Venetoclax-based combinations for acute myeloid leukemia: optimizing their use in Latin-America.

Objectives: Venetoclax combinations are a new standard for patients with acute myeloid leukemia (AML). We aimed to evaluate the safety and efficacy of these combinations in a period of accelerated approval in Latin-America.Methods: This observational study evaluated adults with acute myeloid leukemia who received venetoclax-based therapy in 11 public or private centers in Mexico and Peru for both newly diagnosed or relapsed and refractory AML.Results: Fifty patients were included; 28 with newly diagnosed (ND) AML and 22 with relapsed/refractory (RR) disease. ND patients were older (64 vs. 40 years; p < 0.001) with a lower functional capacity (ECOG ≥2 64.3% vs 9%; p < 0.001). Venetoclax was frequently combined with azacytidine (60%) and prophylactic azoles (82%) with a median maximum dose of 200 mg (range, 100-600 mg). Hematologic toxicities were common. Complete response rates including patients with incomplete hematopoietic recovery were 78.6% in ND and 45.5% in RR patients, with a median overall survival of 9.6 (95% CI 3.7-15.5) and 8 months (95% CI 4.8-11.2).Discussion: Our study showed a preferred use of venetoclax plus azacytidine over cyatrabine. Patients in the first-line setting were similar to those in the landmark studies, while most patients with relapsed disease had received prior intensive therapies. Responses were favorable, with a median survival in agreement to other reports, albeit shorter than that observed in the randomized phase-3 trials.Conclusion: Venetoclax-based therapy in AML was effective despite dose reductions and prophylactic antifungals in two middle-income countries outside of a clinical trial setting.

Diagnostic concordance of pathological methods and reports of hematopathologists compared to local nonspecialized pathologists in the diagnosis of lymphoma in Mexico.

OBJECTIVES: To assess the concordance between lymphoma diagnoses made via tissue biopsy by local pathologists and also to assess the after review of these specimens by more specialized hematopathologists. METHODS: A prospective, non-interventional and multicenter study was conducted at seven sites in Mexico from January 2017 to October 2017. Eligible biopsies were sampled from patients with a previous diagnosis of lymphoma on lymph node biopsy or a diagnosis of extranodal lymphoma, with adequate amount and tissue preservation for the review analysis. The biopsy tissues reviewed by local pathologists were also reviewed by hematopathologists participating in the study. The concordance in diagnosis results was classified into three categories: diagnostic agreement, minor discrepancy and major discrepancy. RESULTS: Out of 111 samples received, 105 samples met the eligibility criteria and were included for full analysis. The median patient age (range) was 54 (16-94) years. A diagnostic agreement was observed in 23 (21.9%) biopsies, minor discrepancies were observed in 32 (30.5%) biopsies and major discrepancies were observed in 50 (47.6%) biopsies. Diagnostic concordance varied across the seven study sites; the rate of major discrepancies ranged from 0% to 100% and the rate of diagnostic agreement ranged from 0% to 81.8%. Out of the 105 reviewed biopsies, a total of 89 cases were diagnosed as lymphoma by hematopathologists. CONCLUSIONS: This study showed that major discrepancies were observed following the review by hematopathologists compared with that of the local pathologist's initial diagnosis in nearly one-half cases. In addition, there was a wide variation in the percentage of diagnostic agreements and discrepancies among different study sites.

Acute Promyelocytic Leukemia: A Long-Term Retrospective Study in Mexico.

BACKGROUND: The present retrospective study reviewed acute promyelocytic leukemia (APL) cases recorded in Mexico between January 2007 and January 2017. The primary objective of the study was to evaluate overall survival (OS) in Mexican patients with APL. Secondary objective was to evaluate the impact of induction treatment with different anthracyclines on OS, event-free survival (EFS) and complications in this patient population. METHODS: The medical charts of patients referred to medical institutions in Mexico from January 2007 through January 2017 for the treatment of suspected APL were reviewed retrospectively. Patients aged 15 - 75 years, in whom the diagnosis of APL was confirmed, who had an Eastern Cooperative Group performance status of 0 - 2, and who were eligible for combined treatment with intensive chemotherapy and all-trans retinoic acid (ATRA), were included in the study. Study participants received induction and consolidation treatment with ATRA plus either daunorubicin or idarubicin, followed by 2 years of single-agent ATRA as maintenance therapy. Patients who were unable to pay for ATRA treatment received anthracycline-based induction and consolidation, with methotrexate plus mercaptopurine as maintenance therapy. RESULTS: A total of 360 patients from 21 public and private hospitals were included in the study. The median age of the population was 37 years, and 51% were male. Of the 360 patients, 205 (57%) vs. 155 (43%) received daunorubicin vs. idarubicin as induction treatment for APL. ATRA was administered to 201 (98%) patients in the daunorubicin group vs. 138 (89%) in the idarubicin group (P = 0.001), and was initiated at diagnosis in 92% vs. 73% of recipients, respectively (P = 0.0001). At 150 months, OS and EFS for the entire population were 84% and 79%, respectively. Both OS (90% vs. 76%, P = 0.003) and EFS (85% vs. 72%, P = 0.001) were significantly prolonged in daunorubicin vs. idarubicin recipients. Rates of complications were similar in the two groups. CONCLUSIONS: As arsenic trioxide (ATO) is not currently available in Mexico, anthracycline plus ATRA is the mainstay of treatment for APL here. Our results confirm the efficacy of this strategy, with high OS and EFS rates being observed 12.5 years after diagnosis.

Prescription Patterns of Daratumumab in Patients with Multiple Myeloma in Underprivileged Circumstances: A Multicenter Experience in Mexico.

BACKGROUND: Despite novel therapies, multiple myeloma (MM) remains an incurable malignancy, daratumumab (DARA) being a major game changer, may be a good option for treatment. AIMED OF THE STUDY: To assess the prescription patterns of DARA in patients with MM in Mexico. METHODS: 47 patients with MM were analyzed in 13 different hospitals in Mexico. RESULTS: Five (10.5%) of patients received DARA as first line therapy, 13 (27.5%) as second line, whereas 29 (62%) received its in ≥3rd line. In 32% DARA was used in combination with dexamethasone, 64% received DARA on a triple combination, and 4% as a 4 drug combination. Eighty three percent of patients had a response, including 32% in complete remission. Progression free survival (PFS) was higher in patients in ISS stage 1, and in patients achieving ≥PR. Overall survival (OS) was lower in patients not achieving ≥PR, in patients having increased LDH, and extramedullary disease. Grade 1-2 infusion related reactions were present in 34%, and grade 3-4 neutropenia and lymphopenia in 25 and 17% of the patients. CONCLUSIONS: In Mexico, 62% of patients with MM received DARA as a third or further line of treatment. DARA employed as a doublet or triplet combination is useful in relapsed/refractory patients with tolerable adverse events.

Mieloma múltiple en tiempos de SARS-CoV-2 (COVID-19) en México / Multiple myeloma in times of SARS-CoV-2 in Mexico

Resumen El mieloma múltiple (MM) es una enfermedad oncológica heterogénea en su componente molecular que a su vez genera una variabilidad clínica. Su riesgo se define de acuerdo con el Sistema Internacional de Estatificación Revisado, que considera: niveles serios altos de deshidrogenasa láctica y Beta2 microglobulina, niveles bajos de albúmina y la presencia de alguna alteración citogenética, del 17p13, t(14;14), y t(14;16); el grupo de alto riesgo se caracteriza por una recaída temprana y supervivencia corta. En este momento de pandemia por enfermedad por coronavirus 2019 (COVID-19), el manejo de los pacientes con MM se ha afectado indirectamente por la falta de oportunidad en el diagnóstico y el manejo; además de existir datos que sugieren que el estado de inmunosupresión propio de la enfermedad aunado a la terapia inmunosupresora e inmunomoduladora los hace de alto riesgo de complicarse y fallecer cuando adquieren la COVID-19. Sin embargo, no existen registros propios de mieloma que lo corroboren y en los registros de COVID-19/cáncer las complicaciones se reportan principalmente en cáncer de pulmón y los que están dentro de las cuatro semanas de haber recibido quimioterapia intensa. En México y Latinoamérica en una encuesta breve solo se encontraron casos aislados, pero aún falta analizar los datos. La baja frecuencia de pacientes con MM y COVID-19 probablemente esté dada por los cuidados y aislamiento que de antemano se tiene con ellos. Dado que el MM es una enfermedad heterogénea, debemos seguir evaluando el riesgo al diagnóstico y dar el tratamiento pleno a los de alto riesgo. Para ello debemos ajustar las medidas para reducir el riesgo de exposición a la COVID-19, reducir en la medida de lo posible las visitas a las unidades de atención, ajustar los tratamientos de primera línea de acuerdo con las características propias de cada paciente y monitorizar con pruebas para COVID-19 a los pacientes con terapias intensas y aquellos que requieren de trasplante de células progenitoras hematopoyéticas. La pandemia por COVID-19 es una catástrofe sin presente, no solo por la morbimortalidad propia de la infección, también ha generado saturación de los servicios de salud, incrementando las complicaciones y fallecimientos de otras enfermedades por la falta de oportunidad en la atención y el MM no es la excepción.

Abstract Multiple Myeloma (MM) is a heterogeneous oncological disease in its molecular component that in turn generates clinical variability, its risk is defined according to the Revised International Staging System, which considers: serious high levels of DHL and Beta2 microglobulina, low levels of albumin and the presence of some cytogenetic alteration, [del 17p13, t (14; 14), and t ( 14; 16)], the high-risk group is characterized by early relapse and short survival. At this time of the SARS-CoV-2 (COVID-19) pandemic, the management of patients with multiple myeloma has been indirectly affected by the lack of opportunity in diagnosis and management. In addition to there are data that suggest that the state of immunosuppression typical of the disease, combined with immunosuppressive and immunomodulatory therapy, makes them at high risk of complicating themselves and dying when they acquire the disease from COVID-19. However, there are no proper myeloma registries to corroborate this and in the COVID-19/cancer registries complications are reported mainly in lung cancer and those that are within 4 weeks of receiving intense chemotherapy. In Mexico and Latin America a brief survey only found isolated cases, the data has yet to be analyzed. The low frequency of patients with MM and COVID-19 is probably due to the care and isolation that is had with them beforehand. Since MM is a heterogeneous disease, we must continue to evaluate the risk at diagnosis and give full treatment to those at high risk, for this we must adjust the measures to reduce the risk of exposure to COVID-19, reduce visits to care units as much as possible, adjust first-line treatments according to the characteristics of each patient and monitor patients with intensive therapies and those requiring transplantation with tests for COVID-19 of hematopoietic progenitor cells. The COVID-19 pandemic is a catastrophe without a present, not only due to the morbidity and mortality of the infection, it has also generated saturation of health services, increasing complications and deaths from other diseases due to the lack of opportunity in care and Multiple Myeloma is no exception.

Epistasis analysis of metabolic genes polymorphisms associated with ischemic heart disease in Yucatan. / Análisis de epistasia de polimorfismos de genes metabólicos asociados a cardiopatía isquémica en Yucatán.

OBJECTIVE: Epistasis is a type of genetic interaction that could explain much of the phenotypic variability of complex diseases. In this work, the effect of epistasis of metabolic genes and cardiovascular risk on the susceptibility to the development of ischemic heart disease in Yucatan was determined. METHODS: Case-control study in 79 Yucatecan patients with ischemic heart disease and 101 healthy controls matched by age and origin with cases. The polymorphisms -108CT, Q192R, L55M (paraoxonase 1; PON1), C677T, A1298C (methylenetetrahydrofolate reductase; MTHFR), and the presence/absence of the glutathione S-transferase T1 (GSTT1) gene were genotyped. Epistasis analysis was performed using the multifactorial dimensional reduction method. The best risk prediction model was selected based on precision (%), statistical significance (P<0.05), and cross-validation consistency. RESULTS: We found an independent association of the null genotype GSTT1*0/0 (OR=3.39, CI: 1.29-8.87, P=0.017) and the null allele (OR=1.86, CI: 1.19-2.91, P=0.007) with ischemic heart disease. The GSTT1*0 deletion and the 677TT genotype (MTHFR) were identified as being at a high cardiovascular risk, whereas the GSTT1*1 wild type genotype and the CC677 variant were at low risk. The gene-environment interaction identified the GSTT1 gene, C677T polymorphism (MTHFR), and hypertension as the factors that best explain ischemic heart disease in the study population. CONCLUSIONS: The interaction of the MTHFR, GSTT1 and hypertension may constitute a predictive model of risk for early onset ischemic heart disease in the population of Yucatan.

Prognostic tumor sequencing panels frequently identify germ line variants associated with hereditary hematopoietic malignancies.

Next-generation sequencing (NGS)-based targeted gene capture panels are used to profile hematopoietic malignancies to guide prognostication and treatment decisions. Because these panels include genes associated with hereditary hematopoietic malignancies (HHMs), we hypothesized that these panels could identify pathogenic germ line variants in malignant cells, thereby identifying patients at risk for HHMs. In total, pathogenic or likely pathogenic variants in ANKRD26, CEBPA, DDX41, ETV6, GATA2, RUNX1, or TP53 were identified in 74 (21%) of 360 patients. Germ line tissue was available for 24 patients with 25 pathogenic or likely pathogenic variants with variant allele frequencies >0.4. Six (24%) of these 25 variants were of germ line origin. Three DDX41 variants, 2 GATA2 variants, and a TP53 variant previously implicated in Li-Fraumeni syndrome were of germ line origin. No likely pathogenic/pathogenic germ line variants possessed variant allele frequencies <0.4. This study demonstrates that NGS-based prognostic panels may identify individuals at risk for HHMs despite not being designed for this purpose. Furthermore, variants known to cause Li-Fraumeni syndrome as well as known pathogenic variants in genes such as DDX41 and GATA2 are especially likely to be of germ line origin. Thus, tumor-based panels may augment, but should not replace, comprehensive germ line-based testing and counseling.

High response rate to low-dose rituximab plus high-dose dexamethasone as frontline therapy in adult patients with primary immune thrombocytopenia.

UNLABELLED: Corticosteroids as initial therapy for primary immune thrombocytopenia achieve a low rate of sustained remission. METHODS: We prospectively evaluated the efficacy, safety, and response duration of low-dose rituximab plus high-dose dexamethasone as frontline therapy in newly diagnosed primary immune thrombocytopenia patients. One cycle of dexamethasone, 40 mg/d/intravenously for four consecutive days, plus weekly intravenous rituximab, 100 mg for four doses, was delivered. RESULTS: Twenty-one consecutive adults were enrolled. The overall response at day +28 was 90.5%. Complete sustained response at 6 months and relapse rate were 76.2% and 15.8%, respectively, compared with 30% and 62.5% for a historical group who had received standard treatment with prednisone (P = 0.005 and P = 0.004). There was a 9.5% incidence of adverse effects. CONCLUSIONS: The combination of low-dose rituximab and high-dose dexamethasone as frontline therapy for adults with primary immune thrombocytopenia was effective and had a high overall response rate and a low incidence of relapse.