Kikuko Kuriyama

Requirement for Etoposide in the Treatment of Epstein-Barr Virus–Associated Hemophagocytic Lymphohistiocytosis

PURPOSE We sought to identify the clinical variables most critical to successful treatment of Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH). PATIENTS AND METHODS Among the factors tested were age at diagnosis (< 2 years or > or = 2 years), time from diagnosis to initiation of treatment with or without etoposide-containing regimens, timing of cyclosporin A (CSA) administration during induction therapy, and the presence or absence of etoposide. RESULTS By Kaplan-Meier analysis, the overall survival rate for the entire cohort of 47 patients, most of whom had moderately severe to severe disease, was 78.3% +/- 6.7% (SE) at 4 years. The probability of long-term survival was significantly higher when etoposide treatment was begun less than 4 weeks from diagnosis (90.2% +/- 6.9% v 56.5% +/- 12.6% for patients receiving this agent later or not at all; P <.01, log-rank test). Multivariate analysis with the Cox proportional hazards model demonstrated the independent prognostic significance of a short interval from EBV-HLH diagnosis to etoposide administration (relative risk of death for patients lacking this feature, 14.1; 95% confidence interval, 1.16 to 166.7; P =.04). None of the competing variables analyzed had significant predictive strength in the Cox model. However, concomitant use of CSA with etoposide in a subset of patients appears to have prevented serious complications from neutropenia during the first year of treatment. CONCLUSION We conclude that early administration of etoposide, preferably with CSA, is the treatment of choice for patients with EBV-HLH.

Management of severe neutropenia with cyclosporin during initial treatment of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis

Severe neutropenia (absolute neutrophil count <500/μ1) is probably due to the combined effects of dysregulated cytokine production and chemotherapeutic agents, and is one of the risk factors in the initial treatment of patients with Epstein-Barr virus-related hemophagocytic lymphohistiocytosis (EBV-HLH). We report here 9 cases of neutropenic HLH, of which 8 were treated with cyclosporin (CSA, 2-6 mg/kg/day; continuous infusion, or 6mg/kg/day; per os, for periods ranging from 9 days to 8 weeks) in the initial neutropenic phase during induction treatment using corticosteroids and etoposide. Five of the 6 cases, in which CSA treatment was started early (before the second week of induction), survived the critical period with recovery of neutrophil counts within a week. The remaining 3 cases, in which CSA was introduced later or not at all, died of infection. Based on these results, we recommend a prompt short-term CSA infusion during neutropenic episodes in the most common treatment regimen of etoposide and corticosteroids in patients with HLH. Improved neutrophil recovery as a result of CSA treatment makes it possible to continue immunochemotherapy safely and obtain improved patient outcomes.

Risk of Etoposide-Related Acute Myeloid Leukemia in the Treatment of Epstein-Barr Virus—Associated Hemophagocytic Lymphohistiocytosis

We studied the impact of etoposide on the prognosis of 81 patients (77 of whom were children <15 years old) with Epstein-Barr virus—associated hemophagocytic lymphohistiocytosis (EBV-HLH).The study group received a median cumulative dose of 1500 mg/m2 etoposide (range, 0–14,550 mg/m2), with a median follow-up period of 44 months (range, 20–88 months) from the diagnosis. Only 1 patient, who received 3150 mg/m2 etoposide, developed therapy-related acute myeloid leukemia (t-AML), at 31 months after diagnosis. Excluding 9 patients who underwent hemopoietic stem cell transplantation during the course of treatment, the prognosis was poorer for those patients who received less than a 1000 mg/m2 cumulative dose of etoposide. Our results indicate that the risk of etoposide-related t-AML is low. An appropriate dosage of etoposide for the treatment of EBV-HLH would be in the range of 1000 to 3000 mg/m2. However, even at these doses, care must be taken to prevent the rare risk of t-AML.

A novel missense mutation (1060G → C) in the phosphoglycerate kinase gene in a Japanese boy with chronic haemolytic anaemia, developmental delay and rhabdomyolysis

Summary. We report the case of a 3‐year‐old Japanese boy with phosphoglycerate kinase 1 (PGK1) deficiency (Online Mendelian Inheritance in Man entry 311800). The patient had anaemia and jaundice at birth, necessitating exchange transfusions for 2 d. After one red blood cell transfusion at age 2 months, his Hb level was 8–9 g/dl, his reticulocyte counts were 300–500 × 109/l, and his total bilirubin level was 25·65–42·75 µmol/l. The patient suffered two episodes of respiratory infection‐associated haemolytic crisis and rhabdomyolysis during early infancy. At age 3·0 years, his developmental milestones (developmental quotients measured using the Tsumori–Inage methods) score was 49% (normal 74–131%), and his height was below average by −2·0 standard deviations. The diagnosis of PGK1 deficiency was made based on his remarkably low (< 10% of normal) erythrocyte PGK enzyme activity level and the identification of a novel missense (1060G→C) PGK1 gene mutation. This mutation results in the Ala‐353Pro amino acid substitution, which has been designated PGK Kyoto. The patient developed the full clinical symptoms of PGK1 deficiency including haemolytic anaemia, myopathy, central nervous system disorder and growth retardation, which is unusual.

Molecular Analysis of Latent Membrane Protein 1 in Patients with Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis in Japan

Latent membrane protein 1 (LMP1) of Epstein-Barr virus (EBV) is considered to be an oncoprotein because it is crucial for B-lymphocyte transformation. Since a 30 base pair (bp) deletion in the carboxy-terminal portion of the LMP1 gene was found in a CAO cell line derived from nasopharyngeal carcinoma containing EBV, an association between EB viral genetic alteration and tumorigenicity has been postulated. In this study we have analyzed LMP1 DNA isolated from 10 Japanese patients with EBV-associated hemophagocytic lymphohistiocytosis (EBV-HLH). In all HLH patients, we found the 30bp deletion and 4-8-tandem repeats of the sequence DNGPQDPDNTD in the LMP1 gene. Furthermore, detailed amino acid (aa) sequence analysis revealed that 7 aa substitutions identical to those found in CAO-LMP1 but not in B95.8 cell line-LMPl were found in all the HLH cases. NF-κB assay revealed that HLH-LMP1 activated NF-κB significantly more than that of B95.8-LMP1 (p=0.032). We conclude that EBV from all of our HLH cases shared common genetic characteristics with EBV obtained from the CAO cell line, which is distinct from the wild-type EBV isolated from the B95.8 cell line. These data suggest that the mutational changes of the LMP1 gene may play an important role in the pathogenesis of these fatal EBV-related disorders.

Prognostic Value of Early Response to Treatment Combined with Conventional Risk Factors in Pediatric Acute Lymphoblastic Leukemia

To determine useful prognostic factors in treating childhood acute lymphoblastic leukemia (ALL), we correlated conventional risk factors and bone marrow response 14 days after induction chemotherapy. Our study included 116 precursor B-cell (n = 104) and T-cell (n = 12) ALL patients treated with our protocol between 1988 and 1999. The patients were classified into 3 initial risk groups on the basis of conventional risk factors (56 in the low-risk, 33 in the high-risk, and 27 in the very high-risk groups). All patients received similar systemic chemotherapy regimens before the evaluation of their bone marrow on day 14. We evaluated the marrow of 69 patients as M1 (less than 5% blasts), 25 as M2 (5%–25% blasts), and 22 as M3 (more than 25% blasts). Although all patients attained an initial complete remission (CR), relapse was noted in 33 of the 116 patients, and 15 patients died. All of the M1 marrow patients, irrespective of the initial risk group, showed the best event-free survival rate (85.1% ± 4.4%), the lowest relapse rate (14.5%), and the highest attainment of a second CR (100%); they were defined as the new R1 prognostic group. The low-risk patients with M2 or M3 marrow (R2 group) had a relatively high relapse rate, but all of these relapsed patients were treated successfully with subsequent therapy. High- or very high-risk patients with M2 or M3 marrow (R3 group) had the worst prognosis. Our new prognostic definition (R1, R2, R3) incorporating day 14 marrow findings is useful to tailor early-phase treatments for better therapeutic results in childhood ALL.

Use of rituximab to treat refractory Diamond-Blackfan anemia.

Abstract:  We report here the first case with Diamond‐Blackfan anemia (DBA) who responded to rituximab. The patient is an 8‐yr‐old Japanese girl with refractory DBA accompanied by complex congenital heart disease. She received two doses of rituximab, 375 mg/m2/wk. She became transfusion independent 6 months after the treatment without any serious side effect. However, after 8 months of transfusion‐free period, her condition returned to the pretreatment level with recovery of peripheral B cells. Rituximab may be a successful therapy for refractory DBA where B cells play a crucial role in the pathogenesis of the severe anemia.

Risk Factors for Cytomegalovirus Retinitis Following Bone Marrow Transplantation From Unrelated Donors in Patients With Severe Aplastic Anemia or Myelodysplasia

Two cases of cytomegalovirus (CMV) retinitis following bone marrow transplantation (BMT) from unrelated donors are reported. 1 patient had been treated for severe aplastic anemia (SAA) and the other for hypoplastic myelodysplastic syndrome (MDS). Because first line therapy with antithymocyte globulin (ATG) and cyclosporin A (CsA) had failed, BMT was performed following a conditioning regimen of ATG, cyclophosphamide, and total lymphoid irradiation. Treatment for CMV retinitis was successfully carried out with gancyclovir (systemic and intraocular injection), foscarnet, and photocoagulation (Case 1) and gancyclovir and foscarnet (Case 2). Both patients also developed Epstein-Barr virus—associated lymphoproliferative disease (EBV-LPD). We compared these 2 cases with 14 SAA patients who did not develop CMV retinitis after BMT using marrow from either HLA-identical siblings (n = 9) or from unrelated donors (n = 5). Unlike the retinitis patients, the latter 5 patients received ATG only once.The retinitis patients had significantly lower CD4+ T-cell levels in their peripheral blood than the 14 patients who did not develop CMV retinitis. We believe that repeated treatment with ATG and transplantation from unrelated donors may lead to immune dysfunction that could increase the likelihood of CMV retinitis, as well as LPD. For such BMT patients, regular ophthalmic examinations and careful testing for CMV antigenemia are recommended.

Health-related quality of life in Japanese children with acute lymphoblastic leukemia during and after chemotherapy

Quality of life (QOL) as a treatment outcome has not yet been evaluated among patients receiving a specific treatment regimen by treatment phase in a consistent manner. This exploratory cross‐sectional study evaluated the QOL of children with acute lymphoblastic leukemia (ALL) receiving one of the most popular treatment regimens in Japan (Japan Association of Childhood Leukemia Study ALL‐02 revised protocol).