Acalabrutinib and its use in the treatment of chronic lymphocytic leukemia.

Bruton's tyrosine kinase inhibitors have changed the treatment landscape for chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL) and lymphoplasmacytic lymphoma dramatically. In 2019, acalabrutinib was approved by the US FDA for the treatment of treatment-naive and relapsed/refractory CLL and MCL. Acalabrutinib monotherapy was found to be effective and safe in CLL patients. In ASCEND and ELEVATE treatment-naive studies, acalabrutinib monotherapy and the combination with obinutuzumab demonstrated improved efficacy and an acceptable safety profile. The triple combination with venetoclax showed a high rate of molecular remission without an impaired safety profile. Adverse events, with an occurrence rate of >20%, were as follows: grade 1-2 myelosuppression, gastrointestinal toxicity, rash, constitutional symptoms; grade 3 or 4 toxicities were syncope, pneumonia, hypertension, atrial fibrillation, neutropenia and thrombocytopenia.

Additional chromosome abnormalities, BCR-ABL tyrosine kinase domain mutations and clinical outcome in Hungarian tyrosine kinase inhibitor-resistant chronic myelogenous leukemia patients.

BACKGROUND: Additional chromosome abnormalities (ACAs), mutations of the BCR-ABL tyrosine kinase domain (TKD) and BCR-ABL splice variants may cause resistance to first- and second-generation tyrosine kinase inhibitors (TKIs) in chronic myelogenous leukemia (CML) and Philadelphia-positive (Ph+) acute lymphoid leukemia (ALL). METHODS: Karyotyping and BCR-ABL TKD mutation screening were performed in 71 imatinib-resistant CML patients and 6 Ph+ ALL patients. A total of 56 out of these 77 patients received second-generation TKI. RESULTS: ACAs were present in 30 of 65 imatinib-resistant patients (46%). In 27 of 74 imatinib-resistant patients (36%), 15 different BCR-ABL TKD mutations were detected. Mutations were found in 25% of chronic-phase patients (12/47), 33% of accelerated-phase patients (5/15), 71% of blast crisis CML patients (5/7) and 100% of ALL patients. In nilotinib-resistant patients, Y253H, T315I and F359I/V mutations were detected; in dasatinib-resistant patients, L248M, E279K and T315I mutations were detected. T315I was found more frequently in patients on dasatinib than on imatinib therapy. The presence of ACAs predicted shorter survival during first- and second-generation TKI therapy, while TKD mutations only influenced survival during second-generation TKI therapy. CONCLUSION: For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis.

The prognostic impact of germline 46/1 haplotype of Janus kinase 2 in cytogenetically normal acute myeloid leukemia.

BACKGROUND: Prognostic risk stratification according to acquired or inherited genetic alterations has received increasing attention in acute myeloid leukemia in recent years. A germline Janus kinase 2 haplotype designated as the 46/1 haplotype has been reported to be associated with an inherited predisposition to myeloproliferative neoplasms, and also to acute myeloid leukemia with normal karyotype. The aim of this study was to assess the prognostic impact of the 46/1 haplotype on disease characteristics and treatment outcome in acute myeloid leukemia. DESIGN AND METHODS: Janus kinase 2 rs12343867 single nucleotide polymorphism tagging the 46/1 haplotype was genotyped by LightCycler technology applying melting curve analysis with the hybridization probe detection format in 176 patients with acute myeloid leukemia under 60 years diagnosed consecutively and treated with curative intent. RESULTS: The morphological subtype of acute myeloid leukemia with maturation was less frequent among 46/1 carriers than among non-carriers (5.6% versus 17.2%, P = 0.018, cytogenetically normal subgroup: 4.3% versus 20.6%, P = 0.031), while the morphological distribution shifted towards the myelomonocytoid form in 46/1 haplotype carriers (28.1% versus 14.9%, P = 0.044, cytogenetically normal subgroup: 34.0% versus 11.8%, P = 0.035). In cytogenetically normal cases of acute myeloid leukemia, the 46/1 carriers had a considerably lower remission rate (78.7% versus 94.1%, P = 0.064) and more deaths in remission or in aplasia caused by infections (46.8% versus 23.5%, P = 0.038), resulting in the 46/1 carriers having shorter disease-free survival and overall survival compared to the 46/1 non-carriers. In multivariate analysis, the 46/1 haplotype was an independent adverse prognostic factor for disease-free survival (P = 0.024) and overall survival (P = 0.024) in patients with a normal karyotype. Janus kinase 2 46/1 haplotype had no impact on prognosis in the subgroup with abnormal karyotype. CONCLUSIONS: Janus kinase 2 46/1 haplotype influences morphological distribution, increasing the predisposition towards an acute myelomonocytoid form. It may be a novel, independent unfavorable risk factor in acute myeloid leukemia with a normal karyotype.

HFE C282Y mutation as a genetic modifier influencing disease susceptibility for chronic myeloproliferative disease.

Iron metabolism has been implicated in carcinogenesis and several studies assessed the potential role of genetic variants of proteins involved in iron metabolism (HFE C282Y, TFR S142G) in different malignancies. Few reports addressed this issue with relation to chronic myeloproliferative disorders (CMPD). The aims of our study were (a) to examine the potential associations of CMPD development with genetic modifiers of iron metabolism in a large cohort of CMPD patients; (b) to examine associations of genetic variants of proteins involved in iron metabolism; and acquired JAK2 V617F mutation with clinical characteristics of CMPD. HFE C282Y was genotyped in 328 CMPD patients and 996 blood donors as controls, HFE H63D, and TFR S142G were tested in CMPD patients and 171 first time blood donors. JAK2 V617F mutation was tested in CMPD patients and in 122 repeated blood donors. Decreased C282Y allele frequency (allele frequency+/-95% confidence interval) was found in the CMPD group (1.8%+/-1.0%) compared with controls (3.4%+/-0.8%; P=0.048). TFR S142G allele frequency was reduced among V617F-negative CMPD patients (34.8%+/-7.6%) compared with controls (47.8%+/-5.4%; P=0.02). The frequency of JAK2 V617F was 75.9% (249 of 328) in the CMPD group. At presentation, elevated hemoglobin levels were found in V617F-positive patients compared with V617F-negative counterparts (P<0.000). Vascular complications (26.6% versus 15.2%; P=0.039) as well as female gender (57.4% versus 41.8%; P=0.019) were more common in V617F-positive patients. We found that HFE C282Y might be associated with a protective role against CMPD. Because chronic iron deficiency or latent anemia may trigger disease susceptibility for CMPD, HFE C282Y positivity may be a genetic factor influencing this effect.

Drugs, gene transfer, signaling factors: a bench to bedside approach to myocardial stem cell therapy.

In the past few years, the dogma that the heart is a terminally differentiated organ has been challenged. Evidence from preclinical investigations emerged that there are cells, even in the heart itself, that may be able to restore impaired cardiac function after myocardial infarction. Although the exact mechanisms by which the infarcted heart can be repaired by stem cells are not yet fully defined, there is a new optimism among cardiologists that this treatment will prove successful in addressing the cause of heart failure after myocardial infarction-myocyte loss. Despite the promising preliminary data of human myocardial stem cell trials, scientists have also focused on the possibility of enhancing the underlying mechanisms of stem cell repair to gain healthier myocardial tissue. Attempts to induce neo-angiogenesis by transfecting stem cells with signaling factors (such as VEGF), to raise the number of endothelial progenitor cells with medical treatments (such as statins), to transfect stem cells with heat shock protein 70 (as a cardioprotective agent against ischemia) and to enhance the healing process after myocardial infarction with the use of various forms of stimulating factors (G-CSF, SCF, GM-CSF) have been made with notable results. In this article, we summarize the evidence from preclinical and clinical myocardial stem cell studies that have addressed the possibility of enhancing the regenerative capacity of cells used after myocardial infarction.

[Role of the activating mutation Val617Phe of Janus kinase 2 gene in myeloproliferative diseases and significance of its detection]. / A 2-es típusú Janus tirozin kináz Val617Phe aktiváló pontmutáció szerepe és kimutatásának jelentosége myeloproliferatív szindrómában.

The Val617Phe point mutation of Janus kinase 2 gene is believed to participate in the pathogenesis of myeloproliferative syndrome characterised by the clonal alteration of hematopoietic stem cells. According to current results, the frequency of Val617Phe activating mutation is around 80% in polycythaemia vera, 35% in essential thrombocythemia, and 50% in chronic idiopathic myelofibrosis. The diagnoses of polycythemia vera, essential thrombocythemia and idiopathic myelofibrosis were so far based on the exclusion of secondary factors as well as bone marrow biopsy histology. The goal of the present work was to establish simple molecular genetic techniques for the routine testing of Janus kinase 2 gene Val617Phe mutation, and to compare the clinical phenotypes of Val617Phe mutation positive and negative myeloproliferative syndromes. We employed the allele specific polymerase chain technique for detection of Val617Phe mutation in 252 patients with myeloproliferative syndrome. We measured Val617Phe frequency as 85,4% (117/137) in polycythemia vera, 56,6% (56/99) in essential thrombocythemia, and 87,5% (14/16) in idiopathic myelofibrosis. We found significantly elevated hemoglobin levels and white blood cell counts (measured at the time of diagnosis) in Val617Phe-positive polycythemia vera and essential thrombocythemia patient groups compared to Val617Phe-negative patients. However, the frequencies of splenomegaly and other complications (thrombosis, bleeding, transformation to acute leukemia) were not significantly different between the mutation-positive and negative groups. In conclusion, the non-invasive mutation analysis of the Janus kinase 2 Val617Phe is suitable for routine laboratory application and helps the differential diagnosis of myeloproliferative syndrome. Although the exact role of Val617Phe mutation testing has not yet been identified on the basis of a broad professional consensus, the testing is suggested in cases of erythrocytoses and thrombocytoses of unknown origin.

Successful combined antifungal salvage therapy with liposomal amphothericin B and caspofungin for invasive Aspergillus flavus infection in a child following allogeneic bone marrow transplantation.

The emergence of new antifungal compounds with alternative mechanisms of action and improved tolerability has opened up new therapeutic possibilities for the use of combined antifungal treatment in life-threatening systemic fungal infections. A case report of an 8-year-old allogeneic stem cell transplant recipient who developed a central venous catheter tunnel infection caused by Aspergillus flavus is presented here. In spite of conventional and subsequent liposomal amphotericin B therapy the infection progressed rapidly and the necrosis extended further to the thoracic wall, pleura and the right lung. Combined treatment consisting of liposomal amphotericin B and caspofungin was instituted. After 30 days of dual therapy the deep fungal infection resolved and the extensive soft tissue defect showed scarring. One year post-transplant, the patient is well, with normal bone marrow function and full donor chimerism. Although there is limited clinical data on the effectiveness of echinocandins in pediatric patients with documented invasive fungal infections, this case report shows that combining liposomal amphotericin B with caspofungin could be advantageous.

[Experiences with the first, Hungarian autologous bone marrow cell transplantation in acute myocardial infarction]. / Akut szívizom-infarctusban végzett elso magyar autológ csontveloi o'ssejt transzplantációk során szerzett tapasztalataink.

Intracoronary transfer of autologous bone marrow cells promotes recovery of left ventricular systolic function in patients with acute myocardial infarction. Although the exact mechanisms of stem cell therapy are still intensely debated, the concept of stem cell therapy has already been introduced into the clinical practice--at least as an adjunctive therapy in clinical trials. In this article the authors report their experiences about the first Hungarian phase I. trial in bone marrow stem cell transplantation after acute myocardial infarction. So far, four patients with acute ST elevation myocardial infarction were eligible and recruited into the trial. All patients received purified, autologous bone marrow stem cells into the re-opened infarct related artery via a second catheterisation. The primary end point of the study is ejection fraction, which is measured by cardiac MRI at the beginning and 6 months after recruitment. So far, cell transfer did not increase the risk of adverse clinical events or proarrhythmic effects.