Clofarabine and Adult Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a clonal, malignant disease of hematopoietic tissues that is characterized by accumulation of abnormal blast cells, principally in the marrow and impaired production of normal blood cells. The unsatisfactory clinical outcomes of AML patients urged the development of new therapy strategies, one of which includes the implementation of new nucleoside analogs. Clofarabine has offered new promising perspectives within induction and consolidation therapies. This chapter will evaluate the efficacy and tolerability of clofarabine as a single agent and in combination therapy, including hematopoietic stem cell transplantation, for AML patients

The Role of <em>BAALC</em> Gene in the Transformation of Myeloid Progenitor Cells to Acute Myeloid Leukemia

One of the unanswered questions in hematology is the question concerning disorders in the regulation of gene expression in different subtypes of acute myeloid leukemia (AML), leading to changes in the functional activity of certain genes and acting as a component of a series of events in the leukemogenesis. One example of such a gene is BAALC gene (brain and acute leukemia and cytoplasmic), localized in chromosome 8, which plays a role in the regulation of myeloid progenitors’ differentiation. This role is associated with several other oncogenes, such as HoxA9, ERK, and RUNX1. Gene interactions determine normal proliferation and differentiation of cells, and any disturbances could lead to leukemic development. What is the role of BAALC in normal/impaired balance? What are the connections of BAALC with the mutations established in AML: FLT3, NPM1, etc.? What are the correlations of its overexpression with clinical and laboratory findings in AML patients? What are the changes in the expression of BAALC, after successful therapy of AML and after therapy failure? Can we use it as a predictive marker in AML patients? This chapter summarizes available data about functions of BAALC gene, the frequency of overexpression, and its importance as a predictive marker in the development of AML

Acute myeloid leukemia associated with rapid acquisition of FLT3-internal tandem duplications, ecotropic virus integration site-1 and Wilms′ tumor 1 genes overexpression 4 months after an intermediate-risk myelodysplastic syndrome diagnosis

The myelodysplastic syndromes (MDS) are heterogeneous diseases with the different time period of progression to acute myeloid leukemia (AML). We report a case of a 38-year-old male with intermediate risk MDS, presence of normal karyotype and no expression of FLT3-internal tandem duplications (ITD), ecotropic virus integration site-1 (EVI-1) and Wilms′ tumor 1 (WT1). Four months later, overt AML was diagnosed. The presence of normal karyotype was once again observed, but the molecular analysis revealed FLT3-ITD presence and over-expression of WT1 and EVI-1 genes. Complete remission was achieved after high-dose induction chemotherapy, and high-dose cytarabine consolidation was carried out. Three months later a relapse with a fatal outcome occurred. The case is the first report of a quick MDS progression to AML within 4 months due to rapid acquisition of several molecular abnormalities. This case suggests that frequent molecular screening for relevant genetic abnormalities might be useful for early detection of disease progression, particularly in normal karyotype cases

Absolute Monocyte and Platelet Counts May Provide Additional Prognostic Information in Primary Gastric Diffuse Large B-cell Lymphoma Patients Treated with Rituximab and CHOP

Introduction: Primary gastric diffuse large B cell lymphoma (PG-DLBCL) is the most common histological subtype of primary gastric lymphoma. The standard of care of PG-DLBCL patients is the combination rituximab-based immunochemotherapy (R-CHOP). Re-cently, different host-related factors have been shown to have significant prognostic significance in non-Hodgkin lymphoma. However, data regarding their prognostic contribution to PG-DLBCL are limited. Aim: To assess the prognostic impact of a panel of simple, cost-effective laboratory variables which are easy to apply in routine labora-tory use for R-CHOP-treated PG-DLBCL patients in an attempt to identify those among them that are high-risk category.Materials and methods: We retrospectively assessed the possible prognostic impact of different laboratory markers in 42 R-CHOP treated PG-DLBCL patients treated between 2004 and 2014 and followed at a single institution.Results: The estimated 5-year overall (OS) and progression-free survival (PFS) of the whole group were 80.9% and 78%, respectively. The absolute monocyte and platelet counts in univariate analysis predicted PFS and OS when analyzed as continuous and dichotomized variables. On multivariate analysis performed with factors included in the stage-modified International Prognostic Index (m-IPI), the absolute monocyte and platelet counts remained independent predictors of PFS and OS. Therefore, the absolute monocyte and platelet counts were combined to generate a prognostic index that identified patients with an especially poor overall survival. Conclusions: This prognostic index was independent of the m-IPI and could provide additional prognostic information for better stratification of these patients

Secondary acute myeloid leukemia and de novo acute myeloid leukemia with myelodysplasia-related changes - close or complete strangers?

Aim: To compare the main features of patients with secondary acute myeloid leukemias (AMLs) after post-myelodysplastic syndrome (AML-post-MDS) or post-myeloproliferative neoplasms (AML-post-MPN) and myeloid blast crisis of chronic myeloid leukemia (CML-BC) vs. de novo AMLs with myelodysplastic characteristics (dn-AML-MDS). Materials and methods: Bone marrow/peripheral blood samples of 94 patients with secondary AMLs (30 with AML-post-MDS, 20 with AML-post-MPN, and 14 with CML-BC) and 30 with dn-AML-MDS were included. Demographic, morphological, phenotypic, cytogenetic, and survival data were analyzed. Results: Comparative analysis showed no differences in sex and age, except for the younger age in CML-BC (p=0.005). Leukocytosis was a prevalent feature of CML-BC vs. AML-post-MPN, AML-post-MDS and dn-AML-MDS (p<0.001). At leukemia onset, thrombocytopenia was characteristic of AML-post-MDS and dn-AML-MDS whereas normal PLT counts were found in AML-post-MPN and CML-BC (p=0.001). Dysplasia in ≥2 lineages was observed in almost all dn-AML-MDS (96.8%) and AML-post-MDS (100%) compared to AML-post-MPN (33.3%) and none of the CML-BC (p=0.001). Aberrant co-expression of 1-4 lymphoid-associated markers was detected in 67.5% of all patients, including CD7, CD19, CD56, and CD22. We found chromosome aberrations in 57.8% of patients, more frequently in dn-AML-post-MDS than in AML-post-MPN, CML-BC, and AML-post-MDS. While NPM1 mutations distribution was similar in the two MDS-related AML groups, FLT3-ITD was higher in AML-post-MDS (26.3%) than in dn-AML-MDS (4.5%) (p=0.049). Regarding EVI1, CML-BC (80%) and AML-post-MPN (37.5%) showed higher incidence of gene overexpression compared to AML-post-MDS (13.3%) and dn-AML-MDS (5.0%) (p=0.001). Median time to leukemia was significantly shorter in AML-post-MDS (4.80±1.04 months) than in AML-post-MPN (20.3±2.86 months) and CML-BC (34.7±16.3 months) (p=0.008), and median overall survival was poor in all groups. Conclusions: Similarities and differences between patients with secondary AMLs may represent different biology which translates into different clinical course and may require different therapeutic approach in future

NPM1 Gene Type A Mutation in Bulgarian Adults with Acute Myeloid Leukemia: A Single-Institution Study

OBJECTIVE: Mutations of the nucleophosmin (NPM1) gene are considered as the most frequent acute myeloid leukemia (AML)- associated genetic lesion, reported with various incidences in different studies, and type A (NPM1-A) is the most frequent type. However, since most series in the literature report on the features of all patients regardless of the type of mutation, NPM1-A(+) cases have not been well characterized yet. Therefore, we evaluated the prevalence of NPM1-A in Bulgarian AML patients and searched for an association with clinical and laboratory features. METHODS: One hundred and four adults (51 men, 53 women) were included in the study. NPM1-A status was determined using allele-specific reverse-transcription polymerase chain reaction with co-amplification of NPM1-A and β-actin and real-time quantitative TaqMan-based polymerase chain reaction. Patients received conventional induction chemotherapy and were followed for 13.2±16.4 months. RESULTS: NPM1-A was detected in 26 (24.8%) patients. NPM1-A mutation was detected in all AML categories, including in one patient with RUNX1-RUNX1T1. There were no differences associated with the NPM1-A status with respect to age, sex, hemoglobin, platelet counts, percentage of bone marrow blasts, splenomegaly, complete remission rates, and overall survival. NPM1-A(+) patients, compared to NPM1-A(-) patients, were characterized by higher leukocyte counts [(75.4±81.9)x109/L vs. (42.5±65.9)x109/L; p=0.049], higher frequency of normal karyotype [14/18 (77.8%) vs. 26/62 (41.9%); p=0.014], higher frequency of FLT3-ITD [11/26 (42.3%) vs. 8/77 (10.4%); p=0.001], and lower incidence of CD34(+) [6/21 (28.8%) vs. 28/45 (62.2%); p=0.017]. Within the FLT3-ITD(-) group, the median overall survival of NPM1-A(-) patients was 14 months, while NPM1-A(+) patients did not reach the median (p=0.10). CONCLUSION: The prevalence of NPM1-A mutation in adult Bulgarian AML patients was similar to that reported in other studies. NPM1-A(+) patients were characterized by higher leukocyte counts, higher frequency of normal karyotypes and FLT3- ITD, and lower incidence of CD34(+), supporting the idea that the specific features of type A mutations might contribute to the general clinical and laboratory profile of NPM1(+) AML patients