Selinexor in Patients from Argentina with Multiple Myeloma Treated with Multiple Prior Therapies: A Case Series.

BACKGROUND Numerous treatment options are available for patients with multiple myeloma (MM). Because of the course of the disease, most patients will experience serial relapse or the MM will become refractory to most of these treatments, leaving patients with few or no treatment options over time. Selinexor, a treatment with a novel mechanism of action, is an oral selective inhibitor of nuclear export (SINE) compound that blocks exportin 1, the major nuclear exporter of tumor suppressor proteins. CASE REPORT In this case series, we report on treatment with the weekly oral administration of selinexor combined with bortezomib and dexamethasone (XVd) in 3 patients from Argentina who were heavily treated (5-7 prior therapies) for MM that relapsed or was refractory to each previous treatment. Two patients had the high-risk cytogenetic abnormality del(17p). All 3 patients experienced efficacy with XVd reaching a best response of partial response or very good partial response. These responses were consistent with those of patients from the BOSTON study who were treated with XVd but were less heavily pretreated (1-3 prior therapies) and had a shorter median time since diagnosis of MM (7 years vs 3.7 years). The 3 patients experienced adverse events (AEs) that included nausea, thrombocytopenia, asthenia, and fatigue, which were similar to the most commonly reported AEs associated with selinexor treatment. CONCLUSIONS With its oral administration, novel mechanism of action, and responses in heavily pretreated patients, selinexor may help to address an important clinical need in the treatment of patients with relapsed/refractory MM.

Venetoclax-resistant CLL cells show a highly activated and proliferative phenotype.

Venetoclax treatment has demonstrated efficacy and a safety profile in chronic lymphocytic leukemia (CLL) patients, however the emergence of resistant cells is a current complication. We and others, previously reported that the activation of CLL cells by signals that mimic microenvironment stimuli favors the upregulation of anti-apoptotic proteins from B cell lymphoma-2 (BCL-2) family that are not targeted by venetoclax, reducing malignant cell sensitivity to the drug. We here studied venetoclax-resistant CLL cells generated in vitro by autologous activated T lymphocytes, and found that they showed an aggressive phenotype characterized by increased expression of activation and proliferation markers. Moreover, surviving cells expressed high levels of B cell lymphoma-extra-large (BCL-XL) and/or myeloid cell leukemia-1 (MCL-1), and a sustained resistance to a second treatment with the drug. Interestingly, the spleen tyrosine kinase (SYK) inhibitor entospletinib, and the phosphoinositide 3-kinase delta (PI3Kδ) inhibitor idelalisib, reduced T cell activation, impaired the generation of leukemic cells with this aggressive phenotype, and were able to restore CLL sensitivity to venetoclax. Our data highlight a novel combination to overcome resistance to venetoclax in CLL.

Mild COVID-19 Illness as a Risk Factor for Venous Thromboembolism.

Introduction From the beginning of the current coronavirus disease 2019 (COVID-19) pandemic, there is cumulative evidence suggesting that patients hospitalized due to this disease are at a high risk for venous thromboembolism (VTE). The association between mild non-hospitalized illness and VTE is unclear. The purpose of this research is to assess the association between VTE and mild COVID-19 infection. Methods A case-control study was conducted. The cases were adult patients diagnosed with VTE from March 1, 2020 to March 31, 2021. The controls were randomly chosen adult patients who required healthcare services that were equivalent to those of the cases, for any cause, during the same time period, without a VTE diagnosis. To assess the association between mild COVID and VTE, a multivariate logistic regression analysis was conducted, considering other thromboembolic risk variables, such as age, gender and active cancer, among others. A p-value <0.05 was considered statistically significant. Results A total of 186 cases and 475 controls were analyzed. There were 21 (11.3%) and 31 (6.5%) patients infected with mild COVID-19 in the previous three months in the groups of cases and controls, respectively. Mild COVID-19 infection was statistically significant as a risk factor for VTE both in the univariate analysis and in the multivariate analysis, OR=1.82 (95% CI 1.02-3.26) and OR=2.62 (95% CI 1.34-5.13), respectively. Conclusion Mild COVID-19 infection might be an independent risk factor for VTE. We conclude that the results suggest some thromboprophylaxis strategy should be considered in certain patients with COVID-19 infection in an outpatient fashion.

Clinical characteristics and evolution of hematological patients and COVID-19 in Argentina: a report from the Argentine Society of Hematology.

Individuals with malignancies and COVID-19 have a lower survival compared with the general population. However, the information about the impact of COVID-19 on the whole hematological population is scarce. We aimed to describe the 30th day overall survival (OS) after COVID-19 infection in patients with a hematological disease in Argentina. A completely anonymous survey from the Argentine Society of Hematology was delivered to all the hematologists in Argentina; it started in April 2020. A cut-off to analyze the data was performed in December 2020 and, finally, 419 patients were reported and suitable for the analysis (average age: 58 years, 90% with malignant diseases). After the COVID-19 diagnosis, the 30-day OS for the whole population was 80.2%. From the entire group (419), 101 (24.1%) individuals required intensive care unit admission, where the 30-day OS was 46.6%. Among allogeneic stem cell transplant recipients, the 30-day OS was 70.3%. Factors associated with a low OS were two or more comorbidities, an active hematological disease and history of chemotherapy. In individuals with the three factors, the 30-day OS was 49.6% while the 30-day OS in those without those factors was 100%. Patients with hematological diseases have a higher mortality than the general population. This group represents a challenge and requires careful decision-making of the treatment in order not to compromise the chances of cure.

El presente estudio tuvo por objetivo primario conocer la mortalidad de pacientes con enfermedad hematológica que presentaron infección por COVID-19 en Argentina. Para ello se difundió una encuesta desde la Sociedad Argentina de Hematología (SAH) entre los hematológos para informar sobre los pacientes con enfermedades hematológicas y diagnóstico de infección por SARS- CoV-2, entre el 19/4/2020, y el 7/12/2020. Se incluyeron individuos de todas las edades con diagnóstico de enfermedad hematológica benigna o maligna e infección por SARS-CoV-2 confirmada por técnica de RTPCR. Se analizaron 419 pacientes (mediana 58 años; 90% enfermedades malignas). La supervivencia al día 30 fue de 80.2%. La supervivencia fue menor en aquellos que requirieron internación (74.2%), cuidados intensivos (46.6%) y asistencia respiratoria mecánica (36.8%). Entre los trasplantados alogénicos la supervivencia fue 70.3%. Los factores vinculados a la supervivencia global fueron las comorbilidades, el estado de la enfermedad al momento de la infección y el antecedente de quimioterapia. Se pudo establecer un score en el que aquellos que tuvieron un puntaje de 4 alcanzaron una supervivencia del 49.6% al día 30, mientras que la de los pacientes con score 0 fue del 100% a 30 días. En comparación con la población general, los pacientes con enfermedades hematológicas presentan una mayor mortalidad vinculada al COVID-19, motivo por el cual es primordial definir pautas destinadas a disminuir la exposición de los mismos sin comprometer las posibilidades de beneficiarse del tratamiento de la enfermedad de base.

Clinical characteristics and evolution of hematological patients and COVID-19 in Argentina: a report from the Argentine Society of Hematology / Características clínicas y evolución de pacientes hematológicos y COVID-19 en Argentina: datos de la Sociedad Argentina de Hematología

Abstract Individuals with malignancies and COVID-19 have a lower survival compared with the general population. However, the information about the impact of COVID-19 on the whole hematological population is scarce. We aimed to describe the 30th day overall survival (OS) after COVID-19 infection in pa tients with a hematological disease in Argentina. A completely anonymous survey from the Argentine Society of Hematology was delivered to all the hematologists in Argentina; it started in April 2020. A cut-off to analyze the data was performed in December 2020 and, finally, 419 patients were reported and suitable for the analysis (average age: 58 years, 90% with malignant diseases). After the COVID-19 diagnosis, the 30-day OS for the whole population was 80.2%. From the entire group (419), 101 (24.1%) individuals required intensive care unit admission, where the 30-day OS was 46.6%. Among allogeneic stem cell transplant recipients, the 30-day OS was 70.3%. Factors associated with a low OS were two or more comorbidities, an active hematological disease and history of chemotherapy. In individuals with the three factors, the 30-day OS was 49.6% while the 30-day OS in those without those factors was 100%. Patients with hematological diseases have a higher mortality than the general population. This group represents a challenge and requires careful decision-making of the treatment in order not to compromise the chances of cure.

Resumen El presente estudio tuvo por objetivo primario conocer la mortalidad de pacientes con enfermedad hematológica que presentaron infección por COVID-19 en Argentina. Para ello se difundió una encuesta desde la Sociedad Argentina de Hematología (SAH) entre los hematológos para informar sobre los pacientes con enfermedades hematológicas y diagnóstico de infección por SARS- CoV-2, entre el 19/4/2020, y el 7/12/2020. Se incluyeron individuos de todas las edades con diagnóstico de enfermedad hematológica benigna o maligna e infección por SARS-CoV-2 confirmada por técnica de RT-PCR. Se analizaron 419 pacientes (mediana 58 años; 90% enfermedades malignas). La supervivencia al día 30 fue de 80.2%. La supervivencia fue menor en aquellos que requirieron internación (74.2%), cuidados intensivos (46.6%) y asistencia respiratoria mecánica (36.8%). Entre los trasplantados alogénicos la supervivencia fue 70.3%. Los factores vinculados a la supervivencia global fueron las comorbilidades, el estado de la enfermedad al momento de la infección y el antecedente de quimioterapia. Se pudo establecer un score en el que aquellos que tuvieron un puntaje de 4 alcanzaron una supervivencia del 49.6% al día 30, mientras que la de los pacientes con score 0 fue del 100% a 30 días. En comparación con la población general, los pacientes con enfermedades hematológicas presentan una mayor mortalidad vinculada al COVID-19, motivo por el cual es primordial definir pautas destinadas a disminuir la exposición de los mismos sin comprometer las posibilidades de beneficiarse del tratamiento de la enfermedad de base.

Real-world outcomes for the treatment of relapsed/refractory multiple myeloma patients with lenalidomide-dexamethasone combinations in a Latin American country. A retrospective cohort study from grupo argentino de mieloma múltiple.

OBJECTIVES: We compared the efficacy of lenalidomide-dexamethasone (Rd) based treatments for relapsed/refractory multiple myeloma patients (pts), in a real-world setting. In addition, we evaluated adverse events (AE), progression-free survival (PFS) and overall survival (OS). METHODS: In our retrospective, multicentric study, 156 pts with RRMM were included. 74/156 pts (47%) were refractory to bortezomib (V) and 43/156 (27%) pts to lenalidomide (R), with 24/156 (15%) of pts double refractory. Eighty-six pts (55%) received Rd with carfilzomib (KRd), 30 pts (19%) bortezomib (VRd), 30 pts (19%) daratumumab (DRd), and 10 pts (6%) ixazomib (IRd). RESULTS: The overall response (ORR) (≥ partial response) for the entire cohort was 71%, with a very good partial response rate or better (≥VGPR) of 35%. We found no significant differences in CR or ≥VGRP rates between treatments (p:0.229). Regardless of the combination received, those patients who achieved CR had significantly improved PFS (p: 0.007). The most frequent cause of treatment discontinuation was disease progression in 55/156 pts (35%). 8 pts (5%) discontinued treatment due to treatment-related adverse events (AE). CONCLUSION: This is the first report of Rd combinations for the treatment of RRMM in Latin America. All combinations proved to be effective with an acceptable toxicity.

Three Years Sustained Complete Remission Achieved in a Primary Refractory ALK-Positive Anaplastic T Large Cell Lymphoma Treated with Crizotinib.

The prognosis of the primary refractory anaplastic lymphoma kinase (ALK+) anaplastic T large cell lymphoma is ominous. The identification of molecular targets with potential to drive oncogenesis remains a cornerstone for the designing of new selective cancer therapies. Crizotinib is a selective ATP-competitive inhibitor for ALK, approved for its use in lung cancer with rearrangements on ALK gene. The reported cases describe the use of crizotinib as a bridging strategy prior to allotransplantation; there are no reported prolonged survivals under monotherapy with Crizotinib. We report a case of a primary refractory ALK+ anaplastic large-cell lymphoma that sustains complete response after 3 years of crizotinib monotherapy.

Primary NK/T cell lymphoma nasal type of the colon.

Since nasal NK/T-cell lymphoma and NK/T-cell lymphoma nasal type are rare diseases, colonic involvement has seldom been seen. We report a case of a patient with a primary NK/T-cell lymphoma nasal type of the colon. The patient had no history of malignant diseases and was diagnosed after exhaustive study in the context of fever of unknown origin. The first therapeutic approach followed the DA-EPOCH-protocol: etoposide, prednisone, doxor-rubicin, vincristine and cyclophosphamide. The persistence of constitutional symptoms after the first treatment course motivated the switch to a second line following the SMILE-protocol: dexamethasone, metotrexate, ifosfamide, E.coli L-asparaginase, and etoposide. Despite intensive chemotherapy, the patient died 2 months after the diagnose of an extranodal NK/T-cell lymphoma of the colon and 4 months after the first symptomatic appearance of disease.

[Secondary hemophagocytic syndrome due to recurrent infections in a severely burned patient]. / Síndrome hemofagocítico secundario a infecciones graves en un quemado.

The hemophagocytic syndrome represents an infrequent, occasionally misdiagnosed and usually fatal heterogeneous entity. Infections, drugs, autoimmune diseases and cancer are often triggers of the secondary hemophagocytic syndrome. Its physiopathogenic mechanism is explained by an impaired and inefficacious function of the NK and T cytotoxic cells that leads to an ineffective and uncontrolled immune response, inducing cellular damage, multiorganic failure with macrophage proliferation and hemophagocytosis. The main objective of the different therapeutic options, commonly combinations of steroids and chemotherapy, is the suppression of the uncontrolled immune response. Occasionally, the clinical condition of some patients represents a contraindication for intensive treatment. We report a case of a severely burned patient that fulfilled the revised criteria for the hemophagocytic syndrome and was successfully treated with the combination of intravenous immunoglobulins and steroids.

Síndrome hemofagocítico secundario a infecciones graves en un quemado / Secondary hemophagocytic syndrome due to recurrent infections in a severely burned patient

El síndrome hemofagocítico constituye una entidad infrecuente, heterogénea, subdiagnosticada, y muchas veces fatal. En los casos secundarios, los desencadenantes pueden ser numerosos, tales como infecciones, fármacos, enfermedades autoinmunes y neoplasias. El mecanismo fisiopatogénico se explica por la presencia de una función disminuida o defectuosa de células NK y linfocitos T citotóxicos, que resulta en una activación inmune inefectiva y descontrolada, conduciendo al daño celular, falla multiorgánica y proliferación macrofágica con hemofagocitosis. Existen diferentes opciones terapéuticas, mayormente combinaciones de citostáticos y esteroides, cuyo objetivo es la supresión de la respuesta inmune descontrolada. Ocasionalmente, la condición clínica de algunos pacientes con síndrome hemofagocítico impide la utilización de esquemas terapéuticos intensivos. Comunicamos el caso de un paciente quemado grave, que reúne los criterios diagnósticos de síndrome hemofagocítico, quien presentó una evolución favorable con el tratamiento combinado de esteroides e inmunoglobulinas endovenosas.

The hemophagocytic syndrome represents an infrequent, occasionally misdiagnosed and usually fatal heterogeneous entity. Infections, drugs, autoimmune diseases and cancer are often triggers of the secondary hemophagocytic syndrome. Its physiopathogenic mechanism is explained by an impaired and inefficacious function of the NK and T cytotoxic cells that leads to an ineffective and uncontrolled immune response, inducing cellular damage, multiorganic failure with macrophage proliferation and hemophagocytosis. The main objective of the different therapeutic options, commonly combinations of steroids and chemotherapy, is the suppression of the uncontrolled immune response. Occasionally, the clinical condition of some patients represents a contraindication for intensive treatment. We report a case of a severely burned patient that fulfilled the revised criteria for the hemophagocytic syndrome and was successfully treated with the combination of intravenous immunoglobulins and steroids.

Síndrome hemofagocítico secundario a infecciones graves en un quemado / Secondary hemophagocytic syndrome due to recurrent infections in a severely burned patient

El síndrome hemofagocítico constituye una entidad infrecuente, heterogénea, subdiagnosticada, y muchas veces fatal. En los casos secundarios, los desencadenantes pueden ser numerosos, tales como infecciones, fármacos, enfermedades autoinmunes y neoplasias. El mecanismo fisiopatogénico se explica por la presencia de una función disminuida o defectuosa de células NK y linfocitos T citotóxicos, que resulta en una activación inmune inefectiva y descontrolada, conduciendo al daño celular, falla multiorgánica y proliferación macrofágica con hemofagocitosis. Existen diferentes opciones terapéuticas, mayormente combinaciones de citostáticos y esteroides, cuyo objetivo es la supresión de la respuesta inmune descontrolada. Ocasionalmente, la condición clínica de algunos pacientes con síndrome hemofagocítico impide la utilización de esquemas terapéuticos intensivos. Comunicamos el caso de un paciente quemado grave, que reúne los criterios diagnósticos de síndrome hemofagocítico, quien presentó una evolución favorable con el tratamiento combinado de esteroides e inmunoglobulinas endovenosas.(AU)

The hemophagocytic syndrome represents an infrequent, occasionally misdiagnosed and usually fatal heterogeneous entity. Infections, drugs, autoimmune diseases and cancer are often triggers of the secondary hemophagocytic syndrome. Its physiopathogenic mechanism is explained by an impaired and inefficacious function of the NK and T cytotoxic cells that leads to an ineffective and uncontrolled immune response, inducing cellular damage, multiorganic failure with macrophage proliferation and hemophagocytosis. The main objective of the different therapeutic options, commonly combinations of steroids and chemotherapy, is the suppression of the uncontrolled immune response. Occasionally, the clinical condition of some patients represents a contraindication for intensive treatment. We report a case of a severely burned patient that fulfilled the revised criteria for the hemophagocytic syndrome and was successfully treated with the combination of intravenous immunoglobulins and steroids.(AU)

Síndrome hemofagocítico secundario a infecciones graves en un quemado. / [Secondary hemophagocytic syndrome due to recurrent infections in a severely burned patient].

The hemophagocytic syndrome represents an infrequent, occasionally misdiagnosed and usually fatal heterogeneous entity. Infections, drugs, autoimmune diseases and cancer are often triggers of the secondary hemophagocytic syndrome. Its physiopathogenic mechanism is explained by an impaired and inefficacious function of the NK and T cytotoxic cells that leads to an ineffective and uncontrolled immune response, inducing cellular damage, multiorganic failure with macrophage proliferation and hemophagocytosis. The main objective of the different therapeutic options, commonly combinations of steroids and chemotherapy, is the suppression of the uncontrolled immune response. Occasionally, the clinical condition of some patients represents a contraindication for intensive treatment. We report a case of a severely burned patient that fulfilled the revised criteria for the hemophagocytic syndrome and was successfully treated with the combination of intravenous immunoglobulins and steroids.

[Reactive hemophagocytic syndrome in critical care patients. Report of 4 cases]. / Sindrome hemofagocitico reactivo en pacientes graves. Comunicacion de 4 casos.

Reactive hemophagocytic syndrome or hemophagocytic lymphohistiocytosis comprises a variety of disorders, many of them associated with infection. It is characterized by hemophagocytosis, with cytopenia involving at least two cellular lines, increase in cytokines and serum ferritin. The clinical course resembles sepsis, sharing similar physiopathological features. We propose that hemophagocytic syndrome is an underdiagnosed entity in the critical care setting; simple tests aid to identify which patients should undergo diagnostic procedures. We discuss current therapeutic approaches.