Ibrutinib plus Bendamustine and Rituximab in Untreated Mantle-Cell Lymphoma.

BACKGROUND: Ibrutinib, a Bruton's tyrosine kinase inhibitor, may have clinical benefit when administered in combination with bendamustine and rituximab and followed by rituximab maintenance therapy in older patients with untreated mantle-cell lymphoma. METHODS: We randomly assigned patients 65 years of age or older to receive ibrutinib (560 mg, administered orally once daily until disease progression or unacceptable toxic effects) or placebo, plus six cycles of bendamustine (90 mg per square meter of body-surface area) and rituximab (375 mg per square meter). Patients with an objective response (complete or partial response) received rituximab maintenance therapy, administered every 8 weeks for up to 12 additional doses. The primary end point was progression-free survival as assessed by the investigators. Overall survival and safety were also assessed. RESULTS: Among 523 patients, 261 were randomly assigned to receive ibrutinib and 262 to receive placebo. At a median follow-up of 84.7 months, the median progression-free survival was 80.6 months in the ibrutinib group and 52.9 months in the placebo group (hazard ratio for disease progression or death, 0.75; 95% confidence interval, 0.59 to 0.96; P = 0.01). The percentage of patients with a complete response was 65.5% in the ibrutinib group and 57.6% in the placebo group (P = 0.06). Overall survival was similar in the two groups. The incidence of grade 3 or 4 adverse events during treatment was 81.5% in the ibrutinib group and 77.3% in the placebo group. CONCLUSIONS: Ibrutinib treatment in combination with standard chemoimmunotherapy significantly prolonged progression-free survival. The safety profile of the combined therapy was consistent with the known profiles of the individual drugs. (Funded by Janssen Research and Development and Pharmacyclics; SHINE ClinicalTrials.gov number, NCT01776840.).

Antithrombin supplementation attenuates heparin resistance in plasma spiked with Gla-domainless factor Xa S195A in vitro.

BACKGROUND: Andexanet alfa is a Gla-domainless mutant (S195A) factor Xa (GDXa) approved for acute reversal of oral factor Xa inhibitors. Cardiac surgery patients exposed to andexanet before cardiopulmonary bypass often exhibit severe heparin resistance. There is a paucity of data on the effectiveness and optimal dosage of antithrombin use in this setting. The objective of this study was to evaluate the in vitro effect of increased heparin with antithrombin levels on attenuating heparin resistance induced by GDXa. METHODS: Heparinised normal pooled plasma and cardiopulmonary bypass plasma were spiked with GDXa 4 µM. Tissue factor-activated thrombin generation was used to assess heparin reversal effects of GDXa and restoration of anticoagulation with additional heparin with and without antithrombin. Serum thrombin-antithrombin complex, antithrombin activity, and tissue factor pathway inhibitor were also measured in tissue factor-activated, recalcified cardiopulmonary bypass plasma spiked with GDXa. RESULTS: In normal pooled plasma, GDXa-induced heparin reversal was mitigated by maintaining a high heparin concentration (12 U ml-1) and supplementing antithrombin (1.5-4.5 µM) based on peak and velocity of thrombin generation. Heparin reversal by GDXa was also demonstrated in cardiopulmonary bypass plasma, but supplementing both heparin (8 U ml-1) and antithrombin (3 µM) attenuated GDXa-induced changes in peak and velocity of thrombin generation by 72.5% and 72.2%, respectively. High heparin and antithrombin levels attenuated thrombin-antithrombin complex formation in tissue factor-activated, GDXa-spiked cardiopulmonary bypass plasma by 85.7%, but tissue factor pathway inhibitor remained depleted compared with control cardiopulmonary bypass plasma. CONCLUSIONS: Simultaneous supplementation of heparin and antithrombin mitigate GDXa-induced heparin resistance by compensating for the loss of tissue factor pathway inhibitor.

Subcutaneous epcoritamab monotherapy in Japanese adults with relapsed/refractory diffuse large B-cell lymphoma.

Epcoritamab is a subcutaneously administered CD3xCD20 bispecific Ab that showed deep, durable responses with a manageable safety profile in patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) in the global multicenter pivotal phase II trial EPCORE NHL-1. Here, we present results from the similar EPCORE NHL-3 phase I/II trial evaluating epcoritamab monotherapy in Japanese patients with R/R CD20+ B-cell non-Hodgkin's lymphoma previously treated with two or more lines of therapy. Epcoritamab was dosed subcutaneously in 28-day cycles; once weekly during cycles 1-3, every 2 weeks during cycles 4-9, and every 4 weeks from cycle 10 until disease progression or unacceptable toxicity. Step-up dosing and cytokine release syndrome (CRS) prophylaxis were used during treatment cycle 1. As of January 31, 2022, 36 patients received treatment with 48 mg epcoritamab monotherapy. At a median follow-up of 8.4 months, overall response and complete response rates by independent review committee were 55.6% and 44.4%, respectively. The median duration of response, duration of complete response, and overall survival were not reached at the time of data cut-off. The most common treatment-emergent adverse events of any grade were CRS (83.3%), injection-site reactions (69.4%), infections (44.4%), neutropenia (38.9%), hypokalemia (27.8%), and decreased lymphocyte count (25.0%). Cytokine release syndrome occurrence was predictable; events were primarily low grade (grade 1-2), all resolved, and none led to treatment discontinuation. These encouraging results are consistent with previous findings and support the ongoing clinical evaluation of epcoritamab for the treatment of R/R DLBCL, including in earlier treatment lines.

Eosinophil-rich variant of nodal marginal zone lymphoma: a clinicopathological study of 11 cases.

AIMS: Tissue eosinophilia is commonly observed in T-cell and classic Hodgkin lymphomas, but rarely in B-cell lymphomas. Herein, we present the first report of a case series on nodal marginal zone lymphoma (NMZL) with tissue eosinophilia. METHODS AND RESULTS: All 11 patients in this study had nodal disease at primary presentation. The mean age at diagnosis was 64 years. The mean follow-up period was 39 months, and all patients were alive. Nine of the 11 patients (82%) showed no recurrence, but the other two patients experienced recurrence in the lymph nodes or skin. Marked eosinophilic infiltration was observed in all biopsied lymph nodes. Nine of the 11 patients had a preserved nodular architecture with expanded interfollicular areas. The other two patients showed diffuse lymphoma cell infiltration with effacement of nodal architecture. One of them was diagnosed as having diffuse large B-cell lymphoma transformed from NMZL because large cells accounted for >50% of the lymphoma cells and formed sheet-like patterns. Cells were positive for CD20 and BCL2 and negative for CD5, CD10, and BCL6. Some patients showed myeloid cell nuclear differentiation antigen (MNDA) positivity. All patients showed B-cell monoclonality via flow cytometry, southern blotting, and/or polymerase chain reaction (PCR). CONCLUSION: All patients showed distinctive morphological features and could be misdiagnosed with peripheral T-cell lymphoma due to their eosinophil-rich backgrounds. The predominance of B cells, absence of histiocytes, and high endothelial venules in the interfollicular areas are key factors for diagnosis. B-cell monoclonality is the most reliable evidence of differentiation. We designated this type of lymphoma as an eosinophil-rich variant of NMZL.

Dose-escalation part of Phase I study of single-agent mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma.

OBJECTIVE: This dose-escalation part of an ongoing Phase I study assessed the tolerability, safety and pharmacokinetics of mosunetuzumab in Japanese patients with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). METHODS: Mosunetuzumab was administered intravenously, with step-up dosing in a 3 + 3 design, on Days 1, 8 and 15 of Cycle 1, and Day 1 of each subsequent 21-day cycle for up to 17 cycles to patients across five cohorts with different target doses (2.8, 6.0, 13.5, 27.0 or 60.0 mg). RESULTS: As of 5 July 2022, 23 patients had received mosunetuzumab. The median patient age was 63.0 years, 56.5% of patients were male, and 69.6% of patients had diffuse large B-cell lymphoma, 17.4% had transformed follicular lymphoma (FL) and 13.0% had FL. The median number of prior lines of therapy was 4. Mosunetuzumab was well tolerated and there were no deaths. The most common adverse events (any grade) were neutropenia/neutrophil count decreased (47.8%) and cytokine release syndrome (34.8%). Most cytokine release syndrome events were Grade 1/2 (one Grade 3), and most occurred within 24 hours of the first dose of mosunetuzumab. The apparent half-life of mosunetuzumab was 4.1-5.0 days. Two patients achieved a complete response, and 11 patients achieved a partial response. CONCLUSIONS: This study demonstrated that mosunetuzumab has an acceptable safety profile and antitumor activity in Japanese patients with relapsed/refractory B-cell NHL. The recommended Phase II dose of 1.0/2.0/60.0/60.0/30.0 mg was tolerable and there were no new or different safety signals compared with the global Phase I study.

Factors for the optimal selection of granulocyte colony-stimulating factor preparations and predictors for R-CHOP dose reductions/delays among patients with non-Hodgkin B-cell lymphoma (STOP FN in NHL 2 subanalysis).

BACKGROUND: A classification tree was used to analyze background factors for granulocyte colony-stimulating factor (G-CSF) preparation selection for febrile neutropenia (FN) prophylaxis in Japanese patients with non-Hodgkin B-cell lymphoma receiving the first R-CHOP cycle. METHODS: This was a subanalysis of the retrospective observational study STOP FN in NHL 2 (UMIN000029534). Patient characteristics, changes in neutrophil count, incidence and severity of neutropenia, and risk factors for dose reduction/delay of R-CHOP were assessed by G-CSF formulation. RESULTS: Among 234 patients in cycle 1, 25.6% received no G-CSF preparation, 52.1% received daily G-CSF, and 22.2% received pegfilgrastim. Pegfilgrastim use was most frequent among patients aged ≥ 80 years, while that of daily G-CSF was most frequent in patients with lymphocyte count (LC) < 1000 cells/µL. Changes in neutrophil count were more marked with pegfilgrastim compared with daily G-CSF and no G-CSF. Relevant factors for G-CSF preparation selection in the first R-CHOP cycle were age ≥ 80 years and LC < 1000 cells/µL; for chemotherapy dose reduction were FN onset in cycle 1 and female sex; and for dose delay was hemoglobin (< 12 g/dL). After cycle 2 and onward, pegfilgrastim use increased markedly (72.6%) compared with cycle 1 (22.2%), with significantly greater proportions continuing pegfilgrastim use and switching from daily G-CSF. CONCLUSION: Relevant factors for G-CSF preparation selection were age ≥ 80 years and LC < 1000 cells/µL. The use of pegfilgrastim increased markedly after cycle 2. These results may be useful for selecting appropriate G-CSF preparations in the first R-CHOP cycle. TRIAL REGISTRATION: UMIN000029534; registered on 13 October 2017, https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000033733 .

Incidence and risk factors for febrile neutropenia in Japanese patients with non-Hodgkin B cell lymphoma receiving R-CHOP: 2-year experience in a single center (STOP FN in NHL 2).

BACKGROUND: Myelosuppressive chemotherapy-induced febrile neutropenia (FN) is a life-threatening condition. Patients receiving granulocyte colony-stimulating factors (G-CSF) have shorter duration of neutropenia, faster recovery from fever, and shorter duration of antibiotics use. Most strategies for FN prevention using daily G-CSF and pegfilgrastim are based on overseas studies. Data on Japanese patients were lacking; thus, we previously determined the incidence of FN in non-Hodgkin B cell lymphoma (B-NHL) patients at our center. Here, we aimed to gain additional insights into pegfilgrastim use in this population. METHODS: This single-center, retrospective, observational study (STOP FN in NHL 2) enrolled patients with B-NHL who underwent a regimen comprising rituximab and CHOP therapy over a 2-year period (January 2015-June 2017). The incidence of FN in cycle 1 of chemotherapy, risk factors for FN development, and use of daily G-CSF and pegfilgrastim were evaluated. RESULTS: We evaluated 239 patients: 61 patients did not receive G-CSF and 178 received G-CSF. The incidence of FN was 10.5% (95% confidence interval [CI] 6.9-15.1%) in cycle 1 and 13.0% (95% CI 9.0-17.9%) in all cycles. The FN incidence was significantly lower (P = 0.0008) in patients receiving daily G-CSF and pegfilgrastim than patients not receiving G-CSF. Significant risk factors for FN were age ≥ 65 years, albumin < 3.5 g/dL, hemoglobin < 12 g/dL, and no prophylaxis with daily G-CSF/pegfilgrastim during cycle 1. CONCLUSIONS: The incidence of FN in cycle 1 and in all cycles and the identified risk factors were similar with those we previously reported; thus, our results validate previous findings. TRIAL REGISTRATION: UMIN000029534.

BCL2 expression in DLBCL: reappraisal of immunohistochemistry with new criteria for therapeutic biomarker evaluation.

Overexpression of the BCL2 is associated with a poor prognosis in diffuse large B-cell lymphoma (DLBCL). The assessment of MYC immunohistochemistry (IHC) is becoming optimized, whereas the criteria for BCL2 positivity are highly variable. Furthermore, data on the frequency and prognostic value of BCL2 positivity are conflicting. We aimed to evaluate BCL2 expression by IHC and assess the prognostic significance of the histopathologically scored BCL2 expression in 456 patients with DLBCL uniformly treated with standard immunochemotherapy (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone, R-CHOP). We initially designed 4-grade BCL2 scoring criteria, from 0 to 3+, and found that ∼40% of DLBCL showed strong BCL2 expression (score 3+). The scores from the pathologist's visual estimation were confirmed to be reliable using a digital image analysis. A retrospective survival analysis revealed that BCL2 score 3+ was a significant prognostic factor independent of the international prognostic index (IPI), the IHC-determined cell of origin, and the MYC protein/rearrangement status in a training set (n = 218). The adverse prognostic impact of BCL2 score 3+ was confirmed in a validation set (n = 238). We also developed a prognostic model consisting of 3 groups with a combined BCL2 score and MYC protein/rearrangement status. Patients with BCL2 score 3+ showed a higher treatment failure rate; therefore, alternative therapeutic strategies should be considered for these patients. A highly selective BCL2 inhibitor, venetoclax, was recently introduced as breakthrough therapy. Our BCL2 scoring system could readily be used by pathologists to evaluate patients with DLBCL who might benefit from BCL2-targeted therapies.

Epstein-Barr virus-negative extranodal "true" natural killer-cell lymphoma harbouring a KDM6A mutation.

Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKTL) is an extranodal aggressive T or NK-cell lymphoma that is characteristically associated with Epstein-Barr virus (EBV) infection and cytotoxic tissue-destructive features. Although ENKTL is described as a distinct entity according to the 2008 WHO classification, a considerable complexity is associated with the differential diagnosis of other T-cell lymphomas with respect to tumour cell origins, locations, and the presence of EBV infection, as well as molecular and cytogenetic abnormalities. Here, we report a rare case of EBV-negative ENKTL, where the absence of EBV in the true NK-lineage cells was confirmed by extensive phenotypic and genotypic analyses. Furthermore, using the next-generation sequencing approach, we identified mutations in the tumour suppressor genes KDM6A and TP53. The clinicopathological characteristics were almost similar to those of EBV-positive ENKTL, except for the absence of EBV and histologically apparent angioinvasiveness. This is the first reported ENKTL case with mutations in the KDM6A gene. KDM6A is one of the histone-modifying genes that are mutated in many human diseases including haematological cancers. Epigenetic regulation of gene expression has recently been demonstrated in ENKTL, and a similar pathway is thought to play an oncogenic role in EBV-negative ENKTL. Our report shows the extent of comprehensive examination required before making a definitive diagnosis for NK- and T-cell neoplasms and broadens the therapeutic options for potential targets.

Delayed recovery of serum immunoglobulin G is a poor prognostic marker in patients with follicular lymphoma treated with rituximab maintenance.

Clinical trials involving various treatment schedules for rituximab maintenance have been conducted for patients with follicular lymphoma (FL) and have not confirmed their impact on serum immunoglobulin (sIg) levels until the completion of maintenance. However, the long-term use of rituximab is a concern because of circulating plasma cell-depletion risk, suggesting that the mechanism of change in sIg levels after RM has not been determined. Additionally, the relationship between host humoral immunity and the prognosis of patients with B cell malignancies has not been determined. We retrospectively investigated data from 213 patients with FL from a single institute who achieved at least a partial response with rituximab, cyclophosphamide, vincristine, and prednisolone with or without doxorubicin. Of these, 166 patients underwent RM with a median period of 1.6 years. A significantly delayed recovery of sIgG levels was observed in the maintenance group until 3 years after RM in comparison to the observation group. A multivariate analysis showed that a sIgG level of < 718 mg/dl 1 year after RM was an independent predictor for poor progression-free survival (PFS) (hazard ratio, 2.3; P = 0.04). Therefore, the sIgG levels scarcely recovered and were significantly delayed after RM, leading to shorter PFS in patients with FL.

Effects of Helicobacter pylori eradication on serum lipid levels.

The purpose was to clarify the effects of Helicobacter pylori (H. pylori) eradication on the changes in serum lipid levels by comparing subjects with and without continuous H. pylori infection. The study subjects were 774 individuals (males 536, females 238, mean age 52.6 years) who visited between April 2013 and March 2016 for annual medical checkups. Serum total cholesterol, high-density lipoprotein cholesterol (HDLC), low-density lipoprotein cholesterol (LDLC), and triglyceride levels, and LDLC/HDLC ratio were compared between the subjects with and without H. pylori infection, as well as those with H. pylori eradication subjects. The HDLC level in the H. pylori-positive group was significantly lower as compared to the H. pylori-negative group. The serum level of HDLC in subjects with successful eradication of H. pylori tended to be higher, while the serum levels of total cholesterol, LDLC, and triglycerides tended to be lower in comparison to subjects with continuous H. pylori infection. In addition, the LDLC/HDLC ratio in the H. pylori-positive group was significantly higher than that in the H. pylori-negative group, and successful H. pylori eradication tended to reduce that ratio. In conclusion, successful eradication of H. pylori may have favorable effects on lipid metabolism.

Incidence and risk factors of febrile neutropenia in patients with non-Hodgkin B-cell lymphoma receiving R-CHOP in a single center in Japan.

PURPOSE: The incidence of and risk factors for febrile neutropenia (FN) in Japanese non-Hodgkin B-cell lymphoma (B-NHL) patients receiving rituximab, cyclophosphamide, doxorubicin, vincristine, and predonisolone (R-CHOP) chemotherapy are unknown. We conducted this study to address this issue. METHODS: In this single-center, retrospective, observational study, 466 patients with B-NHL who completed an R-CHOP regimen within a 7-year period and who planned to undergo at least three cycles of this regimen were analyzed. The following FN-related factors were assessed: fever, infection, disease state, neutrophil count, and prophylactic interventions such as use of antibiotics and/or granulocyte colony-stimulating factor (G-CSF). We simulated the FN incidence and 95% confidence interval (CI) of patients without prophylaxis with G-CSF (cycle 1) using bootstrap sampling. RESULTS: The incidence of FN was 9.1% (42 of 462) in cycle 1 and 12.3% (57 of 462 patients) throughout all cycles, with 73.7% (42/57) developing FN during cycle 1. Risk factors for FN among patients with B-NHL treated with R-CHOP were albumin <35 g/L (p = 0.0047), relative dose intensity <85% (p = 0.0007), and lack of prophylaxis with G-CSF (p = 0.0006) in cycle 1. In the simulation analysis, the estimated FN incidence in cycle 1 was 16.2% (95% CI [10.9-22.2]). CONCLUSIONS: At 9.1% in cycle 1 and 12.3% throughout all cycles, the incidence of FN was lower than previously reported, possibly reflecting the appropriate use of G-CSF in this clinical setting. For patients with risk factors, the prophylaxis with G-CSF may decrease the occurrence of FN.

Efficacy of chemotherapy in extremely elderly patients with diffuse large B-cell lymphoma.

The safety and effective dose of chemotherapy in treating non-Hodgkin lymphoma in elderly patients is yet to be established. In this study, we assessed the prognosis of diffuse large B-cell lymphoma (DLBCL) in elderly patients (≥75 years) treated with an optimal dose of R-CHOP. No significant differences were observed in progression-free survival between elderly patients and patients aged <74 years with DLBCL. Furthermore, no differences were observed between full-dose R-CHOP and 80% dose R-CHOP groups. Median relative dose intensity was 0.80 in elderly patients with DLBCL. Thus, our data suggested that 80% dose R-CHOP is tolerable and effective in these patients.

Ricolinostat (ACY-1215) induced inhibition of aggresome formation accelerates carfilzomib-induced multiple myeloma cell death.

Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome-proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti-MM effects, even in bortezomib-resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY-1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ-induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.

Absolute peripheral monocyte count at diagnosis predicts central nervous system relapse in diffuse large B-cell lymphoma.

Recently, elevated peripheral blood monocyte counts at diagnosis have been shown to be an independent marker associated with poor prognosis in patients with both non-Hodgkin and Hodgkin lymphoma. In this study, we retrospectively analyzed the data from a total of 550 patients with diffuse large B-cell lymphoma and evaluated the relationship between central nervous system relapse and absolute monocyte counts at diagnosis. Twenty-six patients developed central nervous system relapse. The central nervous system relapse-free survival rate was significantly lower in patients with the absolute monocyte counts ≥ 0.51 × 10(9)/L (87.8% versus 96.4%; P<0.001). This association was independently significant after adjusting for other significant factors, including systemic relapse as a time-dependent covariate by multivariate analysis (hazard ratio 2.46; 95% confidence intervals 1.05-5.75; P=0.039). These results suggest that the absolute monocyte count at diagnosis is an independent significant risk factor for central nervous system relapse in patients with diffuse large B-cell lymphoma.

Effects of universal vs bedside leukoreductions on the alloimmunization to platelets and the platelet transfusion refractoriness.

BACKGROUND: Multiple platelet exposure induces anti-HLA and/or anti-HPA antibody production, which may cause platelet transfusion refractoriness (PTR). In Japan, the universal pre-storage leukocyte reduction (ULR) was fully implemented since 2006, but prior to ULR, in our institution, leukocyte reduction filters were routinely used at the bedside (bedside leukoreduction, BSLR) for all onco-hematological patients receiving multiple platelet transfusions. OBJECTIVE: We retrospectively compared patients receiving platelet transfusions in the era of ULR with those of BSLR era. MATERIALS AND METHODS: Patients of the BSLR group (409 cases) and the ULR group (586 cases) were compared in terms of alloimmunization and immunological PTR. The clinico-pathological features, including gender, history of pregnancy, number of exposed transfusion donors, periods of transfusion, and prior stem cell transplantation were compared, and the risk factors of alloimmunization were determined. RESULTS: The antibody detection rate was significantly higher in the ULR compared to BSLR group (8.7% vs. 5.4%), as well as the immunological PTR rate (7.3% vs. 3.2%). By the multivariate analysis, female gender and the number of platelet donor exposure, but not universal leukoreduction or transfusion period, were found to be the risk factors strongly associated with alloantibody formation. CONCLUSION: Although ULR may be superior to BSLR in terms of preventing non-hemolytic transfusion reactions, BSLR was found to be as effective as ULR in terms of preventing platelet alloimmunization and refractoriness. Thus, BSLR should be actively indicated as a realistic alternative in developing countries, before the universal leukoreduction is fully implemented.

The role of alloantibodies against human platelet antigen-15 in multiply platelet transfused patients.

BACKGROUND: Several studies have documented the role of antibodies against human platelet (PLT) antigen (HPA)-15 in alloimmune-mediated thrombocytopenia including neonatal alloimmune thrombocytopenia, PLT transfusion refractoriness (PTR), and posttransfusion purpura in Caucasian persons. However, the relevance of anti-HPA-15 in PTR among the Japanese population is still unclear. STUDY DESIGN AND METHODS: The sera of 305 multiply PLT transfused (MPT) patients, previously investigated for the presence of human leukocyte antigen (HLA) and HPA antibodies by mixed passive hemagglutination, were reexamined for the presence of HPA-15 alloantibodies, using the monoclonal antibody-specific immobilization of PLT antigens (MAIPA) technique. RESULTS: Among the 305 MPT samples, antibodies against HPA-15 alloantigen was detected in seven (2.3%), two (0.66%) being anti-HPA-15a and five (1.64%) being anti-HPA-15b. Additionally, one case of CD109 panreactive antibody was found (0.33%). Among them, one aplastic anemia patient with blood group O developed multispecific anti-HLA and anti-HPA-15b alloantibody after MPTs. However, transfusion with HLA-matched PLTs of blood group AB did not result in adequate PLT count increment. Analysis of the possible influence of immune anti-A and anti-B by the MAIPA assay resulted negative, indicating that anti-HPA-15b is responsible for the refractory state in this patient. CONCLUSION: In this study, we found alloimmunization against HPA-15a and -15b in Japanese populations and demonstrated the relevance of these antibodies in a patient with PTR.