Masuho Saburi

New-onset food allergy following cord blood transplantation in adult patients.

New-onset food allergy has been recognized as one of the complications after liver transplantation, especially in pediatric patients, which was closely associated with tacrolimus administration in several studies. One prospective study reported that 21% of pediatric patients receiving liver transplantation developed new-onset food allergy. In contrast to the extensive investigation of food allergy after liver transplantation, food allergy after hematopoietic stem cell transplantation has not been fully evaluated. In bone marrow or peripheral blood stem cell transplantation, allergic disease can be transferred from donors. However, cord blood donors are considered free from allergic disease, and the development of food allergy in cord blood transplantation (CBT) recipients is probably due to the dysregulated immune reconstitution. Recently, sporadic cases of newonset food allergy after CBT have been reported, including five pediatric and two adult patients. To elucidate its incidence and clinical features, we retrospectively evaluated patients who developed new-onset food allergy after CBT. This is a single-institutional retrospective study using the institutional database and medical records of adult patients who underwent CBT for hematological disorders between October 2001 and June 2014 at Keio University Hospital (Tokyo, Japan). This retrospective study was approved by the Ethical Committee of Keio University School of Medicine. After excluding three cases of graft rejection, one case of autologous bone marrow recovery and three cases of insufficient data, 51 patients (male, 31; female, 20) who achieved donor cell myeloid engraftment and survived longer than 30 days after CBT were selected and enrolled into the analysis. Median age of the patients at transplantation was 49 years (range, 18–64), and median follow-up time was 16.9 months (range, 1.4–149.7). Underlying diseases were hematological malignancies, except in one patient with aplastic anemia. The GvHD prophylaxis was cyclosporine A (CsA)-based in 25 patients and tacrolimus-based in 26. Raw foods were avoided during the neutropenic period after transplantation, and grapefruit was avoided until calcineurin inhibitors were discontinued. A diagnosis of food allergy was made on the basis of the clinical presentations repeatedly observed after the oral intake of a specific food, and on the basis of the positive results of the oral food challenge and/or radioallergosorbent tests for specific IgE against the allergens. The probability of food allergy was estimated on the basis of cumulative incidence curves to accommodate deaths due to any causes and the second hematopoietic stem cell transplantation as the competing event. Analyses were performed with EZR, a graphical user interface for R. Of the 51 patients, 3 patients developed food allergy at 5, 6 and 10 months after CBT, respectively. The medical histories of the three patients were not remarkable for any food allergies. The cumulative incidence of food allergy was estimated to be 6.6% (95% confidence interval, 1.7–16.4%) at 1 year after transplantation (Figure 1). The clinical characteristics of the three patients who developed food allergy are shown in Table 1. The patients were aged 19, 55 and 57 years at transplantation, and all developed food allergy within 1 year after CBT. All patients had repeated episodes of the same symptoms shortly after taking specific foods, which prompted the physicians to suspect food allergy. Together with such clinical presentations, the diagnosis of food allergy and incriminated allergens was confirmed by 0 50 100 150 0.0 0.2 0.4 0.6 0.8 1.0

Nephrotoxicity of concomitant use of tacrolimus and teicoplanin in allogeneic hematopoietic stem cell transplant recipients

Both tacrolimus and glycopeptide antibiotics are known to be nephrotoxic, and are often concomitantly given after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. The aim of this study is to evaluate the nephrotoxicity of concomitant use of tacrolimus and glycopeptide antibiotics in HSCT recipients. We retrospectively evaluated 67 patients who received intravenous tacrolimus and teicoplanin concomitantly for >4 days after allogeneic HSCT for hematologic diseases. Therapeutic drug monitoring (TDM) was performed in all patients for both tacrolimus and teicoplanin. The median age of the patients was 48 years (range: 16–62), and the median duration of the co‐administration of tacrolimus and teicoplanin was 11 days (range: 4–40). The mean serum creatinine (sCr) level tended to be elevated after the co‐administration (from 0.69 ± 0.26 to 0.75 ± 0.30 mg/dL; P = 0.08); however, a 2‐fold or greater increase in sCr was observed only in 2 (3.0%) patients. Increased sCr was reversible, and no patient required hemodialysis. These results suggest that the incidence of clinically significant nephrotoxicity can be minimized if the TDM of each drug is properly applied.

Other Iatrogenic Immunodeficiency-associated Lymphoproliferative Disorder, Hodgkin Type, following Epstein-Barr Viral Hepatitis in a Patient with Rheumatoid Arthritis

A 59-year-old man with an 18-year history of rheumatoid arthritis who had been treated with steroids, methotrexate, and infliximab presented with a high-grade fever, cervical lymphadenopathy, and hepatosplenomegaly. Epstein-Barr virus (EBV) hepatitis was diagnosed based on the liver histology and EBV antibody titer. The symptoms improved temporarily, but five months later, the fever, skin rash, jaundice, and thrombocytopenia relapsed. Bone marrow and liver biopsies demonstrated infiltration with Reed-Sternberg cells. Based on these findings, the patient was diagnosed with other iatrogenic immunodeficiency-associated lymphoproliferative disorder (OIIA-LPD), Hodgkin lymphoma type. This case followed a rare clinical course, in that acute hepatitis preceded the diagnosis of OIIA-LPD.

Reduced-dose cyclophosphamide in combination with fludarabine and anti-thymocyte globulin as a conditioning regimen for allogeneic hematopoietic stem cell transplantation for aplastic anemia

patients received grafts from HLA-matched (high-resolution) unrelated donors. Patient and donor characteristics are shown in Table 1. The conditioning regimen was given following that described in a previous report by Okuda et al. [8] with a modification in the dosage of ATG. The regimen consisted of fludarabine (30 mg/kg) and CY (25 mg/ kg) each on days −6 to −3, and ATG (Thymoglobulin; 1.25 mg/kg) on days −4 and −3. Except in the case of one patient (No. 6) who had received a limited number of blood transfusions before transplantation, total body irradiation (TBI; 2 Gy) was delivered at a single fraction on day −2 or −1. TBI was delivered with ovarian shielding in three young female patients (Cases 1–3) to spare ovarian function [8]. Tacrolimus or cyclosporine A (CSA) and shortterm methotrexate were given as graft-versus-host disease (GVHD) prophylaxis. The administration of lenograstim at a dose of 5 μg/kg was started one day after the bone marrow infusion and continued until neutrophil recovery was achieved. Cytomegalovirus (CMV) reactivation was monitored by CMV antigenemia assay, which triggered the preemptive therapy with ganciclovir or foscarnet [9]. The day of myeloid engraftment was defined as the first day of three consecutive days when the absolute neutrophil count exceeded 0.5 × 10/L. Regimen-related toxicities of grades 2–3 were diarrhea (n = 5), nausea (n = 5), oral mucositis (n = 2), and liver dysfunction (n = 2); grade 4 toxicities were not observed. Bacteremia was documented in three patients, and was successfully treated with antimicrobial treatment. CMV reactivation was observed in four patients, and was successfully managed with preemptive therapy. None of the cases developed lymphoproliferative disorder. Other transplant outcomes as well as clinical courses are listed in Table 1. One patient (Case 1) developed acute GVHD of the skin (Grade 2) during the tapering of CSA, but the other patients To the Editor: We read with great interest the recent report by Ashizawa et al. showing a favorable outcome of allogeneic hematopoietic stem cell transplantation (HSCT) for aplastic anemia by use of a conditioning regimen consisting of reduced-dose cyclophosphamide (CY: total 100 mg/kg), fludarabine, and anti-thymocyte globulin (ATG) [1]. Although the outcome seems favorable, some issues remain to be solved with this regimen, including mixed chimerism and late-onset cytopenia. In addition, the small number of cases has limited the impact of their conclusion. Although there have been attempts to reduce the dose of CY in the conditioning regimen for aplastic anemia, the optimal dose of CY has yet to be established [2–7]. Based on a previous study by the same institute, we also applied the same conditioning regimen for patients with aplastic anemia undergoing allogeneic HSCT [8]. In the present report, we present several of these cases, which we believe further support and reinforce the conclusions of Ashizawa et al. We would also like to present our data on the recovery of ovarian function after transplantation in young female patients as another potential advantage of this regimen. Between November 2010 and October 2011, six patients with aplastic anemia underwent allogeneic bone marrow transplantation (BMT) at Keio University Hospital (Tokyo, Japan) after being conditioned with the regimen described below. Three patients received grafts from human leukocyte antigen (HLA)-identical siblings and the remaining three

Rare concurrent indolent B-cell lymphoma and plasmablastic transformation of myeloma

An 81-year-old woman presented to our hospital with leukocytosis and abnormal lymphocytes. Her white blood cell count was 8970/μl (abnormal cells, 34%). Abnormal cells were small, atypical nucleated lymphocytes with a high nucleus-to-cytoplasm ratio, round nuclei and basophilic cytoplasm, with short polar villi. Flow cytometry (FCM) with CD45-gating analysis revealed that the abnormal lymphocytes in the peripheral blood were positive for CD19, CD20, CD23, CD25, FMC-7, cytoplasmic CD22, cytoplasmic CD79a, immunoglobulin (Ig)M, and λ, and negative for CD5, CD10, CD103, CD138, and κ. No superficial lymph nodes were palpable. Mild anemia, a slight increase in total serum protein and soluble interleukin-2 receptor levels was detected, and mild splenomegaly was noted on ultrasonography of the abdomen. Neither protein electrophoresis, bone marrow examination nor systemic screening by computed tomography (CT) were conducted. Matutes’ system of diagnosis for chronic lymphocytic leukemia (CLL) yielded a score of only 1 point (CD23 positive).1 Cytomorphology and surface markers of abnormal lymphocytes in the peripheral blood were negative for characteristics of CLL or hairy cell leukemia (HCL). The patient was therefore followed without any treatment under a presumptive diagnosis of indolent B-cell non-Hodgkin lymphoma. Two years later, anemia worsened with elevation of the serum IgG level to 5440 mg/dl. Serum albumin, IgA and IgM were suppressed concurrently. Protein electrophoresis demonstrated an M spike in the γ-fraction and M protein of the IgG-κ type was found by immune-electrophoresis, but the serum free-light chain ratio was within the normal range. Examination of bone marrow aspirate revealed the concurrent infiltration of abnormal lymphocytes (48.6%) and plasma cells (26.0%) (Fig. 1). Bone marrow biopsy was not conducted. Abnormal lymphocytes in the bone marrow were similar in morphology and surface markers by FCM CD45-gating analysis to those in the peripheral blood. By FCM CD38-gating analysis, a population of cells with high expression of CD38 was positive for cytoplasmic CD79a, CD138, and κ, whereas a population of cells with low expression of CD38 was positive for CD19, CD20, CD23, cytoplasmic CD79a, and λ (Fig. 2A, 2B). Chromosomal analysis by G-banding of the bone marrow demonstrated 47, XX, +3 and 47, XX, +3, t(2; 13) (q35; q14) in one-twentieth of the cells in the mitotic phase. Pathological findings of the bone marrow clots were mainly Rare concurrent indolent B-cell lymphoma and plasmablastic transformation of myeloma

Hypofibrinogenemia associated with steroid therapy for the patients who developed GVHD after allogeneic stem cell transplantation

Hypofibrinogenemia (plasma fibrinogen level <150 mg/dl) is occasionally observed after allogeneic hematopoietic stem cell transplantation, and its etiology is often difficult to determine. We herein report that steroids administered for the treatment of graft-versus-host disease (GVHD) are associated with the development of hypofibrinogenemia. We retrospectively analyzed the plasma fibrinogen (Fg) levels in 15 consecutive patients who had been administered 1 mg/kg/day (1 mg/kg group) or 2 mg/kg/day (2 mg/kg group) methylprednisolone for the treatment of Grade II to IV acute GVHD. Hypofibrinogenemia had developed in 8 of the 15 patients (53%) by day 50 after the start of steroid treatment, and was observed in 2 of 6 patients in the 1 mg/kg group and 6 of 9 in the 2 mg/kg group. A significant decrease in the Fg level was observed in the 2 mg/kg group (the median value before starting steroid treatment and that on the 20th day after starting steroid treatment were 506 mg/dl and 180 mg/dl, respectively, P=0.0013). Other possible causes of hypofibrinogenemia, including liver dysfunction or disseminated intravascular coagulation, were confirmed in only 3 patients during the observation period. In conclusion, hypofibrinogenemia commonly occurs in patients treated with steroids, especially those administered 2 mg/kg/day methylprednisolone for the treatment of GVHD.