Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients

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 >= 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

Outcomes of Allogeneic Hematopoietic Cell Transplantation in Children and Young Adults with Chronic Myeloid Leukemia: A CIBMTR Cohort Analysis

Chronic myeloid leukemia (CML) in children and young adults is uncommon. Young patients have long life expectancies and low morbidity with hematopoietic cell transplantation (HCT). Prolonged tyrosine kinase inhibitor (TKI) use may cause significant morbidity. In addition indication for HCT in patients in first chronic phase is not established

The Mutational Landscape in Chronic Myelomonocytic Leukemia and Its Impact on Allogeneic Hematopoietic Cell Transplantation Outcomes: A Center for Blood and Marrow Transplantation Research (CIBMTR) Analysis

Somatic mutations are recognized as an important prognostic factor in chronic myelomonocytic leukemia (CMML). However, limited data are available regarding their impact on outcomes after allogeneic hematopoietic cell transplantation (HCT). In this registry analysis conducted in collaboration with the Center for International Blood and Marrow Transplantation Registry database/sample repository, we identified 313 adult patients with CMML (median age: 64 years, range, 28- 77) who underwent allogeneic HCT during 2001-2017 and had an available biospecimen in the form of a peripheral blood sample obtained prior to the start of conditioning. In multivariate analysis, a CMML-specific prognostic scoring system (CPSS) score of intermediate-2 (HR=1.46, P=0.049) or high (HR=3.22, P=0.0004) correlated significantly with overall survival. When the molecularly informed CPSS-Mol prognostic model was applied, a high CPSS-Mol score (HR=2 P=0.0079) correlated significantly with overall survival. The most common somatic mutations were in ASXL1 (62%), TET2 (35%), KRAS/NRAS (33% combined), and SRSF2 (31%). DNMT3A and TP53 mutations were associated with decreased overall survival (HR=1.70 [95% CI: 1.11-2.60], P=0.0147 and HR=2.72 [95% CI: 1.37-5.39], P=0.0042, respectively) while DNMT3A, JAK2, and TP53 mutations were associated with decreased disease-free survival (HR=1.66 [95% CI: 1.11-2.49], P=0.0138, HR=1.79 [95% CI: 1.06-3.03], P=0.0293, and HR=2.94 [95% CI: 1.50-5.79], P=0.0018, respectively). The only mutation associated with increased relapse was TP53 (HR=2.94, P=0.0201). Nonetheless, the impact of TP53 mutations specifically should be interpreted cautiously given their rarity in CMML. We calculated the goodness of fit measured by Harrell\u27s C-index for both the CPSS and CPSS-Mol, which were very similar. In summary, via registry data we have determined the mutational landscape in patients with CMML who underwent allogeneic HCT, and demonstrated an association between CPSS-Mol and transplant outcomes although without major improvement in the risk prediction beyond that provided by the CPSS

The role of post-remission chemotherapy for older patients with acute myelogenous leukemia

Standard practice in older patients with acute myeloid leukemia (AML) is induction chemotherapy (ICT) followed by post-remission chemotherapy (PRT). We previously reported a median disease-free survival (DFS) and overall survival (OS) for patients in complete remission (CR) of 7.5 and 13.5 months, respectively, in 30 older patients treated with standard ICT and PRT (study A). We designed a subsequent trial excluding PRT (study B). Forty patients with AML age 60 years were treated with ICT consisting of standard dose cytosine arabinoside and mitoxantrone followed with granulocyte-macrophage colony-stimulating factor subcutaneously starting day 11 if the bone marrow aspirate and biopsy was hypocellular. Median age was 68 years. Myelodysplasia preceded AML in 37% of patients. Favourable, normal, and unfavourable karyotypes were seen in 7.5%, 55%, and 37.5% of patients, respectively. Twenty-one patients (52.5%) achieved CR. Median DFS and OS for patients in CR were 6.2 and 10.8 months, respectively. Study A and B differed by the addition of PRT in study A. However, DFS and OS did not differ significantly between patients treated in study A or study B (P = 0.21 and P = 0.15, respectively). PRT has not clearly improved survival in older patients with AML, and therefore the routine addition of chemotherapy to older patients in complete remission is not indicated

Chemotherapy-Related Amenorrhea (CRA) among Premenopausal Patients Treated for Acute Leukemia

Abstract Background: Little is known about the late effects of treatment for acute leukemia on ovarian function. We sought to evaluate the rate of long-term chemotherapy-related amenorrhea (CRA) among premenopausal women treated for acute leukemia. Methods: The Cleveland Clinic database of patients treated for acute leukemia between July 1994 and July 2005 was searched for patients aged 15–44 at diagnosis who were believed to be alive. Thirty of 69 identified patients were excluded due to active disease, on-going treatment or lost to follow-up. Questionnaires regarding menstrual and fertility history were mailed to the remaining 39 patients. Results: Twenty-five patients responded to the questionnaire, 4 of whom were excluded due to lack of menses at the time of diagnosis (n=2), use of Depo-provera at time of diagnosis (n=1) or use of Depo-provera at time of f/u (n=1). The median age of the remaining 21 patients was 30 (range 15 to 44). Thirteen patients had AML and 8 had ALL. Nine of the 21 had undergone myeloablative transplant, 8 allogeneic and 1 autologous. Median f/u time from treatment was approximately 43 months (range 9 to 141). Long-term CRA occurred in 8/21 patients (38%). Only 2/12 patients (17%) who received standard-dose chemotherapy alone had persistent CRA while 6/9 (67%) of those undergoing transplant had persistent CRA (p=0.032, Fisher’s Exact test). The incidence of CRA increased with age: 0/3 patients under age 18, 1/4 patients age 18–25, and 7/14 patients age 26–44 at treatment remained amenorrheic (p=0.042, 1-sided Cochran-Armitage test). Only 2 patients reported attempts at fertility following treatment. One patient reported delivering three children, the other patient was amenorrheic and was undergoing fertility treatment. Conclusions: These findings suggest that a substantial minority of young survivors of acute leukemia will experience premature ovarian failure. Increasing age at treatment and transplant are associated with a greater risk of long-term CRA