Molecular and cellular markers for measurable residual disease in acute lymphoblastic leukemia / Marcadores celulares y moleculares para la enfermedad residual medible en la leucemia linfoblástica aguda

Abstract Acute leukemia is the leading cause of death in children worldwide, particularly in developing countries where the growing number of cases with unfavorable prognosis and high risk of early relapse have positioned pediatric cancer as a priority. The late and imprecise diagnosis, malnutrition and unfavorable environmental conditions, and toxicity-associated therapy are some of the factors that compromise the success of the treatment and affect survival rates in vulnerable regions. An early and exhaustive classification of malignant neoplasms at the clinical debut and the proper follow-up of treatment’s response constitute one of the most powerful prognostic factors. Remarkably, the ultrasensitive detection of residual and relapse clones that determine the minimal/measurable residual disease (MRD) has been a milestone in the comprehensive management of hematologic malignancies that favorably improve the complete remission cases. In this review, we discuss the scientific and technological advances applied to laboratory diagnosis in MRD determination: from the multiparametric immunophenotyping to next-generation sequencing and cytomics. As a result of multidisciplinary research in the main concentration oncology centers and laboratories, residual leukemia detection strategies that combine molecular analysis and cellular markers are recommended as the most valuable tools, making them the paradigm for stratification campaigns in vulnerable regions.

Resumen La leucemia aguda es la principal causa de muerte por enfermedad en la población infantil mundial, en particular en los países con economías en desarrollo, donde el creciente número de casos con pronóstico desfavorable y riesgo de recaídas tempranas ha posicionado a esta enfermedad como una prioridad de salud. El diagnóstico tardío y de baja precisión, la ausencia de condiciones favorables de alimentación y entorno ambiental, así como la toxicidad asociada a la terapia, son algunos de los factores que condicionan el éxito del tratamiento y afectan las tasas de supervivencia en las regiones más vulnerables. La clasificación temprana y exhaustiva del tumor maligno en la presentación clínica y durante el seguimiento de respuesta al tratamiento es uno de los más poderosos factores pronósticos. En especial, la detección ultrasensible de clonas residuales y reemergentes que determinan la enfermedad residual mínima medible ha sido un hito en el manejo integral de las neoplasias hematológicas y ha impactado favorablemente en las cifras de remisión completa. En esta revisión se comentan los avances científicos y tecnológicos aplicados al diagnóstico de laboratorio y a la determinación de la enfermedad residual mínima: desde la inmunofenotipificación multiparamétrica hasta la secuenciación y la citómica de última generación. Como resultado de las investigaciones multidisciplinarias en los principales centros oncológicos de concentración y los laboratorios de clase mundial, las estrategias de detección de la leucemia residual que combinan análisis moleculares y marcadores celulares han sido recomendadas como las de mayor utilidad, por lo que son el paradigma para las campañas de estratificación en las regiones vulnerables.

Impact of hHLA-DPB1 matching on clinical outcomes after haploidentical-related hematopoietic stem cell transplantation

ABSTRACT Background: The impact of HLA-DPB1 compatibility and its role as a transplantation antigen in haploidentical-related hematopoietic stem cell transplant (haplo-R-HSCT) have not been established, and a negative effect on survival has been suggested. Objective: The objective of the determine was to study the frequency and clinical effects of incompatibility at the HLA-DPB1 locus in the haplo-R-HSCT setting. Methods: Clinical records and electronic files of 91 patients with a hematological disease who underwent haplo-HSCT from January 2009 to October 2017 in a university medical center were scrutinized. Overall survival (OS) was estimated by the Kaplan-Meier method; the cumulative incidence of transplant-related mortality (TRM) and relapse rates was determined. Acute graft-versus-host disease was assessed by binary logistic regression. Cox regression model with a 95% confidence interval was used to examine the association between the different variables and their effect on OS. Results: Of the 91 donor-recipient pairs, 24 (26.37%) shared complete DPB1 identity, 60 (65.93%) had a mismatch at one allele, and 7 (7.70%) were mismatched at two alleles. Twenty-four different HLA-DPB1 alleles were found; the most frequent were DPB1*04:01 (34.1%) and DPB1*04:02 (27.5%). Two-year OS, the cumulative incidence of TRM and relapse was 51.3 ± 6.8%, 28 ± 6% and 60 ± 7.8% for all haplo-related transplants, respectively, with no statistical difference between HLA-DPB1 matched and partially matched patients. In Cox regression analysis, no risk factors associated with OS, TRM, or relapses were identified. Conclusion: HLA-DPB1 mismatching in the haplo-R-HSCT setting did not influence transplant outcomes and was clinically tolerable. A high degree of homozygosity was found.

Experience with Evans syndrome in an academic referral center

To document the experience of one referral service with patients diagnosed with Evans syndrome, the treatment and response and to briefly review current treatment strategies and results.METHODS: Patients enrolled in this study fulfilled criteria for Evans syndrome. Data were retrieved from the clinical files and electronic databases of the Department of Hematology, Hospital Universitario "Dr. José Eleuterio González". Treatment modalities and response and the use of additional therapies were evaluated. The literature was reviewed in the context of the clinical course of the studied patients.RESULTS: Six patients were diagnosed with Evans syndrome in the study period. Patient 1 was treated with steroids, relapsed twice and was again treated with steroids. Patient 2 treated initially with steroids plus intravenous immunoglobulin was subsequently lost to follow-up. A good response was achieved in Patients 3 and 4, who were treated with steroids plus rituximab; patient 4 also received danazol as a second-line therapy. However both relapsed and subsequently underwent splenectomy at ten and nine months, respectively. One patient, number 5, treated with steroids, danazol and rituximab did not relapse within four years of follow-up and Patient 6, who received steroids plus danazol did not relapse within three years of follow-up.CONCLUSION: Evans syndrome is an uncommon hematologic condition rarely diagnosed and not widely studied. Clinicians must have it in mind when evaluating a patient with a positive direct antiglobulin test, anemia and thrombocytopenia, since prognosis depends on its early recognition and opportune therapy, but even this leads to variable results...

Evaluation of hemoglobin performance in the assessment of iron stores in feto-maternal pairs in a high-risk population: receiver operating characteristic curve analysis

By applying receiver operating characteristic curve analysis, the objective of this study was to see whether hemoglobin levels reflect body iron stores in a group of pregnant women at term who, by using serum ferritin as the reference test, had a high pre-test prob- ability of having iron deficiency anemia. Likewise, we evaluated the ability of hemoglobin and maternal serum ferritin levels to predict iron deficiency anemia in newborns. Methods: Hemoglobin and serum ferritin were measured in 187 pregnant women at term belonging to a group with a high pre-test probability of iron deficiency anemia and their newborns. Women with Hb <11.0 g/dL and newborns with cord Hb <13.0 g/dL were classified as anemic. A serum ferritin <12.0 µg/L in women and a cord blood serum ferritin <35.0 µg/L were considered to reflect empty iron stores. Receiver operating characteristic curve analysis was applied to select the cut-off points that better reflected iron stores. Results: The Hb cut-off point selected by receiver operating characteristic curve analysis in women was <11.5 g/dL (sensitivity: 60.82, specificity: 53.33%, Youden Index: 0.450). Most of the newborns had normal Hb which precluded this analysis. Maternal Hb <11.0 g/dL was the cut-off point that best reflected iron deficiency anemia in newborns (sensitivity: 55.88%, specificity: 57.24%, Youden Index: 0.217). The best cut-off point of maternal serum ferritin to reflect empty iron stores in newborns was <6.0 µg/L (sensitivity: 76.47%, specificity: 31.58%, Youden Index: 0.200). Conclusion: Hemoglobin concentration performed poorly to detect iron deficiency anemia in women at term with high risk for iron deficiency and their newborns.