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.

Long-term outcome following imatinib therapy for chronic myelogenous leukemia, with assessment of dosage and blood levels: the JALSG CML202 study.

A prospective multicenter Phase II study was performed to examine the efficacy and safety of imatinib therapy in newly diagnosed Japanese patients with chronic-phase CML. Patients were scheduled to receive imatinib 400 mg daily. Plasma imatinib concentrations were measured by liquid chromatography-tandem mass spectrometry. In 481 evaluable patients, estimated 7-year overall survival (OS) and event-free survival (EFS) at a median follow-up of 65 months were 93% and 87%, respectively. Because imatinib dosage was reduced in many patients due mainly to adverse events, subgroup analysis was performed according to the mean daily dose during the first 24 months of treatment: ≥360 mg (400-mg group; n = 294), 270-359 mg (300-mg group; n = 90) and <270 mg (200-mg group; n = 67). There were no significant differences in OS and EFS between the 300- and 400-mg groups; however, cumulative rates of complete cytogenetic and major molecular responses differed significantly between the two groups. There were no significant differences in mean imatinib trough levels between these two groups for the patients in whom trough levels had been measured. Survival and efficacy in the 200-mg group were markedly inferior to the former two groups. These results suggest that, although a daily dose of 400 mg imatinib is associated with better outcomes, 300 mg imatinib may be adequate for a considerable number of Japanese patients who are intolerant to 400 mg imatinib. Blood level monitoring would be useful to determine the optimal dose of imatinib.

Epidemiologic study on survival of chronic myeloid leukemia and Ph(+) acute lymphoblastic leukemia patients with BCR-ABL T315I mutation.

The BCR-ABL T315I mutation represents a major mechanism of resistance to tyrosine kinase inhibitors (TKIs). The objectives of this retrospective observational study were to estimate overall and progression-free survival for chronic myeloid leukemia in chronic-phase (CP), accelerated-phase (AP), or blastic-phase (BP) and Philadelphia chromosome-positive (Ph)(+) acute lymphoblastic leukemia (ALL) patients with T315I mutation. Medical records of 222 patients from 9 countries were reviewed; data were analyzed using log-rank tests and Cox proportional hazard models. Median age at T315I mutation detection was 54 years; 57% cases were men. Median time between TKI treatment initiation and T315I mutation detection was 29.2, 15.4, 5.8, and 9.1 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. After T315I mutation detection, second-generation TKIs were used in 56% of cases, hydroxyurea in 39%, imatinib in 35%, cytarabine in 26%, MK-0457 in 11%, stem cell transplantation in 17%, and interferon-alpha in 6% of cases. Median overall survival from T315I mutation detection was 22.4, 28.4, 4.0, and 4.9 months, and median progression-free survival was 11.5, 22.2, 1.8, and 2.5 months, respectively, for CP, AP, BP, and Ph(+) ALL patients. These results confirm that survival of patients harboring a T315I mutation is dependent on disease phase at the time of mutation detection.

[Correlation of quantification of major bcr-abl mRNA between TMA (transcription mediated amplification) method and real-time quantitative PCR].

Imatinib mesylate has significantly improved the outcome of patients with CML. In the IRIS trial, major molecular response (MMR), which is defined as the achievement of > or =3 log reduction in bcr-abl mRNA from the standardized baseline, was observed in 40% of CML patients by 12 months. Achievement of an MMR at 18 months is associated with 100% probability of transformation-free survival at 60 months, and MMR is an important goal of therapy. The nucleic acid quantitative "DNA probe FR Amp-CML" kit based on the transcription-mediated amplification method, can measure major bcr-abl mRNA in peripheral blood leukocytes. In this study, we studied the clinical usefulness of Amp-CML for monitoring minimum residual disease by comparison with the European standard nucleic acid quantitative method and real-time quantitative PCR (RQ-PCR) with GAPDH as an internal control, using peripheral leukocytes obtained from patients receiving imatinib treatment. The results indicated that Amp-CML had a significant correlation with Fusion Quant M-BCR (R>0.971, P<0.01), a standard nucleic acid quantitative method used in Europe and RQ-PCR (R>0.974, P<0.01), especially in samples with more than 100 copies/microg RNA of major bcr-abl mRNA. These data suggest that Amp-CML is reliable for monitoring major bcr-abl mRNA in patients having achieved an MMR.

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.

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.

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.

Clinical features of adult acute leukemia with 11q23 abnormalities in Japan: a co-operative multicenter study.

To clarify the clinical features of adult patients with acute leukemia (AL) with 11q23 abnormalities, we performed a retrospective analysis of data from 58 adult Japanese patients: 51 with acute myeloid leukemia (AML), and 7 with acute lymphoblastic leukemia (ALL). The incidences according to fusion partners in AML were: t(9;11), 31.3%; t(11;19), 27.4%; t(6;11), 21.5%. The incidence of patients with t(11;19) was higher than those in the US and Europe, and the incidence of t(4;11) was lower than that in childhood. The results indicated the poor prognosis of AML with 11q23 abnormalities regardless of the fusion partners. AML patients with 11q23 aged <60 years in the first CR who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) showed a more favorable outcome than those treated without allo-HSCT, although the differences were not statistically significant (P = 0.322 for DFS, P = 0.138 for OS). This result suggests that treatment strategies including allo-HSCT may be considered in the first CR in cases of AML with 11q23 abnormalities. However, further studies involving a large number of cases are required to assess the effect of allo-HSCT on adult AL with 11q23 abnormalities.

A novel gene, ANKRD28 on 3p25, is fused with NUP98 on 11p15 in a cryptic 3-way translocation of t(3;5;11)(p25;q35;p15) in an adult patient with myelodysplastic syndrome/acute myelogenous leukemia.

We identified a novel gene fusion of ANKRD28 (ankyrin repeat domain 28) on 3p25 to NUP98 on 11p15 in a patient with adult myelodysplastic syndrome/acute myelogenous leukemia. A partially cryptic 3-way translocation, t(3;5;11)(p25;q35;p15), that had initially been supposed to be t(3;5)(p25;q35) was revealed by precise breakpoint mapping via fluorescence in situ hybridization analysis with bacterial artificial chromosome clones. This translocation produces the expression of 2 in-frame fusion transcripts, the novel ANKRD28-NUP98 and NUP98-NSD1, and 1 out-of-frame NSD1-ANKRD28 transcript. Transient overexpression of ANKRD28-NUP98 in NIH/3T3 cells, but not the C-terminal deletion mutant of ANKRD28 (DeltaC-ANKRD28), caused significantly increased focus formation compared with mock-transfectant controls. ANKRD28-NUP98 was localized in the nucleolus and cytoplasm, whereas ANKRD28 and DeltaC-ANKRD28 were found exclusively in the cytoplasm. Alteration of the subcellular localization of ANKRD28 might have contributed to the leukemogenesis in this case. This report is the first of ANKRD28 as an NUP98 fusion partner, and this case implies that this fusion may be responsible for hematologic malignancies.

Treatment of acute myeloid leukemia patients aged more than 75 years: results of the E-AML-01 trial of the Japanese Elderly Leukemia and Lymphoma Study Group (JELLSG).

The feasibility and effects of combination chemotherapy for very elderly patients with acute myeloid leukemia was examined in 65 patients (including previous myelodysplastic syndrome) aged 76 years or morewith a performance status of 0 - 3. Induction chemotherapy was performed with 30 mg/m2 daunorubicin on days 1 - 3, 150 mg/m2 behenoyl cytosine arabinoside on days 1 - 7, and 70 mg/m2 6-mercaptopurine with 300 mg allopurinol taken orally on days 1 - 7 (BHAC-DM). The complete remission (CR) rate was 38.5%, whereas overall survival at 2 and 5 years was 22.0% and 4.7%, respectively. Two- and 5-year survival of CR patients was 41.8% and 11.2%, respectively. The relapse rate of the 25 CR patients was 64.0% and disease-free survival at 2 and 5 years was 21.0% and 11.2%, respectively. The therapy-related mortality rate at induction was 13.8%. BHAC-DM is feasible and effective for selected very elderly acute myeloid leukemia patients.

[Diffuse large B-cell lymphoma with strongly positive MIB-1 stain and clinical features resembling Burkitt lymphoma].

A 62-year-old woman was admitted to our hospital because of gastric mucosal bleeding. Gastroendoscopy revealed a gastric tumor which was diagnosed from the biopsied specimen as diffuse large B-cell lymphoma (DLBCL). Lymphoma cells had infiltrated the bone marrow showed morphological features resembling Burkitt lymphoma (BL). Nearly 100% of the cells in the bone marrow were positive for MIB-1 immunostaining. The chromosomal study was normal. Surface marker analysis disclosed that the cells were positive for CD10, CD19, CD20 and CD25. As lymphoma cells had infiltrated the central nervous system, combined chemotherapy was performed accompanied with intrathecal administration of anticancer drugs. Although transient improvement was observed, the patient died of the advanced disease three months after admission. As we have shown here, there are some cases of DLBCL with immunohistochemical features resembling BL. Further consideration about the appropriate chemotherapy program for this type of disease might be necessary.

[Successful treatment with CHOP therapy for progressive of primary macroglobulinemia without further increase of serum IgM].

A 61-year-old man with primary macroglobulinemia (PMG) had been followed without any treatment as he had no apparent manifestations. After 1 year and 3 months, he was admitted to our hospital with a fever. No signs or symptoms of infection and no progressive increase of serum IgM levels was observed. Non-Hodgkin's lymphoma was not additionally found. Fever without infection, elevated serum LDH level and further enlargement of the spleen compelled us to diagnose his condition as deterioration of the PMG. An immediate fall in his temperature and serum IgM levels was observed after CHOP therapy. Effective therapy must be discussed in the deterioration of this type of disease.

Prediction of chemosensitivity for patients with acute myeloid leukemia, according to expression levels of 28 genes selected by genome-wide complementary DNA microarray analysis.

To identify genes involved in the sensitivity of acute myeloid leukemia (AML) cells to chemotherapy, we monitored gene-expression profiles of cancer cells from 76 AML patients using a cDNA microarray consisting of 23,040 genes. We identified 63 genes that were commonly overexpressed and 372 genes suppressed in AML. Because these genes represent key molecules for disclosing the molecular mechanisms of AML, they may be potential targets for drug development. We also found 28 that revealed different expression levels between good and poor responders to chemotherapy and appeared to be associated with chemosensitivity. On that basis, we developed a "Drug Response Scoring" system that was correlated well with individual sensitivity to an anticancer drug regimen. Among the 44 cases with positive drug-response scores by our definition, 40 achieved complete remission after treatment, whereas the only 3 of the 20 cases with negative scores responded well to the treatment. An ability to predict chemosensitivity should eventually lead to achievement of our goal of "personalized therapy."

Differential response to stem cell factor and Flt3 ligand by the FAB subtype in acute myeloid leukemia clonogenic cells.

Proliferative response of blast clonogenic cells to various hematopoietic growth factors (HGF), including stem cell factor (SCF) and flt3 ligand (FL) was investigated in 100 patients with acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML) in myeloid crisis (MC). The frequency of spontaneous colony formation was significantly high in CML in MC (55%) and AML French-American-British (FAB) subtype M4 (48%) compared with M2 (16%). No spontaneous colony was formed in any of the patients with M1 and M3. The frequency of proliferative response to various HGF alone and in combination according to FAB subtype and CML in MC was as follows: that to granulocyte colony-stimulating factor (G-CSF) was lowest in M1 and CML in MC (50%) compared with other FAB subtypes (>or=86%), that to granulocyte-macrophage CSF (GM-CSF) was lowest in CML in MC (44%) compared with FAB subtypes (>or=74%), and that to interleukin-3 (IL-3) was lowest in CML in MC (30%) compared with FAB subtypes (>or=78%). SCF and FL stimulated blast colony formation in 11% and 17% of patients with M3, respectively, but there was no response to both, and in 60% and 57% of patients with CML in MC, respectively, with 14% showing a response to both. The frequency of proliferative response to both SCF and FL increased in the order of M1 (33%), M2 (63%), M4-5 (95%), and M6 (100%). The results are summarized as follows: absence of spontaneous colony formation and response to HGF other than SCF and FL, designated as HGF-dependent growth (M3); spontaneous colony formation and lowest response to HGF, designated as autonomous growth (CML in MC); and spontaneous colony formation and highest response to HGF including SCF and FL, designated as autocrine growth (M4-6). M1 and M2 were intermediate between CML in MC and M4-6. The relation between in vitro growth pattern of blast clonogenic cells and prognosis in AML FAB subtype and CML in MC is discussed.

Efficacy of carboplatin with an MEP (mitoxantrone, etoposide and prednisone) regimen for relapsed and CHOP-resistant diffuse large B-cell lymphomas.

Mitoxantrone, etoposide and prednisone (MEP)-based regimens using granulocyte colony-stimulating factor (G-CSF) were designed for relapsed and CHOP-resistant diffuse large B-cell lymphomas in a single institution, and the therapeutic effects and adverse reactions were studied. In a total of 49 patients, the MEP regimen had a 41% (9/22) overall response rate compared with 48% (13/27) for the MEP plus carboplatin (C-MEP) regimen (Chi-squared test, P=0.602). Among 38 CHOP-resistant patients, however, the overall response rate to C-MEP [42% (10/24)] was significantly superior compared with MEP [7% (1/14)] (P=0.023), and the overall survival to C-MEP was superior compared with MEP (P=0.088). Taken together, our results, although non-randomized, suggest that a combination of MEP with carboplatin is better than MEP alone in CHOP-resistant diffuse large B-cell lymphomas.

Multicenter prospective study of interferon alpha versus allogeneic stem cell transplantation for patients with new diagnoses of chronic myelogenous leukemia.

We compared interferon alpha (IFN-alpha) therapy with stem cell transplantation (SCT) for patients with chronic-phase chronic myelogenous leukemia in a multicenter prospective study to investigate the optimal indication and timing of SCT, especially from HLA-matched unrelated donors. Of 257 eligible patients, 145 patients who were younger than 50 years were assigned to the IFN-alpha cohort (n = 87) or the SCT cohort (n = 58), according to family donor availability. In the IFN-alpha cohort, 52 patients received IFN-alpha and chemotherapy (the IFN1 group), and 35 patients received an SCT from an unrelated donor (the U-SCT group). In the SCT cohort, 47 patients received an SCT from a related donor (the R-SCT group). In the IFN1 group, 88% of the patients achieved a complete hematologic response, and 33% achieved a complete cytogenetic response. At a median follow-up period of 53 months, the predicted 6-year survival rate was 72% in the IFN1 group, 81% in the R-SCT group, and 81% in the U-SCT group. When overall survival was evaluated for the IFN-alpha and R-SCT cohorts by intention to treat according to family donor availability, the 6-year survival rates were 76% and 84%, respectively. When the outcomes of the U-SCT and IFN1 groups were compared, the survival rate of U-SCT group patients was significantly better than for IFN1 group patients without a major cytogenetic response and seemed better for IFN1 group patients younger than 35 years. Therefore, U-SCT may be recommendable to patients who fail to achieve a major cytogenetic response in IFN-alpha therapy and to younger patients.

Long-term follow-up of patients with aplastic anemia and refractory anemia responding to combination therapy with recombinant human granulocyte colony-stimulating factor and erythropoietin.

In our previous study, approximately 60% of aplastic anemia (AA) and refractory anemia (RA) patients treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) and recombinant human erythropoietin (rhEpo) showed a multilineage response. In this study, we analyzed the long-term follow-up of the multilineage responders (multi-R). In the follow-up analysis of 11 multi-R (6 AA and 5 RA), 10 patients (5 AA and 5 RA) were evaluable. The range of time from the start of treatment to the final contact was 50 to 125 months. Analysis of survival times revealed a significant difference between multi-R and non-multi-R among AA patients given this treatment (P = .016). One AA and 1 RA patient among the multi-R developed acute leukemia. Of 7 living multi-R, 3 AA and 2 RA patients did not need transfusion at final contact. Four of them maintained the target hemoglobin concentration of more than 11 g/dL for quality-of-life benefit. The findings suggested that this result is an important advantage of this treatment.