Thyroid autoimmunity and hypothyroidism are associated with deep molecular response in patients with chronic myeloid leukemia on tyrosine kinase inhibitors

Abstract Purpose: Thyroid alterations including de novo appearance of thyroid autoimmunity are adverse efects of tyrosine kinase inhibitors, used in solid and hematologic cancer therapy, but the relationship between thyroid alterations during this treatment and the outcome of chronic myeloid leukemia remains unclear. Aim of this study was to investigate whether the presence of thyroid alterations may afect the clinical outcome of chronic myeloid leukemia on tyrosine kinase inhibitors. Methods: We evaluated thyroid function and autoimmunity in 69 chronic myeloid leukemia patients on long-term therapy looking at the association between thyroid abnormalities and disease molecular response. Results: Overall, 24 of 69 (34.8%) had one or more thyroid abnormalities during therapy. A high percentage of patients (21/69, 30.4%) showed thyroid autoimmunity (positive thyroid autoantibodies with ultrasound hypoechogenicity), while clinical and subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, found in 4 of 69 (5.8%) and 3 of 69 (4.3%) of cases. Second-generation tyrosine kinase inhibitors resulted signifcantly associated (14/32, 43.7%) with Hashimoto’s thyroiditis, compared to frst generation (7/37, 18.9%; p=0.03). Interestingly, we also found a signifcant association between euthyroid (14/26, 53.8%) and hypothyroid Hashimoto’s thyroiditis (4/26, 15.4%) in patients with deep molecular response, as compared to euthyroid (3/43, 7%; p=0.0001) and hypothyroid (0/43, 0%; p=0.02) Hashimoto’s thyroiditis patients with major molecular response. Conclusions: Our study confrms and extends our knowledge on the tyrosine kinase inhibitors efects on thyroid, showing that thyroid autoimmunity is frequently observed in chronic myeloid leukemia patients on long-term therapy and is associated with a better oncological response

Low low-density lipoprotein (LDL), cholesterol and triglycerides plasma levels are associated with reduced risk of arterial occlusive events in chronic myeloid leukemia patients treated with ponatinib in the real-life. A Campus CML study

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Patients with myelodysplastic syndromes display several T-cell expansions, which are mostly polyclonal in the CD4⁺ subset and oligoclonal in the CD8⁺ subset

Objective. Immune dysregulation plays a role in the pathophysiology of myelodysplastic syndromes (MDS), as T-cell clones seem to be involved in the inhibition of hematopoietic precursors. The purpose of this study was to analyze the T-cell receptor (TCR) repertoire of MDS patients, focusing on the third complementarity determining region (CDR3) pattern of their CD4+ and CD8+ lymphocyte expansions. Materials and Methods. The study involved 30 patients and 15 age-matched controls. The β-variable (βV) subfamily flow-cytometry analysis was performed on peripheral CD4+ and CD8+ T-cells. Spectratyping TCR-CDR3 analysis was carried out on isolated helper and cytotoxic T lymphocytes after immunomagnetic separation and reverse-transcriptase polymerase chain reaction. Results. We first identified by flow cytometry an increased frequency of expanded βVs in both CD4+ and CD8+ T-cells in MDS patients. We then showed, by spectratyping, that the CDR3 profile was mostly Gaussian in their CD4+ T cells, whereas CD8+ T cells usually showed skewed or oligoclonal CDR3 regions. When we compared spectratyping and flow-cytometry findings in each patient, we showed that most CD4+ lymphocyte expansions detected by flow cytometry had Gaussian CDR3 profiles, whereas most CD8+ expansions were oligoclonal. Conclusion. We confirm that in MDS patients the TCR-βV repertoire is overall extremely contracted, especially in cytotoxic T cells. This pattern is mainly determined by selective proliferations of both helper and cytotoxic T cells, which are, however, mostly polyclonal in the former and oligoclonal in the latter. Such a difference, possibly related to the different human leukocyte antigen restriction, could reflect the selective involvement of cytotoxic T cells either in the anti-tumor immune surveillance or in an autoreactive aggression toward hematopoietic precursors

Health-related quality of life profile of patients with immune thrombocytopenia in the real life is impaired by splenectomy

The impact of splenectomy on health-related quality of life (HRQoL) in patients with immune thrombocytopenia (ITP) remains scarcely explored. Therefore, we evaluated HRQoL with the 36-Item Short-Form Health Survey (SF-36) in an internal cohort of 69 chronic ITP patients, overall and by type of treatment. Of these patients, 26 patients were splenectomized, while other patients were treated medically with thrombopoietin-receptor agonists (TPO-RAs) or immunosuppressive treatment. We also compared HRQoL of the splenectomized patients (internal cohort) with an external cohort of 63 splenectomized ITP patients and the general population. The median follow-up was 10 years (range 1-20). Splenectomized patients had a worse overall HRQoL profile than those who received medical therapy either with TPO-RAs or other treatments (OT), with clinically meaningful differences registered in several domains. These included physical functioning (Delta = - 17.0 and Delta = - 15.2, for TPO-Ras and OT, respectively, p = 0.065), role physical (Delta = - 9.7 and Delta = - 13.8, p = 0.483), and bodily pain (Delta = - 14.2 and Delta = - 18.8, p = 0.053). Compared to the general population, both internal and external splenectomized cohorts had an impaired HRQoL profile. Further studies on HRQoL in splenectomized ITP patients are needed to better understand the long-term impact of this surgical procedure

Increased incidence of infection in patients with myelofibrosis and transfusion-associated iron overload in the clinical setting

Transfusion-associated iron overload may lead to increased risk of infection, but its role in myelofibrosis (MF) has been scarcely explored. We evaluated 106 consecutive patients with primary or secondary MF. Up to 38% of patients were transfusion-dependent (TD) with a median of 14 RBC units received. Median observation time was 36 months (range 3-203). Forty-five percent of patients experienced one or more infectious episodes for a total of 69 infectious events, 13 (19%) of which were severe. The 60-month cumulative incidence of infection was 64.1 ± 6.5%. TD patients showed a higher incidence of infection (HR = 2.13, p = 0.019). Transfusion burden was markedly greater in TD patients with infectious complication (median 24 RBC units vs 15 RBC units; p = 0.012). The 60-month overall survival was 40 ± 5.9%. Lower International Prognostic Scoring System (IPSS) risk (p < 0.0001) and ruxolitinib (p = 0.027) were significantly correlated with higher survival. This real-world study showed increased infections in patients with higher transfusion burden. It may therefore be interesting to further investigate the role of iron chelation in improving infection-free survival in MF patients

Novel monoclonal antibody-based <i>Helicobacter pylori</i> stool antigen test

Background. A number of noninvasive tests have been developed to establish the presence of Helicobacter pylori infection. Although polyclonal antibody-based stool antigen testing has a good sensitivity and specificity, it is less accurate than urea breath testing. Recently, a monoclonal antibody-based stool antigen test demonstrated an excellent performance in diagnosing H. pylori infection in adults and in pediatric populations. Aim. To evaluate the diagnostic accuracy of a novel stool test based on monoclonal antibodies to detect H. pylori antigens in frozen human stool in the pretreatment setting. Patients and Methods. Stool specimens were prospectively collected from 78 patients undergoing gastroscopy and stored at −20°C until tested. Helicobacter pylori infection was evaluated by histology, rapid urease testing and urea breath tests (13C-UBT). Positivity of the three tests was considered the gold standard for H. pylori active infection. Patients with no positive test were considered negative. The gold standard was compare to the results of the monoclonal antibody stool antigen test. Frozen stool specimens were tested using a novel monoclonal-antibody-based enzyme immunoassay (HePy-Stool, Biolife-Italiana, Milan, Italy) . Results. The sensitivity and specificity of the monoclonal stool antigen test were 97%[95% confidence interval, (CI) 86–100] and 94% (95% CI: 81–99), respectively. Negative and positive predictive values were 97% (95% CI: 85–99), and 95% (95% CI: 83–99), respectively. The diagnostic accuracy was 96% (95% CI: 88–99). The likelihood ratio for a positive test was 17 and for a negative test was 0. Conclusions. Although the 13C-UBT is the most accurate among the available noninvasive tests, our results show that an H. pylori stool test using monoclonal antibody might be an excellent alternative

Metabolomic Analysis of Patients with Chronic Myeloid Leukemia and Cardiovascular Adverse Events after Treatment with Tyrosine Kinase Inhibitors

Background: Cardiovascular adverse events (CV-AEs) are considered critical complications in chronic myeloid leukemia (CML) patients treated with second- and thirdgeneration tyrosine kinase inhibitors (TKIs). The aim of our study was to assess the correlation between metabolic profiles and CV-AEs in CML patients treated with TKIs. Methods: We investigated 39 adult CML patients in chronic-phase (mean age 49 years, range 24–70 years), with no comorbidities evidenced at baseline, who were consecutively identified with CML and treated with imatinib, nilotinib, dasatinib, and ponatinib. All patients performed Gas-ChromatographyMass-Spectrometry-based metabolomic analysis and were divided into two groups (with and without CV-AEs). Results: Ten CV-AEs were documented. Seven CV-AEs were rated as 3 according to the Common Toxicity Criteria, and one patient died of a dissecting aneurysm of the aorta. The patients’ samples were clearly separated into two groups after analysis and the main discriminant metabolites were tyrosine, lysine, glutamic acid, ornithine, 2-piperdinecarboxylic acid, citric acid, proline, phenylalanine, threonine, mannitol, leucine, serine, creatine, alanine, and 4- hydroxyproline, which were more abundant in the CV-AE group. Conversely, myristic acid, oxalic acid, arabitol, 4-deoxy rithronic acid, ribose, and elaidic acid were less represented in the CV-AE group. Conclusions: CML patients with CV-AEs show a different metabolic profile, suggesting probable mechanisms of endothelial damage

Detection of Chlamydiae pneumoniae but not Helicobacter pylori DNA in atherosclerosis plaques

Chronic infections have been associated with cardiovascular disease. We used bacterial culture, polymerase chain reaction (PCR), and immunohistochemical staining with anti-vacA and anticagA antibodies to search for Helicobacter pylori and Chlamydiae pneumoniae in atherosclerotic plaques obtained at endarterectomy. Serum IgG antibodies to H. pylori and C. pneumoniae were also determined. Thirty-two patients were enrolled. Anti-H. pylori and anti-C. pneumoniae IgG were present in 72% and 81%, respectively. Culture and PCR for H. pylori of vessel walls and plaques were negative. Atherosclerotic plaque and normal vessel sections from H. pylori-negative and- positive patients showed reactivity with anti-vacA and anti-cagA antibodies. C. pneumoniae DNA was amplified in three atherosclerotic lesions. These findings suggest that the association between H. pylori infection and atherosclerosis does not result from continuing direct effects of H. pylori antigens in the vessel walls. Antigens within vessel atherosclerotic plaques cross-react with H. pylori virulence factors and could act as cofactors in determining instability for the atherosclerotic plaques

Detection of <i>Chlamydiae pneumoniae</i> but not <i>Helicobacter pylori</i> DNA in atherosclerosis plaques

Chronic infections have been associated with cardiovascular disease. We used bacterial culture, polymerase chain reaction (PCR), and immunohistochemical staining with anti-vacA and anticagA antibodies to search for Helicobacter pylori and Chlamydiae pneumoniae in atherosclerotic plaques obtained at endarterectomy. Serum IgG antibodies to H. pylori and C. pneumoniae were also determined. Thirty-two patients were enrolled. Anti-H. pylori and anti-C. pneumoniae IgG were present in 72% and 81%, respectively. Culture and PCR for H. pylori of vessel walls and plaques were negative. Atherosclerotic plaque and normal vessel sections from H. pylori-negative and- positive patients showed reactivity with anti-vacA and anti-cagA antibodies. C. pneumoniae DNA was amplified in three atherosclerotic lesions. These findings suggest that the association between H. pylor infection and atherosclerosis does not result from continuing direct effects of H. pylori antigens in the vessel walls. Antigens within vessel atherosclerotic plaques cross-react with H. pylori virulence factors and could act as cofactors in determining instability for the atherosclerotic plaques