María Jesús Peñarrubia

Experimental and Clinical Regenerative Capability of Human Bone Marrow Cells After Myocardial Infarction

Bone marrow mononuclear cells (BMCs) from 20 patients with extensive reperfused myocardial infarction (MI) were used to assess their myocardial regenerative capability “in vitro” and their effect on postinfarction left ventricular (LV) remodeling. Human BMCs were labeled, seeded on top of cryoinjured mice heart slices, and cultured. BMCs showed tropism for and ability to graft into the damaged mouse cardiac tissue and, after 1 week, acquired a cardiomyocyte phenotype and expressed cardiac proteins, including connexin43. In the clinical trial, autologous BMCs (78±41×106 per patient) were intracoronarily transplanted 13.5±5.5 days after MI. There were no adverse effects on microvascular function or myocardial injury. No major cardiac events occurred up to 11±5 months. At 6 months, magnetic resonance showed a decrease in the end-systolic volume, improvement of regional and global LV function, and increased thickness of the infarcted wall, whereas coronary restenosis was only 15%. No changes were found in a nonrandomized contemporary control group. Thus, BMCs are capable of nesting into the damaged myocardium and acquire a cardiac cell phenotype in vitro as well as safely benefiting ventricular remodeling in vivo. Large-scale randomized trials are needed now to assess the clinical efficacy of this treatment.

RegeneraciÓn miocárdica mediante la implantaciÓn intracoronaria de células madre en el infarto agudo de miocardio

Introduccion y objetivos Trabajos experimentales y clinicos sugieren que el tejido necrotico tiene la capacidad de regenerarse. Nuestro grupo ha comenzado un estudio clinico para demostrar que la implantacion intracoronaria de celulas madre es un procedimiento factible y seguro. Presentamos los resultados de nuestros primeros 5 pacientes. Pacientes y metodo Se ha incluido a pacientes con un infarto agudo de miocardio anterior y una lesion unica en la descendente anterior reparada mediante angioplastia primaria o facilitada. A los 10-15 dias del infarto, se procedio a la extraccion de medula osea. El implante celular se hizo por via intracoronaria. El protocolo de seguimiento incluye ecocardiografia con dobutamina, resonancia magnetica y Holter de ECG basal y a los 6 meses. Resultados Ningun paciente ha tenido un evento cardiaco tras 6 meses de seguimiento. En un paciente se observo un accidente isquemico transitorio sin secuelas. No se han demostrado arritmias en ninguno de los pacientes. El volumen telediastolico no vario a los 6 meses (159 ± 25 y 157 ± 16 ml), el volumen telesistolico disminuyo (77 ± 22 y 65 ± 16 ml) y la fraccion de eyeccion aumento (53 ± 7 y 58 ± 8%), aunque no hubo diferencias significativas. En los 3 pacientes en los que la ecocardiografia con dobutamina descarto viabilidad, si hubo una disminucion significativa de los volumenes. Conclusiones El implante intracoronario de celulas madre en pacientes que han tenido un infarto agudo de miocardio parece un metodo seguro y factible, y podria dar lugar a un remodelado favorable.

Intracoronary stem cell transplantation in acute myocardial infarction

INTRODUCTION AND OBJECTIVES Experimental and clinical studies suggest that necrotic myocardium may have the capacity to regenerate. We have started a clinical study to demonstrate that the intracoronary implantation of stem cells is feasible and safe. The results in our first 5 patients are presented here. PATIENTS AND METHOD We included patients with anterior acute myocardial infarction and isolated stenosis of the left anterior descending artery that was successfully repaired by primary or facilitated angioplasty. Patients received an intracoronary infusion of bone marrow-derived cells 10-15 days after the infarction. The follow-up protocol included low-dose dobutamine echocardiography, magnetic resonance studies and ECG Holter monitoring. RESULTS The procedure was carried out with no complications. No patient had a cardiac event during the first 6 months. One patient had a transient ischemic attack without sequelae. No arrhythmias were found. Left ventricular end-diastolic volume remained the same at 6 months (159+/-25 ml, 157+/-16 ml), left ventricular end-systolic volume decreased (77+/-22 ml, 65+/-16 ml), and the ejection fraction increased (53+/-7%, 58+/-8%) although no statistically significant differences were found. In the 3 patients in whom dobutamine echocardiography ruled out viability, we found a significant reduction in both volumes. CONCLUSIONS Intracoronary bone marrow-derived cell transplantation after an acute myocardial infarction seems to be safe and feasible, and might lead to favorable remodeling.

Successful discontinuation of eltrombopag after complete remission in patients with primary immune thrombocytopenia

Eltrombopag is effective and safe in immune thrombocytopenia (ITP). Some patients may sustain their platelet response when treatment is withdrawn but the frequency of this phenomenon is unknown. We retrospectively evaluated 260 adult primary ITP patients (165 women and 95 men; median age, 62 years) treated with eltrombopag after a median time from diagnosis of 24 months. Among the 201 patients who achieved a complete remission (platelet count >100 × 109/l), eltrombopag was discontinued in 80 patients. Reasons for eltrombopag discontinuation were: persistent response despite a reduction in dose over time (n = 33), platelet count >400 × 109/l (n = 29), patients request (n = 5), elevated aspartate aminotransferase (n = 3), diarrhea (n = 3), thrombosis (n = 3), and other reasons (n = 4). Of the 49 evaluable patients, 26 patients showed sustained response after discontinuing eltrombopag without additional ITP therapy, with a median follow‐up of 9 (range, 6–25) months. These patients were characterized by a median time since ITP diagnosis of 46.5 months, with 4/26 having ITP < 1 year. Eleven patients were male and their median age was 59 years. They received a median of 4 previous treatment lines and 42% were splenectomized. No predictive factors of sustained response after eltrombopag withdrawal were identified. Platelet response following eltrombopag cessation may be sustained in an important percentage of adult primary ITP patients who achieved CR with eltrombopag. However, reliable markers for predicting which patients will have this response are needed. Am. J. Hematol. 90:E40–E43, 2015.

Eltrombopag safety and efficacy for primary chronic immune thrombocytopenia in clinical practice

Eltrombopag is effective and safe in chronic immune thrombocytopenia (ITP). However, clinical trials may not accurately reflect what happens in clinical practice. We evaluated the efficacy and safety of eltrombopag in primary chronic ITP in a real‐world setting.

Do chronic myeloid leukemia patients with late “warning” responses benefit from “watch and wait” or switching therapy to a second generation tyrosine kinase inhibitor?

In the latest recommendations for the management of chronic‐phase chronic myeloid leukemia suboptimal responses have been reclassified as “warning responses.” In contrast to previous recommendations current guidance advises close monitoring without changing therapy. We have identified 198 patients treated with first‐line imatinib, with a warning response after 12 months of treatment (patients with a complete cytogenetic response but no major molecular response [MMR]). One hundred and forty‐six patients remained on imatinib, while 52 patients changed treatment to a second generation tyrosine kinase inhibitor (2GTKI). Changing therapy did not correlate with an increase in overall survival or progression‐free survival. Nevertheless, a significant improvement was observed in the probability of a MMR: 24% vs. 42% by 12 months and 43% vs. 64% by 24 months (P = 0.002); as well as the probability of achieving a deep molecular responses (MR4.5): 1% vs. 17% and 7% vs. 23% by 12 and 24 months, respectively (P = <0.001) .The treatment change to 2GTKI remained safe; however, we have observed a 19% of treatment discontinuation due to side effects. We have observed an improvement of molecular responses after changing treatment to 2GTKI in patients with late suboptimal response treated with imatinib first line. However, these benefits were not correlated with an improvement of progression free survival or overall survival. Am. J. Hematol. 89:E206–E211, 2014.

Hematologic and cytogenetic response to lenalidomide in de novo acute myeloid leukemia with chromosome 5q deletion.

Unlike 5q syndrome, the 5q deletion in acute myeloid leukemia AML) has been associated with a poor outcome [1]. However, a atient subgroup has been identified with more than one normal etaphase in cytogenetic studies and no previous hematologic disrder, in whom the prognosis is similar to that in patients with a ormal karyotype [2]. Clinical trials with lenalidomide in patients ith myelodysplastic syndrome and the 5q deletion have shown a igh rate of response as evaluated with hematologic and cytogeetic parameters [3]. Two cases of AML and 5q deletion after treatment of myelodyslastic syndrome with lenalidomide have been published [4,5]. We escribe here a case of de novo AML and 5q deletion in a patient who chieved hematologic and cytogenetic response with lenalidomide. A 72-year-old woman was referred to our institution in Februry 2006 by her general practitioner because of pancytopenia. he patient referred a 2-month history of weakness and recurent respiratory infections. Laboratory data revealed leukocytes .6 × 109 L−1 (neutrophils 38%), hemoglobin 7.2 g/dL and platelets 9 × 109 L−1 with 5% circulating blasts. A bone marrow aspirate howed AML-M1 with 20% blasts and trilineage dysplasia. Six of en metaphases analyzed in the bone marrow presented the 5q eletion. Conventional chemotherapy was refused by the patient and transfusion program was initiated. Transfusion requirements ncreased steadily, and by January 2007 five to six units of ed blood cells were transfused per month. In June 2007 the atient accepted treatment with lenalidomide. She was started n 10 mg/day during 21 days every 4 weeks. At the beginning f treatment the platelet and white blood cell counts worsned, but the scheduled dose was not changed. After 2 months f lenalidomide therapy, the patient became transfusion indeendent and the platelet and leukocyte counts were normal Fig. 1). In October 2007 a bone marrow exam showed norocellular marrow with signs of mild myelodysplasia and less han 1% myeloblasts. Cytogenetic analysis revealed a normal emale karyotype in all 20 metaphases studied. At the time of his writing (November or December 2008) the patient is still eceiving lenalidomide and her hemoglobin level remains above 2 g/dL. Lenalidomide is an immunomodulatory agent potentially able o correct the morphologic and functional alterations caused by 5q eletion in bone marrow. Its mechanism of action is not fully under-

Cirrosis biliar primaria, síndrome "sicca" y anemia hemolítica autoinmune

La cirrosis biliar primaria (CBP) es un proceso colestático que puede asociarse a diferentes manifestaciones autoinmunes tales como síndrome “sicca”, artritis reumatoidea, esclerodermia, síndrome CREST, fenómeno de Raynaud, enfermedades tiroideas, anemia perniciosa, etc. (1,2). La anemia hemolítica autoinmune (AHAI) es un proceso de etiología diversa comúnmente idiopático, que se ha descrito con escasa frecuencia en asociación con la CBP (3-7).

A new prognostic model identifies patients aged 80 years and older with diffuse large B-cell lymphoma who may benefit from curative treatment: A multicenter, retrospective analysis by the Spanish GELTAMO group

The means of optimally managing very elderly patients with diffuse large B‐cell lymphoma (DLBCL) has not been established. We retrospectively analyzed 252 patients aged 80‐100 years, diagnosed with DLBCL or grade 3B follicular lymphoma, treated in 19 hospitals from the GELTAMO group. Primary objective was to analyze the influence of the type of treatment and comorbidity scales on progression‐free survival (PFS) and overall survival (OS). One hundred sixty‐three patients (63%) were treated with chemotherapy that included anthracyclines and/or rituximab, whereas 15% received no chemotherapeutic treatment. With a median follow‐up of 44 months, median PFS and OS were 9.5 and 12.5 months, respectively. In an analysis restricted to the 205 patients treated with any kind of chemotherapy, comorbidity scales did not influence the choice of treatment type significantly. Independent factors associated with better PFS and OS were: age < 86 years, cumulative illness rating scale (CIRS) score < 6, intermediate risk (1‐2) R‐IPI, and treatment with R‐CHOP at full or reduced doses. We developed a prognostic model based on the multivariate analysis of the 108 patients treated with R‐CHOP‐like: median OS was 45 vs. 12 months (P = .001), respectively, for patients with 0‐1 vs. 2‐3 risk factors (age > 85 years, R‐IPI 3‐5 or CIRS > 5). In conclusion, treatment with R‐CHOP‐like is associated with good survival in a significant proportion of patients. We have developed a simple prognostic model that may aid the selection patients who could benefit from a curative treatment, although it needs to be validated in larger series.