Underweight status at diagnosis is associated with poorer outcomes in adult patients with acute myeloid leukemia: a retrospective study of JALSG AML 201.

Recent studies have described various impacts of obesity and being overweight on acute myeloid leukemia (AML) outcomes in adult patients, but little is known about the impact of being underweight. We compared the outcomes of underweight patients to those of normal weight and overweight patients. Adult patients with AML who registered in the JALSG AML201 study (n = 1057) were classified into three groups: underweight (body mass index [BMI] < 18.5, n = 92), normal weight (BMI 18.5-25, n = 746), and overweight (BMI ≥ 25, n = 219). With the exception of age and male/female ratio, patient characteristics were comparable among the three groups. Rates of complete remission following induction chemotherapy were similar among the three groups (p = 0.68). We observed a significant difference in overall survival (OS), disease-free survival (DFS), and non-relapse mortality (NRM) between underweight and normal weight patients (3-year OS 34.8 vs. 47.7%, p = 0.01; DFS 28.6 vs. 39.8%, p = 0.02; 1-year NRM 6.2 vs. 2.6%, p = 0.05), but not between underweight and overweight patients. In multivariate analysis, underweight was an independent adverse prognostic factor for OS (p < 0.01), DFS (p = 0.01), and NRM (p = 0.04). During the first induction chemotherapy, the incidences of documented infection (DI) and severe adverse events (AEs) were higher in underweight patients than those in normal weight patients (DI 16 vs. 8.1%, p = 0.04; AE 36 vs. 24%, p = 0.05). In conclusion, underweight was an independent adverse prognostic factor for survival in adult AML patients.

The demarcation between younger and older acute myeloid leukemia patients: a pooled analysis of 3 prospective studies.

BACKGROUND: Contemporary treatment protocols for adult acute myeloid leukemia (AML) are age-specific, and older patients are generally treated less intensively than younger patients. However, it remains uncertain whether older but fit patients with AML really need to have their treatment attenuated. METHODS: To evaluate the contribution of age to outcome for patients with AML receiving intensive chemotherapy, data were analyzed for 2276 patients aged less than 65 years who were treated uniformly, regardless of age, in 3 consecutive prospective studies conducted by the Japan Adult Leukemia Study Group. RESULTS: A substantial drop in overall survival (OS) between patients aged 40 to 49 years and 50 to 64 years led to a focus on 2 comparisons: 1) age < 50 versus ≥ 50 years; and 2) age 50 to 54 versus 55 to 59 versus 60 to 64 years. OS was significantly better for patients aged < 50 years than that for those aged ≥ 50 years (49.6% and 37.0% at 5 years; P < .001); older patients were more susceptible to relapse, but not to early death or nonrelapse mortality. The significant differences in OS between these 2 age groups were equally seen for patients with favorable, intermediate, and adverse cytogenetics (P < .001 each). Outcomes for those aged 50 to 54, 55 to 59, and 60 to 64 years were similar, with 5-year OS rates of 38.2%, 35.1%, and 38.0%, respectively (P = .934), and no differences in early death or nonrelapse mortality were observed among these age groups. CONCLUSIONS: These findings justify the use of intensive chemotherapy without dose attenuation toward older but fit patients with AML, at least up to the age of 64 years.

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.

[Anti-smoking education for tobacco-free society].

The Science Council of Japan handed a proposal entitled "For the establishment of tobacco-free society" to the Japanese government in 2008, demanding stronger policy implementation. Among the 7 demands, top priority was placed on"education for improvement of knowledge on health risks of smoking". Ample scientific evidences have proven the health hazards that smoking causes directly and indirectly, which, however, are not well acknowledged among Japanese people, leaving Japan an underdeveloped country in terms of smoke-free society. More education is indispensable in schools and by mass media such as TV. The government must allocate more budgets for the education and advertisements, and, if unsuccessful, should request NHK, which collects mandatory TV reception fees akin to broadcast tax, to assume this task.

Effect of landscape design on depth perception in classical Chinese gardens: A quantitative analysis using virtual reality simulation.

It is common for visitors to have rich and varied experiences in the limited space of a classical Chinese garden. This leads to the sense that the garden's scale is much larger than it really is. A main reason for this perceptual bias is the gardener's manipulation of visual information. Most studies have discussed this phenomenon in terms of qualitative description with fragmented perspectives taken from static points, without considering ambient visual information or continuously changing observation points. A general question arises, then, on why depth perception can vary from one observation point to another along a garden path. To better understand the spatial experience in classical Chinese gardens, this study focused on variations in perceived depth among different observation points and aimed to identify influential visual information through psychophysical experimentation. As stimuli for the experiment, panoramic photos of Liu garden were taken from three positions at Lvyin Pavilion. Considering the effects of pictorial visual cues on depth perception, the photos were processed to create 18 kinds of stimuli (six image treatments * three positions). Two tasks were presented to the participants. In Task 1, 71 participants were asked to rate the depth value of the garden using the magnitude estimation method in a cave automatic virtual environment (CAVE). Statistical analysis of Task 1 revealed that depth values differed significantly among different viewpoints. In Task 2, participants were asked to compare 18 stimuli and 3D images presented on three connected monitors and to judge the depth of the garden using the adjustment method. The results of Task 2 again showed that depth values differed significantly among different viewpoints. In both tasks, ambient information (i.e., the perspective of interior space) significantly influenced depth perception.

A phase II randomized study evaluating azacitidine versus conventional care regimens in newly diagnosed elderly Japanese patients with unfavorable acute myeloid leukemia.

A multicenter phase II study was conducted in 44 elderly (≥ 65 years) Japanese patients with newly diagnosed acute myeloid leukemia (AML) to evaluate whether azacitidine is also effective and feasible in Japanese AML patients. The 28 patients with AML with poor-risk cytogenetics and/or myelodysplasia-related changes (unfavorable AML) were randomly assigned to receive either azacitidine or conventional care regimens (CCR), and the other 16 patients without unfavorable AML received azacitidine alone. The primary endpoint was overall survival. At the median follow-up of 29 months, among the 26 evaluable patients with unfavorable AML, the median survival time (MST) of patients who received azacitidine (N = 14) was 9.6 months and that of patients who received CCR (N = 12) was 5.3 months (HR 0.73; 95% CI 0.31-1.69; log-rank P = 0.459). The MST of all 29 patients who received azacytidine, including the 15 evaluable patients without unfavorable AML, was 12.4 months. Adverse events of azacitidine were manageable and consistent with its established safety profile. Azacitidine tended to prolong survival in newly diagnosed elderly Japanese patients with AML, and was feasible as a front-line therapy for elderly AML patients.

[Phase I study of nelarabine in patients with relapsed or refractory T-ALL/T-LBL].

The safety, tolerability, pharmacokinetics and efficacy of nelarabine were evaluated in adult and pediatric patients with relapsed or refractory T-ALL/T-LBL. Adult patients received nelarabine i.v. over 2 hours on days 1, 3 and 5 in every 21 days, and pediatric patients received this regimen over 1 hour for 5 consecutive days in every 21 days. Safety was evaluated in 7 adult and 6 pediatric patients. Adverse events (AEs) were reported in all patients. Most frequently reported AEs included somnolence and nausea in adult patients and leukopenia and lymphocytopenia in pediatric patients. Five grade 3/4 AEs were reported in both adult and pediatric patients, most of which were hematologic events. There were no dose-limiting toxicities. Efficacy was evaluated in 7 adult and 4 pediatric patients. Complete response was noted in 1 adult and 2 pediatric patients. Higher intracellular ara-GTP concentrations were suggested to be associated with efficacy. Japanese adult and pediatric patients with T-ALL/T-LBL well tolerated nelarabine treatment, warranting further investigation.

Effect of Wall Texture on Perceptual Spaciousness of Indoor Space.

As the main place of people's daily activities, indoor space (its size, shape, colors, material and textures, and so on) has important physical, emotional and health-based implications on people's behavior and quality of life. Material texture is an integral part of architectural environment perception and quality evaluation, but the effect of material texture on perceptual spaciousness lacks the support of experimental data. This research examined the effects between different wall textures on the observer's perception of spaciousness in indoor space, the influence of wall texture changes in different room sizes, and how the associational meaning of texture affects the degree of influence of wall texture on the spaciousness of indoor space. By using VR technology and the magnitude estimation (ME) analysis method, the authors found that the effect of wall texture on perceptual spaciousness varies depending on the wall material, and the textural effect is affected by room size. The perception of spaciousness is influenced by the observer's associational meaning of material texture, and the influence of associational meaning of material texture varies contingent on the room size. In relatively small rooms, the objective aspect (such as hardness, surface reflectivity, texture direction and texture depth) of the wall texture has a significant impact on perceived space. In contrast, the effects of subjective aspects (such as affinity and ecology) become more pronounced in relatively larger rooms. This research makes up for the lack of material texture research in perceptual spaciousness, and provides a new way for the designer to choose materials for the design of a spatial scale.

CMC-544 (inotuzumab ozogamicin) shows less effect on multidrug resistant cells: analyses in cell lines and cells from patients with B-cell chronic lymphocytic leukaemia and lymphoma.

The effect of CMC-544, a calicheamicin-conjugated anti-CD22 monoclonal antibody, was analysed in relation to CD22 and P-glycoprotein (P-gp) in B-cell chronic lymphocytic leukaemia (CLL) and non-Hodgkin lymphoma (NHL) in vitro. The cell lines used were CD22-positive parental Daudi and Raji, and their P-gp positive sublines, Daudi/MDR and Raji/MDR. Cells obtained from 19 patients with B-cell CLL or NHL were also used. The effect of CMC-544 was analysed by viable cell count, morphology, annexin-V staining, and cell cycle distribution. A dose-dependent, selective cytotoxic effect of CMC-544 was observed in cell lines that expressed CD22. CMC-544 was not effective on Daudi/MDR and Raji/MDR cells compared with their parental cells. The MDR modifiers, PSC833 and MS209, restored the cytotoxic effect of CMC-544 in P-gp-expressing sublines. In clinical samples, the cytotoxic effect of CMC-544 was inversely related to the amount of P-gp (P = 0.003), and to intracellular rhodamine-123 accumulation (P < 0.001). On the other hand, the effect positively correlated with the amount of CD22 (P = 0.010). The effect of CMC-544 depends on the levels of CD22 and P-gp. Our findings will help to predict the clinical effectiveness of this drug on these B-cell malignancies, suggesting a beneficial effect with combined use of CMC-544 and MDR modifiers.

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.

Diagnosis of acute myeloid leukemia according to the WHO classification in the Japan Adult Leukemia Study Group AML-97 protocol.

We reviewed and categorized 638 of 809 patients who were registered in the Japan Adult Leukemia Study Group acute myeloid leukemia (AML)-97 protocol using morphological means. Patients with the M3 subtype were excluded from the study group. According to the WHO classification, 171 patients (26.8%) had AML with recurrent genetic abnormalities, 133 (20.8%) had AML with multilineage dysplasia (MLD), 331 (51.9%) had AML not otherwise categorized, and 3 (0.5%) had acute leukemia of ambiguous lineage. The platelet count was higher and the rate of myeloperoxidase (MPO)-positive blasts was lower in AML with MLD than in the other WHO categories. The outcome was significantly better in patients with high (>or=50%) than with low (<50%) ratios of MPO-positive blasts (P < 0.01). The 5-year survival rates for patients with favorable, intermediate, and adverse karyotypes were 63.4, 39.1, and 0.0%, respectively, and 35.5% for those with 11q23 abnormalities (P < 0.0001). Overall survival (OS) did not significantly differ between nine patients with t(9;11) and 23 with other 11q23 abnormalities (P = 0.22). Our results confirmed that the cytogenetic profile, MLD phenotype, and MPO-positivity of blasts are associated with survival in patients with AML, and showed that each category had the characteristics of the WHO classification such as incidence, clinical features, and OS.

Treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia.

In the pre-imatinib era, treatment outcomes of adult patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) were dismal. Despite the use of intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), complete remission and overall survival rates were less than 70% and 20%, respectively. However, imatinib, in combination with conventional chemotherapy, has dramatically changed outcomes, producing approximately 95% complete remission and 50% overall survival with or without allogeneic HSCT. Current research is now focusing on how to prevent relapse. Improvement of postremission therapy is indispensable. Although allogeneic HSCT during first complete remission is still the first choice for feasible patients, post-HSCT imatinib therapy and imatinib plus chemotherapy combinations should also be studied. New BCR-ABL tyrosine kinase inhibitors are expected to improve outcomes in imatinib-resistant leukemia. Our hope is that, in the near future, Ph-positive ALL will become a leukemia in which allogeneic HSCT is offered only for relapsed or refractory cases.

Clinical features and outcome of T-lineage acute lymphoblastic leukemia in adults: a low initial white blood cell count, as well as a high count predict decreased survival rates.

Although biological and clinical features differ between B-lineage acute lymphoblastic leukemia (ALL) and T-lineage ALL (T-ALL), there have been few reports that focused on the prognosis for T-ALL in adults, primarily due to its rarity. Here, we studied the long-term outcomes and prognostic factors specific for adult T-ALL by combining patient data from the three prospective trials conducted by the Japan Adult Leukemia Study Group (JALSG). Among 559 patients whose immunophenotypes could be evaluated, 87 (15.6%) were identified as T-ALL. Of them, 66 patients (75.8%) achieved complete remission, and relapse occurred in 41 patients. With a median follow-up for surviving patients of 7.5 years, the probability of overall survival was 35.0% at 5 years. Risk factor analysis revealed that serum albumin levels, initial white blood cell (WBC) counts, and age had independent values for predicting survival. For WBC, not only the high-count group (50 x 10(9)l(-1) or higher), but also the low-count group (less than 3 x 10(9)l(-1)) showed a significantly lower survival rates than the intermediate-count group (p=0.0055 and 0.0037, respectively). Although our findings need confirmation, these results will be helpful in the identification of prognostically distinct subgroups within adult T-ALL.

Prediction of risk of disease recurrence by genome-wide cDNA microarray analysis in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia treated with imatinib-combined chemotherapy.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) reveals very poor prognosis due to high incidence of relapse when treated with standard chemotherapy. Although >96% of patients with Ph+ALL achieved complete remission (CR) with imatinib-combined chemotherapy in a phase II clinical trial conducted by the Japan Adult Leukemia Study Group (JALSG), 26% of them experienced hematological relapse in a short time after achievement of CR. In this study, to establish a prediction system for risk of relapse, we analyzed gene expression profiles of 23 bone marrow samples from patients with Ph+ALL using cDNA microarray consisting of 27,648 cDNA sequences. Using the 19 randomly-selected test cases, we identified 16 genes that were expressed significantly differently between patients with (n=8) and without (n=11) continuous response; from the list of 16 genes, we selected the 6 'predictive' genes and constructed a numerical scoring system by which the two groups were clearly separated, with positive scores for the former and the negative scores for the latter. Scoring of 4 cases that were reserved from the original 23 cases predicted correctly their clinical responses. In addition, three cases whose BCR-Abl transcript levels failed to reduce sufficiently after induction therapy, also revealed negative scores. We also developed a quantitative reverse transcription-PCR-based prediction system that could be feasible for routine clinical use. Our results suggest that achievement of continuous response with imatinib-combined chemotherapy can be predicted by expression patterns in this set of genes, leading to achievement of 'personalized therapy' for treatment of this disease.

Phase I trial of FLAGM with high doses of cytosine arabinoside for relapsed, refractory acute myeloid leukemia: study of the Japan Adult Leukemia Study Group (JALSG).

This study was designed to determine the optimal high dose for cytosine arabinoside (ara-C) in combination with fludarabine, granulocyte colony-stimulating factor, and mitoxantrone (FLAGM) in adult patients with relapsed or refractory acute myeloid leukemia. Nine patients were enrolled at increasing dosage levels of ara-C (8, 12, and 16 g/m2 per dose level). Ara-C and fludarabine were administered once a day at level 1, once or twice a day at level 2, and twice a day at level 3. All patients had grade 4 hematologic toxicity. The most common adverse events were of grade 2 or less, with nausea and vomiting being the most common (6 events), followed by diarrhea (5 events), and rash (5 events). Of the 13 grade 3 nonhematologic toxicities reported, the 2 most common were febrile neutropenia (6 events) and disseminated intravascular coagulation (3 events). No early deaths were observed. FLAGM with high-dose ara-C was considered safe for patients, and the recommended dosage of ara-C in this study was 2 g/m2 every 12 hours for a total dose of 16 g/m2.

Pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia treated with arsenic trioxide.

PURPOSE: To investigate the pharmacokinetics of arsenic species in Japanese patients with relapsed or refractory acute promyelocytic leukemia (APL) treated with arsenic trioxide (ATO) at a daily dose of 0.15 mg/kg. METHODS: Inorganic arsenic (AsIII and AsV) and the major metabolites monomethylarsonic acid (MAA(V)) and dimethylarsinic acid (DMAA(V)) in plasma and urine collected from 12 Japanese patients were quantified by HPLC/ICP-MS. RESULTS: The plasma concentrations of AsIII and AsV on day 1 reached the similar Cmax (12.4 +/- 8.4 and 10.2 +/- 3.9 ng/ml) immediately after completion of administration followed by a biphasic elimination. The AUC(0-infinity) of AsV was about twice that of AsIII. The appearance of methylated metabolites in the blood was delayed. During the repeated administration, the plasma concentrations of inorganic arsenic reached the steady state. In contrast, the MAA(V) and DMAA(V) concentrations increased in relation to increased administration frequency. The mean total arsenic excretion rate including inorganic arsenic and methylated arsenic was about 20% of daily dose on day 1 and remained at about 60% of daily dose during week 1-4. CONCLUSIONS: This study demonstrates that ATO is metabolized when administered intravenously to APL patients and methylated metabolites are promptly eliminated from the blood and excreted into urine after completion of administration, indicating no measurable accumulation of ATO in the blood.

Molecular target-based treatment of human cancer: summary of the 10th international conference on differentiation therapy.

The 10th International Conference on Differentiation Therapy was held between April 29 and May 3, 2004, in Shanghai, China. In the tradition of previous conferences from this series, which have been held biannually since the first meeting organized 20 years ago by Samuel Waxman and Giovanni Rossi in Sardinia, the organizers of the 10th International Conference on Differentiation Therapy aimed to gather basic and clinical cancer investigators in a setting of plenary sessions, workshops, and poster presentations to maximize the effective exchange of information and foster the establishment of collaborative interactions. Approximately 300 scientists attended the meeting with a mission to discuss targeted approaches to cancer treatment, which stem from our understanding of basic biological processes and the mechanisms of their deregulation during tumorigenesis.