Atsuo Maruta

High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group.

PURPOSE A novel therapeutic approach is urgently needed for BCR-ABL-positive acute lymphoblastic leukemia (ALL). In this study, we assessed the efficacy and feasibility of chemotherapy combined with imatinib. PATIENTS AND METHODS A phase II study of imatinib-combined chemotherapy was conducted for newly diagnosed BCR-ABL-positive ALL in adults. Eighty patients were entered into the trial between September 2002 and January 2005. RESULTS Remission induction therapy resulted in complete remission (CR) in 77 patients (96.2%), resistant disease in one patient, and early death in two patients, as well as polymerase chain reaction negativity of bone marrow in 71.3%. The profile and incidence of severe toxicity were not different from those associated with our historic chemotherapy-alone regimen. Relapse occurred in 20 patients after median CR duration of 5.2 months. Allogeneic hematopoietic stem-cell transplantation (HSCT) was performed for 49 patients, 39 of whom underwent transplantation during their first CR. The 1-year event-free and overall survival (OS) rates were estimated to be 60.0%, and 76.1%, respectively, which were significantly better than those for our historic controls treated with chemotherapy alone (P < .0001 for both). Among the current trial patients, the probability for OS at 1 year was 73.3% for those who underwent allogeneic HSCT, and 84.8% for those who did not. CONCLUSION Our results demonstrated that imatinib-combined regimen is effective and feasible for newly diagnosed BCR-ABL-positive ALL. Despite a relatively short period of observation, a major potential of this treatment is recognized. Longer follow-up is required to determine its overall effect on survival.

The japanese multicenter open randomized trial of ursodeoxycholic acid prophylaxis for hepatic veno-occlusive disease after stem cell transplantation

Hepatic veno‐occlusive disease (VOD) is a common transplant‐related complication of stem cell transplantation. There is no safe and proven therapy for established VOD, and attempts have focused on its prevention. Limited studies have suggested that prophylactic use of ursodeoxycholic acid (UDCA) reduced the incidence of VOD. To confirm the preventive effect of UDCA on VOD, we conducted a prospective, unblinded randomized, multicenter study of UDCA involving 132 patients who underwent stem cell transplantation for a variety of disorders. Sixty‐seven patients were assigned to the UDCA‐treated group, and 65 patients were assigned to the control group. The clinical characteristics of the two groups were similar with respect to primary diagnosis, age, sex, and baseline organ function. The preparative regimen and GVHD prophylaxis did not differ significantly between the two groups. UDCA was highly effective in preventing VOD, which occurred in only 3.0% in the UDCA‐treated group, as opposed to 18.5% in the control group (P = 0.0043). There were no adverse effects attributable to UDCA. The initial promising report of a prophylactic effect of UDCA on VOD after stem cell transplantation was confirmed in this prospective study. Am. J. Hematol. 64:32–38, 2000.

Prospective monitoring of BCR-ABL1 transcript levels in patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia undergoing imatinib-combined chemotherapy.

The clinical significance of minimal residual disease (MRD) is uncertain in patients with Philadelphia chromosome‐positive acute lymphoblastic leukaemia (Ph+ ALL) treated with imatinib‐combined chemotherapy. Here we report the results of prospective MRD monitoring in 100 adult patients. Three hundred and sixty‐seven follow‐up bone marrow samples, collected at predefined time points during a uniform treatment protocol, were analysed for BCR‐ABL1 transcripts by quantitative reverse transcription polymerase chain reaction. Ninety‐seven patients (97%) achieved complete remission (CR), and the relapse‐free survival (RFS) rate was 46% at 3 years. Negative MRD at the end of induction therapy was not associated with longer RFS or a lower relapse rate (P = 0·800 and P = 0·964 respectively). Twenty‐nine patients showed MRD elevation during haematological CR. Of these, 10 of the 16 who had undergone allogeneic haematopoietic stem cell transplantation (HSCT) in first CR were alive without relapse at a median of 2·9 years after transplantation, whereas 12 of the 13 who had not undergone allogeneic HSCT experienced a relapse. These results demonstrate that, in Ph+ ALL patients treated with imatinib‐combined chemotherapy, rapid molecular response is not associated with a favourable prognosis, and that a single observation of elevated MRD is predictive of subsequent relapse, but allogeneic HSCT can override its adverse effect.

Donor leukocyte infusion for Japanese patients with relapsed leukemia after allogeneic bone marrow transplantation : lower incidence of acute graft-versus-host disease and improved outcome

To clarify the role of donor leukocyte infusion (DLI) in the treatment of leukemia relapsing after allo-BMT, data from 100 patients were collected from 46 facilities in Japan and analyzed with respect to the efficacy and adverse effects of donor leukocyte infusion. Complete remission was achieved in 11 of 12 (91%) patients with relapsed chronic myelogenous leukemia (CML) in chronic phase, three of 11 (27%) with CML in the acute phase, eight of 21 (38%) with acute myelogenous leukemia (AML), six of 23 (25%) with acute lymphoblastic leukemia (ALL) and five of 11 (45%) with myelodysplastic syndrome (MDS). The probability of remaining in CR at 3 years was 82% in CML patients in the chronic phase, but 0% in those with CML in the acute phase, 7% in those with AML, 0% with ALL and 33% with MDS. Acute GVHD (⩾2) developed in 31 of 89 (34%) patients with HLA-identical related donors and was fatal for seven (7%). Cytopenia developed in 21 of 94 (22%) with no associated fatalities. When the outcome of patients with CML in CP and MDS was analyzed, development of GVHD, cytopenia, or both, was associated with a higher GVL effect (15 of 16, 93%) than in those without adverse affects (one of 6, 17%). A leukocyte dose of 5 × 107/kg of recipient body weight appeared to be optimal as an initial dose of DLI. Given the relatively low incidence of acute GVHD and the similar GVL effect, DLI may be more beneficial to patients in Japan with recurrent leukemia than to those in Western countries. Bone Marrow Transplantation (2000) 26, 769–774.

Severe cardiac toxicity in hematological stem cell transplantation: predictive value of reduced left ventricular ejection fraction

Eighty patients receiving hematological stem cell transplantation (HCT) with a preparative regimen consisting of total body irradiation (12.5 Gy), cyclophosphamide (4000 or 4500 mg/m2), and thiotepa (400 mg/m2) were evaluated for the development of cardiac toxicity. Patients in whom the pretransplant cumulative dose of anthracycline was more than or equal to 300 mg/m2 showed a lower left ventricular ejection fraction (EF) before HCT compared to patients with less than 300 mg/m2 (0.61 ± 0.09 vs0.67 ± 0.06, P = 0.0010). Patients who had undergone more than or equal to six courses of chemotherapy showed a decreased EF before HCT compared to those after less than six courses (0.67 ± 0.05 vs0.63 ± 0.09, P = 0.03). Three of seven patients (43%) whose pretransplant EF had been less than or equal to 0.55 developed severe cardiac toxicity, characterized by congestive heart failure (CHF) compared with none of 83 patients (0%) whose pretransplant EF had been more than 0.55 (P = 0.00026). Of the three patients who developed severe cardiac toxicity, two were given more than 300 mg/m2 of cumulative anthracycline and underwent 23 courses and six courses of chemotherapy, while the other patient received only two courses of chemotherapy with a total dose of 139 mg/m2 of anthracycline. These results indicate that an increased cumulative dose of anthracycline and number of chemotherapy treatments are correlated with a decrease of the EF and that the EF before HCT is useful for predicting the risk of cardiac complications for recipients who have received chemotherapy. Bone Marrow Transplantation (2001) 27, 307–310.

Immune reconstitution assessed during five years after allogeneic bone marrow transplantation.

Immune reconstitution is an important component of successful allogeneic bone marrow transplantation. Immune reconstitution was evaluated for 5 years after transplantation. While the number of CD8+ T cells and CD56+ cells recovered early post transplantation, a low number of CD4+ and CD4+CD45RA+ T cells and reversal of the CD4/CD8 ratio continued up to 5 years. Although early recovery of IgG and IgM was seen at day 100 post transplantation, serum concentration of IgA was below the normal range at 6 months and increased gradually up to 5 years. Development of acute GVHD did not affect the numbers of CD4+, CD8+, CD4+CD45RA+ and CD4+CD29+ T cells, but the number of CD56+ cells in patients who developed grades II–IV acute GVHD was low. The number of CD4+CD29+ T cells had a tendency to be higher in the patients with extensive chronic GVHD than in those without chronic GVHD 2 years after transplantation whereas the number of CD4+CD45RA+ T cells was low in spite of the absence of chronic GVHD. Serum concentration of IgA was lower in patients with extensive chronic GVHD than in those without chronic GVHD at 180 days. The number of CD4+CD45RA+ cells in 10–19-year-old patients was higher than that in 40–49-year-old patients. Response to the Con A and PHA in 10–19-year-old patients was higher than that in older patients at 1 and 2 years. There was no significant difference in the ability of immune reconstitution between related transplant recipients and unrelated transplant recipients. These results suggest that chronic GVHD and age of patients affected immune reconstitution post transplant. Bone Marrow Transplantation (2001) 27, 1275–1281.

Case Report: Fulminant Hepatitis C Viral Infection After Allogeneic Bone Marrow Transplantation

The authors describe two patients with acute leukemia who died of fulminant hepatitis caused by hepatitis C virus (HCV) after an allogeneic bone marrow transplant, the first such cases reported in Japan. Both had developed posttransfusion hepatitis during chemotherapy to induce remission and for consolidation. Six months after blood transfusion, the blood serum of each patient was positive for HCV antibody and HCV RNA. In each case, there was a transient improvement in liver function after the transplant. However, within 5 months of receiving the transplant and coincident with the withdrawal of cyclosporin A, each patient developed an acute exacerbation of hepatitis. The fulminant hepatitis in our patients may, therefore, have been caused by the reactivation of HCV induced by the immunosuppressive therapy followed by a reconstitution of the immune system.

Karyotype at diagnosis is the major prognostic factor predicting relapse-free survival for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy

In patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy, the presence of secondary chromosome aberrations in addition to (t9;22) at diagnosis represents an independent risk factor for relapse. To identify factors associated with relapse-free survival (RFS), 80 patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia, enrolled in a phase II study of imatinib-combined chemotherapy, were analyzed. The median follow-up of surviving patients was 26.7 months (maximum, 52.5 months). Twenty-eight out of 77 patients who had achieved CR relapsed. The probability of RFS was 50.5% at 2 years. Multivariate analysis revealed that the presence of secondary chromosome aberrations in addition to t(9;22) at diagnosis constitute an independent predictive value for RFS (p=0.027), and increase the risk of treatment failure by 2.8-fold.

Predictive Factors for Central Nervous System Involvement in Non-Hodgkin's Lymphoma: Significance of Very High Serum LDH Concentrations

Factors predictive for central nervous system (CNS) involvement at presentation were investigated in 152 patients with non-Hodgkins lymphoma (NHL) except for lymphoblastic cell lymphoma and small noncleaved cell lymphoma. Twelve patients developed CNS involvement during their disease course. The incidence was 7.9% of all the patients studied and 17.0% of the patients with serum LDH concentration two times the upper limit of normal (2N). By univariate analysis, stage IV disease (P =. 023), a serum LDH concentration S2N (P =. 009), and bone marrow involvement (P =. 016) were risk factors for CNS involvement. Multivariate logistic regression analysis identified a serum LDH concentration 2 N (P =. 032) as an independent predictor for CNS involvement. All 12 patients who developed CNS involvement were among the 126 patients with diffuse lymphoma, whereas none of the 17 patients with follicular lymphoma developed CNS involvement, although the difference was not statistically significant. The median survival of the patients with CNS involvement was only 4.5 months. We conclude that a serum LDH concentration 2N at presentation is a significant predictive factor for CNS involvement for NHL patients without lymphoblastic lymphoma and small noncleaved cell lymphoma. Therefore, we would suggest that CNS prophylaxis should be considered for patients with a serum LDH concentration 2N at presentation and diffuse lymphoma once a complete remission is achieved.

Long-Term Outcome of Human Herpesvirus-6 Encephalitis after Allogeneic Stem Cell Transplantation

Human herpesvirus-6 (HHV-6) encephalitis is recognized as a relatively rare, but sometimes lethal, complication of allogeneic hematopoietic stem cell transplantation (HSCT). Although the development of new diagnostic techniques and antiviral therapy has improved, the prognosis of encephalitis is still unclear. We surveyed 197 patients who underwent allogeneic HSCT between January 2004 and March 2008 at our institution, and 8 (4.0%) were diagnosed as having HHV-6 encephalitis. Five were male and 3 were female, with a median age of 40.5 years. The median onset of HHV-6 encephalitis was 18 days after HSCT, and the median duration of antiviral therapy was 41 days. The median survival time from the onset of encephalitis was 23.1 months (range: 2.7-66.7), and 3 patients died of unrelated causes (sepsis in 2 and gastrointestinal tract bleeding in 1). Cord blood transplantation was identified as the only independent risk factor (relative risk [RR] = 4.98; P = .049) by multivariate analysis. There was no statistical significance of survival after HSCT between the patients with HHV-6 encephalitis and those without HHV-6 encephalitis (the 2-year survival rate was 60% and 52.6%, respectively; P = .617). Four of the 5 surviving patients were unable to return to society because of neuropsychological disorders, including anterograde amnesia and seizures with prominent hippocampal atrophy. Although HHV-6 encephalitis occurring after HSCT is now becoming a curable complication, its sequelae, such as neuropsychological disorders, have a marked influence on the quality of life of long-term survivors. Accordingly, it is necessary to identify risk factors for HHV-6 encephalitis and establish methods for prevention of this complication.