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 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. opens in new tab.

Activating KIR Haplotype Influences Clinical Outcome Following HLA-Matched Sibling Hematopoietic Stem Cell Transplantation.

This is the peer reviewed version of the following article: Heatley, S. L., Mullighan, C. G., Doherty, K., Danner, S., O'Connor, G. M., Hahn, U., . . . Brooks, A. G. (2018). Activating KIR Haplotype Influences Clinical Outcome Following HLA-Matched Sibling Hematopoietic Stem Cell Transplantation. HLA, 92(2), which has been published in final form at https://doi.org/10.1111/tan.13327. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived VersionsNatural killer cells are thought to influence the outcome of hematopoietic stem cell transplant (HSCT), impacting on relapse, overall survival, graft versus host disease and the control of infection, in part through the complex interplay between the large and genetically diverse killer immunoglobulin-like receptor (KIR) family and their ligands. This study examined the relationship between KIR gene content and clinical outcomes including the control of opportunistic infections such as cytomegalovirus in the setting of human leucocyte antigen (HLA)-matched sibling HSCT in an Australian cohort. The presence of the KIR B haplotype which contain more activating receptors in the donor, in particular centromeric B haplotype genes (Cen-B), was associated with improved overall survival of patients with acute myeloid leukemia (AML) undergoing sibling HSCT and receiving myeloablative conditioning. Donor Cen-B haplotype was also associated with reduced acute graft versus host disease grades II-IV whereas donor telomeric-B haplotype was associated with decreased incidence of CMV reactivation. In contrast, we were not able to demonstrate a reduced rate of relapse when the donor had KIR Cen-B, however relapse with a donor Cen-A haplotype was a competing risk factor to poor overall survival. Here we show that the presence of donor activating KIR led to improved outcome for the patient, potentially through reduced relapse rates and decreased incidence of acute GvHD translating to improved overall survival

Latin America: the next region for haematopoietic transplant progress

Haematopoietic cell transplant activity in the 28 countries comprising Latin America is poorly defined. We conducted a voluntary survey of members of the Latin American Bone Marrow Transplantation Group regarding transplant activity 2009–2012. Collated responses were compared with data of transplant rates from the Worldwide Network for Blood and Marrow Transplantation for other geographic regions. Several socio-economic variables were analysed to determine correlations with transplant rates. In total, 94 teams from 12 countries reported 11519 transplants including 7033 autotransplants and 4486 allotransplants. Annual activity increased from 2517 transplants in 2009 to 3263 in 2012, a 30% increase. Median transplants rate (transplant per million inhabitants) in 2012 was 64 (autotransplants, median 40; allotransplants, median 24). This rate is substantially lower than that in North America and European regions (482 and 378) but higher than that in the Eastern Mediterranean and Asia Pacific regions (30 and 45). However, the Latin America transplant rate is 5–8-fold lower than that in America and Europe, suggesting a need to increase transplant availability. Transplant team density in Latin America (teams per million population; 1.8) is 3–4-fold lower than that in North America (6.2) or Europe (7.6). Within Latin America, there is substantial diversity in transplant rates by country partially explained by diverse socio-economic variables including per capita gross national income, health expenditure and physician density. These data should help inform future health-care policy in Latin America

Comparing Outcomes with Bone Marrow or Peripheral Blood Stem Cells as Graft Source for Matched Sibling Transplants in Severe Aplastic Anemia across Different Economic Regions

Bone marrow (BM) is the preferred graft source for hematopoietic stem cell transplantation (HSCT) in severe aplastic anemia (SAA) compared to mobilized peripheral blood stem cells (PBSC). We hypothesized that this recommendation may not apply to those regions where patients present later in their disease course, with heavier transfusion load and with higher graft failure rates. Patients with SAA who received HSCT from an HLA-matched sibling donor from 1995 to 2009 and reported to the Center for International Blood and Marrow Transplant Research or the Japan Society for Hematopoietic Cell Transplantation were analyzed. The study population was categorized by gross national income per capita (GNI) and region/countries into four groups. Groups analyzed were high income countries (HIC), which were further divided into US-Canada (N=486) and other HIC (N=1264), upper middle-income (UMIC) (N=482), and combined lower middle, low income countries (LM-LIC) (N=142). In multivariate analysis, overall survival (OS) was highest with BM as graft source in HIC compared to PBSC in all countries or BM in UMIC or LM-LIC (p<0.001). There was no significant difference in OS between BM and PBSC in UMIC (p=0.32) or LM-LIC (p=0.23). In LM-LIC the 28-day neutrophil engraftment was higher with PBSC compared to BM (97% vs. 77%, p<0.001). Chronic GVHD was significantly higher with PBSC in all groups. Whereas BM should definitely be the preferred graft source for HLA-matched sibling HSCT in SAA, PBSC may be an acceptable alternative in countries with limited resources when treating patients at high risk of graft failure and infective complications

Utility of clinical comprehensive genomic characterization for diagnostic categorization in patients presenting with hypocellular bone marrow failure syndromes

Bone marrow failure (BMF) related to hypoplasia of hematopoietic elements in the bone marrow is a heterogeneous clinical entity with a broad differential diagnosis including both inherited and acquired causes. Accurate diagnostic categorization is critical to optimal patient care and detection of genomic variants in these patients may provide this important diagnostic and prognostic information. We performed real-time, accredited (ISO15189) comprehensive genomic characterization including targeted sequencing and whole exome sequencing in 115 patients with BMF syndrome (median age 24 years, range 3 months - 81 years). In patients with clinical diagnoses of inherited BMF syndromes, acquired BMF syndromes or clinically unclassifiable BMF we detected variants in 52% (12/23), 53% (25/47) and 56% (25/45) respectively. Genomic characterization resulted in a change of diagnosis in 30/115 (26%) including the identification of germline causes for 3/47 and 16/45 cases with pre-test diagnoses of acquired and clinically unclassifiable BMF respectively. The observed clinical impact of accurate diagnostic categorization included choice to perform allogeneic stem cell transplantation, disease-specific targeted treatments, identification of at-risk family members and influence of sibling allogeneic stem cell donor choice. Multiple novel pathogenic variants and copy number changes were identified in our cohort including in TERT, FANCA, RPS7 and SAMD9. Whole exome sequence analysis facilitated the identification of variants in two genes not typically associated with a primary clinical manifestation of BMF but also demonstrated reduced sensitivity for detecting low level acquired variants. In conclusion, genomic characterization can improve diagnostic categorization of patients presenting with hypoplastic BMF syndromes and should be routinely performed in this group of patients

Idarubicin dose escalation during consolidation therapy for adult acute myeloid leukemia

Purpose Higher doses of the anthracycline daunorubicin during induction therapy for acute myeloid leukemia (AML) have been shown to improve remission rates and survival. We hypothesized that improvements in outcomes in adult AML may be further achieved by increased anthracycline dose during consolidation therapy. Patients and Methods Patients with AML in complete remission after induction therapy were randomly assigned to receive two cycles of consolidation therapy with cytarabine 100 mg/m daily for 5 days, etoposide 75 mg/m daily for 5 days, and idarubicin 9 mg/m daily for either 2 or 3 days (standard and intensive arms, respectively). The primary end point was leukemia-free survival (LFS). Results Two hundred ninety-three patients 16 to 60 years of age, excluding those with core binding factor AML and acute promyelocytic leukemia, were randomly assigned to treatment groups (146 to the standard arm and 147 to the intensive arm). Both groups were balanced for age, karyotypic risk, and FLT3–internal tandem duplication and NPM1 gene mutations. One hundred twenty patients in the standard arm (82%) and 95 patients in the intensive arm (65%) completed planned consolidation (P, .001). Durations of severe neutropenia and thrombocytopenia were prolonged in the intensive arm, but there were no differences in serious nonhematological toxicities. With a median follow-up of 5.3 years (range, 0.6 to 9.9 years), there was a statistically significant improvement in LFS in the intensive arm compared with the standard arm (3-year LFS, 47% [95% CI, 40% to 56%] v 35% [95% CI, 28% to 44%]; P = .045). At 5 years, the overall survival rate was 57% in the intensive arm and 47% in the standard arm (P = .092). There was no evidence of selective benefit of intensive consolidation within the cytogenetic or FLT3–internal tandem duplication and NPM1 gene mutation subgroups. Conclusion An increased cumulative dose of idarubicin during consolidation therapy for adult AML resulted in improved LFS, without increased nonhematologic toxicity

Normalisation of haemoglobin and control of breakthrough haemolysis with increased frequency pegcetacoplan dosing in treated paroxysmal nocturnal haemoglobinuria

Abstract Paroxysmal nocturnal haemoglobinura is an acquired life‐threatening haemolytic condition, which is generally well controlled with terminal complement blockade with eculizumab. Whilst almost all patients treated with terminal complement inhibitors develop extravascular haemolysis, only a small proportion of these results in symptomatic anaemia limiting their activities and requiring red cell transfusion. This case highlights the potential role for the C3 inhibitor, pegcetacoplan, in controlling both intravascular and extravascular haemolysis, and is the first case to report on the use of additional doses of pegcetacoplan to control breakthrough haemolysis