Long‐term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia

Studies focused on elderly acute promyelocytic leukemia (APL) are relatively limited. To evaluate prognostic impact in elderly APL, we compared the long‐term outcome of elderly APL patients (60–70 years) with younger patients (15–59 years) treated with all‐trans retinoic acid combined with anthracycline and cytarabine in the Japan Adult Leukemia Study Group (JALSG) APL97 study. Of 283 evaluable patients, 46 (16.3%) were elderly who had more frequent lower platelet (P = 0.04), lower albumin (P = 0.006) and performance status 3 (P = 0.02), higher induction death rate due to differentiation syndrome (P = 0.03), and non‐relapse mortality (NRM) during consolidation therapy (P = 0.001). Overall survival was significantly inferior in elderly patients (P = 0.005), but disease‐free survival and cumulative incidence of relapse were not. Better therapeutic approaches should be considered to reduce NRM during induction and consolidation therapy in elderly APL. This study was registered at http://www.umin.ac.jp/ctrj/ under C000000206.     

Conventional and advanced time series estimation: application to the Australian and New Zealand Intensive Care Society (ANZICS) adult patient database, 1993–2006

Rationale Time series analysis has seen limited application in the biomedical Literature. The utility of conventional and advanced time series estimators was explored for intensive care unit (ICU) outcome series. Methods Monthly mean time series, 1993–2006, for hospital mortality, severity‐of‐illness score (APACHE III), ventilation fraction and patient type (medical and surgical), were generated from the Australia and New Zealand Intensive Care Society adult patient database. Analyses encompassed geographical seasonal mortality patterns, series structural time changes, mortality series volatility using autoregressive moving average and Generalized Autoregressive Conditional Heteroscedasticity models in which predicted variances are updated adaptively, and bivariate and multivariate (vector error correction models) cointegrating relationships between series. Results The mortality series exhibited marked seasonality, declining mortality trend and substantial autocorrelation beyond 24 lags. Mortality increased in winter months (July–August); the medical series featured annual cycling, whereas the surgical demonstrated long and short (3–4 months) cycling. Series structural breaks were apparent in January 1995 and December 2002. The covariance stationary first‐differenced mortality series was consistent with a seasonal autoregressive moving average process; the observed conditional‐variance volatility (1993–1995) and residual Autoregressive Conditional Heteroscedasticity effects entailed a Generalized Autoregressive Conditional Heteroscedasticity model, preferred by information criterion and mean model forecast performance. Bivariate cointegration, indicating long‐term equilibrium relationships, was established between mortality and severity‐of‐illness scores at the database level and for categories of ICUs. Multivariate cointegration was demonstrated for {log APACHE III score, log ICU length of stay, ICU mortality and ventilation fraction}. Conclusions A system approach to understanding series time‐dependence may be established using conventional and advanced econometric time series estimators.     

Pediatric-inspired intensified therapy of adult T-ALL reveals the favorable outcome of NOTCH1/FBXW7 mutations, but not of low ERG/BAALC expression: a GRAALL study

Despite recent progress in the understanding of acute lymphoblastic leukemia (T-ALL) oncogenesis, few markers are sufficiently frequent in large subgroups to allow their use in therapeutic stratification. Low ERG and BAALC expression (E/B(low)) and NOTCH1/FBXW7 (N/F) mutations have been proposed as powerful prognostic markers in large cohorts of adult T-ALL. We therefore compared the predictive prognostic value of N/F mutations versus E/B(low) in 232 adult T-ALLs enrolled in the LALA-94 and Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocols. The outcome of T-ALLs treated in the pediatric-inspired GRAALL trials was significantly superior to the LALA-94 trial. Overall, 43% and 69% of adult T-ALL patients were classified as E/B(low) and N/F mutated, respectively. Strikingly, the good prognosis of N/F mutated patients was stronger in more intensively treated, pediatric-inspired GRAALL patients. The E/B expression level did not influence the prognosis in any subgroup. N/F mutation status and the GRAALL trial were the only 2 independent factors that correlated with longer overall survival by multivariate analysis. This study demonstrates that the N/F mutational status and treatment protocol are major outcome determinants for adults with T-ALL, the benefit of pediatric inspired protocols being essentially restricted to the N/F mutated subgroup.     

The 6th annual meeting of the UK Cord Blood and Adult Stem Cell Group

The meeting was established in 1999 by the UK cord blood immunobiology group. Over the last 6 years the annual meeting has attracted multidiscipline participants interested in the immunobiology of cord blood and the immunology of maternal fetal engraftment from universities, hospitals and cord blood banks throughout the UK and Europe. The 6th annual meeting was held in the Life Bioscience Centre 'Centre for Life' in association with the University of Newcastle upon Tyne. The purpose of this meeting was to bring together the most up-to-date scientific results, both the clinical applications and immunobiology of cord blood stem cells. The meeting, although relatively small-scale, was clearly focused on specific topics and was highly interactive between scientists and clinicians. The meeting was introduced and chaired by Professor Anne Dickinson, University of Newcastle upon Tyne, UK.     

A randomized, partially blinded phase 2 trial of antiretroviral therapy, HIV-specific immunizations, and interleukin-2 cycles to promote efficient control of viral replication (ACTG A5024)

Strategies to limit life-long dependence on antiretroviral therapy (ART) are needed. We randomized 81 human immunodeficiency virus (HIV)-infected subjects to 4 interventional arms involving continued ART plus ALVAC vCP1452 (or placebo) with or without interleukin (IL)-2 infusions. Viral load rebound 12 weeks after ART interruption was then analyzed to assess immune control. Fifty-two subjects reached the study end point. ALVAC recipients had 0.5 log(10) lower virologic rebounds (P=.033). IL-2 plus vaccine boosted CD4(+) T cell counts (P<.001) but did not diminish viral rebound. Significant changes were not detected for HIV-specific lymphoproliferative responses in any arm. This exploratory protocol provides useful clinical data for future therapeutic immunization trial design.     

Expression of CD56 is an unfavorable prognostic factor for acute promyelocytic leukemia with higher initial white blood cell counts

Expression of CD56 has recently been introduced as one of the adverse prognostic factors in acute promyelocytic leukemia (APL). However, the clinical significance of CD56 antigen in APL has not been well elucidated. We assessed the clinical significance of CD56 antigen in 239 APL patients prospectively treated with all‐trans retinoic acid and chemotherapy according to the Japan Adult Leukemia Study Group APL97 protocol. All patients were prospectively treated by the Japan Adult Leukemia Study Group APL97 protocol. The median follow‐up period was 8.5 years. Positive CD56 expression was found in 23 APL patients (9.6%). Expression of CD56 was significantly associated with lower platelet count (P = 0.04), severe disseminated intravascular coagulation (P = 0.04), and coexpression of CD2 (P = 0.03), CD7 (P = 0.04), CD34 (P < 0.01) and/or human leukocyte antigen‐DR (P < 0.01). Complete remission rate and overall survival were not different between the two groups. However, cumulative incidence of relapse and event‐free survival (EFS) showed an inferior trend in CD56⁺ APL (P = 0.08 and P = 0.08, respectively). Among patients with initial white blood cell counts of 3.0 × 10⁹/L or more, EFS and cumulative incidence of relapse in CD56⁺ APL were significantly worse (30.8% vs 63.6%, P = 0.008, and 53.8% vs 28.9%, P = 0.03, respectively), and in multivariate analysis, CD56 expression was an unfavorable prognostic factor for EFS (P = 0.04). In conclusion, for APL with higher initial white blood cell counts, CD56 expression should be regarded as an unfavorable prognostic factor.     

Prophylaxis and therapy of central nervous system involvement in adult acute lymphoblastic leukemia: recommendations of the Polish Adult Leukemia Group

The central nervous system (CNS) is one of the most frequent extramedullary locations of adult acute lymphoblastic leukemia (ALL), affecting approximately 5% of patients at diagnosis. T-lineage ALL, high initial leukocyte counts and mediastinal involvement are the predisposing factors. In case of relapse, if no prophylaxis was administered, the rate of CNS involvement reaches 30-50%. As the prognosis of patients with isolated or mixed CNS relapse is particularly poor, adequate prophylaxis seems critical. The treatment comprises intrathecal cytostatics, cranial and spinal cord irradiation, as well as systemic chemotherapy including agents penetrating to the CNS. This strategy allows a reduction in CNS relapses to less than 5% of cases. Compliance to the prophylactic protocols should be one of the principles in the treatment of adult ALL.