ABSTRACT
Histone H4 acetylation was examined by immunohistochemistry in patients with acute lymphocytic leukaemia (ALL) in first relapse. Univariate and multivariate models identified correlates of complete remission (CR) and overall survival (OS). No variables were associated with achievement of CR. In multivariate analysis, weak histone H4 acetylation [Hazard Ratio (HR) 2·20, 95% confidence interval (CI) 0·93-5·23, P=0·07], shorter interval from diagnosis to relapse (<9 vs. 9-24 vs. >24 months) (HR 1·82, 95% CI 1·20-2·75, P= 0·005), and central nervous system involvement (HR 3·43, 95% CI 1·31-8·99, P=0·01) were independent poor prognostic factors for OS. These data provide a rationale for the use of histone deacetylase inhibitors in the treatment of relapsed ALL.
Subject(s)
Biomarkers, Tumor/metabolism , Histones/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Acetylation , Adult , Aged , Epidemiologic Methods , Female , Humans , Male , Middle Aged , Prognosis , Recurrence , Young AdultABSTRACT
BACKGROUND: Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS). METHODS: Patients > or = 18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis. RESULTS: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis. CONCLUSIONS: These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.
Subject(s)
Histones/metabolism , Neoplasm Recurrence, Local/metabolism , Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism , Acetylation , Adolescent , Adult , Biopsy , Blotting, Western , Bone Marrow/drug effects , Bone Marrow/metabolism , Butyrates/pharmacology , Cells, Cultured , Humans , Immunoenzyme Techniques , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Prognosis , Remission Induction , Survival Rate , Young AdultABSTRACT
The outcome of patients with acute lymphoblastic leukemia (ALL) in first relapse is poor. We retrospectively evaluated patients with ALL in first relapse, 18-60 years of age, to define a prognostic score. For all patients, a scoring system of 0-3 was developed with 1 point for each of the following: age at diagnosis >or=45 years, lactate dehydrogenase (LDH) at the time of relapse >or=1.5 times upper limits of normal (ULN), not proceeding to allogeneic bone marrow transplant (BMT). A similar scoring system was developed for patients proceeding to BMT. LDH >or=1.5 times ULN at the time of relapse predicted poor overall survival. Patients with a prognostic score of greater than 1 have a poor prognosis, even with BMT, and should be considered for treatment with innovative approaches such as Phase 1 clinical trials.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis , Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Adult , Female , Humans , L-Lactate Dehydrogenase/metabolism , Male , Medical Oncology/methods , Middle Aged , Neoplasm Recurrence, Local/diagnosis , Neoplasm Recurrence, Local/pathology , Neoplasm Staging/methods , Prognosis , Recurrence , Retrospective Studies , Treatment OutcomeABSTRACT
We evaluated patients with newly diagnosed ALL treated at the Cleveland Clinic during the years 1996 through 2005. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of complete remission, overall survival and progression-free survival. On univariate analysis, significant prognostic factors included: age at diagnosis (per 10-year increase), poor risk cytogenetics, time to white blood count recovery, and time from induction chemotherapy (IC) to post-remission therapy (PRT). In patients age <60 years without poor risk cytogenetics, time from IC to PRT (per week increase) was a significant prognostic factor by multivariate analysis and was associated with a decreased progression-free survival [HR 1.27, CI (1.04-1.55), p = 0.019] and decreased overall survival [HR 1.34, CI (1.08-1.67), p = 0.009]. Delayed time from IC to PRT (> or =6.6 weeks) was associated with a statistically worse progression-free and overall survival.
