Low incidence of adenovirus hemorrhagic cystitis following autologous hematopoietic stem cell transplantation in the rituximab era

Viral hemorrhagic cystitis (HC) is a frequent complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) but is rare after autologous peripheral blood stem cell transplantation (auto-PBSCT) because immunosuppression is not required in the absence of an allogeneic immune reaction. Recently, auto-PBSCT has been combined with novel anticancer agents targeting specific molecules, such as rituximab; however, these may cause severe immune deficiency and increase the susceptibility of transplant recipients to opportunistic infections. To address this issue, we performed a retrospective analysis of the incidence of viral HC in auto-PBSCT recipients. Of 158 recipients, only 4 cases (2.5%) were diagnosed with viral HC due to adenovirus (ADV), which was significantly less frequent compared with the incidence in allo-HSCT recipients (15.8%). The incidence of HC did not increase with rituximab treatment. This was a single-center retrospective analysis with a small sample size; however, incorporation of rituximab into the treatment of auto-PBSCT recipients did not appear to be a risk factor for developing viral HC. Viral HC is a noteworthy complication after HSCT because of its negative effects on the quality of life and its potential to cause therapy-related mortality [1]. We recently reported different risk factors associated with two viral HCs in allo-HSCT recipients [2]: ADV-HC and BKV-HC. ADV-HC is associated with severe immunodeficiency caused by immunosuppression therapies such as T-cell purging, whereas BKV-HC is associated with allogeneic immune hyperactivity such as graft-versus-host disease (GVHD) or the pre-engraftment immune reaction (PIR) [3]. Auto-PBSCT is characterized by rapid hematologic and immune reconstitution and does not trigger an allogeneic immune reaction that would require immunosuppressive therapy either for prophylaxis or for treatment. Consequently, there is lower incidence and severity of opportunistic infection including viral HC in auto-PBSCT recipients [4,5]. The survival of auto-PBSCT recipients has significantly improved over the recent years because of the incorporation of novel anticancer agents targeting specific molecules into the treatment regimen [6]. One such anticancer agent widely used in this context is rituximab, a chimeric monoclonal anti-CD20 antibody that causes B-lymphocyte depletion. When used alone in patients with lymphoma, rituximab has few effects on the incidence of infectious complications [7,8]. However, the combination of rituximab and high-dose chemotherapy (HDC) may increase the risk of viral infections [9–11], including that caused by the hepatitis-B virus (HBV) [12]. This retrospective study was conducted to clarify the prevalence, clinical features, and risk factors of viral HC after auto-PBSCTand to compare these variables with those of allo-HSCT. A total of 158 patients with hematological disorders or solid tumors hospitalized at our institute from 2000 to 2010 were enrolled. The clinical characteristics of these patients are summarized in Table I. A total of 101 patients had malignant lymphoma (ML), and the remaining 57 patients were diagnosed with acute myelogenous leukemia (AML; n 5 13), plasma-cell disorders (e.g., multiple myeloma or primary amyloidosis; n 5 36), or solid tumors (n 5 8). Patients with one of the following conditions were classified as ‘‘chemotherapy-sensitive’’ (n 5 132): ML and plasma cell disorders in at least partial remission and AML in first complete remission. All other patients (n 5 26) were categorized as ‘‘chemotherapy-resistant.’’ A total of 101 ML patients were treated with the CHOP regimen [13] as induction therapy, HDC as a preparative conditioning regimen, followed by transplantation of unpurged autologous PBSCs. After approval of rituximab for the treatment of ML in Japan, 41 patients with CD20-positive lymphomas was treated with CHOP and auto-PBSCT combined with rituximab. Of these, 35 patients received rituximab in combination with the ranimustine, carboplatin, etoposide, and cyclophosphamide (MCEC) pretransplant regimen [14]. Four patients received rituximab combined with the melphalan, etoposide, cyclophosphamide, and dexamethasone (LEED) regimen [15] and 2 patients received rituximab in combination with other regimens. The remaining 60 ML patients were either treated before approval of the use of rituximab or had CD20-negative lymphoma and received HDC consisting of MCEC (n 5 52), LEED (n 5 2), or another regimen (n 5 6), all without rituximab. Plasma cell disorders (n 5 36) were treated with the VAD regimen [16] or bortezomib-based induction therapy followed by high-dose melphalan before auto-PBSCT [17]. Standard-risk AML patients (n 5 13) achieved complete remission after conventional remission induction and consolidation chemotherapy and received the busulfan, cytarabine, and etoposide (BEA) conditioning regimen followed by auto-PBSCT [18]. Eight patients with solid tumors underwent standard chemotherapies based on each diagnosis and then received auto-PBSCT. Of these, five patients received the high-dose ICE regimen [19]. Acyclovir prophylaxis was used to protect against reactivation of herpes simplex virus (HSV) in all these recipients. Urinalysis was routinely performed at least once a week from the initiation of preparative regimens until discharge from hospital or when clinical signs of cystitis appeared after the discharge. Microscopic or macroscopic hematuria and/or bladder irritation was further analyzed using polymerase chain reaction (PCR) to detect viral DNA (ADV, BKV, and JC virus). Methods for detecting each type of viral DNA have been reported previously [20–22]. In brief, after 2 ml of a urine sample was centrifuged (15,000g for 1 hr), DNA was purified from the sediment using the QIAmp DNA Blood Mini Kit (Qiagen, Hilden, Germany). Next, 5 ml of purified DNA was subjected to PCR using the GeneAmp Kit and GeneAmp PCR System 9600 (PerkinElmer, Boston, MA) with the following primers: AD185S (50-tccagcaacttcatgtccatgg-30) and AD 185A (50-tcgatgacgccgcggt30) for detecting ADV; BKV-1 (50-gcaagtgccaaaactactaat-30) and BKV-2 (50tgcatgaaggttaagcatgc-30) for detecting BKV; and JTP-1 (50-gcagcttagtgattttct-