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Idiopathic thrombocytopenic purpura (ITP), an autoimmune hematologic disorder characterized by severe platelet count reduction, can be treated with romiplostim. However, post-marketing safety and effectiveness data for romiplostim in Japan are scarce. This prospective, observational, post-marketing Specified Use-Results Survey evaluated the real-world safety and effectiveness of romiplostim for 2 years. All patients treated with romiplostim during the survey period were eligible. Of the 1622 patients in the safety analysis set, 94.08% (1526/1622) had chronic ITP. The mean single dose of romiplostim was stable after 12 weeks and remained < 6 μg/kg in approximately 70% of patients until 104 weeks. Within 2 years, 14.92% of patients discontinued romiplostim because of adverse events, while 6.47% discontinued because of suspected adverse drug reactions. In contrast, 14.00% of patients discontinued romiplostim because of symptom improvement. Before romiplostim initiation, platelet count was < 2.0 × 10 4 /µL in 60.54% of patients, and the mean platelet count was 2.84 ± 5.76 × 10 4 /µL. Platelet count was 9.19 ± 13.01 × 10 4 /µL after 4 weeks, and remained between 10.34 ± 10.72 and 12.38 ± 12.63 × 10 4 /µL from 8 to 104 weeks of treatment. No specific concerns were revealed regarding the safety and effectiveness of romiplostim in chronic ITP; the findings demonstrated a favorable risk–benefit balance for romiplostim in this population. Trial registration : UMIN000047864 ( www.umin.ac.jp/ctr ).

Recent sequencing studies demonstrated the MYD88 L265P mutation in more than 70% of primary central nervous system lymphomas (PCNSL), and the clinical significance of this mutation has been proposed as diagnostic and prognostic markers in PCNSL. In contrast, mutational analyses using cell‐free DNAs have been reported in a variety of systemic lymphomas. To investigate how sensitively the MYD88 L265P mutation can be identified in cell‐free DNA from PCNSL patients, we carried out droplet digital PCR (ddPCR) and targeted deep sequencing (TDS) in 14 consecutive PCNSL patients from whom paired tumor‐derived DNA and cell‐free DNA was available at diagnosis. The MYD88 L265P mutation was found in tumor‐derived DNA from all 14 patients (14/14, 100%). In contrast, among 14 cell‐free DNAs evaluated by ddPCR (14/14) and TDS (13/14), the MYD88 L265P mutation was detected in eight out of 14 (ddPCR) and in 0 out of 13 (TDS) samples, implying dependence on the detection method. After chemotherapy, the MYD88 L265P mutation in cell‐free DNAs was traced in five patients; unexpectedly, the mutations disappeared after chemotherapy was given, and they remained undetectable in all patients. These observations suggest that ddPCR can sensitively detect the MYD88 L265P mutation in cell‐free DNA and could be used as non‐invasive diagnostics, but may not be applicable for monitoring minimal residual diseases in PCNSL. Our findings might provide new perspectives on the utility of ddPCR‐based detection of L265P MyD88 mutations in cell‐free DNAs as a non‐invasive diagnostic marker of PCNSL.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening blood disorder characterized by hemolysis and resulting in anemia and fatigue. Current therapies for PNH in Japan rely on complement inhibitors targeting the C5 component of the complement. However, the disease burden of Japanese patients with PNH treated with C5 inhibitors (C5i) remains unclear. To investigate this topic, we conducted a cross-sectional survey study that included 59 Japanese patients with PNH treated with C5i. Although many participants received C5i for 1 year or longer, the mean hemoglobin (Hb) level was 10.2 g/dL. Fatigue and shortness of breath were the most common symptoms at the time of diagnosis and survey. In addition, patients with Hb levels ≥ 10.5 g/dL also reported fatigue, depression and reduced quality of life, albeit to a lesser extent. These results suggest that a substantial burden of illness remains in patients with C5i-treated PNH, likely resulting in low quality of life and effects of symptoms on daily life. This study contributes to understanding the unmet needs of the current therapies for PNH, highlighting the need for novel therapeutics.

The advent of recycling antibodies, leveraging pH-dependent antigen binding and optimized FcRn interaction, has advanced the field of antibody therapies, enabling extended durability and reduced dosages. Eculizumab (Soliris®) demonstrated the efficacy of C5 inhibitors for paroxysmal nocturnal hemoglobinuria (PNH), while its derivative, ravulizumab (Ultomiris®), recognized as a recycling antibody, extended the dosing intervals. However, limitations including intravenous administration and inefficacy in patients with the R885H single-nucleotide polymorphism (SNP) in C5 could necessitate alternative solutions. Crovalimab (PiaSky®), a next-generation recycling antibody, overcomes these challenges with innovative charge engineering, achieving the enhanced cellular uptake of C5–crovalimab complexes and targeting a unique C5 epitope, allowing for efficacy regardless of the R885H SNP. This study highlights crovalimab’s distinctive molecular features, showing its eliminated binding to Fcγ receptors and C1q, alongside its optimized antigen binding characteristics. The impact of charge engineering was reconfirmed in mice, demonstrating faster C5 clearance than recycling antibodies. Notably, in the maintenance dosing regimen, crovalimab neutralizes approximately seven C5 molecules per antibody on average. Furthermore, its design also reduces the viscosity to facilitate high-concentration formulations suitable for subcutaneous delivery. Consequently, crovalimab offers a four-weekly subcutaneous injection regimen for PNH, marking a substantial improvement in treatment convenience and potentially transforming patients’ quality of life.

All Japanese patients with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab were enrolled in post-marketing surveillance (PMS) between June 2010 and August 2019 to assess the long-term effectiveness and safety of eculizumab. The reduction in intravascular hemolysis, the change in hemoglobin (Hb) level, and the change in renal function were assessed to determine the effectiveness of eculizumab. The types and frequencies of adverse events (AEs) were assessed to determine its safety. A total of 632 patients were enrolled and the median treatment duration was 3.6 years. Treatment with eculizumab significantly reduced lactate dehydrogenase (LDH) levels and significantly increased Hb levels. These changes were maintained for up to 5 years of treatment. An estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 and higher LDH level at baseline were associated with increases in Hb levels during eculizumab treatment. The overall incidence of any AE was 69.92/100 patient-years. Hemolysis was the most common AE (6.43/100 patient-years). The incidence of infection-related AEs was 20.57/100 patient-years, and included meningococcal infection in three patients (0.12/100 patient-years). This long-term follow-up of patients with PNH demonstrated the sustained effectiveness of eculizumab and supports its well-established safety profile.

T-cell-mediated severe aplastic anemia (SAA) is typically fatal without prompt hematopoietic stem cell transplantation or intensive immunosuppressive therapy. Although rare cases of spontaneous remission have been reported, the underlying mechanisms remain poorly understood. A 24-year-old woman was incidentally found to have mild pancytopenia during a routine workplace health checkup. Over the subsequent 12 months, her pancytopenia gradually worsened, resulting in exertional dyspnea, purpura, and a diagnosis of SAA. Remarkably, her blood counts began to improve spontaneously 11 days after the diagnosis without any treatment or transfusions. She no longer met the criteria for SAA by day 27 and achieved complete hematologic normalization within three months. At 22 months, flow cytometry and targeted sequencing revealed that 69% of her granulocytes lacked the HLA-A*02:01 - C*03:04 - B*40:02 - DRB1*14:54 haplotype due to acquired loss of heterozygosity, while 23% were glycosylphosphatidylinositol-deficient owing to PIGA mutations. Retrospective digital polymerase chain reaction of diagnostic bone marrow demonstrated that nearly all non-lymphoid cells had already been replaced by HLA allele-lacking clones, whereas glycosylphosphatidylinositol-deficient erythrocytes constituted only 0.25%. These findings suggest that hematologic recovery occurred through the selective expansion of mutant hematopoietic stem cells capable of evading persistent T-cell-mediated destruction. Early identification of HLA allele-lacking leukocytes may help predict spontaneous remission and avoid unnecessary intensive therapy in patients with SAA.

Autoimmune and complement-related hematological side effects have been observed with messenger ribonucleic acid (mRNA) vaccines. Here, we report the incidence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-induced hemolysis in patients with paroxysmal nocturnal hemoglobinuria (PNH). We reviewed the medical records of seventeen patients with PNH visiting the University of Tsukuba Hospital who had received two doses of the SARS-CoV-2 mRNA vaccine between May 2021 and November 2021. Twelve patients were being treated with complement inhibitors. The median age of all patients was 62 years (range 29–89 years).; six were males and eleven were females. Fourteen patients received the BNT162b2 vaccine (Pfizer/BioNTech) and three received the mRNA-1273 vaccine (Moderna). The median percentages of PNH clones in erythrocytes and granulocytes were 37.61% (range 8.11–85.71%) and 59.73% (range 3.76–97.82%), respectively. Of the twelve patients receiving complement inhibitors, only one had a hemolytic reaction after vaccination, but it did not meet the definition of breakthrough hemolysis. By contrast, hemolytic attacks were observed in two of the five untreated patients with PNH, and one of them required a blood transfusion. Appropriate administration of complement inhibitors to patients with PNH may prevent hemolysis induced by SARS-CoV-2 mRNA vaccination.

Paroxysmal nocturnal hemoglobinuria (PNH) is a lifelong, clonal hematologic disease posing life-threatening risks if untreated. The prognosis for PNH has improved with the advent of C5 inhibitors, which are now the standard of care where available. As treatment options continue to expand, healthcare providers can better address both PNH management and the impact of treatment on patients' daily lives. To investigate the burden of disease and key factors taken into consideration when patients with PNH choose their preferred treatment, we conducted an in-depth patient interview survey. Of survey participants ( N  = 30), 70.0% were receiving intravenous C5 inhibitors. Notably, 56.7% of all patients reported needing ≥ 1 hospital visit per month, and 46.7% required a day off from work or school for visits (33.3% among those receiving intravenous C5 inhibitors). A frequently reported burden of PNH treatment was financial concern, including the cost of treatment, hospital visits, and the negative impact on income. Additionally, burden related to waiting times and distance from the hospital and the overall time spent on outpatient PNH care were identified with similar results for patients receiving intravenous C5 inhibitors. These results suggest that the time and effort to get to treatment centers and the time required to receive treatment for PNH were critical unmet needs in PNH care. Our study indicates that persistent burdens associated with current PNH care should be taken into account alongside therapeutic effectiveness when making treatment decisions. Further analysis with a larger sample size is required to confirm these findings.