead to significantly increased polyethylene wear. In summary, a re-evaluation of target zones for intraoperative cup positioning might be considered. In the long-term reduced oxidative embrittlement could lead to superior wear behaviour of vitamin E-blended liners.

Luspatercept, a two-edged sword in beta-thalassemia-associated paravertebral extramedullary hematopoietic masses (EHMs).

Paravertebral extramedullary hematopoietic masses (EHMs) account for up to 15% of extramedullary pseudotumors in beta-thalassemia (BT) and are most likely related to compensatory hematopoiesis. In most cases, pseudotumors are incidentally detected, as the majority of patients are asymptomatic. Since June 2020, luspatercept is approved for the treatment of patients with BT who require regular red blood cell transfusions. Data addressing the safety and efficacy of luspatercept in patients with BT-associated EHMs are pending. To date (May 2022), paravertebral EHMs were observed in two asymptomatic patients out of currently 43 adult patients with BT registered at the Adult Hemoglobinopathy Outpatient Unit of the University Hospital Essen, Germany. In one of them, a paravertebral EHM was diagnosed more than 10 years prior to referral. Throughout observation time, treatment with luspatercept was associated with a clinically significant reduction in transfusion burden while allowing to maintain a baseline hemoglobin concentration of ≥10 g/dL aiming to suppress endogenous (ineffective) erythropoiesis associated with BT. Considering the rarity of paravertebral EHMs in BT, luspatercept might potentially represent a novel therapeutic option for these often-serious disease-associated complications. However, appropriate follow-up investigations are recommended to detect (early) treatment failures secondary to an undesired luspatercept-associated erythroid expansion.

Long-term efficacy, safety and neurotolerability of MATRix regimen followed by autologous transplant in primary CNS lymphoma: 7-year results of the IELSG32 randomized trial.

219 HIV-negative adults ≤70 years with primary CNS lymphoma (PCNSL) were enrolled in the randomized IELSG32 trial. Enrolled patients were randomly assigned to receive methotrexate-cytarabine (arm A), or methotrexate-cytarabine-rituximab (B), or methotrexate-cytarabine-thiotepa-rituximab (MATRix; arm C). A second randomization allocated patients with responsive/stable disease to whole-brain irradiation (WBRT) or carmustine-thiotepa-conditioned autologous transplantation (ASCT). First results, after a median follow-up of 30 months, showed that MATRix significantly improves outcome, with both WBRT and ASCT being similarly effective. However, sound assessment of overall survival (OS), efficacy of salvage therapy, late complications, secondary tumors, and cognitive impairment requires longer follow-up. Herein, we report the results of this trial at a median follow-up of 88 months. As main findings, MATRix was associated with excellent long-lasting outcome, with a 7-year OS of 21%, 37%, and 56% respectively for arms A, B, and C. Notably, patients treated with MATRix and consolidation had a 7-year OS of 70%. The superiority of arm B on arm A suggests a benefit from the addition of rituximab. Comparable efficacy of WBRT and ASCT was confirmed. Salvage therapy was ineffective; benefit was recorded only in patients with late relapse re-treated with methotrexate. Eight (4%) patients developed a second cancer. Importantly, MATRix and ASCT did not result in higher non-relapse mortality or second tumors incidence. Patients who received WBRT experienced impairment in attentiveness and executive functions, whereas patients undergoing ASCT experienced improvement in these functions as well as in memory and quality of life.

Nonunion and Reoperation Following Proximal Interphalangeal Joint Arthrodesis and Associated Patient Factors.

BACKGROUND: Proximal interphalangeal joint (PIPJ) arthrodesis can provide reliable pain relief and restore hand function in patients with PIPJ arthritis. However, there is a paucity of literature on patient-specific preoperative risk factors that are associated with adverse outcomes after PIPJ arthrodeses. Therefore, the primary purpose of this study was to assess preoperative predictors of nonunion and reoperation after PIPJ arthrodesis. METHODS: This study identified all patients who underwent PIPJ arthrodesis at a single community practice between 1987 and 2013. The final analysis included 415 PIPJs treated with arthrodesis. The mean follow-up was 1.3 years. Data on preoperative diagnosis, demographics, comorbidities, and operative techniques were recorded, as well as the occurrence of nonunions and reoperations. Logistic regression models were used to identify independent risk factors of nonunion and reoperation. RESULTS: There were 40 nonunions (10%) and 62 reoperations (15%). Of the reoperations, there were 39 incidences of isolated hardware removal, 9 irrigation and debridement, 8 amputations, 5 revision arthrodeses, and 1 corrective osteotomy. The highest number of nonunions occurred in the traumatic diagnosis group (37%), followed by the rheumatoid group (23%) and the scleroderma group (15%). The highest number of reoperations occurred within the traumatic joint disorder group (40%), followed by the rheumatoid group (24%) and the scleroderma group (11%). Multivariate analysis revealed that male sex (P < .01) and hepatic disease (P = .03) were significant risk factors of nonunion. Male sex was also significantly associated with increased reoperation risk (P < .01). CONCLUSION: Risks of nonunions and reoperations after PIPJ arthrodeses are low; however, these findings may guide clinicians and patients in the preoperative decision-making process and help with targeted postoperative surveillance to mitigate these risks.

Targeting Telomere Biology in Acute Lymphoblastic Leukemia.

Increased cell proliferation is a hallmark of acute lymphoblastic leukemia (ALL), and genetic alterations driving clonal proliferation have been identified as prognostic factors. To evaluate replicative history and its potential prognostic value, we determined telomere length (TL) in lymphoblasts, B-, and T-lymphocytes, and measured telomerase activity (TA) in leukocytes of patients with ALL. In addition, we evaluated the potential to suppress the in vitro growth of B-ALL cells by the telomerase inhibitor imetelstat. We found a significantly lower TL in lymphoblasts (4.3 kb in pediatric and 2.3 kb in adult patients with ALL) compared to B- and T-lymphocytes (8.0 kb and 8.2 kb in pediatric, and 6.4 kb and 5.5 kb in adult patients with ALL). TA in leukocytes was 3.2 TA/C for pediatric and 0.7 TA/C for adult patients. Notably, patients with high-risk pediatric ALL had a significantly higher TA of 6.6 TA/C compared to non-high-risk patients with 2.2 TA/C. The inhibition of telomerase with imetelstat ex vivo led to significant dose-dependent apoptosis of B-ALL cells. These results suggest that TL reflects clonal expansion and indicate that elevated TA correlates with high-risk pediatric ALL. In addition, telomerase inhibition induces apoptosis of B-ALL cells cultured in vitro. TL and TA might complement established markers for the identification of patients with high-risk ALL. Moreover, TA seems to be an effective therapeutic target; hence, telomerase inhibitors, such as imetelstat, may augment standard ALL treatment.

Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

Contemporary Knee Osteotomy in the United States: High Tibial Osteotomy and Distal Femoral Osteotomy Have Comparable Complication Rates despite Differing Demographic Profiles.

Knee osteotomies show efficacy in slowing knee osteoarthritis progression and delaying the need for total knee arthroplasty in younger patients. Despite evolutions in indications, techniques, and hardware that have improved outcomes, longitudinal trends demonstrate a decline in high tibial osteotomy (HTO) and distal femoral osteotomy (DFO) use. Unfortunately, knowledge of the current usage and complications associated with HTO and DFO is limited. The purpose of this study was to compare the preoperative demographics and early complication rates of HTO and DFO. We analyzed the HTOs and DFOs performed between 2006 and 2017 using the ACS-NSQIP (American College of Surgeons National Surgical Quality Improvement Program) database. We compared both groups for preoperative patient demographics (sex, age, race, body mass index [BMI]) and health status variables including functional scores, ASA (American Society of Anesthesiologists) scores, smoking status, and other comorbidities. Emergency and elective status of the patient case, length of hospital stay, operation time, and 30-day postoperative complications were also analyzed. After the exclusion criteria were applied, 321 HTO and 295 DFO patients were included in the final analysis. The HTO group had higher proportions of younger (p < 0.001) and male (p < 0.001) patients with higher BMI (p = 0.007). Racial profiles were similar between the two groups (p = 0.575). Preoperatively, those in the HTO group had more functional independence, better physical status scores, and fewer chronic conditions (p < 0.05). There were no statistically significant differences between HTO and DFO in operative time, postoperative complications, readmission, and reoperation. HTO patients, however, had shorter hospital stays (p < 0.001). Although there are differences in preoperative and operative characteristics of HTO and DFO, early postoperative complications are similar for both groups. Therefore, HTO and DFO can be considered safe and effective treatment options for younger patients with symptomatic unicompartmental knee osteoarthritis.

Infrapatellar Fat Pad Resection or Preservation during Total Knee Arthroplasty: A Systematic Review.

Considerations of how to improve postoperative outcomes for total knee arthroplasty (TKA) have included preservation of the infrapatellar fat pad (IPFP). Although the IPFP is commonly resected during TKA procedures, there is controversy regarding whether resection or preservation should be implemented, and how this influences outcomes. Therefore, the purpose of this systematic review was to evaluate how IPFP resection and preservation impacts postoperative flexion, pain, Insall-Salvati Ratio (ISR), Knee Society Score (KSS), patellar tendon length (PTL), and satisfaction in primary TKA. PubMed, EBSCO host, and SCOPUS were queried to retrieve all reports evaluating IPFP resection or preservation during TKA, which resulted into 488 studies. Two reviewers independently reviewed these articles for eligibility based on pre-established inclusion and exclusion criteria. Eleven studies were identified for final analysis, which reported on 11,996 cases. Patient demographics, type of surgical intervention, follow-up duration, and clinical outcome measures were collected and analyzed. Complete resection was implemented in 3,723 cases (31%), partial resection in 5,458 cases (45.5%), and preservation of the IPFP in 2,815 cases (23.5%). Clinical outcome measures included PTL (5 studies), knee flexion (4 studies), pain (6 studies), KSS (3 studies), ISR (3 studies), and patient satisfaction (1 study). No differences were found following IPFP resection for patient satisfaction (p = 0.98), ISR (p > 0.05), and KSS (p > 0.05). There was mixed evidence for PTL, pain, and knee flexion following IPFP resection versus preservation. Studies of shorter follow-up intervals suggested improved pain following resection, while reports of longer follow-up times indicated that resection resulted in increased pain. Given the mixed data available from the current literature, we were unable to conclude that one surgical technique can definitively be considered superior over the other. More extensive research, including randomized controlled trials, is required to better elucidate potential differences between the surgical handling choices. Future studies should focus on patient conditions in which one technique would be best indicated to establish guidelines for best surgical outcomes in those patients.

Does Increasing Patient Complexity Have an Effect on Medical Outcomes and Lengths-of-Stay after Total Knee Arthroplasty?

A greater number of medically complex patients with multiple comorbidities are now more readily considered for total knee arthroplasty (TKA). Therefore, the purpose of this study was to determine whether comorbidity burden, measured with the Elixhauser Comorbidity Index (ECI), correlated with 90-day medical complications and longer in-hospital lengths-of-stay (LOS) in TKA patients. The PearlDiver supercomputer was queried for all primary TKA patients in the Medicare Standard Analytic Files from 2005 to 2014 using International Classification of Disease, 9th edition codes. Patients were included based on ECI scores, ranging from 1 to 5. ECI 1 patients served as the control cohort, while ECI 2, 3, 4, and 5 patients were considered study cohorts. Each study cohort was matched based on age and gender to the control cohort, resulting in a total of 715,398 patients included for analysis (ECI 1, n = 144,072; ECI 2, n = 144,072; ECI 3, n = 144,072; ECI 4, n = 144,072; ECI 5, n = 139,110). Logistic regression analyses were performed to compare 90-day medical complications and Welch's t-tests were performed to compare LOS between the cohorts. Patients with higher ECI scores were more likely to develop medical complications and have longer LOS compared with matched patients in the control cohort. Compared with matched ECI 1 patients, patients with ECI scores of 2 (odds ratio [OR]: 1.19, 95% confidence interval [CI]: 1.14-1.24), 3 (OR: 1.27, 95% CI: 1.21-1.32), 4 (OR: 1.32, 95% CI: 1.27-1.38), and 5 (OR: 1.33, 95% CI: 1.27-1.39) were significantly more likely to develop 90-day medical complications. Additionally, the mean LOS of patients in the ECI 2 (2.59 ± 1.49 vs. 2.73 ± 1.52 days), ECI 3 (2.59 ± 1.49 vs. 2.88 ± 1.51 days; p < 0.001), ECI 4 (2.59 ± 1.49 vs. 3.01 ± 1.56 days; p < 0.001), and ECI 5 (2.61 ± 1.49 vs. 3.14 ± 1.61 days; p < 0.001) groups were significantly longer than the mean LOS in the control ECI 1 group. In an increasingly complex patient population, associations between comorbidities and outcomes after TKA procedures can guide providers on how to modify their pre- and postoperative care. These results demonstrate that higher ECI scores are associated with a greater likelihood of 90-day medical complications and longer in-hospital LOS.

Dynamics of mutations in patients with essential thrombocythemia treated with imetelstat.

In a phase-2 study, the telomerase inhibitor imetelstat induced rapid hematologic responses in all patients with essential thrombocythemia who were refractory or intolerant to prior therapies. Significant molecular responses were achieved within 3-6 months in 81% of patients with phenotypic driver mutations in JAK2, CALR and MPL. Here, we investigated the dynamics of additional somatic mutations in response to imetelstat. At study entry, 50% of patients carried 1-5 additional mutations in the genes ASXL1, CBL, DNMT3A, EZH2, IDH1, SF3B1, TET2, TP53 and U2AF1. Three patients with baseline mutations also had late-emerging mutations in TP53, IDH1 and TET2. Most clones with additional mutations were responsive to imetelstat and decreased with the driver mutation, including the poor prognostic ASXL1, EZH2 and U2AF1 mutations while SF3B1 and TP53 mutations were associated with poorer molecular response. Overall, phenotypic driver mutation response was significantly deeper in patients without additional mutations (P = 0.04) and correlated with longer duration of response. In conclusion, this detailed molecular analysis of highly pretreated and partly resistant patients with essential thrombocythemia reveals a high individual patient complexity. Moreover, imetelstat demonstrates potential to inhibit efficiently co-incident mutations occurring in neoplastic clones in patients with essential thrombocythemia. (ClinicalTrials.gov number, NCT01243073. N Engl J Med 2015; 373:920-928, DOI: 10.1056/NEJMoa1503479.).

Mutations in PIGA cause a CD52-/GPI-anchor-deficient phenotype complicating alemtuzumab treatment in T-cell prolymphocytic leukemia.

OBJECTIVE: Infusional alemtuzumab followed by consolidating allogeneic hematopoietic stem cell transplantation in eligible patients is considered a standard of care in T-cell prolymphocytic leukemia (T-PLL). Antibody selection against CD52 has been associated with the development of CD52-negative leukemic T cells at time of relapse. Clinical implications and molecular mechanisms underlying this phenotypic switch are unknown. METHODS: We performed flow cytometry and real-time-PCR for CD52-expression and next generation sequencing for PIGA mutational analyses. RESULTS: We identified loss of CD52 expression after alemtuzumab treatment in two of 21 T-PLL patients resulting from loss of GPI-anchor expression caused by inactivating mutations of the PIGA gene. One patient with relapsed T-PLL exhibited a single PIGA mutation, causing a CD52-negative escape variant of the initial leukemic cell clone, preventing alemtuzumab-retreatment. The second patient with continued complete remission after alemtuzumab treatment harbored three different PIGA mutations that affected either the non-neoplastic T cell or the mononuclear cell compartment and resulted in symptomatic paroxysmal nocturnal hemoglobinuria. Next generation sequencing of T-PLL cells collected before the initiation of treatment revealed PIGA wild-type sequence reads in all 16 patients with samples available for testing. CONCLUSION: These data indicate that PIGA mutations were acquired during or after completion of alemtuzumab treatment.

Beneficial effects of eculizumab regardless of prior transfusions or bone marrow disease: Results of the International Paroxysmal Nocturnal Hemoglobinuria Registry.

OBJECTIVES: To evaluate the effects of eculizumab on transfusions and thrombotic events (TEs) in patients with and without prior history of transfusion in the International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry. METHODS: Registry patients enrolled on or before January 1, 2018, initiated on eculizumab no more than 12 months prior to enrollment, having known transfusion status for the 12 months before eculizumab initiation, and ≥12 months of Registry follow-up after eculizumab initiation, were included. RESULTS: Eculizumab treatment was associated with a 50% reduction in transfusions in patients with a transfusion history (10.6 units/patient-year before eculizumab vs 5.4 after; P < .0001), with greater reduction observed in those with no history of bone marrow disease vs those with bone marrow disease. Mean lactate dehydrogenase levels decreased from a mean of 6.7 to 1.4 times the upper limit of normal (ULN) in patients with transfusion history and from 5.1 to 1.2 times ULN in those with no transfusion history. TE and major adverse vascular event rates also decreased by 70% in patients with and without history of transfusion. CONCLUSIONS: The benefit of eculizumab therapy does not appear to be limited to any group defined by transfusion history or bone marrow disease history.

Baseline clinical characteristics and disease burden in patients with paroxysmal nocturnal hemoglobinuria (PNH): updated analysis from the International PNH Registry.

The International Paroxysmal Nocturnal Hemoglobinuria (PNH) Registry (NCT01374360) was initiated to optimize patient management by collecting data regarding disease burden, progression, and clinical outcomes. Herein, we report updated baseline demographics, clinical characteristics, disease burden data, and observed trends regarding clone size in the largest cohort of Registry patients. Patients with available data as of July 2017 were stratified by glycosylphosphatidylinositol (GPI)-deficient granulocyte clone size (< 10%, ≥ 10%-< 50%, and ≥ 50%). All patients were untreated with eculizumab at baseline, defined as date of eculizumab initiation or date of Registry enrollment (if never treated with eculizumab). Outcomes assessed in the current analysis included proportions of patients with high disease activity (HDA), history of major adverse vascular events (MAVEs; including thrombotic events [TEs]), bone marrow failure (BMF), red blood cell (RBC) transfusions, and PNH-related symptoms. A total of 4439 patients were included, of whom 2701 (60.8%) had available GPI-deficient granulocyte clone size data. Among these, median clone size was 31.8% (1002 had < 10%; 526 had ≥ 10%-< 50%; 1173 had ≥ 50%). There were high proportions of patients with HDA (51.6%), history of MAVEs (18.8%), BMF (62.6%), RBC transfusion (61.3%), and impaired renal function (42.8%). All measures except RBC transfusion history significantly correlated with GPI-deficient granulocyte clone size. A large proportion of patients with GPI-deficient granulocyte clone size < 10% had hemolysis (9.7%), MAVEs (10.2%), HDA (9.1%), and/or PNH-related symptoms. Although larger GPI-deficient granulocyte clone sizes were associated with higher disease burden, a substantial proportion of patients with smaller clone sizes had history of MAVEs/TEs.

Long-term outcome of a randomized controlled study in patients with newly diagnosed severe aplastic anemia treated with antithymocyte globulin and cyclosporine, with or without granulocyte colony-stimulating factor: a Severe Aplastic Anemia Working Party Trial from the European Group of Blood and Marrow Transplantation.

This follow-up study of a randomized, prospective trial included 192 patients with newly diagnosed severe aplastic anemia receiving antithymoglobulin and cyclosporine, with or without granulocyte colony-stimulating factor (G-CSF). We aimed to evaluate the long-term effect of G-CSF on overall survival, event-free survival, probability of secondary myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML), clinical paroxysmal nocturnal hemoglobinuria, relapse, avascular osteonecrosis and chronic kidney disease. The median follow-up was 11.7 years (95% CI, 10.9-12.5). The overall survival rate at 15 years was 57±12% in the group given G-CSF and 63±12% in the group not given G-CSF (P=0.92); the corresponding event-free survival rates were 24±10% and 23±10%, respectively (P=0.36). In total, 9 patients developed MDS or AML, 10 only a clonal cytogenetic abnormality, 7 a solid cancer, 18 clinical paroxysmal nocturnal hemoglobinuria, 8 osteonecrosis, and 12 chronic kidney disease, without any difference between patients treated with or without G-CSF. The cumulative incidence of MDS, AML or isolated cytogenetic abnormality at 15 years was 8.5±3% for the G-CSF group and 8.2±3% for the non-G-CSF group (P=0.90). The cumulative incidence of any late event including myelodysplastic syndrome or acute myeloid leukemia, isolated cytogenetic abnormalities, solid cancer, clinical paroxysmal nocturnal hemoglobinuria, aseptic osteonecrosis, chronic kidney disease and relapse was 50±12% for the G-CSF group and 49±12% for the non-G-CSF group (P=0.65). Our results demonstrate that it is unlikely that G-CSF has an impact on the outcome of severe aplastic anemia; nevertheless, very late events are common and eventually affect the prognosis of these patients, irrespectively of their age at the time of immunosuppressive therapy (NCT01163942).

Cold agglutinin disease: current challenges and future prospects.

Cold agglutinin disease (CAD) is a complement-dependent, classical pathway-mediated immune hemolytic disease, accounting for 15-25% of autoimmune hemolytic anemia, and at the same time, a distinct clonal B-cell lymphoproliferative disorder of the bone marrow. The disease burden is often high, but not all patients require pharmacological treatment. Several therapies directed at the pathogenic B-cells are now available. Rituximab plus bendamustine or rituximab monotherapy should be considered first-line treatment, depending on individual patient characteristics. Novel treatment options that target the classical complement pathway are under development and appear very promising, and the C1s inhibitor sutimlimab is currently being investigated in two clinical Phase II and III trials. These achievements have raised new challenges and further prospects, which are discussed. Patients with CAD requiring therapy should be considered for clinical trials.

Design and development of a disease-specific quality of life tool for patients with aplastic anaemia and/or paroxysmal nocturnal haemoglobinuria (QLQ-AA/PNH)-a report on phase III.

To date, instruments to measure quality of life (QoL) specifically for patients with acquired aplastic anaemia (AA) and paroxysmal nocturnal haemoglobinuria (PNH) are lacking altogether. As a consequence, this issue is either underevaluated or alternatively, instruments originally designed for cancer patients are being used. We therefore started to systematically develop a AA/PNH-specific QoL (QLQ-AA/PNH) instrument in these ultra-rare diseases according to European Organisation for Research and Treatment of Cancer (EORTC) guidelines. While phases I and II of the process have previously been published, we now report on the resulting instrument (phase III of this process). As part of the phase III of the evaluation process, we approached patients through physicians, patient support groups, and patient conferences. After participants completed the preliminary questionnaire and reported socio-demographic data, they were interviewed in person or via phone with a debriefing interview to find out whether the items were relevant, easy to understand, and acceptable to patients and whether there was anything missing in the questionnaire. We hypothesised what items could be combined into a scale and calculated Cronbach's alpha to define its preliminary internal consistency. After definition of a priori criteria to keep or delete items, a group of six experts met in person, discussed the results, and decided on in- or exclusion. A total of 48 patients were enrolled, 21 of those suffered from AA (44%), 13 from PNH (27%), and 14 from AA/PNH syndrome (29%). The median time to complete the 69 items was 10 min (range 5-20), mean time 11 min. The compliance criterion (> 95% completion) was fulfilled by 57 items. Twenty-three items were mentioned as especially relevant by ≥ 2% of the patients. Cronbach's alpha of the hypothesised scales ranged from 0.63 (social support) to 0.92 (fear of progression and illness intrusiveness). Finally, 47 items were kept; 16 were deleted, and 5 were changed, while 1 item expanded. This resulted in 54 items in total. As no issues were mentioned to lacking by a minimum of five patients, no items were added to the questionnaire. After completion, the AA/PNH-QoL tool (QLQ-AA/PNH) was translated according to EORTC guidelines into English, French, and Italian. For patients with PNH and AA until now, the standard assessment for QoL was to use the EORTC Quality of Life Questionnaire (QLQ-C30) or the Functional Assessment of Chronic Illness Therapy Fatigue Instrument (FACIT-Fatigue). We herewith present a new instrument aimed to be better tailored to the needs of PNH and AA patients. The anticipated fourth development phase will be performed for psychometric validation; however, we already explored the internal consistency of the hypothesised scales and found the results to be very good. Hence, the new QLQ-AA/PNH with 54 items can be used in trials and clinical studies from now on, according to EORTC strategy even if the scoring algorithm at this point is preliminary and the QLQ-AA/PNH might change slightly after phase IV. This is important, as there are no other disease-specific instruments available for AA/PNH patients right now.

Immunosuppressive therapy (IST) in adult patients with acquired aplastic anemia (AA): A single-center experience over the past 15 years.

OBJECTIVE: Immunosuppressive therapy (IST) with horse anti-thymocyte globulin (hATG) and cyclosporine (CsA) is considered one of the first-line therapies in patients (pts) with acquired aplastic anemia (AA). METHODS: In our single-center, retrospective analysis response rates (RRs) to ATG/CsA at a minimum of 6 mo were evaluated in 67 treatment-naïve (TN) AA pts (52.2% (35/67) females; median age 45 y (range 18-89 y)) being treated at the West German Cancer Center at the Department of Hematology at the University Hospital of Essen between April 2000 and December 2015. RESULTS: Overall 6 mo RRs in TN pts following ATG/CsA were 67.2% (45/67) (5-year OS: 79.5%). In TN hATG-treated pts 6 mo RRs were 75.5% (37/49) (5-year OS: 81%) compared to 44.4% (8/18) (5-year OS 73.5%) following rabbit ATG (rATG). Response to ATG/CsA was dependent of age, absolute reticulocyte count (ARC), and disease severity. Six mo RRs to salvage ATG/CsA in relapsed/refractory (R/R) pts were 37.5% (6/16). CONCLUSION: Our data independently confirm the findings of previous studies that hATG/CsA is superior to rATG/CsA in TN pts. The lack of hATG availability should not result in abstaining it from an indicated ATG therapy, even though ATGAM® is not registered in Germany.

The Effect of Body Mass Index on 30-day Complications After Revision Total Hip and Knee Arthroplasty.

BACKGROUND: We aimed to explore the effect of body mass index (BMI) on 30-day complications after aseptic revision total knee arthroplasty (rTKA) and aseptic revision total hip arthroplasty (rTHA), considering BMI as both a categorical and continuous variable. METHODS: A total of 18,866 patients (9093 rTHA and 9773 rTKA) patients were included for analysis using the American College of Surgeons National Surgical Quality Improvement Project database. Thirty-day rates of readmissions, reoperations, and major and minor complications were compared between different weight categories (overweight: BMI >25 and ≤30 kg/m2; obese: BMI >30 and ≤40 kg/m2; morbidly obese: BMI >40 kg/m2) and the normal weight category (BMI >18.5 and ≤25 kg/m2) using multivariate regression models. Spline regression models were created to study BMI as a continuous variable. RESULTS: Both readmission rates and reoperation rates increased for rTKA as BMI increased (P < .005). There was a linear relationship between BMI and readmission rates for rTKA. Morbid obesity was associated with an increased reoperation rate for rTHA on univariate analysis (P = .022); however, multivariate analysis showed no statistically significant increase in readmission or reoperation rates as BMI increased for rTHA. CONCLUSIONS: The relationship between BMI and complications after revision total joint arthroplasty is a J-shaped curve with the lowest rates of complications occurring around a BMI of 30 kg/m2. The relationship between BMI and perioperative complications is stronger for revision TKA as opposed to revision THA.

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study.

Ravulizumab, a new complement component C5 inhibitor administered every 8 weeks, was noninferior to eculizumab administered every 2 weeks in complement-inhibitor-naive patients with paroxysmal nocturnal hemoglobinuria (PNH). This study assessed noninferiority of ravulizumab to eculizumab in clinically stable PNH patients during previous eculizumab therapy. In this phase 3, open-label, multicenter study, 195 PNH patients on labeled-dose (900 mg every 2 weeks) eculizumab for >6 months were randomly assigned 1:1 to switch to ravulizumab (n = 97) or continue eculizumab (n = 98). Primary efficacy end point was percentage change in lactate dehydrogenase (LDH) from baseline to day 183. Key secondary end points included proportion of patients with breakthrough hemolysis, change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score, transfusion avoidance, and stabilized hemoglobin. In 191 patients completing 183 days of treatment, ravulizumab was noninferior to eculizumab (P inf < .0006 for all end points), including percentage change in LDH (difference, 9.21% [95% confidence interval (CI), -0.42 to 18.84], P = .058 for superiority), breakthrough hemolysis (difference, 5.1 [95% CI, -8.89 to 18.99]), change in FACIT-Fatigue score (difference, 1.47 [95% CI, -0.21 to 3.15]), transfusion avoidance (difference, 5.5 [95% CI, -4.27 to 15.68]), and stabilized hemoglobin (difference, 1.4 [95% CI, -10.41 to 13.31]). The most frequently reported adverse event was headache (26.8%, ravulizumab; 17.3%, eculizumab). No meningococcal infections or discontinuations due to adverse events occurred. Patients with PNH may be safely and effectively switched from labeled-dose eculizumab administered every 2 weeks to ravulizumab administered every 8 weeks. This trial was funded by Alexion Pharmaceuticals, Inc., and is registered at www.clinicaltrials.gov as #NCT03056040.