RESUMEN
The bendamustine-rituximab (BR) schedule is an efficient first-line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression-free (PFS) and overall survival (OS). With a median follow-up of 76.1 months (95% confidence interval [CI] 69.9-80.6), 5-year outcome is still excellent at 66.63% (95% CI 56.09-79.17) for PFS and 80.01% (95% CI 70.82-90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99-27.64) at 66 months. Relapsed patients who received ibrutinib as second-line clearly benefited from this schedule. This confirms current recommendations suggesting BR long-term efficacy as first-line option in WM.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Clorhidrato de Bendamustina , Rituximab , Macroglobulinemia de Waldenström , Humanos , Clorhidrato de Bendamustina/administración & dosificación , Clorhidrato de Bendamustina/uso terapéutico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Macroglobulinemia de Waldenström/mortalidad , Rituximab/administración & dosificación , Rituximab/uso terapéutico , Masculino , Femenino , Anciano , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Francia , Estudios de Seguimiento , Resultado del TratamientoRESUMEN
We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.
Asunto(s)
Síndrome Hipereosinofílico , Mutación , Factor de Transcripción STAT5 , Humanos , Síndrome Hipereosinofílico/genética , Síndrome Hipereosinofílico/tratamiento farmacológico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Anciano , Factor de Transcripción STAT5/genética , Janus Quinasa 2/genética , Transducción de Señal , Janus Quinasa 1/genética , Anciano de 80 o más Años , Pirimidinas/uso terapéutico , Adulto JovenRESUMEN
Conventional therapies for patients with T-cell prolymphocytic leukemia (T-PLL), such as cytotoxic chemotherapy and alemtuzumab, have limited efficacy and considerable toxicity. Several novel agent classes have demonstrated preclinical activity in T-PLL, including inhibitors of the JAK/STAT and T-cell receptor pathways, as well as histone deacetylase (HDAC) inhibitors. Recently, the BCL-2 inhibitor venetoclax also showed some clinical activity in T-PLL. We sought to characterize functional apoptotic dependencies in T-PLL to identify a novel combination therapy in this disease. Twenty-four samples from patients with primary T-PLL were studied by using BH3 profiling, a functional assay to assess the propensity of a cell to undergo apoptosis (priming) and the relative dependence of a cell on different antiapoptotic proteins. Primary T-PLL cells had a relatively low level of priming for apoptosis and predominantly depended on BCL-2 and MCL-1 proteins for survival. Selective pharmacologic inhibition of BCL-2 or MCL-1 induced cell death in primary T-PLL cells. Targeting the JAK/STAT pathway with the JAK1/2 inhibitor ruxolitinib or HDAC with belinostat both independently increased dependence on BCL-2 but not MCL-1, thereby sensitizing T-PLL cells to venetoclax. Based on these results, we treated 2 patients with refractory T-PLL with a combination of venetoclax and ruxolitinib. We observed a deep response in JAK3-mutated T-PLL and a stabilization of the nonmutated disease. Our functional, precision-medicine-based approach identified inhibitors of HDAC and the JAK/STAT pathway as promising combination partners for venetoclax, warranting a clinical exploration of such combinations in T-PLL.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Leucemia Prolinfocítica de Células T/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas de Neoplasias , Anciano , Anciano de 80 o más Años , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Femenino , Humanos , Leucemia Prolinfocítica de Células T/metabolismo , Leucemia Prolinfocítica de Células T/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/antagonistas & inhibidores , Proteínas de Neoplasias/metabolismo , Nitrilos/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Sulfonamidas/farmacologíaRESUMEN
Anti-CD20 monoclonal antibodies are widely used for the treatment of hematological malignancies or autoimmune disease but may be responsible for a secondary humoral deficiency. In the context of COVID-19 infection, this may prevent the elicitation of a specific SARS-CoV-2 antibody response. We report a series of 17 consecutive patients with profound B-cell lymphopenia and prolonged COVID-19 symptoms, negative immunoglobulin G (IgG)-IgM SARS-CoV-2 serology, and positive RNAemia measured by digital polymerase chain reaction who were treated with 4 units of COVID-19 convalescent plasma. Within 48 hours of transfusion, all but 1 patient experienced an improvement of clinical symptoms. The inflammatory syndrome abated within a week. Only 1 patient who needed mechanical ventilation for severe COVID-19 disease died of bacterial pneumonia. SARS-CoV-2 RNAemia decreased to below the sensitivity threshold in all 9 evaluated patients. In 3 patients, virus-specific T-cell responses were analyzed using T-cell enzyme-linked immunospot assay before convalescent plasma transfusion. All showed a maintained SARS-CoV-2 T-cell response and poor cross-response to other coronaviruses. No adverse event was reported. Convalescent plasma with anti-SARS-CoV-2 antibodies appears to be a very promising approach in the context of protracted COVID-19 symptoms in patients unable to mount a specific humoral response to SARS-CoV-2.
Asunto(s)
Anticuerpos Antivirales/inmunología , Linfocitos B/patología , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Sueros Inmunes/administración & dosificación , Linfopenia/terapia , Neumonía Viral/inmunología , Adulto , Anciano , Linfocitos B/inmunología , Transfusión de Componentes Sanguíneos , COVID-19 , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Femenino , Francia , Neoplasias Hematológicas/complicaciones , Humanos , Inmunización Pasiva , Linfopenia/etiología , Linfopenia/patología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/sangre , Neumonía Viral/terapia , Neumonía Viral/virología , SARS-CoV-2 , Sueroterapia para COVID-19RESUMEN
BACKGROUND: The detection of KMT2A gene rearrangements have an important impact on the prognosis and management of acute leukemias. These alterations most commonly involve reciprocal translocations at specific breakpoint regions within KMT2A. To date, more than 100 translocation partner genes of KMT2A have been identified, with different effects on risk stratification. METHODS AND RESULTS: We report the case of a mature plasmacytoid dendritic cells proliferation associated with B lymphoblasts harboring a KMT2A-ARHGEF12 fusion. This rare rearrangement, resulting from a cryptic deletion on the long arm of chromosome 11, is located outside the known major and minor breakpoint regions of KMT2A, not reported to date. The review of the few cases of KMT2A-ARHGEF12 reveals the tendency of this deletion to occur in therapy related hematologic neoplasm and confer unfavorable prognosis. CONCLUSION: This review sheds light into the rare KMT2A-ARHGEF12 fusion in leukemia. Reporting rare chimeras is essential to improve knowledge about the biological mechanism and associated clinical consequences.
Asunto(s)
Leucemia Mieloide Aguda , Proteínas de Fusión Oncogénica/genética , Médula Ósea/patología , Resultado Fatal , Estudios de Seguimiento , Reordenamiento Génico , Humanos , Leucemia Mieloide Aguda/diagnóstico , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/genética , Masculino , Persona de Mediana Edad , Neoplasia Residual/diagnóstico , PronósticoRESUMEN
Histological transformation (HT) to diffuse large B-cell lymphoma (DLBCL) is a rare and poorly reported complication of Waldenström macroglobulinaemia (WM). We performed a retrospective study of 77 WM patients with biopsy-proven transformation to DLBCL. The median time from WM diagnosis to HT was 4·6 years and 16 patients (21%) had never been treated for WM. At HT, extranodal sites were observed in 91% of patients with a rather high incidence of central nervous system, cutaneous or testicular involvement. Fluorodeoxyglucose-positron emission tomography was performed in half of the patients and the median maximum standardized uptake value was 15 for transformed disease. More than 80% of cases with available data for assessment by the Hans' algorithm harboured a non-germinal centre B-cell phenotype. First-line treatment for transformation consisted of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone)-like regimen in 85% of patients. The overall response rate after first-line treatment was 61% and the median overall survival was only 16 months for the entire cohort. Time to transformation above 5 years (P = 0·0004) and elevated LDH (P = 0·02) were associated with worse outcome. Based on these findings, HT should be considered and lead to a biopsy in WM patients presenting with extranodal involvement, elevated LDH and constitutional symptoms. The optimal therapeutic approaches remain to be defined.
Asunto(s)
Transformación Celular Neoplásica/patología , Linfoma de Células B Grandes Difuso/patología , Macroglobulinemia de Waldenström/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Biopsia , Ciclofosfamida/uso terapéutico , Doxorrubicina/uso terapéutico , Femenino , Fluorodesoxiglucosa F18 , Humanos , L-Lactato Deshidrogenasa/sangre , Linfoma de Células B Grandes Difuso/diagnóstico por imagen , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Tomografía de Emisión de Positrones/métodos , Prednisona/uso terapéutico , Pronóstico , Estudios Retrospectivos , Factores de Riesgo , Rituximab , Análisis de Supervivencia , Tomografía Computarizada por Rayos X , Resultado del Tratamiento , Vincristina/uso terapéutico , Macroglobulinemia de Waldenström/diagnóstico por imagenAsunto(s)
COVID-19 , Leucemia Linfocítica Crónica de Células B , Linfoma , Antígenos CD20/genética , Humanos , Inmunoglobulinas , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/patología , Linfoma/tratamiento farmacológico , ARN Mensajero , Rituximab/uso terapéuticoAsunto(s)
Leucemia Linfocítica Crónica de Células B/patología , Neoplasias Cutáneas/patología , Piel/patología , Adulto , Anciano , Anciano de 80 o más Años , Linfocitos B/patología , Femenino , Francia/epidemiología , Humanos , Leucemia Linfocítica Crónica de Células B/epidemiología , Leucemia Linfocítica Crónica de Células B/genética , Masculino , Persona de Mediana Edad , Mutación , Neoplasias Cutáneas/epidemiología , Neoplasias Cutáneas/genética , Resultado del TratamientoAsunto(s)
Anemia Hemolítica Autoinmune , Betacoronavirus , Infecciones por Coronavirus , Pandemias , Neumonía Viral , Anciano , Anemia Hemolítica Autoinmune/epidemiología , Anemia Hemolítica Autoinmune/etiología , Anemia Hemolítica Autoinmune/terapia , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/terapia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonía Viral/complicaciones , Neumonía Viral/epidemiología , Neumonía Viral/terapia , SARS-CoV-2Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Macroglobulinemia de Waldenström/tratamiento farmacológico , Adulto , Anciano , Clorhidrato de Bendamustina/uso terapéutico , Femenino , Humanos , Trastornos Linfoproliferativos/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Rituximab/uso terapéuticoAsunto(s)
Enfermedades Autoinmunes , Enfermedades Hematológicas , Leucemia Linfocítica Crónica de Células B , Purinas/administración & dosificación , Pirazoles/administración & dosificación , Pirimidinas/administración & dosificación , Quinazolinonas/administración & dosificación , Adenina/análogos & derivados , Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/mortalidad , Supervivencia sin Enfermedad , Femenino , Enfermedades Hematológicas/tratamiento farmacológico , Enfermedades Hematológicas/mortalidad , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Leucemia Linfocítica Crónica de Células B/mortalidad , Masculino , Piperidinas , Tasa de SupervivenciaRESUMEN
Emicizumab is a bispecific antibody that mimics the function of factor VIII (FVIII) and is indicated for prophylactic use in patients with congenital hemophilia A with or without inhibitors. Acquired hemophilia A (AHA) is a rare and severe disorder causes by autoantibodies that inhibit FVIII. In AHA, acute bleeding are managed with bypassing agents but several reports described the off-label use of emicizumab. The aim of this article is to describe two cases of AHA treated with emicizumab and a review of the scientific littérature. Reports indicate that the use of emicizumab is efficacious to treat acute bleeding with less thrombotic events thant with bypassing agents and with a reduced hospitalisation duration. Nevertheless biological monitoring is more complicated with assay interferences and a persistent circulation more than 6 months after the last injection was observed for our two patients.
RESUMEN
Immunocompromised individuals such as patients with chronic lymphocytic leukemia (CLL) are at risk of impaired immune responses to vaccination. The objective of our study was to evaluate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific antibody responses in patients with CLL after the first, second, and third doses of the BNT162b2 or mRNA-1273 vaccines and after a single dose for patients with confirmed previous COVID-19. In all, 530 patients were included in the study. Patients received 2 doses at a 4-week interval and a third dose if they were seronegative after the second dose. Response rate was 27% after dose 1 and 52% after dose 2. Post-dose 2 treatment-naïve patients had the highest response rate (72%) followed by patients previously treated by chemoimmunotherapy (60%). Among patients receiving therapy, those receiving Bruton tyrosine kinase inhibitor alone (22%) or in combination with anti-CD20 monoclonal antibodies or venetoclax (0%) had the poorer response rate whereas patients who received venetoclax monotherapy achieved a significantly higher response rate (52%). A multivariable analysis identified age older than 65 years, ongoing CLL treatment, and gamma globulin ≤6 g/L as independent predictors of the absence of seroconversion. Post-dose 2 seronegative patients had a global response rate of 35% after dose 3. This study provides an argument for the use of a third dose and for prophylactic SARS-CoV-2 neutralizing monoclonal antibodies.
Asunto(s)
COVID-19 , Leucemia Linfocítica Crónica de Células B , Vacuna nCoV-2019 mRNA-1273 , Anciano , Anticuerpos Antivirales , Vacuna BNT162 , Vacunas contra la COVID-19 , Humanos , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , ARN Mensajero/genética , SARS-CoV-2RESUMEN
PURPOSE In patients with acute myeloid leukemia (AML), induction chemotherapy is based on standard doses of anthracyclines and cytarabine. High doses of cytarabine have been reported as being too toxic for patients older than age 50 years, but few studies have evaluated intensified doses of anthracyclines. PATIENTS AND METHODS In this randomized Acute Leukemia French Association 9801 (ALFA-9801) study, high doses of daunorubicin (DNR; 80 mg/m(2)/d x 3 days) or idarubicin (IDA4; 12 mg/m(2)/d x 4 days) were compared with standard doses of idarubicin (IDA3; 12 mg/m(2)/d x 3 days) for remission induction in patients age 50 to 70 years, with an event-free survival (EFS) end point. After two consolidation courses based on intermediate doses of cytarabine, patients in continuous remission were randomly assigned to receive or not receive maintenance therapy with recombinant interleukin-2 (rIL-2; 5 x 10(6) U/m(2) x 5 days each month) for a total duration of 12 months. A total of 468 patients entered the study (median age, 60 years). Results Overall complete remission rate was 77% with significant differences among the three randomization arms (83%, 78%, and 70% in the IDA3, IDA4, and DNR arms, respectively; P = .04). However, no significant differences were observed in relapse incidence, EFS, or overall survival among the three arms. In the 161 patients randomly assigned for maintenance therapy, no difference in outcome was observed between the rIL-2 and the no further treatment arms. CONCLUSION Neither intensification of anthracycline doses nor maintenance with rIL-2 showed a significant impact on AML course, at least as scheduled in this trial.