Sumiko Kohashi

Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation

Drug interaction between voriconazole and calcineurin inhibitors is often problematic after allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. We previously demonstrated an unpredictable inter‐individual variability in the magnitude of this drug interaction; however, the route of drug administration was not taken into account. In this study, the drug interaction between voriconazole and calcineurin inhibitors was further analyzed under the condition that both agents were administered orally. Twenty adult recipients of HSCT who had already been on a steady dose of oral cyclosporine A (CsA) and were started on oral voriconazole (400 mg/d) were eligible. The changes in the concentration/dose (C/D) ratio of CsA were evaluated by comparing the trough concentrations of CsA measured before and 7–10 d after initiating voriconazole. The median C/D ratio of CsA increased significantly from 64.1 to 114.3 (ng/mL)/(mg/kg) after initiating voriconazole (p < 0.01), and the median increase was 83.0% (range, 0.3–224.7%). The plasma concentration of voriconazole did not correlate significantly with the increase of the C/D ratio (ρ = −0.18, p = 0.45). These results indicate that the magnitude of drug interaction between oral voriconazole and CsA is widely variable, and it could not be explained by the difference in the blood levels of voriconazole. Further studies are required to elucidate the mechanism for this variability.

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.

Persistent parvovirus B19 infection resulting in red cell aplasia after allogeneic hematopoietic stem cell transplantation

Persistent parvovirus B19 (PVB) infection has been reported sporadically in immunocompromised patients including hematopoietic stem cell and solid organ transplant recipients. However, the pathogenesis of persistent infection has yet to be fully elucidated. We report here a patient with multiple myeloma developing red cell aplasia during the hematopoietic recovery after allogeneic hematopoietic stem cell transplantation (HSCT) caused by PVB. The patient had already had PVB viremia before transplantation and remained asymptomatic. The route of PVB transmission was considered to be direct contact with the patients family member with primary PVB infection 1 month before transplantation. Treatment with intravenous immunoglobulin resulted in prompt resolution of anemia. These findings suggest that monitoring of PVB DNA is recommended for patients undergoing HSCT and having contact with individuals with documented PVB infection, even if they are asymptomatic.

Long‐term follow‐up of reduced‐intensity allogeneic hematopoietic stem cell transplantation for refractory or relapsed follicular lymphoma

Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment for refractory or relapsed follicular lymphoma (FL), transplant-related mortality (TRM) greatly interferes with the success. A variety of reduced-intensity conditionings (RICs) have been used to reduce TRM, but an optimal conditioning for FL has not been fully established. We retrospectively evaluated the outcome of allogeneic HSCT for FL with RIC consisting of fludarabine and melphalan. Nineteen adult patients with relapsed or refractory FL were conditioned with fludarabine (125 mg/m2) and melphalan (140 mg/m2), and received grafts from an HLA-identical sibling (n = 6) or an unrelated donor (n = 13). For the prophylaxis of graft-versus-host disease (GVHD), cyclosporine A or tacrolimus with short-term methotrexate was given. There were no early deaths before engraftment, and all patients achieved engraftment. Three patients died of extensive-type chronic GVHD (n = 2) or bacterial infection (n = 1) without disease progression. With a median follow-up period of 75.2 months (range: 33.3–111.9 months), 16 patients were alive without disease progression. Both the 5-year overall and progression-free survival rates were 84.2% (95% CI: 67.7–100%). These results strongly suggest that allogeneic HSCT with RIC using fludarabine and melphalan could be a promising treatment choice for refractory or relapsed FL.

Sinusitis caused by Exserohilum rostratum after cord blood transplantation for myelodysplastic syndrome: A case report and literature review

Invasive fungal disease is a serious infectious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Exserohilum rostratum is a species causing phaeohyphomycosis, which rarely causes invasive disease in humans. We treated a case of sinusitis caused by E. rostratum after cord blood transplantation (CBT). A 60‐year‐old man with myelodysplastic syndrome, who had a medical history of an operation to correct deviation of the nasal septum, developed sinusitis caused by E. rostratum under prolonged profound neutropenia after a second CBT because of the graft rejection of the first transplantation. Liposomal amphotericin B improved the sinusitis. A literature review revealed nine reported cases of sinusitis caused by E. rostratum, including our case. Although five cases had severe neutropenia at onset (HSCT recipients, n = 2; aplastic anemia, n = 3), the remaining four had no preexisting immunosuppressive conditions. However, three of the four patients had preexisting nasal diseases with or without a history of surgery, as in our case. Excluding our case, the outcome was fatal in five neutropenic patients, whereas the four patients without neutropenia recovered. Although sinusitis caused by E. rostratum is rare, E. rostratum should be recognized as a possible pathogen causing sinusitis in highly immunosuppressed patients such as HSCT recipients. Preexisting nasal disease and/or nasal surgery could be risks for this infection.

Post-transplant lymphoproliferative disorder of the adrenal gland after allogeneic hematopoietic stem cell transplantation: Report of two cases and literature review

Post‐transplant lymphoproliferative disorder (PTLD) is one of the life‐threatening complications after hematopoietic stem cell transplantation (HSCT) and solid organ transplantation (SOT), and it is associated almost exclusively with Epstein–Barr virus (EBV). We herein report 2 cases of EBV‐associated PTLD after allogeneic HSCT localized in the adrenal gland. Both patients developed adrenal tumor within 3 months after HSCT and were successfully treated with rituximab or tapering immunosuppressive agents. Both remained alive without recurrence. A literature review revealed 12 reported cases of PTLD involving the adrenal gland, but the adrenal gland was involved as one of the lesions of advanced‐stage PTLD after SOT. To the best of our knowledge, this is the first report to show cases of isolated EBV‐associated adrenal PTLD after HSCT. PTLD should be recognized as one of the causes of isolated adrenal tumor after HSCT.

Bacteremia due to Rothia mucilaginosa after chemotherapy for myeloid malignancies

The number of reported cases of bacteremia due to Rothia mucilaginosa (R. mucilaginosa), a component of the normal flora of human gastrointestinal tract mucosa, is limited. We encountered three cases of bacteremia due to R. mucilaginosa during neutropenia after chemotherapy for myeloid malignancies. Although all three patients were successfully treated with antimicrobial agents, one patient developed disseminated lesions in the lungs and soft tissue. The portal of R. mucilaginosa bacteremia is reportedly mucositis or dental disorders; however, no such complications were identified in our patients. Even in the absence of a preexisting portal, R. mucilaginosa should be recognized as a potential causative pathogen of bacteremia during neutropenic periods. Accumulations of cases and isolates are required to further elucidate the risk factors for developing R. mucilaginosa bacteremia, its clinical course, and the optimal antimicrobial treatment.

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

Immune-mediated Neuropathy with Anti-disialosyl IgM Antibodies in Diffuse Large B-cell Lymphoma: A Case Report and Literature Review

A 36-year-old man with diffuse large B-cell lymphoma presented with polyneuropathy, and the diagnostic work-up revealed the presence of IgM antibodies against gangliosides with disialosyl residues (GD1b, GD3). He was treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone and received high-dose intravenous immunoglobulin for the treatment of neuropathy. After initiating the treatments, the patients neurological impairment improved dramatically. He currently remains in complete remission without a flare-up of the polyneuropathy. Based upon our experience and other case reports of lymphoma with immune-mediated neuropathy caused by anti-disialosyl ganglioside IgM antibodies, we conclude that determining the anti-ganglioside antibody profile and beginning early treatment should be considered promptly for patients with malignant lymphoma who develop polyneuropathy.