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.
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.
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.
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.).
Mutations in the telomerase complex (TERT and TR) are associated with pulmonary fibrosis and frequent hematologic manifestations. The aim of this study was to characterize the prognosis of lung ...transplantation in patients with TERT or TR mutations.
Patients with documented TERT or TR mutations who received a lung transplant between 2007 and 2013 in France were identified via an exhaustive search of the lung transplantation network, one expert genetic laboratory, and the clinical research network on rare pulmonary diseases.
There were 9 patients (7 men) with TERT (n = 6) or TR (n = 3) mutations who received a single (n = 8) or a double (n = 1) lung transplant for pulmonary fibrosis. Median age was 50 years (range, 35-61 years) at diagnosis and 52 years (range, 37-62 years) at the time of lung transplantation. Thrombocytopenia was present in 7 patients before lung transplantation. After lung transplantation, 6 patients developed myelodysplasia and/or bone marrow failure, directly contributing to death in 4 cases. Anemia was observed in 9 patients, and neutropenia was observed in 3 patients. The median survival after lung transplantation was 214 days (range, 59-1,709 days).
Patients with mutations of the telomerase complex are at high risk of severe hematologic complications after lung transplantation, in particular, bone marrow failure. Specific recommendations should be developed for appropriate guidance regarding hematologic risk assessment before transplantation and management of the post-transplantation immunosuppressive regimen.
Given reports showing a high prevalence of azole resistance in Aspergillus fumigatus, alternatives to azole therapy are discussed when a threshold of 10% of azole-resistant environmental isolates is ...reached. This raises the issue of calculation of this threshold, either on the prevalence of azole-resistant isolates as a whole or on the prevalence of azole-resistant cases in populations at risk of invasive aspergillosis (IA). For isolate evaluation, there are high disparities in routine microbiological procedures for the isolation of A. fumigatus and azole resistance detection. There are also huge differences between the microbiological work-up for diagnosing IA. Some centres rely on galactomannan detection alone without actively trying to culture appropriate samples, which affects reliability of the figures on the prevalence of resistance and thus the threshold of resistance. Moreover, reports from the laboratory could mix up figures from completely different patient populations: frequent azole-resistant isolates from pneumology patients and rare azole-resistant isolates from haematology patients. Therefore, to sum isolates from different specimens and different wards can lead to erroneous calculations for the restricted populations at risk of developing IA. In conclusion, assessing the incidence of azole resistance in A. fumigatus should be based on harmonized consensual microbiological methods and reports should be restricted to IA episodes in identified populations at risk of IA when the issue is to define an operational threshold for modifying recommendations.
The performance of antigen galactomannan (GM) for diagnosing invasive aspergillosis (IA) is hampered by the occurrence of false-positive results. Quantitative PCR has been proposed to improve the ...diagnosis of IA. Therefore, we analyzed the value of performing a PCR test to the GM-positive serum sample. Using a quantitative PCR assay specific for
28S ribosomal DNA, we retrospectively tested 422 GM-positive (Platelia Bio-Rad kit) serum samples collected over 1 year from 147 patients. The cases were classified based on EORTC criteria as "proven," "probable," and "no-IA" before availability of the PCR results. After exclusion of 65 samples for non-reproducibility of GM positivity (
= 62) or PCR inhibition (
= 3), 75 (21.0%) of the remaining 357 samples were PCR-positive. GM and fungal DNA showed a significantly positive correlation (
< 0.0001,
= 0.27, slope = 0.98 ± 0.19). At least one PCR-positive result was observed in 63.3% (31/49) of IA patients and in 13.2% (13/98) of non-IA patients (
< 0.0001). The PCR positivity was also associated with the presence of other microbiological criteria among the 44 patients with IA and complete mycological workup (
= 0.014), as well as a higher mortality rate at six months among the 135 patients with hematological conditions (
= 0.0198). Overall, we found a quantitative correlation between serum GM and circulating DNA with an increased likelihood of IA when both were positive. A PCR-positive result also supported a higher fungal load when GM was already positive. We advocate adding a PCR test for every confirmed GM-positive serum sample.
This prospective longitudinal study examined and compared two measures (prospective and retrospective ones) of post-traumatic growth (PTG) following Hematopoietic Stem-Cell Transplantation (HSCT) and ...their respective relationships with mental health and psychological disposition. We also tested the hypothesis that unwillingness to be in contact with distressing thoughts and feelings-i.e. experiential avoidance-would moderate the relationship between Post-Traumatic Stress Disorder (PTSD) and growth.
This study was carried out with 187 patients. Patients completed the Post-Traumatic Growth Inventory (PTGI) 5 months after HSCT and scales tapping into the five domains of PTGI during hospitalisation and 5 months after HSCT. Mental health and psychological disposition were also assessed prior to hospitalisation. A PTSD scale was administered at the five-month follow-up.
Prospective and retrospective measures of PTG were weakly correlated. Bayesian pre/post-HSCT comparisons in the prospective measure of PTG revealed substantial to very strong decline in four of the five dimensions assessed. Overall, RCI indicated a reliable increase for 5.6% of patients and a reliable decrease for 40.8% of patients. Confirming that retrospective and prospective measures of PTG reflect different processes, they were not related to the same mental health and psychological disposition variables. Moreover, the hypothesis that acquiring positive outcomes from a potentially traumatic experience, such as HSCT, requires direct confrontation with the source of distress was supported in the case of the retrospective measure of growth but not in the case of the prospective measure growth.
Retrospective measures such as the PTGI do not appear to assess actual pre- to post-HSCT change. HSCT seems more linked to psychological decline than to growth.
Weekly blood Toxoplasma gondii DNA screening using real-time quantitative polymerase chain reaction (qPCR) has been implemented in all allogeneic hematopoietic stem cell transplantation (alloHSCT) ...recipients at our hospital. We retrospectively analyzed the consequences of a positive blood qPCR in the management of Toxoplasma infection (TI) and disease (TD).From 2011 to 2020, 52 (4.13%) of 1 257 alloHSCT recipients had at least one positive qPCR, 45 (3.5%) with TI and seven (0.56%) with TD (central nervous system involvement). Forty-four patients were qPCR-positive before day 100, 30 without and 14 with anti-Toxoplasma prophylaxis. Twenty-five of them (56.8%) started or continued prophylactic dosage treatment: all became qPCR-negative, including 20 (80%) receiving only prophylactic dosage treatment. Twenty-four of them (54.5%) received non-prophylactic dosage treatment: qPCR became negative in 22/24 (91.7%), while TI contributed to death in two cases. Six of the eight patients diagnosed after D100 had breakthrough TI or TD. No death was attributable to TI or TD. qPCR kinetics available for 24 patients increased until anti-Toxoplasma treatment began, then decreased with all treatment regimens.Clinical follow-up and qPCR monitoring with quantification of the parasitic load appears a reasonable strategy to avoid TD and to use minimal effective dosage of anti-Toxoplasma treatments.
•Subsequent neoplasms observed in recipients of umbilical cord blood transplantation are rare, although associated with poor survival.•Determining risk factors and lifelong screening for early ...detection of subsequent neoplasms are mandatory to improve survival.
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Subsequent neoplasms (SNs) compromise long-term survivors after hematopoietic cell transplantation. We performed a retrospective analysis of SNs in 10 358 recipients of umbilical cord blood transplantation (UCBT) from 1988 to 2018. SNs developed in 233 patients and 84 were of pediatric age. Indications for UCBT were malignant hematological diseases in 199 patients (85%). Three groups of SNs were observed. Posttransplant lymphoproliferative disorders (PTLD) were reported in 145 patients in a median of 4 months after UCBT. Of these, 9 patients died from relapse, 83 from PTLD, and 24 from transplant-related causes. At last follow-up, 29 were alive; 5-year overall survival (OS) after PTLD diagnosis was 21%. Acute leukemia/myelodysplasia (AL/MDS) was diagnosed in 23 patients in a median of 28 months after UCBT and included 3 donor-cell AL. Four of 23 patients died from relapse of primary disease, 8 from progression of SNs, and 4 from TRM. Seven patients remain alive; the 5-year OS after AL/MDS diagnosis was 36%. Solid tumors (ST) were reported in 65 patients in a median of 54 months after UCBT. Most common tumor sites were lung, thyroid, bone, and soft tissue. A total of 33 patients died (26 owing to ST, 6 to relapse of primary disease, and 1 cause missing). At last follow-up, 32 of 65 patients were alive; the 5-year OS after the diagnosis of ST was 51%. In conclusion, despite their poor outcomes, SNs that occur after UCBT are extremely rare. Identification of risk factors and early detection may help to improve OS.
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