Pegcetacoplan versus Eculizumab in Paroxysmal Nocturnal Hemoglobinuria.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired disease characterized by chronic complement-mediated hemolysis. C5 inhibition controls intravascular hemolysis in untreated PNH but cannot address extravascular hemolysis. Pegcetacoplan, a pegylated peptide targeting proximal complement protein C3, potentially inhibits both intravascular and extravascular hemolysis. METHODS: We conducted a phase 3 open-label, controlled trial to assess the efficacy and safety of pegcetacoplan as compared with eculizumab in adults with PNH and hemoglobin levels lower than 10.5 g per deciliter despite eculizumab therapy. After a 4-week run-in phase in which all patients received pegcetacoplan plus eculizumab, we randomly assigned patients to subcutaneous pegcetacoplan monotherapy (41 patients) or intravenous eculizumab (39 patients). The primary end point was the mean change in hemoglobin level from baseline to week 16. Additional clinical and hematologic markers of hemolysis and safety were assessed. RESULTS: Pegcetacoplan was superior to eculizumab with respect to the change in hemoglobin level from baseline to week 16, with an adjusted (least squares) mean difference of 3.84 g per deciliter (P<0.001). A total of 35 patients (85%) receiving pegcetacoplan as compared with 6 patients (15%) receiving eculizumab no longer required transfusions. Noninferiority of pegcetacoplan to eculizumab was shown for the change in absolute reticulocyte count but not for the change in lactate dehydrogenase level. Functional Assessment of Chronic Illness Therapy-Fatigue scores improved from baseline in the pegcetacoplan group. The most common adverse events that occurred during treatment in the pegcetacoplan and eculizumab groups were injection site reactions (37% vs. 3%), diarrhea (22% vs. 3%), breakthrough hemolysis (10% vs. 23%), headache (7% vs. 23%), and fatigue (5% vs. 15%). There were no cases of meningitis in either group. CONCLUSIONS: Pegcetacoplan was superior to eculizumab in improving hemoglobin and clinical and hematologic outcomes in patients with PNH by providing broad hemolysis control, including control of intravascular and extravascular hemolysis. (Funded by Apellis Pharmaceuticals; PEGASUS ClinicalTrials.gov, NCT03500549.).

Efficacy, Safety and Quality of Life of Pegcetacoplan in Japanese Patients With Paroxysmal Nocturnal Hemoglobinuria Treated Within the Phase 3 PEGASUS Trial.

INTRODUCTION: Pegcetacoplan, the first approved proximal complement C3 inhibitor, showed superiority to eculizumab in improving hemoglobin levels and clinical outcomes in the phase 3 PEGASUS study in patients with paroxysmal nocturnal hemoglobinuria (PNH) and inadequate response to eculizumab. METHODS: This analysis evaluates the efficacy and safety of pegcetacoplan for Japanese patients in PEGASUS, as they are known for different clinicopathologic features compared to non-Asian patients. Ten Japanese patients were enrolled to receive pegcetacoplan (n=5) or eculizumab (n=5) during the 16-week randomized controlled period. All patients received pegcetacoplan monotherapy during the open-label period until Week 48. RESULTS: Treatment with pegcetacoplan improved hemoglobin with a mean change from baseline of 2.4 g/dL at Week 16, which was sustained through 48 weeks. Pegcetacoplan-treated Japanese patients experienced sustained improvements in key secondary efficacy endpoints, including freedom from transfusion, lactate dehydrogenase level, reticulocyte count, and FACIT-Fatigue score. The safety profile was consistent with previously reported data from pegcetacoplan studies. No events of hemolysis, meningococcal infection, or thrombosis were reported in the Japanese population and all Japanese patients remained on treatment throughout the study. CONCLUSION: These data suggest that Japanese patients with PNH can be effectively and safely managed with pegcetacoplan. CLINICALTRIALS: gov identifier: NCT03500549.

Sigle Agent of Posttransplant Cyclophosphamide Without Calcineurin Inhibitor Controls Severity of Experimental Chronic GVHD.

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity following allogeneic hematopoietic cell transplantation (HCT), but its pathogenesis remains unclear. Recently, haplo-identical HCT with post-transplant cyclophosphamide (Haplo-HCT with PTCY) was found to achieve a low incidence rate of acute GVHD and chronic GVHD. However, while the pathogenesis of acute GVHD following Haplo-HCT with PTCY has been well investigated, that of chronic GVHD remains to be elucidated, especially in HLA-matched HCT with PTCY. Based on its safety profile, PTCY is currently applied for the human leucocyte antigen (HLA)-matched HCT setting. Here, we investigated the mechanisms of chronic GVHD following HLA-matched HCT with PTCY using a well-defined mouse chronic GVHD model. PTCY attenuated clinical and pathological chronic GVHD by suppressing effector T-cells and preserving regulatory T-cells compared with a control group. Additionally, we demonstrated that cyclosporine A (CsA) did not show any additional positive effects on attenuation of GVHD in PTCY-treated recipients. These results suggest that monotherapy with PTCY without CsA could be a promising strategy for the prevention of chronic GVHD following HLA-matched HCT.

Bone marrow microenvironment disruption and sustained inflammation with prolonged haematologic toxicity after CAR T-cell therapy.

Mechanisms of prolonged cytopenia (PC) after chimeric antigen receptor (CAR) T-cell therapy, an emerging therapy for relapsed or refractory diffuse large B-cell lymphoma, remain elusive. Haematopoiesis is tightly regulated by the bone marrow (BM) microenvironment, called the 'niche'. To investigate whether alterations in the BM niche cells are associated with PC, we analysed CD271+ stromal cells in BM biopsy specimens and the cytokine profiles of the BM and serum obtained before and on day 28 after CAR T-cell infusion. Imaging analyses of the BM biopsy specimens revealed that CD271+ niche cells were severely impaired after CAR T-cell infusion in patients with PC. Cytokine analyses after CAR T-cell infusion showed that CXC chemokine ligand 12 and stem cell factor, niche factors essential for haematopoietic recovery, were significantly decreased in the BM of patients with PC, suggesting reduced niche cell function. The levels of inflammation-related cytokines on day 28 after CAR T-cell infusion were consistently high in the BM of patients with PC. Thus, we demonstrate for the first time that BM niche disruption and sustained elevation of inflammation-related cytokines in the BM following CAR T-cell infusion are associated with subsequent PC.

Evaluating the efficiency and safety of large-volume leukapheresis using the Spectra Optia continuous mononuclear cell collection protocol for peripheral blood stem cell collection from healthy donors: A retrospective study.

BACKGROUND: Large-volume leukapheresis (LVL) refers to processing of more than three volumes of blood in a single session for peripheral blood stem cell collection. Recently, continuous mononuclear cell collection (cMNC) protocol has been developed using the Spectra Optia system, which is a widely used apheresis device. LVL using the novel protocol has been investigated in patients. However, the efficiency and safety of LVL in healthy donors using this protocol has not been characterized. Therefore, this study aimed to evaluate the efficiency and tolerability of CD34+ collection of LVL with the cMNC protocol in healthy donors. STUDY DESIGN AND METHODS: We retrospectively collected data on LVL (>3 total blood volume) and normal-volume leukapheresis (NVL) performed in healthy donors between October 2019 and December 2021. All procedures were performed using the cMNC protocol. RESULTS: Although pre-apheresis CD34+ cell count was lesser in LVL (23.5 vs. 58.0/µL, p < .001), CD34+ collection efficiency was comparable between LVL and NVL (61.2% vs. 61.4%, p = .966). Platelet loss was significantly higher in LVL compared to NVL (38.0% vs. 29.4%, p < .001), with no correlation between attrition of platelet and processing blood volume. Moreover, the incidence of citrate toxicity during procedures was comparable between the two groups (31.6% vs. 21.4%, p = .322). All LVL procedures could be completed without any adverse events. CONCLUSION: Allogeneic LVL procedure using Spectra Optia cMNC protocol was well tolerated by the donors and resulted in efficient collection of CD34+ cells, which was comparable to that of NVL.

Efficient granulocyte collection method using high concentrations of medium molecular weight hydroxyethyl starch.

BACKGROUND: Granulocyte transfusion therapy is a rational therapeutic option for patients with prolonged, severe neutropenia. Although high molecular weight hydroxyethyl starch (hHES) facilitates the separation of red blood cells during granulocyte collection, renal dysfunction has been noted as a potential side effect. HES130/0.4 (Voluven®) is a medium molecular weight HES (mHES) with superior safety profiles compared to hHES. Although HES130/0.4 is reportedly effective in the collection of granulocytes, we lack studies comparing the efficiency of granulocyte collection using HES130/0.4 and hHES. STUDY DESIGN AND METHODS: We retrospectively collected the data from 60 consecutive apheresis procedures performed on 40 healthy donors at the Okayama University Hospital between July 2013 and December 2021. All procedures were performed using the Spectra Optia system. Based on the HES130/0.4 concentration in the separation chamber, granulocyte collection methods using HES130/0.4 were classified into m0.46, m0.44, m0.37, and m0.8 groups. We used HES130/0.4 and hHES groups to compare the various sample collection methods. RESULTS: The median granulocyte collection efficiency (CE) was approximately 24.0% and 28.1% in the m0.8 and hHES groups, respectively, which were significantly higher than those in the m0.46, m0.44, and m0.37 groups. One month following granulocyte collection with HES130/0.4, no significant changes were observed in serum creatinine levels compared to those before the donation. CONCLUSION: Therefore, we propose a granulocyte collection approach employing HES130/0.4, which is comparable to the use of hHES in terms of the granulocyte CE. A high concentration of HES130/0.4 in the separation chamber was considered crucial for granulocyte collection.

A Case of Radiation-Induced Osteosarcoma with RB1 Gene Alteration Treated by Skull Base Surgery and Craniofacial Reconstruction.

A 35-year-old female presented with headache, photophobia and developed sudden loss of vision after having undergone right-side ophthalmectomy and radiochemotherapy for retinoblastoma in infancy. A neoplastic lesion was found in the left middle cranial fossa and was surgically removed. The diagnosis was radiation-induced osteosarcoma with RB1 gene alteration. Although she received chemotherapy for the residual tumor, it progressed 17 months later. Maximal surgical resection with craniofacial reconstruction was required. We utilized two three-dimensional models for surgical planning. She was discharged without neurological deficits other than loss of light perception subsequent to left ophthalmectomy. In cases where retinoblastoma is treated with radiotherapy, long-term follow-up is necessary to monitor for radiation-induced tumor development.

Low hematocrit reduces the efficiency of CD34+ cell collection when using the Spectra Optia continuous mononuclear cell collection procedure.

BACKGROUND: CD34+ cell collection efficiency (CE) is the determining factor when calculating processed blood volume (PBV) for leukapheresis (LP). However, the factors affecting CE in the continuous mononuclear cell collection (cMNC) protocol performed by the Spectra Optia apheresis system are not well established. STUDY DESIGN AND METHODS: We retrospectively collected the data from 147 consecutive apheresis procedures across 106 healthy donors and 27 patients completed between July 2016 and December 2020 at the Okayama University Hospital. All procedures were performed using the Optia cMNC protocol. RESULTS: The median CD34+ CE2 was significantly higher in the donor samples (64.3%) than in the patient samples (46.8%) (p < .0001). WBC counts, hematocrit, and platelet counts were all significantly higher in the donors than in the patients, and there was a moderate positive correlation between CD34+ CE2 and hematocrit (r = .47, p < .0001), with the equation of the line being y = 1.23x + 12.23. In contrast, there was only a very weak correlation between CD34+ CE2 and WBC or platelet count. In addition, low hematocrit correlated with an increased time to interface formation. CONCLUSION: These data revealed the negative impact of low hematocrit on the efficiency of CD34+ cell collection when using the Optia cMNC protocol and suggest that hematocrit values should also be considered when determining PBV.

Red blood cell depletion in small-volume bone marrow processing using manipulation with third-party red blood cells: A comparison of the performance of the COBE spectra and the spectra Optia systems.

BACKGROUND: For pediatric recipients, red blood cells (RBCs) are added to bone marrow (BM) collections before low RBC volume BM processing using COBE Spectra (COBE) or Spectra Optia (Optia). However, the processing efficiency of this approach has not been evaluated. This study aimed to evaluate RBC depletion and nucleated cell subpopulation recovery rates in third-party RBC-manipulated BM products processed with the COBE or Optia. STUDY DESIGN AND METHODS: We retrospectively collected data on RBC depletion from low RBC volume BM with third-party RBCs (manipulated group) and on conventional large-volume, BM (unmanipulated group) processing performed between September 2010 and December 2021. All procedures were performed using COBE or Optia. RESULTS: The median residual RBC volume in the manipulated group was 9.5 ml in COBE and 2.5 ml in Optia (p = .01). The median total nucleated cell (TNC) and mononuclear cell (MNC) were comparable between the manipulated groups using each cell separator (TNC, 40.8 vs. 47.1%; MNC, 78.3 vs. 79.4%). The manipulation did not adversely affect TNC and MNC recoveries in either device. In addition, Optia achieved similar CD34+ cell recovery to that in large-BM-volume processing using the same device (147.5 vs. 184.5%, p = .112). During a follow-up period, neutrophil engraftment was achieved in all patients who received third-party RBC-manipulated grafts, and platelet engraftment was achieved in all cases, except one. CONCLUSION: The addition of third-party RBC to low RBC volume BM collections from or for pediatric patients does not have any negative impact on either RBC depletion or hematopoietic cell recovery during processing with the widely used cell separator.

Successful neutrophil engraftment supported by granulocyte transfusion in adult allogeneic transplant patients with peri-transplant active infection.

Active infection at the time of allogeneic hematopoietic stem cell transplantation (HSCT) is a risk for non-relapse mortality (NRM) after HSCT. Granulocyte transfusion (GTX) has been used to prevent or treat life-threatening infections in patients with severe neutropenia. However, data are limited on the clinical benefits of GTX during HSCT. We retrospectively analyzed the transplant outcomes of HSCT patients who had undergone GTX between 2012 and 2020. Altogether, 20 patients with documented infection had received 55 GTXs during HSCT. No adverse events were observed during the GTX infusion. The average number of granulocytes was 0.40 (range, 0.10-1.59) × 109/kg. The median neutrophil increment one day after GTX was 515 (range, -6 to 6630)/µl, which was significantly correlated with the infused granulocyte dose (p = 0.0007). A total of 17 of 20 patients achieved neutrophil engraftment. The number of infused granulocytes tended to higher in clinical responders (p = 0.12), and patients receiving ≥ 0.5 × 109/kg showed trend toward to better transplant outcomes (GTX-high vs. GTX-low, 1-year OS; 33% vs. 11%, p = 0.19. 1-year NRM; 44% vs.77%, p = 0.11). The type of red blood sedimenting agents was significantly correlated with the amounts of granulocyte collection. In conclusion, GTX, especially with a high amount of containing granulocytes, could be a safe bridging therapy for neutrophil engraftment after HSCT in patients with active infection.

Analysis of Immunity against Measles, Mumps, Rubella, and Varicella Zoster in Adult Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A Single-Center Experience.

Vaccine-preventable disease (VPD) infections are more severe in immunocompromised hosts. Vaccination against measles, mumps, rubella, and varicella zoster (VZV) (MMRV) is therefore recommended for hematopoietic stem cell transplantation (HCT) recipients. However, studies on adult HCT recipients with VPD infections are limited. At our institution, we have systematically conducted serological MMRV tests as a part of check-up examinations during long-term follow-up (LTFU) after HCT since 2015. This retrospective study aimed to evaluate changes in the serostatus between before and 2 years after allogeneic HCT. Among 161 patients, the pre-transplant seropositivity was 82.7% for measles, 86.8% for mumps, 84.2% for rubella, and 94.3% for VZV. Among 56 patients who underwent LTFU including serological MMRV tests at 2 years after HCT, the percentages maintaining seroprotective antibody levels for measles, mumps, rubella and VZV were 71.5% (40/56), 51.8% (29/56), 48.2% (27/56), and 60.7% (34/56), respectively. Vaccination was recommended for 22 patients, and 12 were vaccinated. Among the 12 vaccinated patients, rates of seroconversion were examined in 2-6 patients for each of the four viruses. They were 100% (3/3) for measles, 33.3% (1/3) for mumps, 50% (3/6) for rubella, and 0% (0/2) for VZV. Further studies are warranted to clarify the effect of vaccination in adult HCT recipients.

Effects of Gram-negative Rod Blood Stream Infection on Acute GVHD in Allogeneic Hematopoietic Stem Cell Transplantation: A Single-institute Analysis.

A bloodstream infection (BSI) is the most common serious infectious complication of hematopoietic stem cell transplantation (HSCT). BSI promotes an inflammatory state, which exacerbates acute graft-versus-host disease (GVHD). We investigated whether a Gram-negative rod bloodstream infection (GNR-BSI), which develops early after allo-HSCT, affected the onset or exacerbated acute GVHD in 465 patients who underwent allo-HSCT from 1995 through 2015 at a single institution. Eighty-eight patients (19%) developed BSI during the study period. Among the cultures, 50 (57%) were Gram-positive cocci (GPC) and 31 (35%) were GNR. Of the 465 patients, 187 (40%) developed acute GVHD of grade II or higher within the first 100 days post-allogeneic HSCT: 124 (27%) had acute GVHD grade II, 47 (10%) had grade III, and 16 (3%) had grade IV. Multivariate analysis revealed that GNR-BSI was a significant risk factor for grade II-IV acute GVHD (grade II-IV: hazard ratio [HR] 1.75, 95% confidence interval [CI] 1.03-2.97; grade III-IV: HR 2.37, 95% CI 1.03-5.43). These results suggest that GNR-BSI may predict the onset and exacerbation of acute GVHD.

Successful Treatment of Acute Promyelocytic Leukemia Complicated with Endometrial Cancer by Arsenic Trioxide.

Acute promyelocytic leukemia (APL) is a hematological emergency that requires urgent intervention because of the high incidence of early hemorrhagic death. When patients with APL experience a synchronous solid organ tumor, the tumor's treatment must also be done properly. Differentiation-inducing therapy using arsenic trioxide (ATO) has less hematological toxicity compared to cytotoxic chemotherapy and might be preferable for untreated APL patients with a synchronous solid organ tumor. Here we describe the first successful case of untreated APL and synchronous endometrial cancer (in an adult Japanese woman) treated with ATO consolidation therapy and the subsequent surgery and chemotherapy for endometrial cancer.

Efficacy of HLA virtual cross-matched platelet transfusions for platelet transfusion refractoriness in hematopoietic stem cell transplantation.

BACKGROUND: Cross-matched platelet (cross-matched PLT) transfusion is effective for immune-mediated platelet transfusion refractoriness (PTR), but is more costly and time-consuming for physical cross-match than using standard PLT units. Recent studies have reported the utility of human leucocyte antigens (HLA) virtual cross-matched PLT (HLA-matched PLT) that is defined as HLA-A/B matched or no antibody against donor-specific antigen. Here, we evaluated the effect of HLA-matched PLTs for PTR in post hematopoietic stem cell transplant (HSCT) recipients. STUDY DESIGN AND METHODS: Our study included a total of 241 PLTs in 16 patients who underwent HSCT at Okayama University Hospital between 2010 and 2017, receiving either HLA-matched or cross-matched PLTs. We calculated the 24-hour corrected count increments (CCI-24) to evaluate the effect of PLTs. A CCI-24 ≥ 4500 was considered to be a successful transfusion. RESULTS: We analyzed 139 cross-matched PLTs and 102 HLA-matched PLTs. In the immune-mediated PTR, the rate of successful transfusion was 60.5% for cross-matched PLT and 63.4% for HLA-matched PLT (p = 0.825). On the other hand, the median CCI-24 for cross-matched PLT transfusions and HLA-matched PLT transfusions were 1856 and 5824 (p < 0.001), with a success rate of 28.1 and 54.1% in cases with non-immune-mediated PTR, respectively (p = 0.001). CONCLUSION: The effectiveness of HLA-matched PLT is not inferior to cross-matched PLT. This result indicates that physical cross-match can be omitted in post HSCT PTR.

Successful Treatment of Metastatic Urothelial Carcinoma after Accurate Diagnosis by Immunohistochemistry.

Urothelial carcinoma usually presents with hematuria, but cases of multiple lymphadenopathy with elevated S-pancreas-1 antigen (SPan-1) levels have not been reported. A 62-year-old Japanese man with lymphadenopathies was diagnosed with an adenocarcinoma of unknown origin and transferred to our hospital for further diagnosis. Serum carbohydrate antigen 19-9 and SPan-1 levels were extremely elevated. Uroplakin III immunostaining was positive in the inguinal lymph node, and cystoscopy revealed the presence of invasive urothelial carcinoma. Treatment with cisplatin and gemcitabine promoted a complete metabolic response for > 4 years. The detection of uroplakin III and serum SPan-1 might help diagnose urothelial carcinoma.

Salvage Haploidentical Transplantation Using Low-dose ATG for Early Disease Relapse after First Allogeneic Transplantation: A Retrospective Single-center Review.

Second allogeneic stem cell transplantation (allo-SCT) is a potentially curative therapy for patients who relapse after first allo-SCT. Human leukocyte antigen (HLA)-haploidentical related donors provide the broad opportunity to conduct second SCT at the appropriate time, but the efficacy of second SCT from haploidentical donors after relapse has not been established. We retrospectively analyzed the records of 33 patients who underwent second SCT. Twenty patients underwent haplo-SCT with low-dose antithymocyte globulin (ATG), and the other 13 patients underwent conventional- SCTs, including HLA-matched related peripheral blood, unrelated bone marrow or cord blood. Three years after the second SCT, the overall survival (OS) and progression-free survival (PFS) of all patients were 32.5% and 23.9%. Multivariate analyses indicated that non-complete response at second SCT, less than 1-year interval to relapse after first- SCT, and total score ≥ 3 on the hematopoietic cell transplantation-specific comorbidity index were significantly associated with a lower PFS rate. The haplo- and conventional- SCT groups showed equivalent results regarding OS, PFS, cumulative incidences of relapse, non-relapse mortality and graft-versus-host disease. The neutropenic period after transplantation was significantly shorter in haplo- SCT than conventional- SCT (10.5 days vs. 16 days, p=0.001). Our analysis revealed that haplo-SCT could be an alternative therapeutic option for relapsed patients after first SCT.

Progressive multifocal leukoencephalopathy after T-cell replete HLA-haploidentical transplantation with post-transplantation cyclophosphamide graft-versus-host disease prophylaxis.

A 52-year-old man suffered from progressive multifocal leukoencephalopathy (PML) after human leukocyte antigen (HLA)-haploidentical transplantation with post-transplantation cyclophosphamide (PTCY). Mirtazapine, mefloquine, and cytarabine failed to improve his symptoms, and he finally died 4.5 months after PML onset. This is the first case report of a patient with PML after HLA-haploidentical transplantation with PTCY. Although T-cell replete HLA-haploidentical transplantation with PTCY has enabled early immune reconstitution, PML should be considered if a patient's mental condition deteriorates.

Dose-adjusted EPOCH chemotherapy for untreated peripheral T-cell lymphomas: a multicenter phase II trial of West-JHOG PTCL0707.

The standard CHOP therapy for peripheral T-cell lymphoma has resulted in unsatisfactory outcomes and it is still not clear what is the optimal front-line therapy. We conducted a multicenter phase II study of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (EPOCH) for untreated peripheral T-cell lymphoma patients. In this prospective study, 41 patients were treated with dose-adjusted-EPOCH as initial therapy: peripheral T-cell lymphoma-not otherwise specified, n=21; angioimmunoblastic T-cell lymphoma, n=17; anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, n=2; and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, n=1. Median patient age was 64 years (range: 32-79 years). According to the International Prognostic Index criteria, 51.2% were at high-intermediate or high risk. The overall response and complete response rates were 78.0% [95% confidence interval (CI): 62.4-89.4%] and 61.0% (95%CI: 44.5-75.8%), respectively. At the median follow up of 24.0 months, the 2-year progression-free survival and overall survival were 53.3% (95%CI: 36.4-67.5%) and 73.2% (95%CI: 56.8-84.1%), respectively. The younger patients (≤ 60 years old) had a high response rate (overall response 94.1% and complete response 70.6%) and survival rate (progression-free survival 62.5% and overall survival 82.4%). The most common grade ≥ 3 adverse events were neutropenia (74.5%), anemia (40.8%), thrombocytopenia (22.0%), and febrile neutropenia (9.0%). Dose-adjusted-EPOCH had a high response rate with a tolerable toxicity profile. Our results indicate that dose-adjusted-EPOCH is a reasonable first-line approach for peripheral T-cell lymphoma patients and may improve outcomes.

Graft-versus-leukemia effect with a WT1-specific T-cell response induced by azacitidine and donor lymphocyte infusions after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Azacitidine (Aza) and donor lymphocyte infusion (DLI) therapy has recently been reported as an effective salvage therapy for relapsed acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Despite the high response rate and relatively long period of remission, most patients relapse again. The immunologic mechanism of the response and limited efficacy remain unknown. CASE REPORT: Aza + DLI therapy was performed for a patient with therapy-related MDS (t-MDS), who had relapsed after allogeneic peripheral blood stem cell transplantation. We observed a powerful graft-versus-leukemia (GVL) effect accompanied by an evident Wilms tumor antigen 1 (WT1)-specific CD8 T-cell response. Remission continued for 15 months, but finally the patient relapsed. The kinetics of the WT1-specific CD8 T cells were inversely associated with WT1 messenger RNA (mRNA), suggesting a WT1-driven GVL effect. DISCUSSION: A difference of T-cell phenotype between the whole T cells and the WT1-specific CD8 T cells was observed. It is of note that the memory phenotype of the WT1-specific T cell was limited and decreased early. The immunoescape mechanism was partly supported by loss of the memory phenotype due to failure of expansion and differentiation. CONCLUSION: Our data suggested that a WT1-specific T-cell response at least partly contributes to the GVL effect induced by Aza + DLI. A strategy for maximizing and maintaining the memory phenotype of the CTL may be required for durable remission.

Anti-IL-12/23 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells.

Chronic graft-versus-host disease (GVHD) is a major cause of late death and morbidity after allogeneic hematopoietic cell transplantation. Recently, in addition to Th2 cells, Th1 and Th17 cells have been shown to contribute to chronic GVHD progression. IL-12 induces Th1 cells and IL-23 plays a role in stabilizing and/or amplifying Th17 cells, as well as in inducing IFN-γ/IL-17 double-producing cells. Because mAb targeting the p40 subunit common to both IL-12 and IL-23 can inhibit both IL-12R and IL-23R-mediated signaling, we investigated the effects of anti-p40 mAb on a well-defined chronic GVHD mice model. Treatment of anti-p40 mAb in allogeneic recipients significantly reduced the severity of clinical and pathological chronic GVHD. Intracellular staining revealed that IFN-γ single-positive (IL-17(-)) and IFN-γ/IL-17 double-positive cells were suppressed in anti-p40 mAb-treated allogeneic recipients compared with control recipients. The cytokine levels of IFN-γ and IL-17 were also decreased in serum from anti-p40 mAb-treated allogeneic recipients. T-bet expression of donor IL-17(+) CD4(+) T cells was reduced significantly in anti-p40 mAb-treated recipients, and this reduction in T-bet expression was associated with IL-22 production by donor T cells. These results suggested that anti-p40 mAb attenuated chronic GVHD via suppression of IFN-γ/IL-17-producing cells, and that targeting the IL-12/IL-23 pathway may represent a promising therapeutic strategy for preventing and treating chronic GVHD.