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Carfilzomib, lenalidomide, and dexamethasone (KRD) therapy is widely used for patients with relapse/refractory multiple myeloma (RRMM). However, the response in patients who underwent assessment for measurable residual disease (MRD) has not been elucidated in a prospective study. We aimed to clarify the response rate and outcome of KRD therapy in patients in RRMM, including those with MRD.Twenty-one consecutive RRMM patients treated with KRD at 4 Japanese Centers between September 2016 and October 2018 were enrolled and assessed for MRD in the bone marrow (cut-off: 1×10The median number of therapy lines before KRD was 3 (range=1-6), and the median number of KRD cycles was 4 (range=1-22). As the best overall response post-KRD therapy, 52% (11/21) of patients achieved a MRD negative complete response, 71% (15/21) achieved stringent complete response/complete response, and 14% (3/21) achieved a very good partial response. MRD negativity was achieved in 12 of 16 (75%) and 14 of 21 (67%) patients during and after KRD treatment, respectively. The 2-year progression-free survival and overall survival from the start of KRD therapy were 100% and 100%, respectively, in MRD-positive cases and 88% and 100%, respectively, in MRD-negative cases (median follow-up=1.8 years). Grade 3/4 toxicities were reported in 15 patients (71%), with thrombocytopenia being the most frequent toxicity (6 patients, 29%).This is the first study that prospectively assessed MRD of patients with RRMM after KRD therapy. KRD treatment achieved a high MRD negativity rate and good outcomes with manageable toxicities.

In immune aplastic anemia (IAA), severe pancytopenia results from the immune-mediated destruction of hematopoietic stem cells. Several autoantibodies have been reported, but no clinically applicable autoantibody tests are available for IAA. We screened autoantibodies using a microarray containing >9000 proteins and validated the findings in a large international cohort of IAA patients (n = 405) and controls (n = 815). We identified a novel autoantibody that binds to the C-terminal end of cyclooxygenase 2 (COX-2, aCOX-2 Ab). In total, 37% of all adult IAA patients tested positive for aCOX-2 Ab, while only 1.7% of the controls were aCOX-2 Ab positive. Sporadic non-IAA aCOX-2 Ab positive cases were observed among patients with related bone marrow failure diseases, multiple sclerosis, and type I diabetes, whereas no aCOX-2 Ab seropositivity was detected in the healthy controls, in patients with non-autoinflammatory diseases or rheumatoid arthritis. In IAA, anti-COX-2 Ab positivity correlated with age and the HLA-DRB1*15:01 genotype. 83% of the >40 years old IAA patients with HLA-DRB1*15:01 were anti-COX-2 Ab positive, indicating an excellent sensitivity in this group. aCOX-2 Ab positive IAA patients also presented lower platelet counts. Our results suggest that aCOX-2 Ab defines a distinct subgroup of IAA and may serve as a valuable disease biomarker.

Objectives Patients with acquired aplastic anemia (AA) without HLA-matched sibling donors or aged >40 years receive immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG). We investigated the relationship between plasma rabbit ATG (r-ATG) concentration and IST response. Methods From May 2012 to October 2017, 81 patients with severe AA who required initial IST were included. A 1:1 block randomization was employed for 2.5 and 3.5 mg/kg doses of r-ATG. Results No significant difference in response rates was observed between the 2.5 and 3.5 mg/kg groups (63% vs. 58%, P = .894). Median r-ATG concentrations on days 14 and 28 after IST were 15.2 (0.0-97.7) and 1.8 (0.0-74.9 µg/mL), respectively. According to r-ATG concentration, response rates were significantly higher in the group with higher r-ATG concentration than in those with lower r-ATG concentration (day 14, 88% vs. 52%; P = .006 and day 28, 79% vs. 46%; P = .005). In multivariate analysis, higher r-ATG concentrations at day 28 were independent predictors of favorable response to IST at 6 months (odds ratio, 0.29; 95% confidence interval, 0.09-0.93; P = .037). Conclusions The present data indicate that higher r-ATG concentration at day 28 resulted in improved IST response.

Although some studies have suggested the effectiveness of hyperbaric oxygen (HBO) therapy for hemorrhagic cystitis (HC) after allogeneic hematopoietic stem cell transplantation (HSCT), the role of HBO has not been established. We compared the treatment outcomes of 8 patients with viral HC (adenovirus [ADV], n = 2; BK virus [BKV], n = 6) treated with HBO (HBO[+]) and 8 patients (ADV, n = 2; BKV, n = 6) treated with conventional therapy (HBO[−]), such as urinary catheterization and intravenous cidofovir. HBO therapy was performed at 2.1 atmospheres for 90 min/day until clinical improvement was achieved. The median number of HBO treatments was 10 (range 8–12). The median duration of HBO treatment was 19.5 days (range 10–23 days). All 8 HBO(+) patients achieved complete remission (CR) at a median of 14.5 days (range 5–25 days). Of the 8 HBO(−) patients, 5 (62.5%) obtained CR and 3 remained symptomatic for 2–6 months. The cumulative incidence of transplant-related mortality at day 100 after allogeneic HSCT was significantly higher in the HBO(−) patients than in the HBO(+) patients (14.2 vs. 0%, P

UNC-93 homolog B1 (UNC93B1) is a key regulator of toll-like receptors (TLRs), pattern recognition receptors that sense invading pathogens and manage the innate immune response and deliver them from the endoplasmic reticulum to their respective endosomal signaling compartments. Several types of TLRs are known to contribute to the inflammatory process after allogeneic hematopoietic stem cell transplantation (SCT), so UNC93B1 might play integral roles there. We investigated the influence of the UNC93B1 single-nucleotide polymorphism (SNP) rs308328 (T>C) on transplant outcomes in a cohort of 237 patients undergoing unrelated HLA-matched bone marrow transplantation (BMT) for hematologic malignancies through the Japan Marrow Donor Program. The donor UNC93B1 C/C genotype was associated with a better 3-year overall survival than the donor UNC93B1 C/T or T/T genotype. An analysis of the UNC93B1 rs308328 genotype may therefore be useful for selecting the donor, estimating the prognosis, and creating therapeutic strategies after allogeneic SCT.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder caused by a mutation of the X-linked PIGA gene, resulting in a deficient expression of glycosylphosphatidylinositol (GPI)-anchored proteins. While large clonal expansions of GPI(-) cells cause hemolytic symptoms, tiny GPI(-) cell populations can be found in healthy individuals and remain miniscule throughout life. The slight expansion of PNH clones often occurs in patients with acquired aplastic anemia (AA), an autoimmune bone marrow (BM) failure caused by autoreactive cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells (HSPCs). The presence of PNH clones is thought to represent the immune pathophysiology of BM failure and be derived from GPI(-) HSPCs that evaded immune attack against HSPCs. However, which mechanisms underlie the selection of GPI(-) HSPCs as well as their overwhelming clonal expansion remains unclear. Ancestral or secondary somatic mutations in GPI(-) HSPCs contribute to the clonal expansion of the aberrant HSPCs in certain patients with PNH; however, it remains unclear whether such driver mutations are responsible for clonal expansion of all patients. Increased sensitivity to TGF-β in GPI(-) HSPCs partly explains the predominance of GPI(-) erythrocytes in immune-mediated BM failure. CD4

A 31-year-old man underwent allogeneic bone marrow transplantation (BMT) for the treatment of transfusion-dependent aplastic anemia (AA) after conditioning with a regimen including fludarabine, cyclophosphamide, and antithymocyte globulin. The patient developed a late graft rejection on day 103 and showed autologous hematologic recovery not requiring transfusions on day 76. Peripheral blood leukocytes were of 100% recipient origin on day 103, and paroxysmal nocturnal hematuria (PNH)-type granulocytes were detected 5 months after BMT. The patient suddenly experienced hemolytic symptoms triggered by cold stimulation, and was diagnosed with autoimmune hemolytic anemia (AIHA) 37 months after BMT. Although anemia was ameliorated by prednisolone (PSL), hemolytic attacks repeatedly occurred, which became refractory to corticosteroids. Moreover, the patient underwent a splenectomy for the steroid-resistant AIHA and achieved AIHA remission without the need for PSL at 53 months after BMT. The immune tolerance breakdown to erythrocyte antigens was thought to have occurred due to various factors including immune AA, medication, cold stimulation, and infection, leading to AIHA development in this case.

Objective In Japan, immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG), and cyclosporine A (CsA) is the standard of care in patients with aplastic anemia (AA) who are not indicated for stem-cell transplantation, although some patients may experience relapse. This study assessed the efficacy and safety of eltrombopag in combination with rabbit-ATG/CsA in IST-naive patients with non-severe or severe AA in Japan. Methods In this non-randomized, open-label, single-arm, phase II study, rabbit-ATG/CsA and eltrombopag were initiated on Days 1 and 15 (±3 days), respectively, and continued for ≥26 weeks; rabbit-ATG was given for 5 days (Days 1 to 5). The primary endpoint was the overall response rate (ORR) at Week 26. Patients Patients with AA who were IST-naive and ≤70 years old or between 71 and 75 years old based on the recommendation of the investigator were enrolled in Japan. Results Of the 11 enrolled patients, 10 started treatment with eltrombopag. The ORRs at Weeks 26 and 52 were 70.0% and 60.0%, respectively. The ORR at Week 26 was 100% (all 3 patients) in patients with non-severe AA and 57.1% (4/7) in patients with severe AA. Among transfusion-dependent patients, 66.7% (4/6) and 62.5% (5/8) became red blood cell- and platelet-transfusion independent, respectively. The most common adverse events were nausea and headache. No deaths or hematologic malignancies were reported. A cytogenetic abnormality was reported in one patient. Conclusion This study confirmed the clinical benefit of eltrombopag plus rabbit-ATG/CsA in IST-naive patients with non-severe or severe AA in Japan.

Idiopathic pure red cell aplasia (PRCA) and secondary PRCA associated with thymoma and large granular lymphocyte leukemia are generally considered to be immune-mediated. The PRCA2004/2006 study showed that poor responses to immunosuppression and anemia relapse were associated with death. PRCA may represent the prodrome to MDS. Thus, clonal hematopoiesis may be responsible for treatment failure. We investigated gene mutations in myeloid neoplasm-associated genes in acquired PRCA. We identified 21 mutations affecting amino acid sequences in 11 of the 38 adult PRCA patients (28.9%) using stringent filtering of the error-prone sequences and SNPs. Four PRCA patients showed 7 driver mutations in TET2, DNMT3A and KDM6A, and 2 PRCA patients carried multiple mutations in TET2. Five PRCA patients had mutations with high VAFs exceeding 0.3. These results suggest that clonal hematopoiesis by stem/progenitor cells might be related to the pathophysiology of chronic PRCA in certain adult patients.

Leukocytes that lack expression of HLA alleles are frequently detected in patients with acquired aplastic anemia (AA) who respond to immunosuppressive therapy, although the exact mechanisms underlying the HLA loss and HLA allele repertoire likely to acquire loss-of-function mutations are unknown. We identified a common nonsense mutation at codon 19 (c.19C>T, p.R7X) in exon 1 (Exon1mut) of different HLA-A and -B alleles in HLA-lacking granulocytes from AA patients. A droplet digital polymerase chain reaction assay capable of detecting as few as 0.07% Exon1mut HLA alleles in total DNA revealed that the mutation was present in 29% (101/353) of AA patients, with a median allele frequency of 0.42% (range, 0.071% to 21.3%). Exon1mut occurred in only 12 different HLA-A (n=4) and HLA-B (n=8) alleles, including B*40:02 (n=31) and A*02:06 (n=15), which correspond to four HLA class I supertypes (A02, A03, B07, and B44). The percentages of patients who possessed at least one of these 12 HLA alleles were significantly higher in the 353 AA patients (92%, P

To determine whether antigen presentation by HLA-DR on hematopoietic stem progenitor cells (HSPCs) is involved in the development of acquired aplastic anemia (AA), we studied the HLA-DR expression on CD45

Acquired chronic pure red cell aplasia (PRCA) develops idiopathically or in association with other medical conditions, including T cell large granular lymphocytic leukemia (T-LGLL) and thymoma. T cell dysregulation is considered a cardinal pathogenesis of PRCA, but genetic-phenotypic associations in T cell abnormalities are largely unclear. We evaluated an extended cohort of 90 patients with acquired PRCA, including 26 with idiopathic, 36 with T-LGLL-associated and 15 with thymoma-associated PRCA, for their T cell immuno-phenotypes, clonalities and STAT3 mutations. TCR repertoire skewing of CD8

Objectives Eltrombopag, a thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA). Cytomorphologic changes in bone marrow after eltrombopag administration are still unclear. This study examined the effect of eltrombopag on cytomorphologic findings using data from prior phase 2 studies (E1201 and E1202). Methods Microscopic examinations were performed in 31 patients with AA (E1201 [n = 21], E1202 [n = 10]). The relationship between hematologic improvement and morphologic findings was also investigated. Results In 5 patients (E1201 [n = 3], E1202 [n = 2]), the bone marrow blast count increased after initiation of eltrombopag treatment compared with screening values. The blast count was less than 5%, and the increase in bone marrow blasts was transient in all 4 patients who had bone marrow examinations at follow-up. In 8 patients (E1201 [n = 5], E1202 [n = 3]), dysplastic forms of megakaryocytes were found in the bone marrow following treatment initiation. Dysmegakaryopoiesis of 10% or more was found in 3 patients. None of the patients revealed micromegakaryocytes. Ten patients showed an increase in bone marrow blasts and/or dysmegakaryopoiesis following treatment initiation. Nine of 10 patients showed hematologic improvement in 1 or more lineages. Conclusions Dysmegakaryopoiesis without micromegakaryocytes and a transient increase of less than 5% in bone marrow blast count may be signs of hematologic improvement with eltrombopag for patients with AA.

The plasticity of induced pluripotent stem cells (iPSCs) with the potential to differentiate into virtually any type of cells and the feasibility of generating hematopoietic stem progenitor cells (HSPCs) from patient-derived iPSCs (iPSC-HSPCs) has many potential applications in hematology. For example, iPSC-HSPCs are being used for leukemogenesis studies and their application in various cell replacement therapies is being evaluated. The use of iPSC-HSPCs can now provide an invaluable resource for the study of diseases associated with the destruction of HSPCs, such as bone marrow failure syndromes (BMFSs). Recent studies have shown that generating iPSC-HSPCs from patients with acquired aplastic anemia and other BMFSs is not only feasible, but is also a powerful tool for understanding the pathogenesis of these disorders. In this article, we highlight recent advances in the application of iPSCs for disease modeling of BMFSs and discuss the discoveries of these studies that provide new insights in the pathophysiology of these conditions.

We sought to determine the efficacy of a new, inexpensive, single-tube 8-color multiparameter flow cytometry (MFC) method (SRL-Flow), which is based on the EuroFlow next-generation flow (NGF) (tube 2 only), to assess minimal residual disease (MRD)-negative status. MRD-negative status is considered a treatment milestone in multiple myeloma (MM). We used 45 bone marrow samples from patients with MM, including 11 cases treated with anti-CD38 monoclonal antibody. The SRL-Flow sample preparation protocol was identical to that of EuroFlow-NGF. The antibody panel for SRL-Flow was as follows: CD138V450/CD27V500/CD38ME (multiepitope)FITC/CD56PE/CD45PerCP-Cy5.5/CD19PE-Cy7/cytoplasmic (Cy) immunoglobulin (Ig) κAPC/CyIgλAPC-H7. To identify abnormal plasma cells (aPCs) of patients with MM who received anti-CD38 monoclonal antibody, we used a panel of anti-CD45 and anti-CD138 antibodies (Abs) rather than a panel of anti-CD45 and anti-CD38 Abs. We comparatively analyzed the total nucleated cell numbers, total PC levels, and MRD levels between the SRL-Flow and EuroFlow-NGF. High correlations (r > 0.9) in total PC and MRD levels were noted among SRL-Flow, original EuroFlow-NGF (2 tubes), and EuroFlow-NGF (tube 2 only), suggesting that SRL-Flow is an inexpensive (< $200 USD/sample as of January of 2019) alternative to EuroFlow-NGF (< $350 USD/sample) for assessing MRD in MM.

In this study, the minimal residual disease (MRD) levels in patients with multiple myeloma (MM) were assessed by comparing the new 8-color single-tube multiparameter flow cytometry method (DuraClone), which reduces the cost of antibodies and labor burden of laboratories, with the EuroFlow next-generation flow (NGF) method. A total of 96 samples derived from 69 patients with MM were assessed to determine the total cell acquisition number (tCAN), percentages of total and normal plasma cells (PCs), and MRD levels using two methods. We found that the tCAN was significantly higher with EuroFlow-NGF than with DuraClone (median 8.6 × 106 vs. 5.7 × 106; p p

The outcome of immunosuppressive therapy (IST) and prognosis in patients with aplastic anaemia (AA) secondary to chemotherapy or radiotherapy for cancers remains unknown. A total of 43 of 2559 patients with AA referred to our hospital had previously received chemoradiotherapy for various types of solid tumours (n = 25) or haematological malignancies (n = 18). Their cancer status was complete remission (CR) in 27, non-CR in 13, and unknown in three. Small populations of glycosylphosphatidylinositol-anchored protein-deficient [GPI(-)] granulocytes were detected in 16 patients (37·2%). Of 18 patients who were treated with IST, 50% improved regardless of the presence of GPI(-) cells. The overall survival (OS) rate was significantly higher in patients with a history of solid tumours patients than in those of haematological malignancies (median OS, 87 vs. 11 months, P = 0·0003), and in patients treated with IST than in those of untreated patients (median OS, 115 vs. 20 months, P = 0·028). Cancer aggravation occurred in two of four patients who were treated with IST while in non-CR of their original cancers. Progression to myelodysplastic syndromes was observed in two patients not possessing GPI(-) cells. IST should thus be considered for patients with AA secondary to chemoradiotherapy for cancers, particularly when their original solid tumours are in CR.

This nationwide multicentre retrospective study was performed to analyze clinical features that predict the prognosis of central nervous system invasion in multiple myeloma (CNS-MM, approximately 1% of MM). Overall, of the 77 adult patients with CNS-MM identified between 2005 and 2016, those diagnosed at MM diagnosis (n = 3) had longer overall survival (OS) than those diagnosed at relapse (n = 74; median: 48·5 vs 2·7 months). Therefore, we compared the relapsed MM with CNS-MM in patients with any treatment (n = 60). Multivariate analyses revealed that lenalidomide treatment [hazard ratio (HR) 0·27, P = 0·003], intrathecal chemotherapy (IT; HR 0·54, P = 0·05), and radiation therapy (RTx; HR 0·33, P

To characterize glycosylphosphatidylinositol-anchored protein-deficient (GPI[−]) and HLA-class I allele-lacking (HLA[−]) hematopoietic stem progenitor cells (HSPCs) in acquired aplastic anemia (AA), we studied the peripheral blood (PB) of 56 AA patients in remission who possessed both (n = 13, Group A) or either GPI(−) (n = 34, Group B) and HLA(−) (n = 9, Group C) cell populations. Seventy-seven percent (10/13) of Group A had HLA(−) cells in all lineages of PB cells, including platelets, while only 23% (3/13) had GPI(−) cells in all lineages, and the median percentage of HLA(−) granulocytes in the total granulocytes (21.2%) was significantly higher than that of GPI(−) granulocytes (0.28%, P

A previous dose‐finding study has suggested that romiplostim is effective in patients with refractory aplastic anaemia (AA) and 10 µg/kg once weekly was recommended as a starting dose. In this Phase II/III, multicentre, open‐label study, romiplostim was administered subcutaneously at a fixed dose of 10 µg/kg once weekly for 4 weeks (weeks 1–4) followed by weekly doses (5, 10, 15 and 20 µg/kg) titrated by platelet response for up to 52 weeks (weeks 5–52). A total of 31 patients with AA who were refractory to immunosuppressive therapy (IST) and thrombocytopenia (platelet count of ≤30 × 109/l) were enrolled. The primary efficacy endpoint of the proportion of patients achieving any haematological (platelet, neutrophil and erythrocyte) response at week 27 was 84% [95% confidence interval (CI) 66–95%]. Trilineage response was 39% (95% CI 22–58%) at week 53. The most common treatment‐related adverse events (AEs) were headache and muscle spasms (each 13%). All AEs were mild or moderate except for three patients with Grade 3 hepatic AEs; no AEs necessitated romiplostim discontinuation. Two patients developed cytogenetic abnormalities, of whom one returned to normal karyotype at last follow‐up. High‐dose romiplostim is effective and well tolerated in the treatment of patients with AA refractory to IST.

The loss of killer cell Ig-like receptor ligands (KIR-Ls) due to the copy number–neutral loss of heterozygosity of chromosome 6p (6pLOH) in leukocytes of patients with acquired aplastic anemia (AA) may alter the susceptibility of the affected leukocytes to NK cell killing in vivo. We studied 408 AA patients, including 261 who were heterozygous for KIR-Ls, namely C1/C2 or Bw6/Bw4, for the presence of KIR-L–missing [KIR-L(−)] leukocytes. KIR-L(−) leukocytes were found in 14 (5.4%, C1 [n = 4], C2 [n = 3], and Bw4 [n = 7]) of the 261 patients, in whom corresponding KIR(+) licensed NK cells were detected. The incidence of 6pLOH in the 261 patients (18.0%) was comparable to that in 147 patients (13.6%) who were homozygous for KIR-L genes. The percentages of HLA-lacking granulocytes (0.8–50.3%, median 15.2%) in the total granulocytes of the patients with KIR-L(−) cells were significantly lower than those (1.2–99.4%, median 55.4%) in patients without KIR-L(−) cells. KIR2DS1 and KIR3DS1 were only possessed by three of the 14 patients, two of whom had C2/C2 leukocytes after losing C1 alleles. The expression of the KIR3DS1 ligand HLA-F was selectively lost on KIR-L(−) primitive hematopoietic stem cells derived from 6pLOH(+) induced pluripotent stem cells in one of the KIR3DS1(+) patients. These findings suggest that human NK cells are able to suppress the expansion of KIR-L(−) leukocytes but are unable to eliminate them partly due to the lack of activating KIRs on NK cells and the low HLA-F expression level on hematopoietic stem cells in AA patients.

Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) is a life-threatening disease characterized by the uncontrolled proliferation of EBV-infected T/NK cells with resultant immune system failure against EBV. While a CD5−HLA-DR+CD8+ T-cell population was previously shown to be EBV-infected cells and a useful marker for monitoring the response to treatment of EBV-HLH, changes in other lymphocyte subsets associated with EBV-HLH treatments have not been closely studied. We herein report a 25-year-old woman with EBV-HLH who presented with a fever, liver failure, and pancytopenia. CD8+ T cells harbored EBV. After failing steroid pulse therapy, one course of CHOP therapy immediately improved her fever and laboratory data and reduced the population of EBV-infected cells. Although the number of EBV-infected cells increased on day 20 of CHOP, a sharp increase in NK cells and normal activated T cells ensued, and the infected cells disappeared without an additional CHOP cycle. She has maintained remission without complications. This rapid immune reconstitution has not been observed in two other patients treated with HLH-2004 protocol-like regimens including prolonged immunosuppressants and etoposide. One cycle of CHOP was thought to have induced the resolution of EBV-HLH by eliminating infected cells as well as inducing the reconstruction of anti-EBV immunity.

Ravulizumab demonstrated noninferior efficacy and comparable safety to eculizumab in two open-label, phase 3 studies in patients with paroxysmal nocturnal hemoglobinuria (PNH) who complement inhibitor-naive (Study 301) or were previously treated with eculizumab (Study 302). This subgroup analysis assessed ravulizumab's efficacy and safety in Japanese patients in Studies 301 and 302, who are known to have different clinicopathologic features from white patients. Patients were randomly assigned (1:1) to eculizumab every-two-weeks or weight-based dosing of ravulizumab every-eight-weeks for 26 weeks. Co-primary endpoints were transfusion avoidance and lactate dehydrogenase (LDH) normalization in Study 301 and percentage change in LDH levels from baseline to day 183 in Study 302. Thirty-three Japanese patients (n = 18 ravulizumab; n = 15 eculizumab) enrolled in Study 301; 12 enrolled in Study 302 (n = 5 ravulizumab; n = 7 eculizumab). In the Study 301 ravulizumab group, 83.3% (15/18) of patients avoided transfusion; the adjusted prevalence of LDH normalization was 52.1%. In the Study 302 ravulizumab group, the least-squares-mean percentage change from baseline in LDH was 8.34%. No deaths or meningococcal infections occurred during the 6-month primary evaluation period in either study. In conclusion, ravulizumab's efficacy and safety were consistent in the Japanese and global patient populations with PNH in the phase 3 studies. Clinical Trial Identifier: NCT02946463; NCT03056040.

Clonal hematopoiesis by hematopoietic stem progenitor cells (HSPCs) that lack an HLA class I allele (HLA − HSPCs) is common in patients with acquired aplastic anemia (AA); however, it remains unknown whether the cytotoxic T lymphocyte (CTL) attack that allows for survival of HLA − HSPCs is directed at nonmutated HSPCs or HSPCs with somatic mutations or how escaped HLA − HSPC clones support sustained hematopoiesis. We investigated the presence of somatic mutations in HLA − granulocytes obtained from 15 AA patients in long-term remission (median, 13 years; range, 2-30 years). Targeted sequencing of HLA − granulocytes revealed somatic mutations ( DNMT3A , n = 2; TET2 , ZRSR2 , and CBL , n = 1) in 3 elderly patients between 79 and 92 years of age, but not in 12 other patients aged 27 to 74 years (median, 51.5 years). The chronological and clonogenic analyses of the 3 cases revealed that ZRSR2 mutation in 1 case, which occurred in an HLA − HSPC with a DNMT3A mutation, was the only mutation associated with expansion of the HSPC clone. Whole-exome sequencing of the sorted HLA − granulocytes confirmed the absence of any driver mutations in 5 patients who had a particularly large loss of heterozygosity in chromosome 6p (6pLOH) clone size. Flow–fluorescence in situ hybridization analyses of sorted HLA + and HLA − granulocytes showed no telomere attrition in HLA − granulocytes. The findings suggest that HLA − HSPC clones that escape CTL attack are essentially free from somatic mutations related to myeloid malignancies and are able to support long-term clonal hematopoiesis without developing driver mutations in AA patients unless HLA loss occurs in HSPCs with somatic mutations.

Late graft failure (LGF) without evidence of residual recipient cells is a serious complication after allogeneic hematopoietic stem cell transplantation (allo-SCT) and often requires stem cell infusion from the same donor when the patient fails to respond to conventional therapies. We screened the peripheral blood (PB) of 14 patients who developed donor-type LGF at 2 to 132 months after allo-SCT for the presence of the markers for immune-mediated bone marrow (BM) failure. Increased glycosylphosphatidyl inositol-anchored protein-deficient (GPI-AP-) leukocytes, which accounted for .009% to 0.147% of the total granulocytes, were detected in 5 patients (severe aplastic anemia, n = 2; follicular lymphoma, n = 1; acute lymphoblastic leukemia, n = 1; myelodysplastic syndromes; n = 1) and 4.7% to 81.2% HLA-allele–lacking leukocytes (HLA-LLs) were detected in 2 patients (acute myelogenous leukemia, n = 1; and myelodysplastic syndromes, n = 1). Three of the 5 patients with increased GPI-AP- leukocytes were treated with antithymocyte globulin (ATG), and 2 patients achieved transfusion independence. These results suggest that immune mechanisms that are similar to acquired aplastic anemia underlie condition of approximately one-half of the patients with donor-type LGF, and that in patients with increased GPI-AP- cells, donor-derived hematopoiesis may be restored by ATG therapy alone without donor stem cell infusion.

Graft failure (GF) is the most critical life-threatening complication of allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia, for which a second transplantation is the only effective treatment. Optimal procedures have not been established for the second transplantation in this setting, however. Here we retrospectively analyzed the outcomes of 22 patients with aplastic anemia, age ≥16 years, who underwent umbilical cord blood transplantation for GF after the first HSCT using the registry database of the Japan Society for Hematopoietic Cell Transplantation. The median age of patients was 36 years (range, 16 to 72 years), and the median time from the first to the second transplant was 77 days (range, 29 to 1061 days). The cumulative incidence of neutrophil engraftment at day 60 post-transplantation was 45.5% (95% confidence interval [CI], 23.6% to 65.0%). With a median follow-up of 50 months, the 4-year overall survival (OS) was 38.5% (95% CI, 18.4% to 58.5%). Mycofenolate mofetil–based graft-versus-host disease prophylaxis demonstrated greater neutrophil recovery than prophylaxis with calcineurin inhibitor alone or methotrexate-based prophylaxis (66.7% versus 37.5%; P = .04). The use of such conditioning regimens as fludarabine + melphalan or cyclophosphamide + low-dose total body irradiation was associated with better engraftment (58.3% versus 30%; P = .05) and better 4-year OS (55.6% versus 20%; P = .05) than other regimens. Although further investigation is needed, umbilical cord blood could be an effective and promising option for stem cell source for urgent second transplantation in patients with aplastic anemia who develop GF after the first HSCT.

Background Most patients with multiple myeloma (MM) are considered to be incurable, and relapse owing to minimal residual disease (MRD) is the main cause of death among these patients. Therefore, new technologies to assess deeper response are required. Patients and methods We retrospectively analyzed 125 patients with MM who underwent high-dose melphalan plus autologous stem-cell transplantation (ASCT) to detect MRD in autograft/bone marrow (BM) cells using a next-generation sequencing (NGS)-based method and allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR). Results NGS-based method was applicable to 90% and this method had at least one to two logs greater sensitivity compared to ASO-PCR. MRD negative by NGS [MRDNGS(−)] (defined as

A “biosimilar” is a biotechnological product with a lower cost profile and equivalent efficacy and safety to the originator, but post-marketing clinical evaluation of biosimilar products has not been adequately conducted. We prospectively investigated the utility of biosimilar filgrastim in 13 peripheral blood stem cell (PBSC) donors from June 2014 to January 2017. In addition, we retrospectively compared these to another 13 PBSC donors mobilized with the originator filgrastim in the same period. Donor characteristics were equivalent between the groups. The median number of CD34+ cells per donor body weight (BW) and blood volume processed (BV) were 4.87 × 106/kg and 25.5 × 103/mL in the biosimilar group and 4.93 × 106/kg and 16.6 × 103/mL in the originator group, respectively. There were no significant differences between the groups in the number of CD34+ cells per donor BW or BV. All adverse events associated with G-CSF were permissive. The total G-CSF cost was significantly lower in the biosimilar group than in the originator group. These findings suggest that biosimilar filgrastim has the same efficacy and short-term safety as originator filgrastim for PBSC mobilization in healthy donors, with economic superiority. Longer follow-up studies are needed to evaluate the incidence of long-term adverse events.

Acquired aplastic anemia (AA) is a hematopoietic disorder caused by an immunologic attack on hematopoietic stem cells (HSCs). The presence of cells with a paroxysmal nocturnal hemoglobinuria (PNH) phenotype or with copy-number neutral loss of heterozygosity of chromosome 6p (6pLOH) suggests an immune-mediated pathophysiology underlying AA. Recently, genomic studies have revealed clonal hematopoiesis by HSCs with altered genes. PIGA, DNMT3A, ASXL1, BCOR, 6pLOH, and HLA class I allele mutations are common in patients with AA. The genomic landscape of AA is distinct from that of the myelodysplastic syndrome or age-related clonal hematopoiesis. This suggests that escape from an autoimmune attack is strongly associated with clonal hematopoiesis in AA. Eltrombopag (EPAG), a thrombopoietin receptor agonist, has recently emerged as a novel therapeutic agent for AA. Further studies are needed to clarify whether EPAG induces clonal expansion of these clones.

Background: Cough variant asthma (CVA) is recognized as a precursor of bronchial asthma (BA). However, the cough response to bronchoconstriction differs between these similar diseases. Repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators may impact the cough response. Methods: We investigated the influence of repeated bronchoconstriction on the cough response to bronchoconstriction using naïve guinea pigs. Bronchoconstriction was induced for 3 consecutive days and changes in the cough response and lipid mediators, such as PGE2, PGI2, and cysteinyl-LTs (Cys-LTs), in BAL fluid (BALF) were assessed. We investigated the effect of endogenous PGI2 on the cough response by employing a PGI2 receptor antagonist. In order to investigate the cough response over a longer period, we re-evaluated the cough response 2 weeks after repeated bronchoconstriction. Results: The number of coughs induced by bronchoconstriction were significantly decreased by repeated bronchoconstriction. The levels of PGE2, PGI2, and Cys-LTs, and the ratio of PGI2/PGE2 were significantly increased, following repeated bronchoconstriction. This decrease in the cough response was suppressed by pretreatment with a PGI2 receptor antagonist. Two weeks after repeated bronchoconstriction, the cough response returned to the same level as before repeated bronchoconstriction along with a concomitant return of lipid mediators, such as PGE2, PGI2, and Cys-LTs and the ratio of PGI2/PGE2. Conclusions: Our results suggest that repeated bronchoconstriction and the resulting imbalance of endogenous lipid mediators contribute to the difference in cough responses to bronchoconstriction in CVA and BA. Keywords: Bronchial asthma (BA), Bronchoconstriction, Cough variant asthma (CVA), Guinea pig, Lipid mediator

The treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti-thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%-91%) vs. 91% (95% CI, 82%-96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA. Trial registration: UMIN000011134.

To the editor: In idiopathic aplastic anemia (IAA), bone marrow failure (BMF) is caused by depletion of hematopoietic stem cells (HSCs), thought to result from a T-cell-mediated autoimmune process.[1][1] Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic disorder characterized by a

Preclinical studies have shown that resveratrol exerts immunomodulatory effects with potential clinical value in the amelioration of autoimmune disorders and cancer prevention; however, little is known about the in vivo effects of this naturally occurring polyphenol on human immune cells. We assessed the effects of repeated doses of resveratrol (1000 mg/day for 28 days) on circulating immune cells in healthy Japanese individuals. Resveratrol was safe and well tolerated and was associated with significant increases in the numbers of circulating γδ T cells and regulatory T cells and resulted in small, yet significant, decreases in the plasma levels of the proinflammatory cytokines TNF-α and MCP-1 and a significant increase in the plasma antioxidant activity compared with the corresponding antioxidant baseline activity and with that in four control individuals. In in vitro studies, resveratrol significantly improved the growth of γδ T cells and regulatory T cells. These findings demonstrate that resveratrol has some clear biological effects on human circulating immune cells. Further studies are necessary to interpret the long-term immunological changes associated with resveratrol treatment.

We describe a case in which uncontrolled chronic disseminated intravascular coagulation (DIC) caused by an aortic aneurysm that was exacerbated by chemotherapy for lung cancer, showed dramatic improvement when warfarin, which was being administered for atrial fibrillation, was replaced by rivaroxaban, a direct oral anticoagulant (DOAC). The present case is interesting because a DOAC was effective in treating DIC due to an aortic aneurysm, whereas warfarin, another oral anticoagulant, was ineffective. In controlling DIC, it is important to inhibit activated coagulation factors such as thrombin and activated factor X, rather than the coagulation factors, which act as substrates.

Data characterizing the safety and effectiveness of eculizumab in patients with paroxysmal nocturnal hemoglobinuria (PNH) are limited. We describe the safety and effectiveness of eculizumab in PNH patients enrolled in a post-marketing surveillance study. Types and frequencies of observed adverse events were similar to those reported in previous clinical trials and no meningococcal infection was reported. Effectiveness outcomes included the reduction of intravascular hemolysis, the change in hemoglobin (Hb) level, the withdrawal of transfusion and corticosteroids, the change of renal function, and overall survival. The effect of eculizumab on intravascular hemolysis was demonstrated by a reduction in lactate dehydrogenase levels at all measurements after baseline. Significant increases in Hb levels from baseline were also observed after 1 month’s treatment with eculizumab (p < 0.01). Of those who were transfusion-dependent at baseline, the median number of transfusions decreased significantly from 18 to 0 unit/year after 1 year of treatment with eculizumab (p < 0.001). An increase in Hb and a high rate of transfusion independence were observed, especially in patients with platelet count ≥150 × 109/L. Approximately 97 % of patients showed maintenance or improvement of renal function. Overall survival rate was about 90 % (median follow-up 1.9 years). These results suggest an acceptable safety profile and favorable prognosis after eculizumab intervention.

Patients with mild hypomegakaryocytic thrombocytopenia (HMT) that does not meet the diagnostic criteria for a definite disease entity may potentially progress to aplastic anaemia (AA) that is refractory to therapy. To clarify the clinical picture of HMT, we prospectively followed 25 HMT patients with white blood cell count >3·0 × 109 /l, haemoglobin level >100 g/l and platelet count of 320 pg/ml) were observed in 11 (44%) patients. Five (four PNH+ and one PNH-) of six TPOhigh patients who were treated with ciclosporin (CsA) showed improvement. Among the 21 patients who were followed without treatment, thrombocytopenia progressed in four of ten TPOlow patients and four of 11 TPOhigh patients. The 3-year failure-free survival rate of the CsA-treated TPOhigh patients (100%) was significantly higher than that of the untreated TPOhigh patients (20%). These results suggest that a significant population of HMT patients has an immune pathophysiology that is similar to AA and may be improved by early therapeutic intervention with CsA.

Relapse remains a major obstacle to the survival of patients with hematologic malignancies after allogeneic hematopoietic stem cell transplantation. A disintegrin-like and metalloprotease with a thrombospondin type 1 motif (ADMATS13), which cleaves von Willebrand factor multimers into less active fragments, is encoded by the ADAMTS13 gene and has a functional single-nucleotide polymorphism (SNP) rs2285489 (C &gt, T). We retrospectively examined whether ADAMTS13 rs2285489 affected the transplant outcomes in a cohort of 281 patients who underwent unrelated human leukocyte antigen (HLA)-matched bone marrow transplantation for hematologic malignancies. The recipient ADAMTS13 C/C genotype, which putatively has low inducibility, was associated with an increased relapse rate (hazard ratio [HR], 3.12, 95% confidence interval [CI], 1.25&ndash, 7.77, P = 0.015), resulting in a lower disease-free survival rate in the patients with a recipient C/C genotype (HR, 1.64, 95% CI, 1.01&ndash, 2.67, P = 0.045). Therefore, ADAMTS13 rs2285489 genotyping in transplant recipients may be a useful tool for evaluating pretransplantation risks.

Eltrombopag, an oral thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA) and has higher exposure in patients of East Asian origin. We evaluated the pharmacokinetics, efficacy, and safety of eltrombopag in Japanese patients with AA refractory or intolerant to immunosuppressive therapy (IST). Twenty-one patients (15 with non-severe AA, six with severe AA) with platelet counts

Allogeneic hematopoietic stem cell transplantation is the sole curative therapy for myelodysplastic syndrome (MDS). However, there is concern regarding graft failure and relapse in patients who undergo cord blood transplantation (CBT). We conducted a retrospective study of the CBT outcomes in MDS patients using the Japanese Data Center for Hematopoietic Cell Transplantation database. Seven hundred fifty-two de novo MDS patients of ≥18 years of age (median, 58 years) undergoing their first CBT between 2001 and 2015 were examined. Two-thirds of the patients were male, and were RAEB. The cumulative incidences of neutrophil and platelet engraftment at day 100 were 77 and 59%, respectively. The 3-year overall survival (OS) was 41% and the median survival of the patients was 1.25 years. A multivariate analysis of pre-transplant variables showed that the age, gender, cytogenetic subgroups, number of RBC transfusions, HCT-CI and year of CBT significantly influenced the outcome. The cumulative incidence of acute graft-versus-host disease (aGVHD) and chronic GVHD (cGVHD) was 32 and 21%, respectively. A survival benefit was observed in patients who developed cGVHD, but not aGVHD. Our results suggest that CBT is an acceptable alternative graft and that a graft-versus-MDS effect can be expected, especially in patients who develop cGVHD.

Contains fulltext : 202845.pdf (Publisher’s version ) (Open Access) 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.

Hematopoietic stem cells (HSCs) that lack HLA-class I alleles as a result of copy-number neutral loss of heterozygosity of the short arm of chromosome 6 (6pLOH) or HLA allelic mutations often constitute hematopoiesis in patients with acquired aplastic anemia (AA), but the precise mechanisms underlying clonal hematopoiesis induced by these HLA-lacking (HLA

An increasing number of patients with lung cancer are undergoing outpatient chemotherapy, and thus, it is very important to maintain the quality of life(QOL)of these patients. Ninjin-Youei-To(TJ-108), a Japanese traditional medicine, has been reported to improve the QOL of patients with advanced cancer. However, the effect of TJ-108 in patients with lung cancer undergoing outpatient chemotherapy is unknown. Therefore, we conducted this study. To investigate factors influencing the QOL of these patients, we administered a QOL questionnaire,"The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs"(QOL-ACD)to 15 patients with non-small cell lung cancer. Factors related to the overall QOL scores and other categories indicating"activity","physical condition","psychological condition","social relationship", and"face scale" were analyzed. No significant decrease in each of the evaluated factors was observed in this study.

Somatic STAT3 mutations were frequently found in PRCA with or without T-LGLL.STAT3 mutation–positive PRCA patients were less responsive to cyclosporine treatment than mutation-negative patients.