Eculizumab is a humanized monoclonal antibody that targets complement protein C5 and inhibits terminal complement-mediated hemolysis associated with paroxysmal nocturnal hemoglobinuria (PNH). The ...molecular basis for the poor response to eculizumab in a small population of Japanese patients is unclear.
We assessed the sequences of the gene encoding C5 in patients with PNH who had either a good or poor response to eculizumab. We also evaluated the functional properties of C5 as it was encoded in these patients.
Of 345 Japanese patients with PNH who received eculizumab, 11 patients had a poor response. All 11 had a single missense C5 heterozygous mutation, c.2654G → A, which predicts the polymorphism p.Arg885His. The prevalence of this mutation among the patients with PNH (3.2%) was similar to that among healthy Japanese persons (3.5%). This polymorphism was also identified in a Han Chinese population. A patient in Argentina of Asian ancestry who had a poor response had a very similar mutation, c.2653C → T, which predicts p.Arg885Cys. Nonmutant and mutant C5 both caused hemolysis in vitro, but only nonmutant C5 bound to and was blocked by eculizumab. In vitro hemolysis due to nonmutant and mutant C5 was completely blocked with the use of N19-8, a monoclonal antibody that binds to a different site on C5 than does eculizumab.
The functional capacity of C5 variants with mutations at Arg885, together with their failure to undergo blockade by eculizumab, account for the poor response to this agent in patients who carry these mutations. (Funded by Alexion Pharmaceuticals and the Ministry of Health, Labor, and Welfare of Japan.).
Posttransplant cyclophosphamide (PTCy:100 mg/kg) has been increasingly used in allogeneic hematopoietic stem cell transplantation, however, few studies compared different doses of PTCy. We conducted ...two consecutive prospective multicenter phase II studies to evaluate the safety and efficacy of 80 mg/kg of PTCy in 137 patients who underwent HLA-haploidentical peripheral blood stem cell transplantation (haploPBSCT) following reduced-intensity conditioning (RIC). GVHD prophylaxis consisted of PTCy at a dose of 40 mg/kg/day on days 3 and 4, tacrolimus, and mycophenolate mofetil. Neutrophil engraftment was achieved in 97% and 96% in the first and second studies, respectively. The incidences of grades II-IV acute GVHD, III-IV acute GVHD, all grade chronic GVHD, and moderate to severe chronic GVHD at 2 years were 26%, 5%, 35%, and 18% in the first study, and 23%, 1%, 28%, and 15% in the second study, respectively. Overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) at 2 years were 51%, 42%, and 18% in the first study, and 58%, 48%, and 16% in the second study, respectively. The rates of off-immunosuppressants in patients who survived without relapse at 2 years were 83 and 76%. Our results suggest that 80 mg/kg of PTCy is a valid option in haploPBSCT following RIC.
We report here that in chronic lymphocytic leukemia (CLL), the propensity to generate clonal B cells has been acquired already at the hematopoietic stem cell (HSC) stage. HSCs purified from patients ...with CLL displayed lymphoid-lineage gene priming and produced a high number of polyclonal B cell progenitors. Strikingly, their maturation into B cells was restricted always to mono- or oligo-clones with CLL-like phenotype in xenogeneic recipients. These B cell clones were independent of the original CLL clones because they had their own immunoglobulin VDJ genes. Furthermore, they used preferentially VH genes frequently used in human CLL, presumably reflecting the role of B cell receptor signaling in clonal selection. These data suggest that HSCs can be involved in leukemogenesis even in mature lymphoid tumors.
► HSCs in CLL have cell-intrinsic propensity to generate clonal CLL-like B cells ► Abnormal karyotypes are not required for appearance of such B cell clones ► The majority of single HSCs in patients with CLL display lymphoid-lineage priming ► HSCs can be involved in oncogenesis even in mature lymphoid tumors
Objective Gastric endoscopic submucosal dissection (ESD) is currently a standard procedure, and proton pump inhibitors (PPIs) are most commonly used to treat post-ESD ulcers. Vonoprazan, a ...potassium-competitive acid blocker (P-CAB), reportedly inhibits gastric acid secretions more effectively than PPIs. Combination therapy of a PPI plus rebamipide is effective for treating larger ulcers. Our goal was to evaluate the effects of vonoprazan plus rebamipide compared to esomeprazole plus rebamipide for the treatment of post-ESD ulcers. Methods First, vonoprazan plus rebamipide (V group) or esomeprazole plus rebamipide (E group) was orally administered to subjects for eight weeks. We then evaluated the ulcer healing process at four and eight weeks after the procedure using a gastric ulcer stage system and by measuring the ulcer size. Patients A total of 84 patients who underwent ESD for gastric neoplasms between September 2015 and December 2017 in Tsuchiura Kyodo General Hospital were included in this randomized controlled trial. Results The ulcer scar rates at week 4 in the V group (n=43) and E groups (n=39) were 20.9% and 15.4%, while those at week 8 were 90.7% and 92.3%, respectively. The ulcer reduction rates at week 4 in the V and E groups were 94.6% and 93.8%, and those at week 8 were 99.7% and 99.3%, respectively. The ulcer scar rates and reduction rates were not significantly different between the two groups. Conclusion Combination therapy consisting of vonoprazan plus rebamipide was not superior to that of esomeprazole plus rebamipide for post-ESD ulcer healing (UMIN000019516).
Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curable treatment option for adolescent and young adult (AYA) patients with myelodysplastic syndrome (MDS). The study aim was to ...evaluate epidemiological data and identify prognostic factors for AYA patients with MDS undergoing allogeneic HSCT. Here, 645 patients were selected from patients enrolled in a multicenter prospective registry for HSCT from 2000 to 2015. The primary endpoint was 3-year overall survival (OS). Survival rates were estimated using the Kaplan-Meier method. Prognostic factors were identified using the multivariable Cox proportional hazards model. The 3-year OS was 71.2% (95% confidence interval CI: 67.4-74.6%). In multivariable analysis, active disease status (adjusted hazard ratio: 1.54, 95% CI: 1.09-2.18, p = 0.016), poor cytogenetic risk (1.62, 1.12-2.36, p = 0.011), poor performance status (2.01, 1.13-3.56, p = 0.016), human leukocyte antigen (HLA)-matched unrelated donors (2.23, 1.39-3.59, p < 0.001), HLA-mismatched unrelated donors (2.16, 1.09-4.28, p = 0.027), and cord blood transplantation (2.44, 1.43-4.17, p = 0.001) were significantly associated with poor 3-year OS. In conclusion, in AYA patients with MDS the 3-year OS following allogeneic HSCT was 71.2%. Active disease status, poor cytogenetic risk, poor performance status, and donor sources other than related donors were associated with poor 3-year OS.
The disease-specific impact of anti-thymocyte globulin (ATG) in allogeneic hematopoietic cell transplantation (allo-HCT) has not been determined. We retrospectively assessed the impact of ATG in ...allo-HCT using nationwide registry data from the Japan Society for Transplantation and Cellular Therapy. We included patients who received their first allo-HCT between 2007 and 2018 for acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), or malignant lymphoma (ML). In total, 8747 patients were included: 7635 patients did not receive ATG and 1112 patients received ATG as GVHD prophylaxis. The median follow-up period of surviving patients was 1457 days. There was no significant impact of pretransplant ATG on the OS or NRM rates in patients with ALL, AML, or ML. In patients with MDS, the probability of 3-year OS was 53.3% in the non-ATG group and 64.2% in the ATG group (P = 0.001). The cumulative incidence rates of relapse and NRM at 3 years were 14.2% and 30.3% (95% CI 27.2-33.3%), respectively, in the non-ATG group and 17.1% and 18.1% in the ATG group (P = 0.15 and P < 0.001). The same finding was observed in a propensity-score matched cohort. Our study suggests that the clinical benefit of ATG could vary among hematological diseases.
We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of ...clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell–replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus-host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versus-leukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection.
•Significant HLA locus mismatches responsible for transplant-related events were determined in 7898 unrelated marrow donor transplants.•This information provides a rationale for use of an algorithm for unrelated donor selection.
This study aimed to clarify the risk factors and prognosis associated with blood stream infection (BSI) in allogeneic hematopoietic cell transplantation (allo-HCT), and the relationship between BSI ...and acute graft-versus-host disease (aGVHD). This retrospective analysis included 11,098 patients in the Japanese national transplant registry. A total of 2172 patients developed BSI after allo-HCT, with 2332 identified pathogens. The cumulative incidences of BSI were 15.5% at 30 days and 20.9% at 100 days after allo-HCT. In a multivariate analysis, severe (grade III-IV) aGVHD was associated with a higher risk of BSI (vs. grade 0-I aGVHD: hazard ratio HR 3.34 95% confidence interval (CI), 2.85-3.92; P < 0.001). In a multivariate analysis, severe aGVHD before BSI was associated with a higher risk of overall mortality after BSI (vs. grade 0-I aGVHD: HR 2.61 95% CI 2.18-3.11; P < 0.001). In addition, BSI (vs. no-BSI: HR 1.20 95% CI, 1.12-1.29; P < 0.001) and severe aGVHD (vs. grade 0-I aGVHD: HR 1.97 95% CI, 1.83-2.12; P < 0.001) were independent risk factors for overall mortality after allo-HCT. In the setting of allo-HCT, severe aGVHD was associated with increases in both BSI incidence and post-BSI overall mortality. Furthermore, BSI was an independent risk factor for overall mortality.
Many drugs are used for unapproved indications in Japan for post hematopoietic stem cell transplant (HCT) complications. To investigate unapproved or off-label drug usage for graft-versus-host ...disease (GVHD) and virus infections after allogeneic HCT, we analyzed the data of Japanese HCT registry. Between 2006 and 2017, 39,941 adults and children received HCT for a variety of disease and their transplant data were captured in the registry. Among them, 14,687 and 8914 patients receiving treatment for acute and/or chronic GVHD, 24,828 patients with cytomegalovirus (CMV) infection or receiving therapies for CMV, and 4943 who received treatment for other viral infections were included in the analyses of off-label or unapproved drugs. For GVHD, mycophenolate mofetil was the most frequently used off-label drug, followed by beclomethasone, infliximab, and etanercept. For viral infections other than CMV, foscarnet was the most frequently used off-label drug. Cidofovir, which is not approved for use in Japan, was mainly used for adenovirus infection. This study demonstrated that numerous off-label and unapproved drugs have been used as key drugs for GVHD and post-transplant viral infection, and the real world date in the transplant registry may serve as an important asset to regulatory purposes.
PDF
