ABSTRACT
Profound immune dysregulation and impaired response to the SARS-CoV-2 vaccine put patients with chronic lymphocytic leukemia (CLL) at risk of severe COVID-19. We compared humoral memory and T-cell responses after booster dose vaccination or breakthrough infection. (Green) Quantitative determination of anti-Spike specific antibodies. Booster doses increased seroconversion rate and antibody titers in all patient categories, ultimately generating humoral responses similar to those observed in the postinfection cohort. In detail, humoral response with overscale median antibody titers arose in >80% of patients in watch and wait, off-therapy in remission, or under treatment with venetoclax single-agent. Anti-CD20 antibodies and active treatment with BTK inhibitors (BTKi) represent limiting factors of humoral response, still memory mounted in ~40% of cases following booster doses or infection. (Blue) Evaluation of SARS-CoV-2-specific T-cell responses. Number of T-cell functional activation markers documented in each patient. The vast majority of patients, including those seronegative, developed T-cell responses, qualitatively similar between treatment groups or between vaccination alone and infection cases. These data highlight the efficacy of booster doses in eliciting T-cell immunity independently of treatment status and support the use of additional vaccination boosters to stimulate humoral immunity in patients on active CLL-directed treatments.
Subject(s)
COVID-19 , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , SARS-CoV-2 , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , COVID-19 Vaccines , Antibodies , Interleukin-2 Receptor alpha Subunit , Immunity, Cellular , Antibodies, Viral , VaccinationABSTRACT
Newly introduced highly effective treatment options increase the importance of minimal residual disease measurement in chronic lymphocytic leukemia. Minimal residual disease is gaining interest mainly as a predictive marker; however, clinical significance of minimal residual dis-ease in chronic lymphocytic leukemia in many different situations remains unresolved. Factors with a possible impact on the clinical significance of minimal residual disease are as follows: technique for minimal residual disease quantification, treatment regimen, peripheral blood vs. bone marrow analysis or timeâ-point for sampling. Highly sensitive methods now available to evaluate minimal residual disease can detect a single chronic lymphocytic leukemia cell in 10(-4)-â10(-5) leukocytes using either alleleâ-specific oligonucleotide polymerase chain reaction or multicolor flow cytometry. Minimal residual disease quantification as a surrogate marker to assess treatment efficacy in routine hematological practice has to be further evaluated.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/therapy , Flow Cytometry , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Neoplasm, Residual , PrognosisABSTRACT
INTRODUCTION: Multiple myeloma is a common plasma cell neoplasia usually accompanied by the formation of osteolytic foci, whereas osteosclerotic myeloma is a very rare form of plasma cell dyscrasia. When osteosclerotic myeloma is detected, osteosclerotic foci are usually part of the POEMS syndrome. Osteosclerotic myeloma without other manifestations of the POEMS syndrome is an unusual finding. CASE DESCRIPTION: In a 46-year-old woman, osteosclerotic changes of the temporoparietal region caused soft tissue induration over this lesion, which initiated further investigation. Imaging studies subsequently showed multiple osteosclerotic foci in the skull. Examination of blood proteins revealed 8â g/L of IgG-lambda monoclonal immunoglobulin, subclass IgG1. In search of the cause of the osteosclerotic changes, FDG-PET/CT was performed, which revealed no FDG accumulation, i.e., no other tumor (breast or stomach cancer). Low-dose CT showed irregular bone structure, but not significant osteolytic or osteosclerotic foci. To map the extent of osteosclerotic changes, NaF-PET/CT imagination followed, which revealed multiple spots with high fluoride accumulation. A parietal bone biopsy showed osteosclerosis with minor clonal plasma cell infiltration. Trepanobioptic bone marrow sampling revealed an infiltration of bone marrow with atypical plasma cells in 8%. Flow-cytometric examination of bone marrow showed 0,37% of plasma cells, however predominantly (91%) clonal with lambda expression. MRI of the brain identified asymptomatic meningeal thickening. There was no evidence of POEMS syndrome in the patient; thus, we concluded the diagnosis as monoclonal gammopathy of clinical significance with osteosclerosis which was previously termed osteosclerotic multiple myeloma. CONCLUSION: Monoclonal gammopathy of clinical significance (MGCS) with osteosclerotic skeletal changes, documented on CT and multiple foci with intensive osteoneogenesis, documented on NaF-PET/CT without evidence of POEMS syndrome, is an extremely rare form of plasma cell dyscrasia. This publication documents the unique clinical manifestations of IgG-lambda type plasma cell proliferation without signs of POEMS syndrome and the role of NaF-PET/CT imaging. Classification of this disease as MGSC with osteosclerotic manifestations is more consistent with the indolent nature of the disease with a significantly better prognosis, compared with multiple myeloma.
Subject(s)
Multiple Myeloma , Osteosclerosis , Humans , Middle Aged , Female , Osteosclerosis/diagnostic imaging , Osteosclerosis/etiology , Osteosclerosis/pathology , Multiple Myeloma/complications , Multiple Myeloma/pathology , Multiple Myeloma/diagnostic imaging , Positron Emission Tomography Computed Tomography , Paraproteinemias/complications , Paraproteinemias/pathologyABSTRACT
The TOTEM collaboration has measured the proton-proton total cross section at âs=8 TeV using a luminosity-independent method. In LHC fills with dedicated beam optics, the Roman pots have been inserted very close to the beam allowing the detection of ~90% of the nuclear elastic scattering events. Simultaneously the inelastic scattering rate has been measured by the T1 and T2 telescopes. By applying the optical theorem, the total proton-proton cross section of (101.7±2.9) mb has been determined, well in agreement with the extrapolation from lower energies. This method also allows one to derive the luminosity-independent elastic and inelastic cross sections: σ(el)=(27.1±1.4) mb; σ(inel)=(74.7±1.7) mb.
ABSTRACT
Chronic lymphocytic leukemia (CLL) is the most frequent, yet by conventional therapy still incurable, leukemia in the Western world. Accumulating evidence of the role of B âcell receptor (BCR) pathway in CLL B âcell bio-logy suggests the possible use of BCR inhibitors for targeted therapy. Recently published results of clinical trials of three different molecules (fosfamatinib, ibrutinib and GSâ1101) targeting BCRassociated kinases (Syk, Btk, PI3K) showed impressive clinical activity in CLL. These findings will likely modify treatment approaches for chronic lymphocytic leukemia and some other B âcell lymphomas in the near future. Herein, we review the data on BCR pathway deregulation in malignant CLL B âcells, and the results of clinical trials utilizing fosfamatinib, ibrutinib and GSâ1101.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/metabolism , Receptors, Antigen, B-Cell/antagonists & inhibitors , Signal Transduction/physiology , Adenine/analogs & derivatives , Humans , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Phosphoinositide-3 Kinase Inhibitors , Piperidines , Protein Kinase Inhibitors/therapeutic use , Protein-Tyrosine Kinases/antagonists & inhibitors , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Receptors, Antigen, B-Cell/metabolism , src-Family Kinases/antagonists & inhibitorsABSTRACT
BACKGROUND: Chromosomal aberrations play an important role as prognostic factors in chronic lymphocytic leukemia (CLL). These aberrations are mostly detected by fluorescent in situ hybridization (FISH), as chromosomal banding analysis has been scarce due to low proliferative activity of malignant B-lymphocytes in vitro. In 2006, a new method using stimulation with IL-2 and CpG oligonucleotide DSP30 for metaphase generation in CLL was published [1]. The objective of our study was to verify the efficacy of stimulation and to evaluate if the method is suitable for routine diagnostics. PATIENTS AND METHODS: In total, peripheral blood samples of 369 CLL patients were analyzed in parallel by chromosomal banding analysis and by FISH probes for 13q14, 11q22-23, CEP12 and 17p13. RESULTS: Out of 369 patients, 307 (83%) were successfully stimulated for metaphase generation. Chromosomal aberrations were detected in 243 (79%) out of 307 patients evaluated by chromosomal banding analysis. Other aberrations that are not included into standard FISH panel were detected in patients karyotypes, e.g. del(6q), del(14q), t(14;18)(q32;q21), t(11;14)(q13;q32) and t(18;22)(q21;q11). One hundred and three (42%) patients showed complex aberrant karyotype not detected by FISH analysis. CONCLUSION: Stimulation with IL-2 and oligonucleotide DSP30 is an efficient method how to induce proliferation of malignant B-lymphocytes and allows detection of a substantial number of chromosomal aberrations in addition to those detected by standard FISH panel. Using this method in routine diagnostics is helpful particularly in identification of patients with complex aberrant karyotype.
Subject(s)
Chromosome Banding , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Adult , Aged , Aged, 80 and over , Chromosome Aberrations , Chromosomes, Human, Pair 11 , Chromosomes, Human, Pair 13 , Female , Gene Expression Profiling , Gene Expression Regulation, Leukemic , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Humans , In Situ Hybridization, Fluorescence , Interleukin-2/pharmacology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Male , Middle Aged , Oligonucleotides , Tumor Cells, CulturedABSTRACT
BACKGROUND: Pediatric-inspired protocols with prospective monitoring of minimal residual disease (MRD) are considered the standard of intensive treatment for adults with acute lymphoblastic leukemia (ALL). They have been used in the Czech Republic since 2007. PATIENTS AND METHODS: Two hundred and ninety-seven patients aged 18-65 years were treated at five hematology centers between 2007-2020 according to the GMALL 07/2003 protocol. This is a retrospective analysis of their treatment outcomes. RESULTS: In the Ph-negative cohort, 189 (93.1%) patients achieved complete remission, 5 (2.4%) patients were refractory, and early mortality was 3.0%. Seventy (34.5%) patients experienced relapse in a median of 10.6 months. Overall survival (OS) at 3 and 5 years was 63.5% and 55.9%, disease-free survival (DFS) at 3 and 5 years was 54.5% and 49.7%, respectively. Young adults under 35 years of age (P = 0.015), patients without initial CNS infiltration (P = 0.016), with MRD negativity before consolidation treatment (P < 0.001), transplanted in the 1st complete remission (P < 0.001), and subjects treated after 2012 (P = 0.05) had significantly better overall survival. In a multivariate analysis, MRD at week 11 was the only independent factor affecting OS (HR 3.06; P = 0.006). For DFS, baseline CNS infiltration (HR 2.08; P = 0.038) and MRD at week 11 (HR 2.15; P = 0.020) were significant. In the Ph-positive cohort, 84 (89.4%) patients achieved complete remission, 1 (1.0%) patient was refractory, early mortality was 4.3%. Twenty-six (27.7%) patients relapsed in a median of 8.6 months. Survival at 3 and 5 years was 57.2% and 52.4% for OS and 50.2% and 44.9% for DFS, respectively. Transplanted patients and patients diagnosed after 2012 had statistically better overall survival (P < 0.001). CONCLUSION: The introduction of pediatric-inspired protocols with treatment intensification according to MRD levels resulted in a significant improvement in the survival outcomes of adult patients with ALL.
Subject(s)
Hematopoietic Stem Cell Transplantation , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Young Adult , Humans , Adult , Retrospective Studies , Prospective Studies , Czech Republic/epidemiology , Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Disease-Free Survival , Neoplasm, Residual/diagnosisABSTRACT
BACKGROUND: The outcome of children with refractory/relapsed malignancies remains poor and novel therapies are urgently required. One of the promising approaches is metronomic chemotherapy. We present the clinical results of 74 children with advanced solid tumors treated according to treatment recommendation with data registry in three European pediatric centers. METHODS: COMBAT (Combined Oral Metronomic Biodifferentiating Antiangiogenic Treatment) included low-dose daily temozolomide, etoposide, celecoxib, vitamin D, fenofibrate and retinoic acid. From 2004 to 2010, 74 children were enrolled. RESULTS: The 2-year overall survival (OS) was 43.1% (median 15.4, range 1.3-69.9 months). Of the 74 patients, 50 patients (68%) died and 24 are alive: 6 (8%) with progressive disease, 7 (9%) with stable disease/partial response and 11 (15%) in complete response. Median time to response was 6 months. Of 62 patients with initially measurable disease, 25 (40%) had radiological response or stable disease. Fourteen of 25 showing clinical benefit responded within the first 6 months. The treatment was well tolerated on an outpatient basis. Regarding non-hematological toxicity of grade ≥2, hepatotoxicity of grade 3 occurred in 8 children and grade 3 cheilitis in 16 children. CONCLUSION: COMBAT is a feasible and effective treatment option for patients with relapsing/refractory malignancies. The treatment is well tolerated with a low acute toxicity profile.
Subject(s)
Angiogenesis Inhibitors/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Neoplasms/drug therapy , Registries , Administration, Metronomic , Adolescent , Adult , Celecoxib , Child , Child, Preschool , Dacarbazine/administration & dosage , Dacarbazine/analogs & derivatives , Etoposide/administration & dosage , Europe , Feasibility Studies , Female , Fenofibrate/administration & dosage , Humans , Infant , Isotretinoin/administration & dosage , Male , Pyrazoles/administration & dosage , Sulfonamides/administration & dosage , Temozolomide , Vitamin D/administration & dosage , Young AdultABSTRACT
UNLABELLED: Alemtuzumab, the humanized monoclonal anti-CD52 antibody, is an effective agent in the treatment of fludarabine-refractory chronic lymphocytic leukemia (CLL). Due to many specific issues associated with alemtuzumab treatment, the Working Committee of Czech CLL Study Group developed these guidelines. SUMMARY OF RECOMMENDATIONS: (1) The main indication of alemtuzumab is fludarabine-refractory CLL. (2) Further possible indications include first-line treatment (in patients who cannot be treated by fludarabine-containing regimens), therapy of patients with del 17p, treatment of refractory autoimmune cytopenias and management of patients with severe cytopenias due to bone marrow infiltration. (3) The treatment should last 12 weeks and should not be terminated prematurely if there are no signs of CLL progression; bone marrow aspirate/biopsy can be performed after 12 weeks of treatment. (4) Subcutaneous administration of alemtuzumab seems to be equally effective with advantageous reduction of infusion-related adverse events. (5) Patients treated with alemtuzumab must receive combined antimicrobial prophylaxis against Pneumocystis jiroveci and herpetic viruses. Cytomegalovirus viremia should be monitored using weekly PCR from peripheral blood. (6) Use of alemtuzumab in combinations and consolidation/maintenance protocols must be considered experimental and needs optimization within prospective clinical trials. (7) Alemtuzumab treatment should be conducted by an experienced hematologist within a center of intensive hematology care.
Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Alemtuzumab , HumansABSTRACT
UNLABELLED: Reduced-intensity conditioning (RIC) is widely used for allogeneic stem cell transplantation (SCT). Here we present our long-term experience with RIC regimen consisting of fludarabine (30 mg/m2/day on days -10 to -5), busulfan (4mg/kg/day on days -6 and -5) and antithymocyte globulin (ATG Fresenius, 10 mg/kg/day on days -4 to -1) (Flu-Bu-ATG) in a cohort of 71 patients with various hematological malignancies including chronic myeloid leukemia (24 patients), acute myeloid leukemia (19 patients), lymphoma (20 patients), multiple myeloma (3 patients), myelodysplastic syndrome (3 patients), and myelofibrosis (2 patients). The median age was 50 years. The overall response rate was 87%, including 83% CR and 4% PR. The incidence of acute and chronic GVHD was 35% and 52% and the cumulative incidence of non-relapse mortality at 1 year and 4 years was 8% and 14%. With the median follow-up of 55.0 months, the 2- and 4-year event-free survival (EFS) was 49.0% and 40.3%, and the overall survival (OS) was 73.2% and 62.6%, respectively. Gender, age at SCT, type of donor, disease status at SCT, previous autologous transplantation, and complete chimerism by day +100 did not significantly influence EFS and OS. In a multivariate analysis, no presence of chronic GVHD (p=0.029, HR: 2.5),and diagnosis other than CML (p=0.018, HR: 4.6), and CD34+ dose < 5x106/kg (p=0.010, HR: 2.8) were significant predictors of poor OS. Flu-Bu-ATG protocol is a RIC regimen that combines effective disease control with low non-relapse mortality and acceptable toxicity profile. KEYWORDS: reduced-intensity conditioning, fludarabine, busulfan, antithymocyte globulin.
Subject(s)
Antilymphocyte Serum/therapeutic use , Busulfan/therapeutic use , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Transplantation , Transplantation Conditioning , Vidarabine/analogs & derivatives , Adolescent , Adult , Aged , Cohort Studies , Drug Therapy, Combination , Female , Follow-Up Studies , Graft vs Host Disease/prevention & control , Hematologic Neoplasms/mortality , Humans , Immunosuppressive Agents/therapeutic use , Male , Middle Aged , Survival Rate , Time Factors , Transplantation, Homologous , Treatment Outcome , Vidarabine/therapeutic use , Young AdultABSTRACT
BACKGROUND: Patients with B-cell chronic lymphocytic leukemia (CLL) with 17p deletion respond poorly to chemotherapy. This retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL in the various cytogenetic subgroups. PATIENTS AND METHODS: Data were collected from 105 consecutive, pretreated, cytogenetically defined patients who had received alemtuzumab. Response, progression-free survival (PFS), and overall survival (OS) were assessed. RESULTS: The hierarchic incidence of cytogenetic abnormalities was: 13q deletion (as sole abnormality), 18%; trisomy 12, 13%; 11q deletion, 19%; 17p deletion, 33%; and none of these, 16%. Overall response rate (ORR) was 43% in the total cohort and 49% in the subgroup of 17p-deleted patients (n = 35). From the start of alemtuzumab monotherapy, median PFS in the total cohort and in the subgroup of 17p-deleted patients was 7.0 and 7.1 months, respectively. Median OS in the total cohort and in 17p-deleted patients was 32.8 and 19.1 months, respectively. The poor-risk group of patients with CLL (i.e. fludarabine resistant, 17p deletion; n = 20) showed encouraging ORR, PFS, and OS (35%, 7.0 and 19.2 months, respectively). CONCLUSIONS: Alemtuzumab was effective in treating patients with CLL across the cytogenetic categories evaluated, but there were differences. In patients with CLL with 17p deletion quite favorable ORR, PFS, and OS were achieved.
Subject(s)
Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/adverse effects , Antibodies, Neoplasm/therapeutic use , Chromosome Aberrations , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Aged , Aged, 80 and over , Alemtuzumab , Antibodies, Monoclonal, Humanized , Antineoplastic Agents/therapeutic use , Chemotherapy, Adjuvant , Chromosome Aberrations/statistics & numerical data , Disease Progression , Drug-Related Side Effects and Adverse Reactions/genetics , Female , Genetic Predisposition to Disease , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/mortality , Male , Middle Aged , Retrospective Studies , Risk Assessment , Risk Factors , Survival Analysis , Treatment OutcomeABSTRACT
In order for the schools of medicine to produce high quality physicians, they have to provide high quality education as well as they must ensure that knowledge building is taking place in the course of the programme and that the students whose efforts and/or abilities do not allow achievement of the required criteria are eliminated. Exams used to be the standard quality control tool. However, current information technologies allow doubling-up of this control; retaining the traditional examinations but preceding them with the requirement to complete multiple-choice tests. The text summarizes our experience with examining the students' mental presence during teaching with tests and our plans for the combined form of exit control using tests, completion of which will be prerequisite to admission to the exam itself. We do not believe that tests should completely replace exams but we do believe that the requirement to pass the exam should only take place following previous successful completion ofa test. This is achievable ifwe manage to establish a computer teaching room, i.e. examination room, and transform a vast number of questions into high quality multiple choice tests.
Subject(s)
Education, Medical , Educational Measurement , Czech Republic , Humans , TeachingABSTRACT
In the Czech Republic, anagrelid is used according to the recommendations of the Czech Working Group on Myeloproliferative Disorders for treatment ofthrombocythaemias associated with chronic myeloproliferative disorders--mainly essential thrombocythaemia and, regularly, reports are being presented from the Register of Patients Treated with Thromboreductin, most recently last year (Vnitr Lék 2009; 55: I-XII). The Register commenced in 2005 and from then it aims to determine detailed clinical and laboratory profiles of the patients. The structure of the Register has changed significantly in the course of its existence, reflecting the reports from each of the analyses conducted so far. Also, the data entry in the database improves every year and it reaches 97% on some of the items. The longest evaluation period in some of the patients is 108 months. By April 2010, the Register database contained data on 717 patients. Of these, 672 patients with the diagnosis of a Ph-negative chronic myeloproliferative disorder were evaluated. This year's analysis included the patients with essential thrombocythaemia, polycythaemia vera and primary myelofibrosis only. The analysis included 418 women and 254 men with median age of50 years. Unlike the first years, 2/3 of the current sample are non pretreated patients, meaning that the patients reach the specialized centres early in their treatment. Also, patients, and the older patients in particular, are more frequently treated with combined regimens including Thromboreductin. We increasingly observe hypertension as one of the monitored risk factors preceding the disease and laboratory parameters showJAK2 mutation in more than a half of patients while some form ofthrombotic diathesis is found in the anamnesis of 7-10% of patients. Some bleeding is observed in 1-5% of the registered patients. In comparison to the previous years, this is a decrease in the prevalence of clinical symptoms prior to the disease onset; this is very likely associated with an earlier patient diagnosis within the asymptomatic phase of the disease. Therapeutically, we achieve a fast treatment response but there still are 16.3% of sufficient afterone year of treatment. Thromboreductin dose is increasing but even in this group it does not exceeds the mean of 2.38 mg per 24 hours. Complications are observed in 6.2% of patients in the first year of therapy, and ofthese, thrombotic events in about 2.5% and (small) bleeding complications in 4% of patients. The data suggest that we still do not reach treatment response in a certain proportion of patients after a year of their therapy. Even though the care results from the analysed data improve every year, the Register helps to uncover some issues that still remain, such as treatment intensification and other treatment modifications.
Subject(s)
Platelet Aggregation Inhibitors/therapeutic use , Polycythemia Vera/drug therapy , Primary Myelofibrosis/drug therapy , Quinazolines/therapeutic use , Thrombocythemia, Essential/drug therapy , Adult , Aged , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/adverse effects , Platelet Count , Polycythemia Vera/blood , Primary Myelofibrosis/blood , Quinazolines/adverse effects , Thrombocythemia, Essential/bloodABSTRACT
INTRODUCTION: We present two years' experience in the treatment of adult acute lymphoblastic leukemia (ALL) according to the German GMALL 07/2003 study protocol at CELL (Czech leukemia study group--for life) hematological centers in the Czech Republic. METHODS: A total number of 37 patients were included in this analysis. We evaluated complete remission and molecular remission rate, incidence of relapse, patients' status at the end of the follow-up period, incidence of chemotherapy-related adverse events and causes of death. A statistical analysis of risk factors affecting survival was carried out. RESULTS: Complete remission was achieved in 36 (97%) patients and molecular remission in 16 (62%) of 26 evaluable patients. Disease relapse occurred in 5 (14%) patients. At the end of the follow-up period with a median of 261 days, 28 (76%) patients were alive in complete remission, one (3%) with relapsed disease and 8 (22%) dead. Treatment toxicity resulted in death in 5 cases, relapse or progression of ALL in 3 patients. Adverse events most often followed consolidation I, induction phase I, consolidation II and induction phase II. Infectious complications in the context of febrile neutropenia, GIT mucositis and side effects of PEG-asparaginase were the most common adverse events observed. The toxicity of allogeneic transplantation was not unexpected, four (25%) patients died after transplantation. Two-year progression-free and overall survival were 66% and 70%, respectively. High risk ALL, age over 35 years, CNS infiltration, disease relapse and permanent minimal residual disease were identified as the major adverse prognostic risk factors. Practical experiences and possible pitfalls of the protocol are described in the discussion. CONCLUSION: Our initial impression is promising. The treatment is feasible, the results very good and the toxicity acceptable. Patients at high risk should be headed to allogeneic transplantation, since the results ofconsolidation chemotherapy alone are very poor in this group. We believe that this study protocol could become a standard adult acute lymphoblastic leukemia treatment in the Czech Republic.
Subject(s)
Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Hematopoietic Stem Cell Transplantation , Humans , Middle Aged , Remission Induction , Young AdultABSTRACT
cDNA microarray technology is widely used in various biological and medical disciplines to determine gene expression profiles. Unfortunately, this technology requires a large quantity of input RNA. Since there is an increasing need for more precise analyses of defined cell subpopulations with low cell counts, working protocols using a minimal number of input cells are required. Optimal RNA isolation and its accurate amplification are crucial to the success of these protocols. The HL-60 cell line was used in the search for a suitable protocol that can be used for clinical samples of CD34+ haematopoietic cells obtained from bone marrow. The goal was to discover the best method for isolating and amplifying RNA from a small number of cells. Our evaluation of various methods and kits available in the market revealed that the combination of RNAqueous Kit for RNA isolation and the SenseAmp Plus Kit for one-round RNA amplification produced the best results. This article presents a verified protocol describing a reliable and reproducible method for obtaining enough input RNA for microarray experiments when the number of cells is limited.
Subject(s)
Oligonucleotide Array Sequence Analysis/methods , Cells, Cultured , HL-60 Cells , Humans , Nucleic Acid Amplification Techniques/methods , RNA/genetics , RNA/isolation & purificationABSTRACT
OBJECTIVE: To summarize available data concerning hematologic malignancies in pregnancy. DESIGN: Review article. SETTING: Department of Obstetrics and Gynekology, Fakulty of Medicine, Masaryk University and University Hospital Brno. METHODS: Compilation of published data from scientific literature. CONCLUSIONS: Cancer complicating pregnancy is a rare coexistence. The incidence is approximately 1 in 1,000 pregnancies. The most frequent hematologic malignant tumor is Hodgkin's lymphoma, leukemia is less frequent and myeloproliferative diseases complicating pregnancy are sporadic coexistence. Symptoms of these deseases are often nonspecific and disguised in pregnancy, then the diagnosis can be late. It is imperative that a multidisciplinary team involving hematooncologist and obstetrician (pediatric specialist) care for patient with hematologic malignancies. Cleary, every patient have to know whole prognosis and all risk factors of treatment. Optimum timing of delivery is after 36th week of pregnancy (when chemotherapy is ended more than two weeks ago). We prefer vaginal delivery to caesarean section.
Subject(s)
Pregnancy Complications, Neoplastic , Female , Hodgkin Disease/diagnosis , Hodgkin Disease/therapy , Humans , Leukemia/diagnosis , Leukemia/therapy , Myeloproliferative Disorders/diagnosis , Myeloproliferative Disorders/therapy , Pregnancy , Pregnancy Complications, Hematologic/diagnosis , Pregnancy Complications, Hematologic/therapy , Pregnancy Complications, Neoplastic/diagnosis , Pregnancy Complications, Neoplastic/therapyABSTRACT
Abnormalities of the TP53 gene are associated with a particularly severe prognosis in patients with B-cell chronic lymphocytic leukemia (B-CLL). This tumor-suppressor is mostly inactivated by the deletion of one and point mutation of the other allele and has not been previously shown to be hypermutated in B-CLL. We identified two patients whose lymphocytes showed repeatedly an extensive proportion of TP53 mutated cells by FASAY analysis (the yeast functional assay) and harbored various TP53 mutations, mostly single-base substitutions, in individual cells. The mutation targeting exhibited characteristic traits of the somatic hypermutation process. In the first patient (harboring the unmutated IgVH locus) a significant bias to point mutations at CG pairs (21/25; P=0.009), their remarkable preference for the RGYW/WRCY motives (28%) and the highest expression of the activation-induced cytidine deaminase (AID) mRNA among the 34 tested B-CLL samples. In the second patient no CG bias was observed but the targeting of point mutations into the RGYW/WRCY motives was even more prominent here (7/16; 44%). Moreover, six out of eight point mutations affecting AT pairs were localized in the WA/TW motives, which are also characteristic for the somatic hypermutations. This patient, who was IgVH-mutated, already did not express any significant amount of the AID transcript. Our findings add a new aspect to the mosaic of the p53 mutability in B-CLL.
Subject(s)
Genes, p53 , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Mutation , Cytidine Deaminase/genetics , Humans , Lymphocytes/pathology , Point Mutation , Somatic Hypermutation, ImmunoglobulinABSTRACT
UNLABELLED: Alemtuzumab in chronic lymphocytic leukemia treatment: retrospective analysis of outcome according to cytogenetics SUMMARY: Alemtuzumab is effective in B-cell chronic lymphocytic leukemia (CLL) with 17p deletion, which responds poorly to chemotherapeutic agents. Our retrospective study evaluated the benefit of alemtuzumab monotherapy in unselected patients with advanced CLL, categorized by cytogenetic profile. Data were collected from 74 consecutive who had received alemtuzumab. Median of previous therapies was 2. The incidence of cytogenetic abnormalities was: trisomy 12, 10%; 13q deletion, 13%; 11q deletion 25%; 17p deletion, 26%; none of these, 26%. The overall response rate was 65% (11% complete remission, 54% partial remission) in the whole cohort. From start of alemtuzumab therapy, median progression-free survival was 217 days, median time to alternative treatment was 287 days, and median overall survival was 999 days in the total cohort, respectively. Alemtuzumab was effective across all cytogenetic categories evaluated. There were no statistically significant differences between subgroups in the level of efficacy.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neoplasm/therapeutic use , Antineoplastic Agents/therapeutic use , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Adult , Aged , Alemtuzumab , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal, Humanized , Antibodies, Neoplasm/adverse effects , Antineoplastic Agents/adverse effects , Female , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/genetics , Male , Middle Aged , Treatment OutcomeABSTRACT
The registry of patients treated with Thromboreductin (anagrelide) in the Czech Republic contains data concerning patients that have been treated using this drug since 2004. As of June 2009, the total number of patients was 549. The current analysis focused mainly on evaluation of anagrelide dosage needed to achieve a complete response in high-risk patients: reduction in platelet count to below 400 x 10(9)/l, which was also considered as reaching the therapeutic goal. The outcomes of the registry confirm that although anagrelide (Thromboreductin) is a very effective platelet-reducing agent, the administration of which is related to a low incidence of adverse effects and complications, the therapeutic goal is not achieved in all cases and or despite a quick treatment response, the therapeutic goal is achieved more slowly.
Subject(s)
Myeloproliferative Disorders/complications , Platelet Aggregation Inhibitors/therapeutic use , Quinazolines/therapeutic use , Thrombocythemia, Essential/drug therapy , Thrombocytosis/drug therapy , Adult , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Thrombocytosis/complicationsABSTRACT
BACKGROUND: New diagnostics and treatments, including the use of new drugs, have advanced considerably the treatment of acute lymphoplastic leukemia (ALL) in the past few years. Monoclonal antibodies and immunoconjugates targeting antigens CD19 and CD22 show greater efficacy and more favourable toxicity profiles than standard salvage chemotherapeutic protocols. Two of these drugs - blinatumomab and inotuzumab ozogamicin - have already made their way into clinical practice. Ponatinib and other new generation tyrosine kinase inhibitors allow dose reduction of intensive cytostatic regimens in Ph-positive ALL patients and slowly start to overshadow the importance of allogeneic hematopoietic cell transplants. For the time being, their use is reserved for relapsed/refractory ALL, but they are already available as a first line therapy in clinical trials. An entirely new group of living drugs is emerging for the treatment of ALL - chimeric antigen receptor T-cells produced by genetic modification of native human cells. Chimeric antigen receptor T-cells can be looked upon as in vitro trained professional blast killers. They show an efficacy never seen before for the treatment of relapsed/refractory ALL. On the other hand, this treatment still presents significant risks, mainly due to cytokine release syndrome. Ruxolitinib, mTOR inhibitors, bortezomib, and other drugs for targeted treatment of ALL are currently being evaluated in clinical trials. PURPOSE: The article focuses on current options and news in the field of relapsed and refractory ALL treatment. This work was created at Masaryk University as part of the project “New Approaches in Research, Diagnostics and Therapy of Hematological Malignancies VI”, number MUNI/A/1105/2018, supported by Czech Ministry of Education, Youth and Sports in 2019. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 28. 8. 2018 Accepted: 10. 1. 2019.