Tohru Sakura

Human herpesvirus 6 meningoencephalitis in allogeneic hematopoietic stem cell transplant recipients

We retrospectively investigated the clinical characteristics of human herpesvirus 6 (HHV-6) meningoencephalitis within 100 days after allogeneic hematopoietic stem cell transplantation (HSCT). Of 1148 patients who received transplants between January 1999 and December 2003, 11 patients (0.96%) with HHV-6 meningoencephalitis were identified. Ten of 11 recipients received hematopoietic stem cells from donors other than HLA-identical siblings. Confusion was the most frequent central nervous system (CNS) symptom, and a skin rash with high-grade fever preceded the CNS symptoms in 9 patients. Magnetic resonance imaging of the brain showed an abnormal increased T2 signal in the hypothalamus of 5 patients. Eight patients were treated with ganciclovir, and an improvement of CNS symptoms was obtained in 3 patients; 3 patients treated with acyclovir showed no improvement. Improvement in the meningoencephalitis seemed less frequent in patients with abnormal findings in the hypothalamus than in those without such findings. Because the symptoms of HHV-6 meningoencephalitis mimicked those of cyclosporine- or tacrolimus-induced encephalopathy, the drugs were withdrawn at the onset of CNS symptoms in 10 patients, resulting in the development of grade IV graft-versus-host disease (GVHD) in 5 patients.Three patients died of HHV-6 menin-goencephalitis, and 6 died of other causes, including GVHD. In conclusion, HHV-6 meningoencephalitis is a rare but potentially life-threatening complication in patients who undergo allogeneic HSCT. Careful assessment of the clinical findings and the brain may allow early and precise diagnosis of HHV-6 meningoencephalitis and contribute to improving its prognosis.

Incidence, risk factors and outcomes of bronchiolitis obliterans after allogeneic stem cell transplantation

Bronchiolitis obliterans (BO) after allogeneic stem cell transplantation (allo-SCT) is a late-onset, life-threatening respiratory complication that significantly reduces a patient’s quality of life. We retrospectively analysed the incidence of and risk factors for BO in allo-SCT recipients. In 2087 patients who underwent allo-SCT between January 1994 and June 2005 and survived >90 days after transplantation, 57 patients developed BO with a 5-year cumulative incidence of 2.8%. The median time interval from transplantation to BO diagnosis was 335 days (range 83–907 days). The 5-year cumulative incidence of BO was 1.62% in bone marrow transplantation (BMT) from related donors, 3.83% in peripheral blood stem cell transplantation (PBSCT) from related donors (R-PBSCT), 2.91% in BMT from unrelated donors and 2.65% in unrelated cord blood transplantation. The incidence of BO after R-PBSCT was significantly higher than that after any other type of allo-SCT (p = 0.02). R-PBSCT (p = 0.019) and preceding chronic graft-versus-host disease (GVHD) (p < 0.001) were BO-associated risk factors. Overall 5-year survival of patients with BO from the time of diagnosis was 45.4%, significantly less than those without (77.5% from day 335, p < 0.001). R-PBSCT recipients with existent chronic GVHD have a high risk of developing BO, and need extensive care and repeated pulmonary function tests.

Central Nervous System Relapse of Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Little information is available regarding central nervous system (CNS) relapse of adult leukemia after allogeneic hematopoietic stem cell transplantation (HSCT). Therefore, we reviewed the data of 1226 patients with acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), and chronic myelogenous leukemia (CML) who received first allogeneic HSCT between 1994 and 2004, using the database of the Kanto Study Group for Cell Therapy (KSGCT), and analyzed the incidence, risk factors, and outcome of patients with CNS relapse. Twenty-nine patients developed CNS relapse at a median of 296 (9-1677) days after HSCT with a cumulative incidence of 2.3%. Independent significant factors associated with CNS relapse included ALL as the underlying diagnosis (relative risk [RR] = 9.55, 95% confidence interval [CI] = 1.26-72.2, P = .029), nonremission at HSCT (RR = 2.30, 95% CI = 1.03-5.15, P = .042), the history of CNS invasion before HSCT (RR = 5.62, 95% CI = 2.62-12.0, P = 9.2 x 10(-6)), and the prophylactic intrathecal chemotherapy after HSCT (RR = 2.57, 95% CI = 1.21-5.46, P = .014). The 3-year overall survival (OS) after CNS relapse was 18%. In 7 of 29 patients with CNS relapse, leukemia was observed only in CNS. Three of 7 patients were alive without systemic relapse, resulting in 3-year survival after CNS relapse of 46%. Although the outcome of patients with CNS relapse was generally poor, long-term disease-free survival could be achieved in some patients.

Prevalence and Clinical Characteristics of Acute Myeloid Leukemia Associated with Disseminated Intravascular Coagulation

Disseminated intravascular coagulation (DIC) is one of the important complications to develop in patients with acute myeloid leukemia (AML). While acute promyelocytic leukemia (APL) is a strong risk factor for DIC, other clinical features have not been fully defined. We retrospectively analyzed 161 consecutive adult patients with de novo non-APL AML. DIC was diagnosed in 52 patients (32%); 28 patients at diagnosis and 24 soon after the initiation of induction chemotherapy. Leukocyte counts, C-reactive protein, and lactate dehydrogenase were significantly higher in the DIC+ group. Negative expressions of CD13, CD19, CD34, and HLA-DR were more prevalent in the DIC+ group. On multivariate logistic-regression analysis, variables that were independently associated with the development of DIC were high C-reactive protein, high leukocyte count, negative expressions of CD13 and HLA-DR, and cytogenetics with a normal karyotype or 11q23 abnormality. Although DIC is considered to be associated with serious morbidity and occasional mortality, we did not find any significant differences in the complete remission rate, overall or disease-free survival between DIC+ and DIC- groups. This study is the first to define the clinical characteristics associated with DIC in patients with non-APL AML, but exactly how and when DIC should be treated remains to be determined.

Myelodysplastic syndrome with eosinophilia in bone marrow

Summary. Clinical features were investigated in 114 patients with de novo myelodysplastic syndrome (MDS) diagnosed over the past 10 years, and eight cases (7%) were complicated with eosinophilia in the bone marrow. Two patients had refractory anaemia (RA), five had RA with excess of blasts (RAEB), and one had RAEB in transformation. Their bone marrow cells exhibited trilineage dysplasia and morphological abnormalities in eosinophils. Cytogenetics revealed major karyotype abnormalities (MAKA) in five patients. Survival durations were significantly shorter than those of other MDS patients. Our study suggests that marrow eosinophilia in MDS is strongly related to the coexistence of MAKA.

Ultrastructural Abnormalities of Bone Marrow Erythroblasts in Refractory Anemia

Ultrastructural abnormalities of erythroblasts in 30 patients with refractory anemia (RA) according to FAB classification were studied. Nuclear clefts, iron-laden mitochondria, and myelin figures in cytoplasm were most frequently observed. Eleven patients (36.7%) with nuclear clefts of erythroblasts had a higher platelet count and higher incidence of cytogenetic abnormalities linked to poor prognosis than the patients without nuclear clefts. They also had a higher frequency of leukemic transformation and shorter survival than the patients without nuclear clefts. The nuclear clefts of erythroblasts, which are the result of impairment of DNA metabolism or nuclear formation and fusion during mitosis, may be one of the adverse prognostic factors for patients with RA.

X-Linked Lymphoproliferative Disease in an Adult

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic vasculitis.The causative gene for XLP was identified asSH2D1A/DSHP/SLAM-associated protein (SAP) in 1998, and genetic analysis has been used for the definite diagnosis of XLP. Diagnosis for most patients occurs at ages younger than 10 years, and there are few adult patients. Here we describe a 23-year-old man with hypogammaglobulinemia and EBV-associated hemophagocytic lymphohistiocytosis and a diagnosis of XLP. In addition, the patient showed type 1 helper T-cell (Th1) skewing, as has been described inSap knock-out mice. Th1/Th2 imbalance in humans, as well as in mice, may play an important role in the pathogenesis of XLP.

All-trans-retinoic acid as a possible cause of acute pancreatitis even in the absence of hypertriglyceridemia

The standard therapy for patients affected by acute promyelocytic leukemia (APL) is the administration of all-trans-retinoic acid (ATRA). ATRA therapy is usually well-tolerated, but it also has the potential to induce toxicity. The most severe side effect of ATRA is retinoic acid syndrome; the next is acute pancreatitis, which is a rare but serious adverse event mostly due to hypertriglyceridemia. We herein report a patient who developed ATRA-induced acute pancreatitis without hypertriglyceridemia. A 17-year-old female presented to our hospital complaining of a 3-week history of dyspnea. Her peripheral blood counts were: Hb: 4.5 g/dL, WBC: 0.96 9 10/L with 9% blasts, and platelets: 48 9 10/L. The biochemistry findings were significant only regarding the serum lactate dehydrogenase level of 276 IU/L. A bone marrow examination revealed an abnormal cellularity, thus indicating APL, while a cytogenetic study showed the presence of t(15;17) (q22;q21). The patient was treated with ATRA for the purpose of remission induction. On the second day of ATRA treatment, she suffered acute epigastric and upper left quadrant pain, and laboratory tests showed an elevation of amylase to 7,600 IU/L (normal range: 49–136 IU/L) and lipase to 1,680 IU/L (normal range: 11–53 IU/L), with no marked increases in triglyceride (TG). Computed tomography of the abdomen revealed no abnormal findings in either the biliary ducts or pancreas. With the cessation of ATRA, the symptoms rapidly disappeared and the pancreas-derived enzyme level thereafter decreased to the normal range. The peak level of TG was only 145 mg/dL (normal range: 30–149 mg/dL) throughout the entire course. The patient was then treated with arsenic trioxide therapy without experiencing any subsequent complications, and she has since remained in complete remission for 8 months after starting the induction treatment. Four cases of acute pancreatitis associated with the use of ATRA have been described [1–4], but only one of these presented without hypertriglyceridemia, which is one of the common side effects of ATRA [4, 5]. Our case is the second such case. The pathogenesis of ATRA-induced acute pancreatitis without hypertriglyceridemia is not clear. Cytokines, such as IL-8, IL-1beta, and TNF-alpha, have been shown to be intimately involved in the inflammatory response to acute pancreatitis in general [6]. Teng et al. suggested that the increased expression of these cytokines in APL cells induced by ATRA may also play a role in the pathogenesis of ATRA-induced acute pancreatitis [4, 7]. As far as the case of Teng et al. is concerned, however, this suggestion remains controversial because of the recurrence of an elevated lipase level with a second ATRA treatment even after achieving complete remission in his case. His case rather suggests that either allergic or autoimmune mechanisms might play critical roles in the development of ATRA-induced acute pancreatitis. On the other hand, the activation of pancreatic stellate cells (PSCs) is known to be implicated in the production of pancreatic fibrosis and associated with the loss of retinol-containing fat droplets, which are stored in quiescent PSCs. Recent studies have demonstrated that retinol and its ATRA metabolites induce quiescence in activated PSCs and decreased collagen synthesis [8]. Pancreatic fibrosis, which is the process of repair after pancreatic injury, is prevented by ATRA, and then proinflammatory cytokines might be upregulated and lead to ATRA-induced acute pancreatitis. T. Hoshino (&) N. Hatsumi S. Takada T. Sakura S. Miyawaki Leukemia Research Center, Saiseikai Maebashi Hospital, Kamishinden-machi, 564-1, Maebashi, Gunma 371-0821, Japan e-mail: takumihoshino4249@yahoo.co.jp

Retrospective analysis of prognostic factors for Waldenstrӧm macroglobulinemia: a multicenter cooperative study in Japan.

Although population-based cancer registries have reported lower incidence of Waldenstrӧm macroglobulinemia (WM) in East Asia than in Western countries, previous retrospective analyses have found the clinical features of WM to be similar in these two populations. To clarify the characteristics of Japanese WM patients, we retrospectively analyzed clinical and laboratory characteristics, treatments, outcomes, and prognostic factors in 93 patients with WM. Based on the Second International Workshop on WM (IWWM-2) criteria, symptomatic WM was found in 73 (78.5%) and asymptomatic WM in 20 (21.5%) of cases examined. The median overall survival (OS) was similar to that in reports from Western countries. Patients receiving treatment regimens including rituximab exhibited significantly better survival than those not given rituximab. Although prognostic factors for WM in Western countries may not apply to Japanese patients, our finding that newly diagnosed WM patients with pleural effusion have a poorer prognosis suggests that this may be a novel predictor of adverse prognosis in symptomatic WM.

Persistence of anti-HLA antibody after cord blood transplantation engraftment in acute myelogenous leukemia: a potential marker of minimal residual disease, but not a significant factor in secondary humoral engraftment failure.

The presence of pre-transplant anti-HLA antibodies in recipients of cord blood transplantation (CBT) is associated with failed engraftment. However, only a small number of studies have reported that recipient-derived anti-HLA antibodies persist after CBT and have potential impact on the outcome. Of 61 patients who underwent HLA-mismatched CBT at Saiseikai Maebashi Hospital, three patients were identified as having anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB. All patients achieved successful engraftment. However, the three patients with the pre-transplant anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB continued to produce these antibodies even after engraftment; the persistence of these antibodies served as a sensitive minimal residual disease (MRD) marker. In contrast, donor HLA-specific and newly produced third party antibodies were not detectable even after relapse. The persistence of anti-HLA antibodies even after engraftment may be a potential marker for MRD, but is not a significant factor in secondary humoral engraftment failure.