A New Paradigm of Cardio-Hematological Monitoring in Chronic Myeloid Leukemia Patients Treated With Tyrosine Kinase Inhibitors.

Significant progress has been achieved in treating patients with onco-hematological diseases, including chronic myeloid leukemia (CML). This is primarily associated with the development of targeted therapy involving tyrosine kinase inhibitors (TKIs), such as imatinib, nilotinib, bosutinib, dasatinib, and ponatinib. Along with the increased survival of patients with CML, special attention has recently been paid to cardiovascular complications in CML patients due to the prevalence of cardiovascular diseases in the general population and the toxicity profile of targeted drugs. This article presents the strategy for reducing cardiovascular risk in CML patients treated with TKIs. We discuss the components of cardiovascular risk in CML patients and the findings of current studies. Current data confirm the increased cardiovascular risk in the CML population compared to the general population, which necessitates the widespread introduction of cardiovascular prevention strategies in CML patients. The pharmacokinetics and pharmacodynamics of TKIs on the cardiovascular system are discussed. We propose two main approaches in the strategy of cardiovascular risk prevention in patients with CML, namely, before the start of TKI administration and during TKI treatment. This article presents the diagnostic assessment before prescribing TKIs, as well as while monitoring TKI therapy, and discusses the features of the choice of TKIs depending on patients' general and cardiovascular comorbidity. Emphasis is placed on the risk stratification in patients with CML following general population algorithms, lifestyle modifications, and statin therapy for achieving the target levels of cardiovascular indicators. We also discuss unsolved questions in the current clinical guidelines and ways to further develop a cardiovascular risk-reducing strategy for CML patients.

The signs of negative selection in IGHV framework regions are associated with worse overall survival of chronic lymphocytic leukemia patients.

The mutational status of the variable region of the immunoglobulin heavy chain (IGHV) genes remains the most significant prognostic factor in chronic lymphocytic leukemia (CLL) patients. However, the groups of mutated (M) and unmutated (UM) patients are also heterogeneous, and additional markers are used for a more accurate prognosis. The aim of our work was to determine the prognostic value of the signs of antigen selection determined by BASELINe statistics in M IGHV sequences of CLL patients. Clinical data, IGHV gene configuration, TP53, NOTCH1, SF3B1 mutations were analyzed in 127 CLL patients with M IGHV sequences. The median OS of patients with negative selection in the framework regions (FWRs) of IGHV genes was 120 months compared to 202 month in other CLL patients (P = 0.016). In multivariate Cox regression analysis Binet stage C vs A + B (P < 0.0001), SF3B1 mutations (P < 0.0001), negative selection in the FWRs (HR P = 0.007), and age ≥65 years (P = 0.034) were powerful adverse prognostic factors for OS in CLL patients with M IGHV genes. These preliminary data suggest that the signs of antigen-driven selection may be used as a prognostic factor in CLL patients with M IGHV genes in combination with other markers.

Cancers after Chornobyl: From Epidemiology to Molecular Quantification.

An overview and new data are presented from cancer studies of the most exposed groups of the population after the Chornobyl accident, performed at the National Research Center for Radiation Medicine (NRCRM). Incidence rates of solid cancers were analyzed for the 1990-2016 period in cleanup workers, evacuees, and the general population from the contaminated areas. In male cleanup workers, the significant increase in rates was demonstrated for cancers in total, leukemia, lymphoma, and thyroid cancer, as well as breast cancer rates were increased in females. Significantly elevated thyroid cancer incidence was identified in the male cleanup workers cohort (150,813) in 1986-2012 with an overall standardized incidence ratio (SIR) of 3.35 (95% CI: 2.91-3.80). A slight decrease in incidence rates was registered starting at 25 years after exposure. In total, 32 of 57 deaths in a group of cleanup workers with confirmed acute radiation syndrome (ARS) or not confirmed ARS (ARS NC) were due to blood malignancies or cancer. Molecular studies in cohort members included gene expression and polymorphism, FISH, relative telomere length, immunophenotype, micronuclei test, histone H2AX, and TORCH infections. Analysis of chronic lymphocytic leukemia (CLL) cases from the cohort showed more frequent mutations in telomere maintenance pathway genes as compared with unexposed CLL patients.

Novel Score-based Decision Approach in Chronic Myeloid Leukemia Patients After Acute Toxic Imatinib-induced Liver Injury.

The tyrosine kinase inhibitor (TKI) imatinib in rare cases can cause acute toxic hepatitis, hepatic failure, and death. Currently, the choice of further chronic myeloid leukemia (CML) therapy in patients after acute hepatotoxicity is still a difficult question, which requires a complex individual approach based on the clinical guidelines of adverse event management. Data about the further follow-up strategy approach in patients with CML after acute toxic imatinib-induced liver injury are of concern, and at times controversial. In addition, one of the questions is about the necessity and safety of the imatinib therapy resumption after acute hepatotoxicity. In some publications, imatinib resumption without the recurrence of hepatotoxicity has been discussed; in others, imatinib resumption with the recurrence of imatinib hepatotoxicity has been mentioned. There are a few publications about the experience of administration of the second-line TKIs after acute imatinib hepatotoxicity. There are no clear data on which factors the physician's decision should be based on in patients with CML after acute toxic imatinib-induced liver injury. Imatinib should be restarted or withdrawn, when and for whom second-line therapy should be started. The physician's decision is usually based on the published data of similar cases, personal experience, and the severity of hepatotoxicity. We have discussed the clinical guidelines devoted to the peculiarities of the patient's management after acute toxic imatinib-induced hepatitis and main strategy approaches. A complex score-based decision algorithm for choosing the further strategy approach after acute toxic imatinib-induced hepatitis in patients with CML has been presented. The following parameters should be assessed: the grade of hepatotoxicity reaction, the presence of liver transplantation or imatinib-induced liver cirrhosis and its possible pathogenetic mechanism, the presence of early molecular response (EMR) to imatinib therapy defined as three-month BCR-ABL1 ≤10% according to the international scale (BCR-ABL1IS ) or/and six-month BCR-ABL1 IS <1%; and the presence of the offender concomitant drug that probably caused the drug interaction with imatinib and the presence of viral hepatitis reactivation identified by polymerase chain reaction (PCR).

Сase Report of Acute Toxic Imatinib-induced Hepatitis in a Patient with Chronic Myeloid Leukemia, Sulfa Allergy, and Rheumatoid Arthritis.

The introduction of imatinib has substantially changed the approaches to the therapy of chronic myeloid leukemia. However, this drug can cause hepatic failure and death in rare cases. This report describes a clinical case of acute, toxic imatinib-induced hepatitis in a 56-year-old woman with chronic myeloid leukemia and concomitant sulfa allergy and rheumatoid arthritis. The patient developed acute imatinib-induced hepatitis after three months of treatment with imatinib and three days after increasing the imatinib dosage from 400 mg per day to 600 mg per day, resolving within three months after imatinib discontinuation and prednisolone administration. This confirms the necessity of great caution during imatinib therapy and the monitoring of liver tests. Approximately 25 reports about clinical cases of imatinib-induced hepatitis have been published up to the present.

Epidemiology of Late Health Effects in Ukrainian Chornobyl Cleanup Workers.

This article summarizes the results of 30 y of follow-up of cancer and noncancer effects in Ukrainian cleanup workers after the Chornobyl accident. The number of power plant employees and first responders with acute radiation syndrome under follow-up by the National Research Center for Radiation Medicine decreased from 179 in 1986-1991 to 105 in 2011-2015. Cancers and leukemia (19) and cardiovascular diseases (21) were the main causes of deaths among acute radiation syndrome survivors (54) during the postaccident period. Increased radiation risks of leukemia in the Ukrainian cohort of 110,645 cleanup workers exposed to low doses are comparable to those among survivors of the atomic bomb explosions in Japan in 1945. Additionally, an excess of chronic lymphocytic leukemia was demonstrated in the cleanup workers cohort for 26 y after the exposure. A significant excess of multiple myeloma incidence [standardized incidence rate (SIR) 1.61 %, 95% confidence interval (CI) 1.01-2.21], thyroid cancer (SIR 4.18, 95% CI 3.76-4.59), female breast cancer (SIR 1.57 CI 1.40-1.73), and all cancers combined (SIR 1.07; 95% CI 1.05-1.09) was registered. High prevalence was demonstrated for cardio- and cerebrovascular diseases and mental health changes. However, the reasons for the increases require further investigation. To monitor other possible late effects of radiation exposure in Chornobyl cleanup workers, analytical cohort and case-control studies need to include cardiovascular pathology, specifically types of potentially radiogenic cancers using a molecular epidemiology approach. Possible effects for further study include increased rates of thyroid, breast, and lung cancers and multiple myeloma; reduction of radiation risks of leukemia to population levels; and increased morbidity and mortality of cleanup workers from cardio- and cerebrovascular pathology.

Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation-exposed Chornobyl cleanup workers.

BACKGROUND: Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR-CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. METHODS: A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). RESULTS: Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival. CONCLUSIONS: No significant enrichment in copy-number abnormalities at CLL-associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation.

Clinical relevance of TP53 polymorphic genetic variations in chronic lymphocytic leukemia.

OBJECTIVES: To analyze the distribution of single nucleotide polymorphisms (SNPs) in the TP53 gene in chronic lymphocytic leukemia (CLL) patients and to evaluate their associations with clinical behavior of the disease. METHODS: SNPs in exons and parts of adjacent introns of the TP53 gene were analyzed in 235 CLL patients observed during 2005-2012 years. Data on individuals of European descent from the 1000 Genomes Project data set were used as a reference. RESULTS: In the recessive model of inheritance, we found borderline associations between CLL risk and C/C genotype of rs1642785 (p=0.048); G/G genotype of rs2909430 (in men only; p=0.036) and Pro72Pro genotype of rs1042522 (in men only; p=0.045). Risk of CLL was increased also in carriers of rare haplotypes (p=0.0049). Besides, genotypes Pro72Pro of rs1042522, C/C of rs1642785, and G/G of rs2909430 were associated with an increased incidence of TP53 mutations. Median of overall survival in rs1800372 carriers was comparable to that of patients with TP53 mutations. Other evaluated SNPs were not associated with survival. CONCLUSION: Our data suggest that some TP53 variants may affect the risk of CLL. rs1800372 polymorphism might be the marker of unfavorable prognosis of the disease.

Chronic Lymphocytic Leukemia in Chornobyl Cleanup Workers.

This paper describes the chronic lymphocytic leukemia (CLL) incidence in a cohort of 110,645 (enlarged later to 152,520) male Ukrainian cleanup workers of the Chornobyl (Chernobyl) accident who were exposed to a range of radiation doses over the 1986-1990 time period. The standardized incidence rates are presented for a 27-y period after the exposure. For 2007-2012 period, the authors have identified the incident CLL cases in an enlarged cohort of 152,520 persons by linkage of the cohort file with the Ukrainian National Cancer Registry (NCRU). CLL data for the previous period (1987-2006) were identified in a frame of the Ukrainian-American leukemia study in the original cohort of 110,645 male clean-up workers. A significant CLL incidence excess was shown for the entire study period 1987-2012, with more prominent levels for the earliest years (1987-1996) when the standardized incidence rate (SIR) value was estimated to be 3.61 with 95% confidence interval from 2.32 to 4.91. In 2007-2012, the CLL incidence decreased substantially but still exceeded the national level although not significantly. In parallel, the several studies were performed at the National Research Center for Radiation Medicine (NRCRM) to explore if any clinical and cytogenetic features of CLL existed in the clean-up workers. The clinical study included 80 exposed and 70 unexposed CLL cases. Among the major clinical differences of the CLL course in the clean-up workers were a shorter period of white blood cells (WBC) doubling (10.7 vs. 18.0; p<0.001), frequent infectious episodes, lymphoadenopathy and hepatosplenomegaly (37 vs. 16), higher expression for CD38, and lower expression for ZAP-70 antigen.

A phase 2 study of the BH3 mimetic BCL2 inhibitor navitoclax (ABT-263) with or without rituximab, in previously untreated B-cell chronic lymphocytic leukemia.

We evaluated the safety and biologic activity of the BH3 mimetic protein, navitoclax, combined with rituximab, in comparison to rituximab alone. One hundred and eighteen patients with chronic lymphocytic leukemia (CLL) were randomized to receive eight weekly doses of rituximab (arm A), eight weekly doses of rituximab plus daily navitoclax for 12 weeks (arm B) or eight weekly doses of rituximab plus daily navitoclax until disease progression or unacceptable toxicity (arm C). Investigator-assessed overall response rates (complete [CR] and partial [PR]) were 35% (arm A), 55% (arm B, p = 0.19 vs. A) and 70% (arm C, p = 0.0034 vs. A). Patients with del(17p) or high levels of BCL2 had significantly better clinical responses when treated with navitoclax. Navitoclax in combination with rituximab was well tolerated as initial therapy for patients with CLL, yielded higher response rates than rituximab alone and resulted in prolonged progression-free survival with treatment beyond 12 weeks.

CD38 gene polymorphism and risk of chronic lymphocytic leukemia.

rs6449182 CD38 gene polymorphism was determined by polymerase chain reaction with restriction of products in 328 chronic lymphocytic leukemia (CLL) patients and 271 age- and sex-matched controls. An association between GG genotype and CLL risk was found in the whole group of patients (OR=2.12; p=0.009) and in patients with unmutated immunoglobulin heavy chain variable genes (OR=2.17; p=0.011) comparing to the controls. In the subgroup of 174 controls with evaluated lipids the genotype distributions in CLL patients and dyslipidemic controls were similar. An association between GG genotype and CLL risk was significant compared to controls without lipids' abnormalities (OR=3.92; p=0.006).

DNA repair polymorphisms in B-cell chronic lymphocytic leukemia in sufferers of Chernobyl Nuclear Power Plant accident.

An association between DNA repair gene polymorphisms, environmental factors, and development of some types of cancer has been suggested by several studies. Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in the clean-up workers of the Chernobyl Nuclear Power Plant (NPP) accident and it has some specific features. Therefore, we have studied the possible differences in DNA repair gene polymorphisms in CLL patients depending on ionizing radiation (IR) exposure history and their clinical characterictics. Arg399Gln XRCC1, Thr241Met XRCC3, and Lys751Gln XPD polymorphisms were studied in 64 CLL patients, exposed to IR due to the Chernobyl NPP accident, 114 IR-non-exposed CLL patients, and 103 sex- and age-matched IR-exposed controls using polymerase chain reaction-restriction fragment-length polymorphism analysis. All investigated polymorphisms were equally distributed between two groups of CLL patients and IR-exposed controls, except that that there was a significant reduction of the common homozygous Lys/Lys XPD genotype among IR-exposed CLL patients (23.7%) compared with IR-exposed controls (45.6%), OR = 0.37; 95% CI = 0.18-0.75; (P = 0.005). The number of IR-non-exposed CLL patients (37.4%) with the Lys/Lys XPD genotype was also decreased compared to IR-exposed controls, although this difference was not significant (P = 0.223). These preliminary data suggest a possible modifying role of Lys751Gln XPD polymorphism for the development of CLL, expecially in radiation-exposed persons.

Molecular and clinical features of chronic lymphocytic leukemia with stereotyped B-cell receptors in a Ukrainian cohort.

A fraction of chronic lymphocytic leukemia (CLL) carries highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity-determining region-3 (HCDR3), often associated with a restricted selection of IG(K/L)V light chains. We analyzed the features of CLL expressing homologous HCDR3 in a cohort of 264 Ukrainian patients by merging them with a recently published reference series of 1426 cases. This approach allowed us to identify 96/264 (36%) cases as expressing homologous HCDR3, subdivided into 47 subsets. Among these, 27 apparently novel subsets were identified, although most of them were composed of two sequences per subset ('potential subsets'). CLL cases belonging to several stereotyped subsets showed HCDR3 homologies with various autoreactive clones. Our analysis identified molecular and clinical features of a Ukrainian cohort of patients with CLL.

Chronic lymphocytic leukemia patients exposed to ionizing radiation due to the Chernobyl NPP accident--with focus on immunoglobulin heavy chain gene analysis.

Clinical data and immunoglobulin variable heavy chain (IgVH) gene configuration were analyzed in 47 CLL patients, exposed to ionizing radiation (IR) due to Chernobyl NPP accident, and 141 non-exposed patients. Clean-up workers of the second quarter of 1986 (n=19) were picked out as separate group with the highest number of unmutated cases (94.4%), increased usage of IgVH1-69 (33.3%) and IgVH3-21 (16.7%) genes, high frequency of secondary solid tumors (6 cases) and Richter transformation (4 cases). These preliminary data suggest that CLL in the most suffered contingent due to Chernobyl NPP accident might have some specific features.