Shuntaro Ikegawa

Fecal microbiota transplantation for patients with steroid-resistant acute graft-versus-host disease of the gut

Increasing evidence indicates that the gut microbiota is closely associated with acute graft-versus-host disease (aGVHD) in stem cell transplantation (SCT). Fecal microbiota transplantation (FMT) could represent an alternative treatment option for aGVHD. However, FMT for SCT patients carries a potential risk of infection by infused microbiota because of the severely immunosuppressed status. We therefore conducted a pilot study to evaluate the safety of FMT in SCT. A total of 4 patients with steroid-resistant (n = 3) or steroid-dependent gut aGVHD (n = 1) received FMT. No severe adverse events attributed to FMT were observed. All patients responded to FMT, with 3 complete responses and 1 partial response. Temporal dynamics of microbiota seemed to be linked to the gut condition of patients and peripheral effector regulatory T cells also increased during response to FMT. FMT was safely performed in our patients and might offer a novel therapeutic option for aGVHD. This trial was registered at the University Hospital Medical Information Network (https://upload.umin.ac.jp/cgi-open-bin/icdr_e/ctr_view.cgi?recptno=R000017575) as #UMIN000015115.

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.

Clinical impact of CD25 expression on outcomes of allogeneic hematopoietic stem cell transplant for cytogenetically intermediate-risk acute myeloid leukemia

Approximately 50% of adult patients with acute myeloid leukemia (AML) do not show clonal chromosome aberrations at diagnosis, and although this group shows an intermediate prognosis, a minority of patients eventually become long-term survivors. [1]. Th is emphasizes the need for new molecular markers that can be used to predict disease aggressiveness and to determine the leukemic response to treatment, including allogeneic hematopoietic stem cell transplant (allo-HSCT) [2]. Recent data have shown that molecular analysis of the presence of mutated FMS-like tyrosine kinase-3 (FLT3), nucleophosmin 1 (NPM1), CCAAT/ enhancer-binding protein alpha (CEBPA), mixed lineage leukemia (MLL) or neuroblastoma RAS viral oncogene homolog (N-Ras) may be useful for this purpose [3]. However, molecular analyses may be costly and not always available, as not all the mutations are detected by sequencing. As an alternative approach, we may be able to focus on distinct clinical features that depend on specifi c genetic aberrations. For example, patients with a FLT3-internal tandem duplication (ITD) mutation tend to have higher white blood cell count and blast count [4], and moreover a high percentage of these patients may have high CD25 (the α -chain of the interleukin-2 [IL-2] receptor) antigen expression as observed with fl ow cytometry [5 – 7]. Recent studies have shown that CD25 is highly expressed in chemotherapy-resistant, cell cycle-quiescent leukemic stem cells, and high CD25 expression may be associated with an unfavorable outcome after conventional chemotherapy, including autologous and allogeneic transplant [5 – 7]. Th us, evaluation of CD25 expression may be an alternative, cost-eff ective non-molecular tool for cytogenetically intermediate (CI)-AML. Here we report the clinical impact of surface expression of the CD25 antigen on transplant outcomes in a total of 40 patients with CI-AML who underwent allo-HSCT in a single institution. In this study, intermediate-risk AML included patients with a normal or indeterminate karyotype. Bone marrow and peripheral blood samples from 40 patients with CI-AML were available for analysis of CD25 expression at the initial diagnosis. Th ese patients eventually underwent allo-HSCT in our institution between January 2001 and January 2013. We list the chemotherapies, conditioning regimens and outcomes (Supplementary Table I to be found online at http://informahealthcare.com/doi/ abs/10.3109/10428194.2014.974044). Patients with French – American – British (FAB) classifi cation M3 were excluded. Flow cytometry analyses were performed in-house using standard immunofl uorescence methods with monoclonal antibodies directed against CD2, CD3, CD4, CD5, CD7, CD8, CD10, CD11b, CD13, CD14, CD19, CD20, CD25, CD33, CD34, CD38, CD41, CD56 and human leukocyte antigen (HLA)-DR antigens, and were considered to be positive if at least 20% of leukemic blasts expressed the antigen [5]. Th e cut-off level of CD25 depends on the report, for example 10% [6,7] and 20% [5]. Generally the cut-off level of 20% has been known as the standard, and we consider this as the best cut-off level to exclude false-positive results. Transplant procedures have been described in detail elsewhere [8]. Myeloablative conditioning mainly included busulfan (3.2 mg/kg for 4 days) and cyclophosphamide (60 mg/kg for 2 days). Th e main preparative regimen for the reduced-intensity procedure consisted of fl udarabine (30 mg/m 2 for 6 days), melphalan (40 mg/m 2

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.

Impact of prior azacitidine on the outcome of allogeneic hematopoietic transplantation for myelodysplastic syndrome

To clarify the clinical impact of prior use of azacitidine (AZA) on outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for myelodysplastic syndrome (MDS), we retrospectively reviewed the clinical outcomes of 15 MDS patients who were treated with AZA before allo-HSCT (AZA group). We compared the outcomes of these 15 patients with 52 MDS patients who were solely given the best supportive care (BSC) before allo-HSCT (BSC group). Although patients in the AZA group were older with higher International Prognostic Scoring System (IPSS) scores compared to patients in the BSC group, no significant differences were found between the two groups in overall survival (OS), disease-free survival (DFS), cumulative incidence of relapse (CIR) or non-relapse mortality. However, in patients with a higher IPSS score (Int-2/High), pre-transplant AZA may provide better OS and DFS and lower CIR. Acute graft-versus-host disease rates were similar between the two groups. These results should be reassuring to patients with high-risk MDS receiving AZA before allo-HSCT.

A Case of Neurolymphomatosis in the cauda Equina Diagnosed by an Open Biopsy

Neurolymphomatosis is a rare form of extranodal malignant lymphoma defined as the infiltration of malignant lymphocytes into the central or peripheral nerve. We herein report a case of neurolymphomatosis in the cauda equina diagnosed by an open surgical biopsy. He presented with muscle weakness, atrophy, numbness and hypoesthesia in the bilateral lower extremities with the accumulation of 18fluoro-2-deoxyglucose (FDG) in the bilateral cauda equina. Cerebrospinal fluid cytology (three times) and flow cytometry (two times) and biopsies of the left sural nerve, bone marrow, paranasal sinus and left testis were all negative for malignancy, so finally we performed a surgical open biopsy of the cauda equina by laminectomy and diagnosed him with diffuse large B-cell lymphoma in the cauda equina. He was successfully treated with the disappearance of the FDG accumulation for a long time. The present case suggested that an early open biopsy of the cauda equina may be considered for cases of suspected neurolymphomatosis in the cauda equina for a good outcome.

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 patients mental condition deteriorates.

Cytomegalovirus meningitis in a patient with relapsed acute myeloid leukemia

Cytomegalovirus meningitis/meningoencephalitis is a potentially fatal complication following hematopoietic stem cell transplantation that causes significant morbidity and mortality. In the pre-transplant setting, a few cases involving lymphoid malignancies have been reported. However, there have been no reports of patients with myeloid malignancies. A 36-year-old man with relapsed acute myeloid leukemia received high-dose cytarabine-containing salvage chemotherapies and then developed grade 4 lymphopenia for more than one month. Subsequently, the patient developed pyrexia, accompanying headache, nausea, and vomiting with no abnormal brain imaging. Despite receiving antimicrobial treatment, his febrile status and headache persisted. Given that the patient had symptoms consistent with viral meningitis with no evidence of etiology other than positive cytomegalovirus-DNA in his cerebrospinal fluid and cytomegalovirus pp65 antigenemia, cytomegalovirus meningitis was diagnosed. After commencing ganciclovir treatment, the patient’s headache and febrile status rapidly improved. Cytomegalovirus meningitis/meningoencephalitis is rare before hematopoietic stem cell transplantation, but may be useful in differential diagnoses in heavily treated acute myeloid leukemia patients with central nervous system symptoms.

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