ABSTRACT
Imatinib is the most common first-line tyrosine kinase inhibitor (TKI) used to treat chronic-phase chronic myeloid leukemia (CP-CML). However, only a proportion of patients achieve major molecular response (MMR), so there is a need to find biological factors that aid the selection of the optimal therapeutic strategy (imatinib vs. more potent second-generation TKIs). The aim of this retrospective study was to understand the contribution of germline single-nucleotide variants (gSNVs) in the achievement of MMR with imatinib. In particular, a discovery cohort including 45 CP-CML patients was analyzed through the DMET array, which interrogates 1936 variants in 231 genes related to the absorption, distribution, metabolism and excretion (ADME) process. Variants statistically significant in the discovery cohort were then tested in an extended and independent cohort of 137 CP-CML patients. Finally, a total of 7 gSNVs (ABCG1-rs492338, ABCB11-rs496550, ABCB11-rs497692, CYP2D6-rs1135840, CYP11B1-rs7003319, MAT1A-rs4934027 and SLC22A1-rs628031) and one haplotype in the ABCB11 gene were significantly associated with the achievement of MMR with first-line imatinibtreatment. In conclusion, we identified a genetic signature of response to imatinib in CP-CML patients that could be useful in selecting those patients that may benefit from starting imatinib as first-line therapy, therefore avoiding the toxicity related to second-generation TKIs.
ABSTRACT
BACKGROUND: Autoimmune hemolytic anemia (AIHA) is a rare entity during pregnancy. The fetal risk is determined primarily by the ability of autoantibodies to cross the placental barrier. Currently, the establishment of a standardized antenatal care in cases with AIHA remains as a pending issue. CASES: Firstly, we describe a case of a 17-week pregnant woman that was diagnosed with cold agglutinin mediated (C3 and IgM) AIHA. Treatment was started with prednisone, showing initial improvement, but requiring intravenous gammaglobulins at 27 weeks. During the fetal follow-up, all studies showed normal results. In the third trimester, when there was a clinic and analytic maternal improvement, an unexpected fetal death occurred. Secondly, we present a case of a 30-week pregnant woman, diagnosed with warm antibody (IgG) AIHA. Despite the ability of IgG to cross the placental barrier, the serial measurements of the Middle Cerebral Artery (MCA) peak systolic velocity were always normal and childbirth occurred at term without any adverse perinatal outcome. CONCLUSION: During pregnancy, identification of the type antibodies in AIHA is crucial to estimate the potential maternal and fetal risks and to establish the follow-up. The interaction of the complement cascade with the coagulation cascade could be an explanation for a perinatal adverse outcome despite the inability of the IgM to cross the placental barrier.
Subject(s)
Anemia, Hemolytic, Autoimmune , Anemia, Hemolytic, Autoimmune/drug therapy , Autoantibodies , Female , Follow-Up Studies , Humans , Placenta , Pregnancy , Prenatal CareABSTRACT
Tyrosine kinase inhibitors have dramatically changed the outcome of chronic myeloid leukemia (CML), and nowadays, one of the main treatment goals is the achievement of deep molecular responses (DMRs), which can eventually lead to therapy discontinuation approaches. Few biological factors at diagnosis have been associated with this level of response. Telomere length (TL) in peripheral blood cells of patients with CML has been related to disease stage, response to therapy and disease progression, but little is known about its role on DMR. In this study, we analyzed if age-adjusted TL (referred as "delta-TL") at diagnosis of chronic phase (CP)-CML might correlate with the achievement of DMR under first-line imatinib treatment. TL from 96 CP-CML patients had been retrospectively analyzed at diagnosis by monochrome multiplex quantitative PCR. We observed that patients with longer age-adjusted telomeres at diagnosis had higher probabilities to achieve DMR with imatinib than those with shortened telomeres (P = 0.035 when delta-TL was studied as a continuous variable and P = 0.047 when categorized by the median). Moreover, patients carrying long telomeres also achieved major molecular response significantly earlier (P = 0.012). This study provides proof of concept that TL has a role in CML biology and when measured at diagnosis of CP-CML could help to identify patients likely to achieve DMR to first-line imatinib treatment.
ABSTRACT
The most frequent BCR-ABL1-p210 transcripts in chronic myeloid leukemia (CML) are e14a2 and e13a2. Imatinib (IM) is the most common first-line tyrosine-kinase inhibitor (TKI) used to treat CML. Some studies suggest that BCR-ABL1 transcript types confer different responses to IM. The objective of this study was to correlate the expression of e14a2 or e13a2 to clinical characteristics, cumulative cytogenetic and molecular responses to IM, acquisition of deep molecular response (DMR) and its duration (sDMR), progression rate (CIP), overall survival (OS), and treatment-free remission (TFR) rate. We studied 202 CML patients, 76 expressing the e13a2 and 126 the e14a2, and correlated the differential transcript expression with the above-mentioned parameters. There were no differences in the cumulative incidence of cytogenetic responses nor in the acquisition of DMR and sDMR between the two groups, but the e14a2 transcript had a positive impact on molecular response during the first 6 months, whereas the e13a2 was associated with improved long-term OS. No correlation was observed between the transcript type and TFR rate.
Subject(s)
Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Niacinamide/analogs & derivatives , Protein Kinase Inhibitors/therapeutic use , Pyrazoles/therapeutic use , Adult , Aged , Aged, 80 and over , Female , Fusion Proteins, bcr-abl/antagonists & inhibitors , Humans , Male , Middle Aged , Niacinamide/adverse effects , Niacinamide/therapeutic use , Protein Kinase Inhibitors/adverse effects , Pyrazoles/adverse effects , Treatment Outcome , Young AdultSubject(s)
DNA Mutational Analysis/methods , DNA/genetics , High-Throughput Nucleotide Sequencing , Primary Myelofibrosis/genetics , Receptors, Thrombopoietin/genetics , Thrombocythemia, Essential/genetics , Adult , Aged , Aged, 80 and over , DNA (Cytosine-5-)-Methyltransferases/genetics , DNA Methyltransferase 3A , DNA-Binding Proteins/genetics , Dioxygenases , Exons/genetics , Female , Humans , Male , Middle Aged , Phosphoproteins/genetics , Primary Myelofibrosis/diagnosis , Primary Myelofibrosis/mortality , Prognosis , Proto-Oncogene Proteins/genetics , RNA Splicing Factors/genetics , Thrombocythemia, Essential/diagnosis , Thrombocythemia, Essential/mortalityABSTRACT
No disponible
Subject(s)
Humans , Female , Middle Aged , Cryptococcosis/complications , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/drug therapy , Cryptococcosis/drug therapy , Opportunistic Infections/diagnosis , Opportunistic Infections/pathology , Risk Factors , Amphotericin B/administration & dosage , Antibodies, Monoclonal/administration & dosage , Cryptococcus neoformans/isolation & purification , Cryptococcus neoformans/drug effects , Flucytosine/administration & dosage , Fluconazole/administration & dosageSubject(s)
Cryptococcus neoformans/isolation & purification , Lymphoma, T-Cell/complications , Meningitis, Cryptococcal/diagnosis , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Confusion/etiology , Female , Humans , Lymphoma, T-Cell/drug therapy , Meningitis, Cryptococcal/complications , Middle AgedABSTRACT
Over half of chronic myeloid leukemia (CML) patients in deep molecular response do not lose the major molecular response (MMR) after stopping treatment with tyrosine kinase inhibitors (TKI). This strategy is safe in clinical trials, but its applicability in the real-life setting remains unsettled. We describe the outcomes after TKI discontinuation in a nationwide series of 236 CML patients. Median follow-up from treatment discontinuation was 21.5 months and 5 patients died from CML-unrelated causes. TKI therapy was reinitiated due to MMR loss (n = 52), increase ≥ 1 log in BCR-ABL transcript level without losing MMR (n = 12), patient preference (n = 2), and withdrawal syndrome (n = 1). Treatment-free remission rate at 4 years was 64% (95% confidence interval, CI: 55%-72%). Cumulative incidence of molecular recurrence at 3 years was 33% (95% CI: 26%-38%). TKI treatment for < 5 years and MR4.5 duration shorter than 4 years were both associated with higher incidence of molecular recurrence. No patient had disease progression. Response status at last control was: MR4.5 (n = 196), MR4 (n = 15), MMR (n = 14), complete cytogenetic response (n = 10), and other (n = 1). A significant increase in Hb and cholesterol levels was observed after imatinib withdrawal. Our results demonstrate that TKI treatment discontinuation is feasible in real-life clinical practice.
Subject(s)
Anticarcinogenic Agents/therapeutic use , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/drug therapy , Protein Kinase Inhibitors/therapeutic use , Aged , Anticarcinogenic Agents/administration & dosage , Anticarcinogenic Agents/adverse effects , Biomarkers , Drug Resistance, Neoplasm , Female , Follow-Up Studies , Fusion Proteins, bcr-abl/antagonists & inhibitors , Fusion Proteins, bcr-abl/genetics , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/mortality , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Male , Middle Aged , Proportional Hazards Models , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/adverse effects , Recurrence , Treatment OutcomeABSTRACT
No disponible
Subject(s)
Humans , Female , Aged , Cerebellopontine Angle/physiopathology , Stroke/diagnosis , Kidney Neoplasms/diagnosis , Lymphoma, B-Cell/diagnosis , Lymphoma, Large B-Cell, Diffuse/diagnosisSubject(s)
Brain Infarction/etiology , Cerebellopontine Angle/blood supply , Kidney Glomerulus/pathology , Lymphoma, Large B-Cell, Diffuse/diagnosis , Vascular Neoplasms/diagnosis , Aged , Antibodies, Monoclonal, Murine-Derived/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biopsy , Bone Marrow/pathology , Cyclophosphamide/administration & dosage , Diagnostic Imaging , Doxorubicin/administration & dosage , Female , Humans , Kidney Glomerulus/blood supply , Kidney Glomerulus/diagnostic imaging , Lymphoma, Large B-Cell, Diffuse/complications , Lymphoma, Large B-Cell, Diffuse/drug therapy , Prednisone/administration & dosage , Radiography , Rituximab , Vascular Neoplasms/complications , Vincristine/administration & dosageABSTRACT
Fundamento y objetivo: Varios estudios han demostrado la viabilidad de trasplante de células madre autólogas (ASCT) en pacientes con linfoma y el virus de la inmunodeficiencia humana (VIH). La infección por VIH se ha descrito como un factor de riesgo para la movilización de los pobres. El objetivo de este estudio fue comparar los resultados de dos estrategias de movilización de las células madre sanguíneas periféricas (CMSP) en pacientes con linfoma y la infección por VIH en siete hospitales españoles. Pacientes y métodos: Las variables recogidas fueron: características demográficas, clínicas y biológicas, quimioterapias anteriores y los resultados, así como las estrategias de movilización de (clasificados en dos grupos: 1) G-CSF, y 2) el G-CSF de quimioterapia +). Resultados: Entre enero de 2000 y mayo de 2010, 42 pacientes con linfoma y la infección por VIH fueron remitidos para ASCT. La tasa de éxito en la movilización (colección> 1,60 × 10 6 células CD34 / kg) con el primer régimen fue del 67%, sin diferencias entre los pacientes movilizados con G-CSF o con G-CSF + quimioterapia (16 [72%] y 12 [60%], respectivamente, p = 0,382). El estado del linfoma en el momento de la movilización fue el único factor para la movilización de éxito (20/22 pacientes [91%] en remisión completa [RC] movilizado adecuadamente frente a 5/12 [58%] en remisión parcial [RP], p = 0,038). Conclusiones: En los pacientes con linfoma y la infección por el VIH, la movilización con G-CSF fue tan eficaz como la movilización con quimioterapia seguida de G-CSF. El estadio de la enfermedad antes de la movilización fue el principal factor de riesgo para el éxito de la movilización, con mejores resultados en los pacientes movilizados en remisión del linfoma (AU)
Background and objective: Several studies have demonstrated the feasibility of autologous stem cell transplantation (ASCT) in patients with lymphoma and human immunodeficiency virus (HIV) infection. HIV infection has been described as a risk factor for poor mobilization. The aim of this study was to compare the results of two mobilization strategies of peripheral blood stem cells (PBSC) in patients with lymphoma and HIV infection in seven Spanish hospitals. Patients and methods: The following variables were collected: demographic, clinical and biological features, previous chemotherapies and outcomes, as well as mobilization's strategies (classified in two groups: 1) G-CSF, and 2) G-CSF + chemotherapy). Results: Between January 2000 and May 2010, 42 patients with lymphoma and HIV infection were referred for ASCT. The rate of successful mobilization (collection >1.60 × 106 CD34 cells/kg) with the first regimen was 67%, with no differences between those patients mobilized with G-CSF or with G-CSF + chemotherapy (16 [72%] and 12 [60%], respectively; p=0.382). The status of the lymphoma at the time of mobilization was the only factor for successful mobilization (20/22 patients [91%] in complete remission [CR] mobilized adequately versus 5/12 [58%] in partial remission [PR]; p=0.038). Conclusions: In patients with lymphoma and HIV infection, mobilization with G-CSF was as effective as mobilization with chemotherapy followed by G-CSF. The stage of disease prior to the mobilization was the main risk factor for the success of mobilization, with better results in patients mobilized in remission of the lymphoma (AU)
Subject(s)
Humans , Peripheral Blood Stem Cell Transplantation/methods , Lymphoma, AIDS-Related/drug therapy , Hematopoietic Stem Cell Mobilization/methods , HIV Infections/drug therapy , HIV/pathogenicityABSTRACT
No disponible
Subject(s)
Humans , Male , Aged , Lymphoma/pathology , HIV Infections/complications , Testicular Neoplasms/pathology , OrchiectomyABSTRACT
No disponible
Subject(s)
Humans , Male , Young Adult , Hodgkin Disease/complications , Crohn Disease/complications , Azathioprine/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Epilepsy/complicationsSubject(s)
Azathioprine/therapeutic use , Crohn Disease/drug therapy , Hodgkin Disease/diagnosis , Immunosuppressive Agents/therapeutic use , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Azathioprine/adverse effects , Crohn Disease/complications , Hodgkin Disease/chemically induced , Humans , Immunosuppressive Agents/adverse effects , Male , Young AdultABSTRACT
BACKGROUND AND OBJECTIVE: Several studies have demonstrated the feasibility of autologous stem cell transplantation (ASCT) in patients with lymphoma and human immunodeficiency virus (HIV) infection. HIV infection has been described as a risk factor for poor mobilization. The aim of this study was to compare the results of two mobilization strategies of peripheral blood stem cells (PBSC) in patients with lymphoma and HIV infection in seven Spanish hospitals. PATIENTS AND METHODS: The following variables were collected: demographic, clinical and biological features, previous chemotherapies and outcomes, as well as mobilization's strategies (classified in two groups: 1) G-CSF, and 2) G-CSF + chemotherapy). RESULTS: Between January 2000 and May 2010, 42 patients with lymphoma and HIV infection were referred for ASCT. The rate of successful mobilization (collection >1.60 × 10(6) CD34 cells/kg) with the first regimen was 67%, with no differences between those patients mobilized with G-CSF or with G-CSF + chemotherapy (16 [72%] and 12 [60%], respectively; p=0.382). The status of the lymphoma at the time of mobilization was the only factor for successful mobilization (20/22 patients [91%] in complete remission [CR] mobilized adequately versus 5/12 [58%] in partial remission [PR]; p=0.038). CONCLUSIONS: In patients with lymphoma and HIV infection, mobilization with G-CSF was as effective as mobilization with chemotherapy followed by G-CSF. The stage of disease prior to the mobilization was the main risk factor for the success of mobilization, with better results in patients mobilized in remission of the lymphoma.
