Yasushi Senoo

Donor lymphocyte infusion for extranodal NK/T cell lymphoma, nasal type, relapsed after allogeneic hematopoietic SCT.

Extranodal NK/T cell lymphoma, nasal type (ENKL), is a rare type of non-Hodgkins lymphoma derived from natural killer (NK) cells in most cases and is closely associated with EBV.1 Nasal ENKL of limited stage has a relatively good prognosis when treated with high-dose radiotherapy with chemotherapy; however, in refractory or relapsed cases, the prognosis is dismal.2 Allogeneic hematopoietic cell transplantation (HCT) has been performed for a limited number of cases of ENKL, which led to a cure in some.3 Graft-vs-lymphoma (GVL) effects are possible in these cases, although anti-lymphoma effects of drugs or irradiation in the conditioning regimens are not excluded.

CD25 expression on residual leukemic blasts at the time of allogeneic hematopoietic stem cell transplant predicts relapse in patients with acute myeloid leukemia without complete remission

Abstract Recent studies have shown that CD25 expression at the time of diagnosis of acute myeloid leukemia (AML) may be associated with an unfavorable outcome. We focus on patients with AML without complete remission (CR) and examine the clinical correlation between surface CD25 expression at the time of transplant and subsequent transplant outcomes. We observed a significant difference in overall survival (OS), disease-free survival (DFS) and cumulative incidence of relapse (CIR) between CD25 positive (+) (n = 22) and negative (−) groups (n = 44) (2-year OS; CD25 (+) group: 5% vs. CD25 (−) group: 40%, p < 0.0001, 2-year DFS; 5% vs. 29%, p < 0.0001, 2-year CIR; 77% vs. 52%, p = 0.03). Multivariate analysis showed that CD25 expression was an independent adverse factor for OS (p = 0.002) and relapse (p = 0.001). Patients with AML with residual CD25 positive blasts at the time of transplant may require additional therapy before or after transplant to improve survival.

Allogeneic hematopoietic stem cell transplant overcomes poor prognosis of acute myeloid leukemia with myelodysplasia-related changes

Recent studies have shown that acute myeloid leukemia with myelodysplasia-related changes (AML-MRC) exhibits a worse clinical outcome than AML not otherwise specified (AML-NOS). However, transplant outcomes of patients with AML-MRC have not been reported compared to patients with AML-NOS. We analyzed transplant outcomes among 147 patients with AML-MRC or AML-NOS who underwent allogeneic hematopoietic stem cell transplant (allo-HSCT) in a single institution. There were no significant differences in the 2-year overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) between the two groups (2-year OS: 48% vs. 59%; 2-year CIR: 37% vs. 35%; 2-year NRM: 19% vs. 13%). Subgroup analysis adjusting for age and disease status demonstrated the same results between the two groups. Furthermore, multivariate analysis showed that AML-MRC was not an independent prognostic factor for poor prognosis in the setting of allo-HSCT (p = 0.7). These results suggest that allo-HSCT may overcome the poor prognosis of AML-MRC.

Mycophenolate mofetil is effective only for involved skin in the treatment for steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation

Dear Editor, Recently, mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), has been used for acute graft-versus-host disease (aGVHD) prophylaxis and as a treatment for steroid-refractory aGVHD (SR-aGVHD) [1–4]. In the setting of treatment for SR-aGVHD, only a few studies [2–4] have analyzed the individual response in three involved organs (only skin, only liver, and only gut) in a small number of patients treated with MMF. No study has reported the response in two or more involved organs. We evaluated whether MMF is effective for one, two, or three involved organs in patients who had received MMF for SR-aGVHD. From 2004 to 2014, we identified 42 patients who received oral MMF for the treatment of SR-aGVHD (grade I, n = 7; grade II–IV, n = 35) (Supplemental Table 1). Transplant procedures have been described in detail elsewhere [5]. All patients received aGVHD prophylaxis with cyclosporine (CsA) or tacrolimus (FK) as well as short-term methotrexate. aGVHD, SRaGVHD, and responses to MMF were diagnosed and graded according to previously established criteria [2, 6]. MMF was orally administered at a median dose of 1333 mg/day (range 500–3000) in addition to standard CsA or FK with more than 1 mg/kg steroid. Twice the initial amount of MMF was administered when aGVHD had not improved or worsened after the initiation of MMF treatment. The median duration of MMF administration was 97 days (range 11–674 days). Four weeks after the initiation of MMF, 24 patients achieved complete response (CR), 4 had partial response (PR), and 14 patients had no response (NR). The response including all organs was comparable in related or unrelated donor transplantation, and in bone marrow transplantation or peripheral blood stem cell transplantation (Supplemental Fig. 1a, d). All three recipients from human leukocyte antigen (HLA)-haploidentical donors received conditioning with antithymocyte globulin, and the response was NR (Supplemental Fig. 1b, c). However, the response was similar in HLA matched and one mismatched donor transplantation (Supplemental Fig. 1b). Regarding the involved organs, the response rate in patients who developed only skin GVHD was higher than in those with only liver, only gut, skin and liver, liver and gut, skin and gut, or all three organs (92.3 vs. 0, 0, 20, 0, 37.5, 0 %, respectively, p < 0.001, Fig. 1a). The response in skin was similar to that in liver among patients who developed skin and liver SR-aGVHD (CR and PR rate 20 vs. 20 %, Fig. 1b). Moreover, the response in skin was similar to that in gut among patients who developed skin and gut SRaGVHD (CR rate 50 vs. 37.5 %, Fig. 1c). This study demonstrated that patients with only skin SRaGVHD responded to MMF better than those with only liver, only gut, skin and liver, or skin and gut aGVHD. Furthermore, the response rate in skin was low, similar to that in liver or gut Electronic supplementary material The online version of this article (doi:10.1007/s00277-016-2854-0) contains supplementary material, which is available to authorized users.

Severe Hypoxemia in a Healthy Donor for Allogeneic Hematopoietic Stem Cell Transplantation after Only the First Administration of Granulocyte-Colony Stimulating Factor

Background: Granulocyte-colony stimulating factor (G-CSF) is widely used to mobilize peripheral blood stem cells (PBSCs) in healthy donors. A few reports have shown that some healthy donors developed acute respiratory distress syndrome or capillary leak syndrome after more than several rounds of G-CSF administration or leukapheresis. Case Report: We report the case of a healthy donor for allogeneic stem cell transplantation who developed severe hypoxemia 1 h after only the first administration of G-CSF. The donor was administered 10 μg/kg G-CSF (lenograstim) subcutaneously for PBSC mobilization. 1 h after the first administration of G-CSF, the donor suddenly presented with dry cough and dyspnea. The oxygen saturation by pulse oximetry (SpO2) in the room air was 88%. An electrocardiogram and chest radiography revealed no abnormalities. We excluded other causes of severe hypoxemia and diagnosed the donor with hypoxemia due to G-CSF administration, which was subsequently terminated. The donor was administered 2 l/min oxygen via a nasal cannula and 100 mg hydrocortisone intravenously. He subsequently recovered, and SpO2 in the room air returned to 98% 10 h after hypoxemia. Conclusion: These respiratory symptoms might be related to anaphylactoid or hypersensitivity reaction. The donors should be observed for at least 1 h after the first administration of G-CSF.

Breakthrough Candida guilliermondii (Meyerozyma guilliermondii) fungemia after cord blood transplantation for extranodal NK-cell lymphoma with azole prophylaxis

Fluconazole (FLCZ) is an azole antifungal agent and it has shown excellent clinical activities in suppressing fungemia with Candida albicans after hematopoietic stem cell transplantation. Increased administration of prophylactic FLCZ seems to have given rise to the relatively higher incidence of more resistant Candida non‐albicans infection. We present a case with a rare breakthrough fungemia with C. guilliermondii after cord blood transplantation for Extranodal NK cell Lymphoma, nasal type (ENKL), during antifungal prophylaxis with FLCZ. High level of caution is needed for the breakthrough, especially after long‐term azole administration.

Severe Infection of Pseudomonas aeruginosa during Eculizumab Therapy for Paroxysmal Nocturnal Hemoglobinuria

Eculizumab is the complement inhibitor administered to ameliorate intravascular hemolysis in paroxysmal nocturnal hemoglobinuria. Whether or not the inhibitory mechanism may also increase the susceptibility to non-Neisserial infection is unclear. A 73-year old woman presented with bacteremia, cholecystitis and liver abscess with Pseudomonas aeruginosa. Although she had been neutropenic for 21 years, she had no history of severe infection before eculizumab had been administered. The infection with P. aeruginosa was successfully controlled with antibiotics, granulocyte colony-stimulating factor and cholecystectomy. The present case might be representative of less common bacterial infections than Neisseria spp. among patients treated with eculizumab.

Frequent STAT3 mutations in CD8+ T cells from patients with pure red cell aplasia

Dysregulation of T-cell-mediated immunity is responsible for acquired pure red cell aplasia (PRCA). Although STAT3 mutations are frequently detected in patients with T-cell large granular lymphocytic leukemia (T-LGLL), which is often complicated by PRCA and which is also reported to be associated with acquired aplastic anemia (AA) and myelodysplastic syndrome (MDS), whether STAT3-mutated T cells are involved in the pathophysiology of PRCA and other types of bone marrow failure remains unknown. We performed STAT3 mutation analyses of the peripheral blood mononuclear cells from PRCA patients (n = 42), AA (n = 54), AA-paroxysmal nocturnal hemoglobinuria (AA-PNH; n = 7), and MDS (n = 21) using an allele-specific polymerase chain reaction and amplicon sequencing. STAT3 mutations were not detected in any of the 82 patients with AA/PNH/MDS but were detected in 43% of the 42 PRCA patients. In all 7 STAT3-mutation-positive patients who were studied, the STAT3 mutations were restricted to sorted CD8+ T cells. The prevalence of STAT3 mutation in idiopathic, thymoma-associated, autoimmune disorder-associated, and T-LGLL-associated PRCA was 33% (5 of 15), 29% (2 of 7), 20% (1 of 5), and 77% (10 of 13), respectively. The STAT3-mutation-positive patients were younger (median age, 63 vs 73 years; P= .026) and less responsive to cyclosporine (46% [6 of 13] vs 100% [8 of 8]; P= .0092) in comparison with STAT3-mutation-negative patients. The data suggest that STAT3-mutated CD8+ T cells may be closely involved in the selective inhibition of erythroid progenitors in PRCA patients.

Erythrocytosis after allogeneic hematopoietic stem cell transplantation

We read with great interest the recent report by Atilla et al.1 showing posttransplant erythrocytosis (PTE) following allogeneic hematopoietic stem cell transplantation (alloHSCT). Because the small number of cases has limited the impact of their conclusion, we would like to present the clinical features of our adult patients who developed erythrocytosis after alloHSCT. The study included 1540 patients who underwent alloHSCT in our institution between 1986 and 2014. Patients who had a history of pretransplant erythrocytosis, those who smoked after alloHSCT, or patients who relapsed after alloHSCT were not included in this analysis. Erythrocytosis was defined as a hemoglobin (Hb) level >18.5 g/dL in males and >16.5 g/dL in females, based on the WHO 2008 definition.2 Patients with a Hb level >17.0 g/dL in males or >15.0 g/dL in females and who had an increased Hb level of 2 g/dL or an elevated red cell mass (125%) compared to the individual’s baseline value were included. Seven patients were diagnosed with PTE (Table 1). The primary diseases were aplastic anemia (AA) (n = 4) and myelodysplastic syndrome refractory anemia (MDS (RA)) (n = 3). The median time from alloHSCT to the diagnosis of PTE was 776 days (range 2921561 days). Erythropoietin (EPO) levels were within the normal limit (median: 7.5 mU/mL, range 2.812.4 mU/mL), and the JAK2V617F mutation was not detected in any patients. No patients had leukocytosis, thrombocytosis, hyperviscosity symptoms, or splenomegaly. One patient developed Grade 0I acute graftversushost disease (GVHD), and Grade IIIV acute GVHD was observed in six patients. Four patients had chronic GVHD, and one patient was receiving calcineurin inhibitors (CIs) at the time of diagnosis of PTE. Six patients not taking CIs were diagnosed at a median of 370 days (range 165993 days) after the withdrawal of CIs. All causes for secondary polycythemia were ruled out by relevant investigations. Only one patient was managed with phlebotomies. Regarding the pathogenesis of PTE in renal recipients, excess EPO release from the native kidneys and nonEPO factors such as insulinlike growth factor1 may promote erythrocytosis.3 In the setting of

Disseminated nocardiosis after unrelated bone marrow transplantation

Nocardiosis is a rare bacterial infection occurring mainly in patients with deficient cell‐mediated immunity. Although disseminated nocardiosis after allogeneic hematopoietic stem cell transplantation (allo‐HSCT) is a rare complication, it is associated with high mortality. Moreover, after allo‐HSCT, nocardiosis may be mistaken for other bacterial or fungal infections because clinical and radiographic findings of pulmonary, cerebral, and cutaneous nocardiosis lesions are non‐specific. Here, we report a case of disseminated nocardiosis (caused by Nocardia abscessus) with skin, pulmonary, liver, lymph node, and multiple brain abscesses in a patient after allo‐HSCT. The patient initially responded clinically and radiographically to imipenem/cilastin and trimethoprim‐sulfamethoxazole therapy. Clinicians should be aware of the possibility of nocardiosis in allo‐HSCT recipients who are treated with multiple immunosuppressive agents to control chronic graft‐versus‐host disease. Accurate diagnosis and identification of disseminated nocardiosis is important to ensure administration of the correct antibiotic regimen.