Hirokazu Okumura

Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study

We conducted a multi-institutional randomized study to determine whether high-dose daunorubicin would be as effective as standard-dose idarubicin in remission-induction therapy for newly diagnosed adult patients younger than 65 years of age with acute myeloid leukemia. Of 1064 patients registered, 1057 were evaluable. They were randomly assigned to receive either daunorubicin (50 mg/m(2) daily for 5 days) or idarubicin (12 mg/m(2) daily for 3 days) in combination with 100 mg/m(2) of cytarabine by continuous infusion daily for 7 days as induction therapy. Complete remission was achieved in 407 (77.5%) of 525 patients in the daunorubicin group and 416 (78.2%) of 532 in the idarubicin group (P = .79). Patients achieving complete remission received intensive postremission therapy that consisted of either 3 courses of high-dose cytarabine or 4 courses of standard-dose therapy. Overall survival rates at 5 years were 48% for the daunorubicin group and 48% for the idarubicin group (P = .54), and relapse-free survival rates at 5 years were 41% and 41% (P = .97), respectively. Thus, high-dose daunorubicin and standard-dose idarubicin were equally effective for the treatment of adult acute myeloid leukemia, achieving a high rate of complete remission and good long-term efficacy. This study is registered at http://www.umin.ac.jp/ctrj/ as C000000157.

Brain Natriuretic Peptide Is a Predictor of Anthracycline-Induced Cardiotoxicity

Anthracyclines are effective antineoplastic drugs, but they frequently cause dose-related cardiotoxicity. The cardiotoxicity of conventional anthracycline therapy highlights a need to search for methods that are highly sensitive and capable of predicting cardiac dysfunction. We measured the plasma level of brain natriuretic peptide (BNP) to determine whether BNP might serve as a simple diagnostic indicator of anthracycline-induced cardiotoxicity in patients with acute leukemia treated with a daunorubicin (DNR)-containing regimen. Thirteen patients with acute leukemia were treated with a DNR-containing regimen. Cardiac functions were evaluated with radionuclide angiography before chemotherapies. The plasma levels of atrial natriuretic peptide (ANP) and BNP were measured at the time of radionuclide angiography. Three patients developed congestive heart failure after the completion of chemotherapy. Five patients were diagnosed as having subclinical heart failure after the completion of chemotherapy. The plasma levels of BNP in all the patients with clinical and subclinical heart failure increased above the normal limit (40 pg/ml) before the detection of clinical or subclinical heart failure by radionuclide angiography. On the other hand, BNP did not increase in the patients without heart failure given DNR, even at more than 700 mg/m2. The plasma level of ANP did not always increase in all the patients with clinical and subclinical heart failure. These preliminary results suggest that BNP may be useful as an early and sensitive indicator of anthracycline-induced cardiotoxicity.

Human Herpesvirus 6 (HHV-6) Reactivation and HHV-6 Encephalitis After Allogeneic Hematopoietic Cell Transplantation: A Multicenter, Prospective Study

BACKGROUND The epidemiology of human herpesvirus 6 (HHV-6) encephalitis after allogeneic hematopoietic cell transplantation (HCT) and its relationship with HHV-6 reactivation have not been sufficiently characterized. METHODS This prospective, multicenter study of 230 allogeneic HCT recipients investigated the epidemiology of HHV-6 reactivation and HHV-6 encephalitis. Plasma HHV-6 DNA load was prospectively evaluated twice weekly until 70 days after HCT. RESULTS Cumulative incidence of positive HHV-6 DNA and high-level HHV-6 reactivation (plasma HHV-6 DNA ≥10(4) copies/mL) at day 70 after HCT was 72.2% and 37.0%, respectively. Multivariate analysis identified myeloablative conditioning (hazard ratio [HR], 1.9; P = .004), umbilical cord blood transplantation (UCBT) (HR, 2.0; P = .003), and male sex (HR, 1.6; P = .04) as risk factors for displaying high-level HHV-6 reactivation. HHV-6 encephalitis occurred in 7 patients, and cumulative incidence at day 70 was 3.0%. None of the144 patients without high-level HHV-6 reactivation and 7 of 86 patients (8.1%) with high-level HHV-6 reactivation developed HHV-6 encephalitis (P = .0009). Prevalence of HHV-6 encephalitis was significantly higher among patients receiving UCBT than in patients with other sources (cumulative incidence at day 70, 7.9% vs 1.2%, P = .008). In each of 7 patients with HHV-6 encephalitis, central nervous system (CNS) symptoms developed concomitant with peak plasma HHV-6 DNA (range, 21 656-433 639 copies/mL). CONCLUSIONS High levels of plasma HHV-6 DNA are associated with higher risk of HHV-6 encephalitis. UCBT is a significant risk factor for HHV-6 encephalitis. HHV-6 encephalitis should be considered if CNS dysfunction develops concomitant to high-level plasma HHV-6 DNA after allogeneic HCT.

Primary gastrointestinal follicular lymphoma involving the duodenal second portion is a distinct entity: A multicenter, retrospective analysis in Japan

We conducted a multicenter, retrospective study to determine the anatomical distribution and prognostic factors of gastrointestinal (GI) follicular lymphoma (FL). This study included 125 patients with stage I and II1 GI–FL. Of the 125 patients, the small intestine was examined in 70 patients, with double‐balloon endoscopy and/or capsule endoscopy. The most frequently involved GI–FL site was the duodenal second portion (DSP) (81%), followed by the jejunum (40%); 85% of patients with involvement of the DSP also had jejunal or ileal lesions. The absence of abdominal symptoms and macroscopic appearance of multiple nodules were significantly present in the DSP‐positive group. During a median follow up of 40 months, six patients showed disease progression. Patients with involvement of the DSP had better progression‐free survival (PFS) than those without such involvement (P = 0.001). A multivariate analysis revealed that male sex, the presence of abdominal symptoms, and negative involvement of the DSP were independently associated with poor PFS. In conclusion, most patients with GI–FL have duodenal lesions associated with multiple jejunal or ileal lesions. Gastrointestinal follicular lymphomas involving the DSP might be a distinct entity showing a favorable clinical course. (Cancer Sci 2011; 102: 1532–1536)

Origin and fate of blood cells deficient in glycosylphosphatidylinositol‐anchored protein among patients with bone marrow failure

Peripheral blood from 489 recently diagnosed patients with aplastic anaemia (AA) and 316 with refractory anaemia (RA) of myelodysplastic syndrome was evaluated to characterize CD55−CD59− [paroxysmal nocturnal haemoglobinuria (PNH)]‐type blood cells associated with bone marrow (BM) failure. PNH‐type cells were detected in 57% and 20% of patients with AA and RA, respectively. The percentages of PNH‐type granulocytes ranged from 0·003% to 94·2% and the distribution was log‐normal with a median of 0·178%. Serial analyses of 75 patients with PNH‐type cells over 5 years revealed that the percentage of PNH‐type cells constantly increased in 13 (17%), persisted in 44 (59%), disappeared in the remaining 18 (24%) although even in the ‘Disappearance’ group, PNH‐type granulocytes persisted for at least 6 months. A scattergram profile of PNH‐type cells unique to each patient persisted regardless of the response to immunosuppressive therapy and only single PIGA mutations were detected in PNH‐type granulocytes sorted from four patients. These findings suggest that the PNH‐type cells in patients with BM failure are derived from single PIGA mutant haematopoietic stem cells even when their percentages are <1% and their fate depends on the proliferation and self‐maintenance properties of the individual PIGA mutants.

Immature platelet fraction for prediction of platelet engraftment after allogeneic stem cell transplantation.

Platelet regeneration represents an important and separate element in the engraftment process for allogeneic stem cell transplantation. Fully automated flow cytometry using blood cell counters now allows reliable quantification of reticulated platelets, expressed as the immature platelet fraction (IPF). We studied the kinetics of IPF in six patients grafted with allogeneic peripheral blood stem cell transplantation (PBSCT), 12 patients with bone marrow transplantation (BMT) and seven patients with cord blood transplantation (CBT). Preconditioning therapy caused an immediate and rapid fall in tri-lineage hematopoiesis. IPF rose transiently above 3% after a mean duration of 11 days post-PBSCT, 18 days post-BMT and 19 days post-CBT. This was 1, 4 and 13 days earlier than platelet engraftment, respectively. A linear correlation model showed a close association between the rise of IPF and tri-lineage engraftment after transplantation. IPF counting may thus provide an accessible measure of thrombopoietic activity, leading to early evaluation of marrow function and allowing monitoring of platelet regeneration.

Mycophenolate Mofetil Is Effective and Well Tolerated in the Treatment of Refractory Acute and Chronic Graft-versus-Host Disease

We enrolled 11 patients with refractory graft-versus-host disease (GVHD) in a prospective trial evaluating the efficacy of mycophenolate mofetil (MMF). Four (67%) of the 6 patients with acute GVHD and all 5 patients with chronic GVHD responded to MMF. Ten (91%) of the 11 patients were able to decrease steroid use (median decrease, 86%; range, 25%-100%). After a median follow-up of 18 months (range, 1-65 months), 7 patients (64%) remained alive. The adverse events were infectious complications (36%), diarrhea (27%), and neutropenia (18%); the only patient discontinuing MMF did so because of grade 4 neutropenia. This preliminary study suggests that MMF is a well-tolerated agent and has a beneficial effect in the treatment of refractory acute and chronic GVHD.

Association between IgG4-related disease and progressively transformed germinal centers of lymph nodes

Progressively transformed germinal centers is a benign condition of unknown pathogenesis characterized by a distinctive variant form of reactive follicular hyperplasia in lymph nodes. We recently reported Ig G4-related disease in progressively transformed germinal centers. However, no large case series has been reported and clinicopathologic findings remain unclear. Here, we report 40 Japanese patients (28 men, 12 women; median age, 56 years) with progressively transformed germinal centers of the lymph nodes who fulfilled the histological diagnostic criteria for IgG4-related disease (IgG4+ progressively transformed germinal centers), with asymptomatic localized lymphadenopathy involving the submandibular nodes in 24, submandibular and cervical nodes in 14, cervical nodes only in 1, and cervical and supraclavicular nodes in 1. In all, 16 (52%) of 31 examined patients had allergic disease. Histologically, the lymph nodes demonstrated uniform histological findings, namely marked follicular hyperplasia with progressively transformed germinal centers, and localization of the majority of IgG4+ plasma cells in the germinal centers. Serum IgG4, serum IgE and peripheral blood eosinophils were elevated in 87%, 92% and 53% of examined patients, respectively. Eighteen patients subsequently developed extranodal lesions (including five who developed systemic disease), which on histological examination were consistent with IgG4-related disease. IgG4+ progressively transformed germinal centers presents with uniform clinicopathological features of asymptomatic localized submandibular lymphadenopathy, which persists and/or relapses, and sometimes progresses to extranodal lesions or systemic disease. Nine patients were administered steroid therapy when the lesions progressed, to which all responded well. We suggest that IgG4+ progressively transformed germinal centers should be included in the IgG4-related disease spectrum.

Japanese phase II study of 90Y-ibritumomab tiuxetan in patients with relapsed or refractory indolent B-cell lymphoma

There is no data about the efficacy and safety of radioimmunotherapy with 90Y‐ibritumomab tiuxetan in patients with relapsed or refractory indolent B‐cell lymphoma pretreated with rituximab‐containing chemotherapy. We focused on this in a Japanese phase II study. Radioimmunotherapy with 90Y‐ibritumomab tiuxetan (11.1 and 14.8 MBq) was evaluated in patients with 100–149 × 109 and >150 × 109 platelets/L, respectively. The primary endpoint was the overall response rate. Forty patients were treated with 90Y‐ibritumomab tiuxetan (18 with 11.1 MBq/kg and 22 with 14.8 MBq/kg). Thirty‐five patients (88%) had been pretreated with rituximab, including 27 (68%) pretreated with rituximab‐containing chemotherapy. The overall response rate was 83% (33/40; 95% confidence interval, 67–93%), and the complete response rate was 68% (27/40; 95% confidence interval, 51–81%). The overall response rates in patients pretreated with rituximab‐containing chemotherapy and rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP) were 83% (19/23) and 94% (17/18), respectively. The median progression‐free survival time of the 40 patients who received 90Y‐ibritumomab tiuxetan was 9.6 months. Toxicity was primarily hematological and mostly transient. No grade 4 non‐hematological toxicity was observed. In conclusion, radioimmunotherapy with 90Y‐ibritumomab tiuxetan is safe and highly effective in patients with relapsed or refractory indolent B‐cell lymphoma, including those pretreated with rituximab‐containing chemotherapy. (ClinicalTrials.gov number NCT00220285) (Cancer Sci 2009; 100: 158–164)

Successful treatment of Epstein-Barr virus-associated natural killer cell large granular lymphocytic leukaemia using allogeneic peripheral blood stem cell transplantation

We report a case of natural killer cell large granular lymphocytic (NK-LGL) leukaemia successfully treated with allogeneic peripheral blood stem cell transplantation (allo-PBSCT). The peripheral blood (PB) revealed an abnormal expansion of LGL that were CD3−, CD16− and CD56+, and had natural killer activity. In situ EBER-1 hybridization of the PB mononuclear cells showed the presence of Epstein–Barr virus (EBV) in the LGL as well as in lymphocytes infiltrating the tonsils and colon. Southern blotting with an EBV-terminal repetitive sequence probe demonstrated clonal proliferation of EBV+ cells. The patient received allo-PBSCT from his HLA-matched sister with a conditioning regimen involving the use of cyclophosphamide and fractionated total body irradiation. The patient promptly recovered trilineage haematopoiesis without graft-versus-host disease, and has been in complete remission without therapy for 10 months since allo-PBSCT, suggesting that allo-PBSCT could eradicate the NK-LGL leukaemic cells.