[Clinical evolution of 31 adult patients with immune thrombocytopenia treated with rituximab]. / Evolución clínica de 31 pacientes adultos con trombocitopenia inmune tratados con rituximab.

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease that could cause different grades of bleeding, which could even threat the patients' life or make them experience poor quality of life. ITP can be treated with rituximab either as a first or second-line therapy option, resulting in an overall response of 60%. The best results have been observed on young women with a short time of disease evolution. Objective: To report the response and clinical evolution by providing therapy with rituximab, which was used as a rescue in adult patients with either persistent or chronical ITP. Material and methods: 4 weekly doses of rituximab were administered to 31 adult patients and it was made a follow-up with them for a year. Results: Out of the 31 patients, a complete response was observed (CR, platelets ≥ 100 x 109 /L) in 22 patients (71%), and a partial response (PR, platelets ≥ 30 and ≤ 99 x 109 /L) in 5 patients (16%); the global response was of 87%. 3 patients relapsed during follow-up and sustained response after rituximab (≥ 12 months) was held in 24 patients, 21 (67%) with CR and 3 (10%) with PR. Side effects were from low to moderate in 13% of patients. Conclusions: Rituximab showed its effectiveness in patients with ITP as a rescue therapy in both chronical and persistent phases. Sustained response ≥ 12 months was of 77%, with good tolerance and acceptable toxicity.

Introducción: la trombocitopenia inmune primaria (TIP) es una enfermedad autoinmune que puede causar hemorragias de diferente intensidad, las cuales llegan a poner en peligro la vida y alteran la calidad de vida de los pacientes. Puede ser tratada con rituximab como primera o segunda línea y la respuesta global es de 60%. Los mejores resultados se han observado en mujeres jóvenes con tiempo breve de evolución. Objetivo: reportar la respuesta y la evolución clínica con el tratamiento de rituximab usado como un rescate en pacientes adultos con TIP en fase crónica o persistente de la enfermedad. Material y métodos: se le administró rituximab de forma semanal por cuatro dosis a 31 pacientes adultos y se les hizo seguimiento durante un año. Resultados: de los 31 pacientes adultos, se observó respuesta completa (RC, plaquetas ≥ 100 x 109 /L) en 22 pacientes (71%) y respuesta parcial (RP, plaquetas ≥ 30 y ≤ 99x 109 /L) en 5 pacientes (16%); la respuesta global fue de 87%. Tres pacientes recayeron durante el seguimiento y la respuesta sostenida (≥ 12 meses) se mantuvo en 24 pacientes, 21 (67%) con RC y 3 (10%) con RP. Los efectos secundarios fueron de leves a moderados en 13% de los pacientes. Conclusiones: el rituximab demostró su utilidad en pacientes con TIP como tratamiento de rescate en las fases crónica y persistente. La respuesta sostenida ≥ 12 meses fue de 77%, con buena tolerancia y toxicidad aceptable.

Helicobacter pylori in esplenectomized patients with immune primary trombocytopenia / Helicobacter pylori en pacientes esplenectomizados con trombocitopenia inmune primaria

Background: Primary Immune Thrombocytopenia (TIP) is an autoimmune disease that accelerates the peripheral destruction of platelets and alters megakaryocytopoiesis. Helicobacter pylori infection and eradication has been associated with an increase in the platelet count in patients with IPT. The aim of this article is to evaluate the platelet response after H. pylori eradication in patients with chronic splenectomized IPT Methods: Between 2008 and 2009, adult patients with a diagnosis of chronic IPT, splenectomized; They were given breath test with carbon 13-labeled urea (PAU13C). Patients who tested positive received eradication treatment with amoxicillin, omeprazole and clarithromycin for 14 days. After 6 weeks of treatment, a second PAU13C was performed. Baseline platelet counts were performed and every six months until the completion of two years. Results: 40 patients, 34 women and 6 men were included, PAU13C was positive in 17 patients (42.5%). H. pylori eradication was obtained in 16 patients (94%) confirmed by post-treatment PAU13C. In the follow-up of the patients it was observed that there was increase of platelets in 7 of the patients with eradication of H. pylori, while of the patients not infected in 9 also an increase of platelets was observed. Conclusions: There were no differences in the increase in platelet count among patients positive or negative to the H. pylori breath test at followup at 24 months.

Introducción: La trombocitopenia inmune primaria (TIP) es una enfermedad autoinmune que acelera la destrucción periférica de las plaquetas y altera la megacariocitopoyesis. La erradicación de la infección por Helicobacter pylori se ha asociado al incremento en la cuenta de plaquetas en los pacientes con TIP. El objetivo de este trabajo fue evaluar la respuesta de plaquetas después de la erradicación del H. pylori en pacientes con TIP crónica esplenectomizados. Métodos: Entre 2008-2009 fueron incluidos pacientes adultos con diagnóstico de TIP crónica, esplenectomizados; se les realizó prueba de aliento con urea marcada con carbono 13 (PAU13C). Los pacientes que resultaron positivos a la prueba recibieron tratamiento de erradicación con amoxicilina, omeprazol y claritromicina por 14 días. Después de 6 semanas de tratamiento, se realizó una segunda PAU13C. Se realizaron cuenta de Plaquetas basal y cada seis meses hasta completar dos años. Resultados: Se incluyeron 40 pacientes, 34 mujeres y 6 hombres, la PAU13C resultó positiva en 17 pacientes (42.5%). La erradicación del H. pylori se obtuvo en 16 pacientes (94%) confirmado por PAU13C postratamiento. En el seguimiento de los pacientes se observó que hubo incremento de las plaquetas en 7 de los pacientes con erradicación del H. pylori, mientras que de los pacientes no infectados en 9 también se observó aumento de plaquetas. Conclusiones: No hubo diferencias en el incremento en la cuenta de plaquetas entre los pacientes positivos o negativos a la prueba de aliento para H. pylori en el seguimiento a 24 meses.

[High-intensity chemotherapy versus palliative chemotherapy in patients over 60 years with acute myeloid leukemia]. / Quimioterapia intensa frente a quimioterapia paliativa en pacientes con leucemia mieloblástica mayores de 60 años.

BACKGROUND: The use of high-intensity chemotherapy (HIC) for acute myeloid leukemia (AML) in the elderly is controversial. In the present study, it was assessed complete remission and overall survival of AML patients over 60 years treated with HIC or palliative chemotherapy. METHODS: Patients with ECOG ≤ 2 and adequate organic function received HIC with a base of cytarabine for five or seven days, and an anthracycline for three days. If patients achieved complete remission of leukemia, they received one or two cycles of consolidation with cytarabine. Palliative treatment consisted of supported measures and/or oral or intravenous low-dose chemotherapy. RESULTS: Seven patients treated with HIC achieved complete remission versus only one in the palliative group. Only one patient died during HIC treatment. Median survival for HIC-treated patients was 13.25 months, and only 3.35 months for patients treated with palliative therapy (p < 0.05). CONCLUSION: AML patients of 60 years or older, with good performance status (ECOG ≤ 2) and adequate organ function, may benefit from HIC treatment, with better survival, compared with palliative therapy.

Introducción: el tratamiento con quimioterapia intensa (QTI) en pacientes con leucemia mieloblástica (LMA) mayores de 60 años es controversial. En el presente estudio se evaluó la remisión completa y la supervivencia global de pacientes con LMA mayores de 60 años, tratados con QTI o quimioterapia paliativa. Métodos: los pacientes con adecuada función orgánica y ECOG ≤ 2 recibieron QTI a base de citarabina por cinco o siete días más un antracíclico por tres días y terapia de soporte. En caso de lograr remisión completa de la leucemia recibieron uno o dos ciclos de consolidación con citarabina. El tratamiento paliativo consistió en medidas de soporte o quimioterapia oral o intravenosa en dosis bajas. Resultados: del grupo de QTI siete pacientes alcanzaron remisión completa, comparados con uno del grupo de quimioterapia paliativa. La supervivencia global fue de 13.25 meses para los pacientes con QTI y de 3.35 meses para los pacientes de quimioterapia paliativa (p < 0.05). Conclusión: es posible que los pacientes con LMA mayores de 60 años de edad se beneficien de recibir QTI, comparada con la quimioterapia paliativa.

[Primary immune thrombocytopenia in adults in Mexico: national characteristics and the relation to international literature]. / Trombocitopenia inmune primaria (TIP) del adulto en México: características nacionales y su relación con la literatura internacional.

In order to identify the clinical approach of a sample of Mexican hematologists for primary immune thrombocytopenia (ITP) in adults in Mexico, we applied an electronic survey via the internet to identify common practices for the diagnosis and treatment of ITP and draw a comparison between the information from these hematologists with international guidelines or the international literature. The results were analyzed using measures of central tendency. The sample was 21 medical hematologists, predominantly from Mexico City (average age: 51.4 years). A total of 66.7% of the surveyed physicians use international guidelines to make therapeutic decisions, and 43% defined ITP including the numerical concept (< 100 x 10(9)/l). We found some differences between requested clinical exams and tests indicated by the guidelines. In first-line treatment (except emergency), 91% of the participants start with prednisone and 24% use dexamethasone. Danazol is used in persistent ITP by most (41%) of the specialists. In second-line treatment, 67% would indicate splenectomy. Some differences were found between clinical practice of the hematologists in Mexico versus guidelines recommendations.

Functional analysis of myelodysplastic syndromes-derived mesenchymal stem cells.

Two different reports, including one from our own group, have recently demonstrated the presence of severe chromosomal abnormalities in mesenchymal stem cells (MSC) from patients with myelodysplastic syndromes (MDS). In the present study, we have assessed whether such cytogenetic abnormalities result in functional deficiencies in vitro. We found that both normal and MDS MSC showed similar expression patterns of cell adhesion molecules and extracellular matrix proteins. MDS MSC layers showed the capability to differentiate towards adipocytes, chondrocytes and osteoblasts, and supported the growth of early umbilical cord blood progenitors in a co-culture system. Unstimulated MDS MSC secreted more IL-1beta and after treatment with TNFalpha, they secreted more SCF, as compared to their normal counterparts. The present study demonstrates that, in spite of harboring severe chromosomal alterations, most of the functional properties of MDS-derived MSC remain normal, including their ability to support normal hematopoiesis in vitro.

Mesenchymal stem cells in myelodysplastic syndromes: phenotypic and cytogenetic characterization.

Bone marrow-derived mesenchymal stem cells (MSC) have been defined as primitive, undifferentiated cells, capable of self-renewal and with the ability to give rise to different cell lineages, including adipocytes, osteocytes, fibroblasts, chondrocytes, and myoblasts. MSC are key components of the hematopoietic microenvironment. Several studies, including some from our own group, suggest that important quantitative and functional alterations are present in the stroma of patients with myelodysplasia (MDS). However, in most of such studies the stroma has been analyzed as a complex network of different cell types and molecules, thus it has been difficult to identify and characterize the cell(s) type(s) that is (are) altered in MDS. In the present study, we have focused on the biological characterization of MSC from MDS. As a first approach, we have quantified their numbers in bone marrow, and have worked on their phenotypic (morphology and immunophenotype) and cytogenetic properties. MSC were obtained by a negative selection procedure and cultured in a MSC liquid culture medium. In terms of morphology, as well as the expression of certain cell markers, no differences were observed between MSC from MDS patients and those derived from normal marrow. In both cases, MSC expressed CD29, CD90, CD105 and Prolyl-4-hydroxylase; in contrast, they did not express CD14, CD34, CD68, or alkaline phosphatase. Interestingly, in five out of nine MDS patients, MSC developed in culture showed cytogenetic abnormalities, usually involving the loss of chromosomal material. All those five cases also showed cytogenetic abnormalities in their hematopoietic cells. Interestingly, in some cases there was a complete lack of overlap between the karyotypes of hematopoietic cells and MSC. To the best of our knowledge, the present study is the first in which a pure population of MSC from MDS patients is analyzed in terms of their whole karyotype and demonstrates that in a significant proportion of patients, MSC are cytogenetically abnormal. Although the reason of this is still unclear, such alterations may have an impact on the physiology of these cells. Further studies are needed to assess the functional integrity of MDS-derived MSC.

Hemoglobin and platelet count effect on platelet yields in plateletpheresis.

BACKGROUND: Platelet transfusion in thrombocytopenic patients, especially those with marrow failure, remains one of the most important support measures available. Treatment success depends on rational use of platelet transfusion. Platelet yield, reflected in transfused platelet dose, influences platelet recovery in the patient and allows prolonging intervals between transfusions. In this study, our main objective was to identify donor laboratory and clinical factors that showed some influence on platelet yield obtained by apheresis. METHODS: Healthy donor laboratory and clinical data were analyzed prior to performing plateletpheresis. Platelet yield was quantified after plateletpheresis procedure was concluded in two different ways: a) prefixed volume of 5,000 mL processed, and b) volume determined according to manufacturer recommendations. Age, gender, hemoglobin concentration, platelet and leukocyte count, height, and weight were included as yield-predicting donor variables. RESULTS: In group A, two variables were significant: donor platelet count and hemoglobin (Hb) concentrations with r = 0.554, and in group B, donor platelet count, Hb concentrations, and volume with r = 0.758. CONCLUSIONS: Donor platelet count and hemoglobin concentrations influence platelet yield: higher platelet count corresponds to higher yield, while hemoglobin shows an inverse relationship, i.e., the lower the hemoglobin concentrations, the higher the platelet yield.

High doses of dexamethasone in adult patients with idiopathic thrombocytopenic purpura.

BACKGROUND: High-dose dexamethasone (DXM) has been used in treatment of patients with idiopathic thrombocytopenic purpura (ITP) who are refractory to other treatments such as prednisone and splenectomy; nevertheless, different studies show variable success rates, this postulated as possibly being due to racial differences. The objective of this study was to determine DXM effectiveness at high doses in Mexican mestizo adult patients diagnosed with ITP with and without splenectomy. METHODS: Nonhospitalized adult patients with ITP were included, eight patients previously splenectomized (group 1) and 11 who had not undergone splenectomy (group 2). Patients received DXM 40 mg/day intravenously (i.v.) during 4 consecutive days every 4 weeks until six cycles were completed. RESULTS: There were no differences between the two groups regarding age (mean 39 vs. 33 years of age) and initial platelet count (M 17 vs. 24 x 10(9)/L). Median evolution time was 84 months for group 1 and 7 months for group 2 (p = 0.002). Of 19 patients, nine achieved a favorable response (FR), six belonged to group 1, and three to group 2 (Fisher p = 0.07). Nevertheless, after 6 months only two group 1 patients and two group 2 patients maintained FR (Fisher exact test p = 1). Patients achieving FR to initiation of second cycle maintained FR at the end of six cycles. CONCLUSIONS: Thus, the previously mentioned high-dose DXM therapy appears to be useful for both patients with ITP with and without splenectomy and high-dose DXM appears to be a good alternative therapy for postsplenectomy and relapse patients. However, duration of FR to treatment was brief; therefore, other treatment plans might be required to achieve longer remission duration. Response was similar to that observed in other studies carried out in different populations; thus, apparently no genetic or racial variations exist. In addition, whether patients not responding after second cycle should continue until completing the 6-month plan or should try a different therapeutic approach must be considered in the treatment plan.

Comparative analysis of the in vitro proliferation and expansion of hematopoietic progenitors from patients with aplastic anemia and myelodysplasia.

Aplastic anemia (AA) and myelodysplasia (MDS) show great similarities in their biology. To date, however, it is still unclear to what extent hematopoietic progenitor cells (HPCs) from AA and MDS share biological properties and what the functional differences are between them. In trying to address this issue, in the present study we have analyzed, in a comparative manner, the proliferation and expansion capacities of bone marrow (BM) progenitor cells from AA and MDS in response to recombinant cytokines. BM samples from normal subjects (NBM) and patients with AA and MDS were enriched for HPC by immunomagnetic-based negative selection. Selected cells were cultured in the absence (control) or in the presence of early-acting cytokines (Mix I), or early-, intermediate- and late-acting cytokines (Mix II). Proliferation and expansion were assessed periodically. In NBM and MDS cultures apoptosis was also determined. In NBM cultures, Mix I induced a nine-fold increase in total cell numbers and a 3.6-fold increase in colony-forming cell (CFC) numbers. In Mix II-supplemented cultures, total cells were increased 643-fold, and CFC 12.4-fold. In AA cultures, no proliferation or expansion were observed in Mix I-supplemented cultures, whereas only a four-fold increase in total cell numbers was observed in the presence of Mix II. In MDS cultures, a 12-fold increase in total cells and a 2.9-fold increase in CFC were observed in the presence of Mix I; on the other hand, Mix II induced a 224-fold increase in total cells and a 5.9-fold increase in CFC. Apoptosis was reduced in cytokine-supplemented cultures from NBM. In contrast, Mix II induced a significant increase in the rate of apoptosis in MDS cultures. Our results demonstrate that, as compared to their normal counterparts, AA and MDS progenitors are deficient in their proliferation and expansion potentials. Such a deficiency is clearly more pronounced in AA cells, which seem to be unable to respond to several cytokines. MDS progenitors, on the other hand, are capable to proliferate and expand in response to cytokines; however, their rate of apoptosis is increased by intermediate- and late-acting cytokines, so that the overall proliferation and expansion are significantly lower than those of normal progenitor cells.

In vitro characterization of hematopoietic microenvironment cells from patients with myelodysplastic syndrome.

In vitro studies on the functional integrity of the hematopoietic microenvironment in myelodysplasia have been controversial. Although some of them suggest that such a microenvironment is functionally normal, there is increasing evidence indicating that there are alterations in the function of microenvironment (adherent) cell layers from myelodysplastic syndromes (MDS) marrow. Adherent cell layers developed in vitro, however, consist of a mixture of different cell types-mostly fibroblasts and macrophages-thus, it is not clear which cell type(s) is(are) functionally abnormal in this disorder. In order to address this issue, in the present study, we first assessed some functional properties of MDS-derived adherent cell layers, as a whole, and then we analyzed those same functional properties after separating these cells into two different populations: a fibroblast-enriched cell layer and a macrophage-enriched cell layer. When whole adherent layers from MDS patients were analyzed, no significant differences were observed, as compared to their normal counterparts, in terms of morphology and total cell number. A major difference, however, was observed when analyzing the production of the cytokines interleukin-6 (IL-6) and tumor necrosis factor (TNF-alpha). Indeed, adherent layers from MDS patients produced higher levels of these cytokines (2- and 22-fold, respectively), as compared to normal layers. When fibroblast- and macrophage-enriched cell layers were analyzed, a higher apoptotic index was observed in those derived from MDS marrow (4% of TUNEL-positive cells in normal fibroblast layers versus 27% in MDS-derived fibroblast layers; 7% of TUNEL-positive cells in normal macrophage layers versus 24% in MDS macrophage layers). Macrophages from MDS marrow produced significantly higher levels of TNF-alpha (nine-fold) than their normal counterparts. MDS-derived fibroblasts, on the other hand, produced higher levels of IL-6 (nine-fold), as compared to normal fibroblasts. Surprisingly, whereas normal fibroblasts showed a discrete production of TNF-alpha, we found a very high production of this cytokine in cultures of fibroblasts from MDS patients. In summary, in the present study we have demonstrated that, at least in vitro, both fibroblasts and macrophages from MDS bone marrow (BM) are functionally abnormal. Such abnormalities include an increased apoptotic index, as well as a high production of both IL-6 and TNF-alpha.

Effect of chemotherapy on thyroid hormone concentration in patients with malignant hematologic diseases

Malignant hematologic diseases are severe illnesses for which complex forms of treatment are used and to wich a great variety of metabolic changes are anticipated. Both lymphomas and leukemias, as well as chemotherapy, can induce abnormalities in thyroid hormone metabolism without overt disease, thus leading to what is know as euthyroid sick syndrome (ESS). In the present report, 25 patients with lymphoma and leukemias were studied to evaluate the effect of chemotherapy on thyroid hormone concentration. After chemotherapy, the most frequent and significant alteration was a decrease in serum triiodothyronine concentration

Tratamiento de la hemoglobinuria paroxística nocturna con globulina antilinfocitaria / Antilymphocyte globulin therapy for paroxysmal nocturnal hemoglobinuria

Objetivo. Evaluar la utilidad de la globulina antilinfocitos T humanos (GAL) en el tratamiento de la hemoglobinuria paroxística nocturna (HPN). Diseño. Estudio prospectivo, no controlado de casos clínicos. Ubicación. Servicio de Hematología, Hospital de Especialidades Centro Médico Nacional Siglo XXI, IMSS, México. Pacientes. Se incluyeron seis pacientes, tres varones y tres mujeres con edad promedio de 37.5 años. El diagnóstico de HPN se estableció por datos clínicos y pruebas de Ham, sucrosa e inulina positivas. Se consideró grave en cuatro enfermos en virtud de su actividad hemolítica continua e intensa, y los requerimientos transfusionales altos (más de dos concentrados de hematíes por mes); cinco de ellos no habían tenido mejoría con esteroides y/o andrógenos; uno no tenía tratamiento previo. Intervención. Se aplicó GAL (Lymphoglobuline Mérieux, Lyon, Francia; lote E 0034) 10 mg/kg/día por cuatro días, en infusión de 20 horas; también recibieron metilprednisolona, 500 mg/día, en infusión de dos horas cambiando, al cabo de siete días, a prednisona de 1 mg/kg y en dosis decrecientes hasta suspenderla en 30 días. Criterios de respuesta. Se valoró por medio del aumento en el nivel de homoglobina, la disminución o ausencia en los requerimientos transfusionales de glóbulos rojos, y la mejoría de la cuenta de plaquetas, granulocitos o ambas, en los tres meses posteriores al tratamiento con GAL. Resultados. En dos enfermos la primera dosis de GAL provocó una reacción anafiláctica y fueron excluidos del estudio. De los cuatro enfermos restantes, sólo dos mostraron respuesta a las 12 semanas post-tratamiento, uno total y otro mínima; ambas respuestas fueron transitorias. En un seguimiento promedio de 12.5 meses, ninguno de los pacientes mostraba mejoría. En los cuatro sujetos hubo necesidad de reiniciar tratamiento en danazol y prednisona. Conclusiones. El paciente con HPN en actividad intensa, la terapéutica con GAL, en las dosis y tiempo dados, no ofreció ningún beneficio. En consecuencia, se deben buscar otras alternativas para tratar a estos enfermos