Yukihiko Kimura

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.

A randomized comparison of 4 courses of standard-dose multiagent chemotherapy versus 3 courses of high-dose cytarabine alone in postremission therapy for acute myeloid leukemia in adults: the JALSG AML201 Study

We conducted a prospective randomized study to assess the optimal postremission therapy for adult acute myeloid leukemia in patients younger than 65 years in the first complete remission. A total of 781 patients in complete remission were randomly assigned to receive consolidation chemotherapy of either 3 courses of high-dose cytarabine (HiDAC, 2 g/m(2) twice daily for 5 days) alone or 4 courses of conventional standard-dose multiagent chemotherapy (CT) established in the previous JALSG AML97 study. Five-year disease-free survival was 43% for the HiDAC group and 39% for the multiagent CT group (P = .724), and 5-year overall survival was 58% and 56%, respectively (P = .954). Among the favorable cytogenetic risk group (n = 218), 5-year disease-free survival was 57% for HiDAC and 39% for multiagent CT (P = .050), and 5-year overall survival was 75% and 66%, respectively (P = .174). In the HiDAC group, the nadir of leukocyte counts was lower, and the duration of leukocyte less than 1.0 × 10(9)/L longer, and the frequency of documented infections higher. The present study demonstrated that the multiagent CT regimen is as effective as our HiDAC regimen for consolidation. Our HiDAC regimen resulted in a beneficial effect on disease-free survival only in the favorable cytogenetic leukemia group. This trial was registered at www.umin.ac.jp/ctr/ as #C000000157.

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.

Severe hemorrhagic complications during remission induction therapy for acute promyelocytic leukemia: incidence, risk factors, and influence on outcome

Background: Even after the introduction of all‐trans retinoic acid (ATRA), early hemorrhagic death remains a major cause of remission induction failure for acute promyelocytic leukemia (APL). Methods: To investigate severe hemorrhagic complications during remission induction therapy with respect to incidence, risk factors, and influence on outcome. Results were analyzed for 279 patients enrolled in the APL97 study conducted by the Japan Adult Leukemia Study Group (JALSG). Results: Severe hemorrhage occurred in 18 patients (6.5%). Although most of them were receiving frequent transfusions, the targeted levels of platelet counts (30 × 109/L) and plasma fibrinogen (1.5 g/L) for this study were reached at the day of bleeding in only 71% and 40%, respectively. Nine of them succumbed to an early death, while the remaining nine patients eventually achieved complete remission (CR). The 5‐yr event‐free survival rate was 68.1% for those who did not suffer severe hemorrhage, and 31.1% for those who did (P < 0.0001). For patients who achieved CR, on the other hand, there was no difference in disease‐free survival between patients with and without severe hemorrhage (P = 0.6043). Risk factor analysis identified three pretreatment variables associated with severe hemorrhage: initial fibrinogen level, white blood cell count, and performance status. Additionally, patients with severe hemorrhage were more easily prone to develop retinoic acid syndrome or pneumonia than patients without hemorrhage. Conclusions: These results indicate that fatal hemorrhage represents a major obstacle in curing APL, and that patients with such high‐risk features may benefit from more aggressive supportive care.

Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis.

Imatinib mesylate-induced hepato-toxicity in chronic myeloid leukemia demonstrated focal necrosis resembling acute viral hepatitis

Pre-transplant imatinib-based therapy improves the outcome of allogeneic hematopoietic stem cell transplantation for BCR-ABL-positive acute lymphoblastic leukemia.

A high complete remission (CR) rate has been reported in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) following imatinib-based therapy. However, the overall effect of imatinib on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is undetermined. Between 2002 and 2005, 100 newly diagnosed adult patients with Ph+ALL were registered to a phase II study of imatinib-combined chemotherapy (Japan Adult Leukemia Study Group Ph+ALL202 study) and 97 patients achieved CR. We compared clinical outcomes of 51 patients who received allo-HSCT in their first CR (imatinib cohort) with those of 122 historical control patients in the pre-imatinib era (pre-imatinib cohort). The probability of overall survival at 3 years after allo-HSCT was 65% (95% confidence interval (CI), 49–78%) for the imatinib cohort and 44% (95% CI, 35–52%) for the pre-imatinib cohort. Multivariate analysis confirmed that this difference was statistically significant (adjusted hazard ratio, 0.44, P=0.005). Favorable outcomes of the imatinib cohort were also observed for disease-free survival (P=0.007) and relapse (P=0.002), but not for non-relapse mortality (P=0.265). Imatinib-based therapy is a potentially useful strategy for newly diagnosed patients with Ph+ALL, not only providing them more chance to receive allo-HSCT, but also improving the outcome of allo-HSCT.

Can eradication therapy for Helicobacter pylori really improve the thrombocytopenia in idiopathic thrombocytopenic purpura? Our experience and a literature review

Helicobacter pylori has recently been postulated to play a role in the pathogenesis of autoimmune diseases, including idiopathic thrombocytopenic purpura (ITP). We investigated the prevalence ofH pylori infection and the effects of its eradication in 61 patients with ITP.H pylori infection was found in 50 patients (83%), an incidence significantly higher than not only healthy volunteers in Japan (60%) but also subjects in other reported ITP series (approximately 43%–71%). In our study, the mean age ofH pylori-positive ITP patients (58.0 years) was significantly higher than that ofH pylori-negative ITP patients (40.5 years). Bacterium eradication efforts were performed in 29 infected ITP patients and succeeded in 27 patients (93%). The 29 patients with eradicatedH pylori infections showed significant increases in platelet counts compared with patients with uneradicated infections or who wereH pylori-negative. During the follow-up period (median, 11.0 months), 16 (55%) of 29 patients achieved a major or a minor response. The patients who achieved a major response had not received previous prednisolone therapy, suggesting a relationship between prednisolone therapy and the response to eradication efforts.The assessment ofH pylori infection and its eradication should be attempted in cases of ITP, because this approach may be a good new strategy for treating some ITP patients, especially elderly Japanese patients. Some regional factors have been suggested as causes ofH pylori-associated ITP.

The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients

The JAK2 V617F tyrosine kinase mutation in myelodysplastic syndromes (MDS) developing myelofibrosis indicates the myeloproliferative nature in a subset of MDS patients

Successful treatment with cyclosporin A for myelodysplastic syndrome with erythroid hypoplasia associated with T‐cell receptor gene rearrangements

Myelodysplastic syndrome (MDS) with erythroid hypoplasia, a rare form of MDS, has not yet been clearly defined. We report four patients with MDS with erythroid hypoplasia who received immunosuppressive therapy. All were elderly, had severe transfusion‐dependent anaemia, morphological evidence of myelodysplasia and a low percentage (3·2–13·6%) of erythroid precursors. Administration of cyclosporin A (CsA) improved their anaemia; all transfusion‐dependent patients achieved transfusion‐independence. An inverted CD4/8 ratio was seen in three patients who also demonstrated T‐cell receptor (TCR)‐β and ‐γ gene rearrangements by Southern blotting and clonality by polymerase chain reaction. Treatment with CsA can be an attractive alternative treatment for patients with MDS with erythroid hypoplasia, which may be associated with a clonal abnormality in T cells.

Clinical Features of Polycythemia Vera and Essential Thrombocythemia in Japan: Retrospective Analysis of a Nationwide Survey by the Japanese Elderly Leukemia and Lymphoma Study Group

We conducted the first nationwide survey to clarify the clinical features, treatment methods, and prognoses for polycythemia vera (PV) and essential thrombocythemia (ET). A 1-page questionnaire was mailed to members of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG). Surveys on 647 patients (PV, 266 patients; ET, 381 patients) were returned and analyzed. Thrombotic events at diagnosis and during follow-up occurred at rates of 15.4% and 8.5%, respectively, in PV cases and 17.6% and 8.7% in ET cases. Splenomegaly was observed in only 28.8% of PV patients and 10.8% of ET patients. The leukocyte alkaline phosphatase score was elevated in only 46.2% of PV patients. The incidences of abnormal karyotypes were less than 10% in both PV and ET cases. The rates of transformation to myelofibrosis were 2.6% in both PV and ET cases, and acute leukemia was noted in 1.1% of PV patients and 2.9% of ET patients. Prognostic factors were thrombotic history for PV and thrombotic history and age (≥60 years) for ET. The present study clearly demonstrated clinical differences between Japanese and Western patients for PV and ET. Concerning the treatment of PV and ET, the study revealed considerable variation among Japanese hematologists. These results suggest the necessity of developing treatment guidelines according to risk stratification that are suitable for Japanese PV and ET patients.