[ABO incompatibility and complications in hematopoietic stem cell transplantation]. / Incompatibilidad ABO en el trasplante de células progenitoras hematopoyéticas y sus complicaciones.

Background: Hematopoietic stem cell transplants (HSCT) can be performed regardless of the ABO group compatibility between donor and recipient. ABO incompatibility in HSCT is related to pure red cell aplasia (PRCA), or passenger lymphocyte syndrome. The impact of ABO incompatibility on graft-versus-host disease and transplant-related mortality is controversial due to the heterogeneity of procedures carried out in different transplant centers. Objective: To determine the prevalence of ABO incompatibility and its complications in a hematopoietic stem transplant unit. Material and methods: An observational, retrospective study was carried out in patients undergoing HSCT from January 2014 to January 2020. All trasplant patients were included. Qualitative variables were analyzed using chi-squared test, and Wilcoxon and Student's t tests were used for quantitative variables. A p < 0.05 was considered significant. Results: 124 patients undergoing HSCT were analyzed, out of which 31 had ABO incompatibility, with a punctual prevalence of 24.4%; among them, 54% presented with major incompatibility, 32% minor incompatibility and 13% bidirectional incompatibility. Three cases of PRCA were reported. There were no differences in survival at one year in both groups. Conclusions: The ABO incompatibility ant its complications were not related to the increase in mortality. Randomized prospective studies are required to define the role of ABO incompatibility in HSCT prognosis.

Introducción: los trasplantes de células progenitoras hematopoyéticas (TCPH) se pueden hacer independientemente de la compatibilidad de grupo sanguíneo ABO entre donador y receptor. La incompatibilidad ABO (IABO) en los TCPH puede presentar complicaciones, como aplasia pura de serie roja (APSR), o síndrome de linfocito pasajero. El impacto de la IABO en la enfermedad del injerto en contra del huésped y la mortalidad relacionada al trasplante es controversial por la heterogeneidad de procedimientos que se hacen en los distintos centros de trasplante. Objetivo: determinar la prevalencia de la IABO y sus complicaciones en los pacientes trasplantados en una unidad de trasplante de progenitores hematopoyéticos. Material y métodos: se hizo un estudio tipo observacional, descriptivo, en pacientes sometidos a TCPH de enero de 2014 a enero de 2020. Se incluyeron todos los pacientes trasplantados. Las variables cualitativas se analizaron con chi cuadrada y para las variables cuantitativas se usó la prueba de Wilcoxon y t de Student. Una p < 0.05 fue significativa. Resultados: se analizaron 124 pacientes sometidos a TCPH y 31 de ellos presentaron IABO, con una prevalencia puntual de 24.4%; entre ellos, 54% presentaron incompatibilidad mayor, 32% incompatibilidad menor y 13% incompatibilidad bidireccional. Se reportaron tres casos de APSR. No hubo diferencias en la supervivencia global a un año en ambos grupos. Conclusiones: la IABO y sus complicaciones no se relacionaron con aumento en la mortalidad. Se requieren estudios prospectivos aleatorizados para definir el papel de la IABO con el pronóstico del trasplante.

Relapsing Myopathy With Granulomatous Inflammation as Chronic Graft vs Host Disease Feature: A Case Report.

BACKGROUND: Graft-vs-host disease (GVHD) is a common complication of allogeneic hematopoietic stem cell transplant. Myopathy is a rare neuromuscular sign of chronic GVHD, with an incidence of less than 4% in all patients. The data are heterogeneous, and no standard criteria exists for diagnosis or treatment. CASE REPORT: We present the case of an 18-year-old man with acute lymphoblastic leukemia, who developed myopathy associated with GVHD 19 months after allogeneic hematopoietic stem cell transplant from an unrelated donor. The patient had a previous history of acute cutaneous and chronic hepatic GVHD. At the time of symptom onset, the immunosuppressive drugs were tapered. He developed with sudden symmetrical proximal muscle weakness that prevented him from walking. Diagnosis was confirmed using magnetic resonance imaging, electromyography, muscle enzymes, and muscle biopsy results. He initially responded to immunosuppressive therapy but relapsed after quick tapering of prednisone, requiring a prolonged course of steroids and an additional dose of immune globulin intravenous. At the moment of the publication, the patient has 9 months free from GVHD relapse. CONCLUSIONS: GVHD-associated myopathy is a rare complication of hematopoietic stem cell transplant and must be suspected in patients with sudden proximal muscle weakness and moderate pain. Diagnosis is challenging and must include magnetic resonance imaging, electromyography, muscle enzymes, and muscle biopsy results. Usually, all patients respond adequately to immunosuppression.

Isolated Renal Relapse in a Post-Allogenic Transplant Adult Patient With Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is an aggressive hematological neoplasm typically more common in children than adults. More prolonged remissions and a potential cure can be achieved if allogeneic hematopoietic stem cell transplantation (allo-HSCT) is performed. Outcomes after allo-HSCT vary significantly among patients, and multiple factors contribute to these outcomes. Isolated extramedullary relapse (iEMR) after allo-HSCT is rare. We present the case of a 43-year-old man who was diagnosed with Philadelphia chromosome-negative (Ph-neg), B-cell ALL and underwent haploidentical allo-HSCT because of high-risk features at diagnosis. One year later, he was admitted to the hospital with facial and peripheral edema, proteinuria, elevated serum creatinine levels, and hypertension. Renal biopsy was performed immediately. Renal infiltration of TdT+ leukemic cells was detected by immunohistochemistry. Bone marrow aspiration, lumbar puncture, and computed tomography (CT) scans were performed to identify other sites of possible relapse. No other sites were identified, and an extramedullary isolated renal relapse was diagnosed. Intensive re-induction with chemotherapy was not possible because of the coronavirus disease 2019 (COVID-19) infection. Six weeks later, a medullary relapse was noted. Medullary infiltration of B-cell ALL after allo-HSCT has a historically poor prognosis; however, iEMR appears to have a better overall prognosis. The optimal treatment for renal iEMR is still a matter of debate.

Transplantation of hematopoietic progenitors in myelofibrosis.

The objective of this work is to generate recommendations on the management of allogeneic stem cell transplantation (allo-SCT) in primary myelofibrosis (PMF). A comprehensive systematic review of articles published between 1999 and 2015 (January) was used as a source of scientific evidence. The recommendations were produced through a Delphi process involving a panel of 23 experts appointed by the European LeukemiaNet and the European Blood and Marrow Transplantation Group. Key questions included patient selection, donor selection, pre-transplant management, conditioning regimen, post-transplant management, prevention, and management of post-transplant relapse. Patients with intermediate-2 or high-risk disease and age < 70 years should be considered candidates for allo-SCT. Patients with intermediate-risk 1 disease and age < 65 years should be considered candidates if they have refractory transfusion-dependent anemia, or a peripheral blood (PB) blast percentage > 2%, or adverse cytogenetics. Splenectomy before transplantation must be decided on a case-by-case basis. Patients with intermediate-2 or high-risk disease who lack a human leukocyte antigen (HLA)-matched sibling or unrelated donor should be enrolled in a protocol that uses HLA non-identical donors. PB was considered the most appropriate source of hematopoietic stem cells for transplants from HLA-matched unrelated donors and siblings. The optimal intensity of the conditioning regimen has yet to be defined. Strategies such as discontinuation of immunosuppressive drugs, infusion of donor lymphocytes, or both were considered adequate to prevent clinical relapse. In conclusion, we provide consensus-based recommendations aimed at optimizing allo-SCT in PMF. Unmet clinical needs were highlighted.

El objetivo de este trabajo es generar recomendaciones sobre el manejo del trasplante alogénico de células madre (alo-SCT) en la mielofibrosis primaria (MFP). Se utilizó una revisión sistemática integral de artículos publicados entre 1999 y 2015 (enero) como fuente de evidencia científica. Las recomendaciones se produjeron mediante un proceso Delphi en el que participó un panel de 23 expertos designados por la European LeukemiaNet y el European Blood and Marrow Transplantation Group. Las preguntas clave incluyeron la selección de pacientes, la selección de donantes, el manejo previo al trasplante, el régimen de acondicionamiento, el manejo posterior al trasplante, la prevención y el manejo de la recaída después del trasplante. Los pacientes con enfermedad de riesgo intermedio 2 o alto y edad < 70 años deben ser considerados candidatos para alo-SCT. Los pacientes con enfermedad de riesgo intermedio 1 y edad < 65 años deben ser considerados candidatos si presentan anemia refractaria dependiente de transfusiones, o un porcentaje de blastos en sangre periférica > 2%, o citogenética adversa. La esplenectomía previa al trasplante debe decidirse caso por caso. Los pacientes con enfermedad de riesgo intermedio 2 o alto que carecen de un hermano compatible con el antígeno leucocitario humano (HLA) o de un donante no emparentado deben inscribirse en un protocolo que utilice donantes no idénticos de HLA. PB se consideró la fuente más apropiada de células madre hematopoyéticas para trasplantes de hermanos y donantes no emparentados compatibles con HLA. La intensidad óptima del régimen de acondicionamiento aún debe definirse. Se consideraron adecuadas estrategias como la suspensión de los fármacos inmunosupresores, la infusión de linfocitos del donante o ambas para evitar la recaída clínica. En conclusión, proporcionamos recomendaciones basadas en consenso destinadas a optimizar el alo-SCT en MFP. Se destacaron las necesidades clínicas insatisfechas.

Essential thrombocythaemia.

Essential thrombocythemia (ET) is a chronic Philadelphia-negative myeloproliferative neoplasm that has its main involvement in the megakaryopoietic lineage, generating sustained thrombocytosis in peripheral blood and an increase in the number of mature megakaryocytes in the bone marrow. In addition to marked thrombocytosis, it is characterized by increased thrombotic or hemorrhagic risk and the presence of constitutional symptoms. Patients with ET have a low but known risk of disease progression to myelofibrosis and/or acute leukemia. The diagnosis is made based on the 2016 WHO criteria. At present, available treatments for patients with ET are mainly aimed at minimizing the risk of thrombosis and/or bleeding.

La trombocitemia esencial (TE) es una neoplasia mieloproliferativa crónica Filadelfia negativa que tiene su principal involucro en la línea megacariopoyética, generando trombocitosis sostenida en la sangre periférica y un incremento en el número de megacariocitos maduros en médula ósea. Además de una marcada trombocitosis, se caracteriza por un mayor riesgo trombótico o hemorrágico y la presencia de síntomas constitucionales. Los pacientes con TE tienen un riesgo bajo, pero conocido, de evolución de la enfermedad a mielofibrosis y/o leucemia aguda. El diagnóstico se realiza con base en los criterios de la Organización Mundial de la Salud del 2016. Los tratamientos actualmente disponibles para los pacientes con TE están dirigidos principalmente a minimizar el riesgo de trombosis y/o hemorragia.

Pregnancy in myeloproliferative neoplasms.

Myeloproliferative neoplasms (MPN) are associated with a significant risk of thrombosis and the hypercoagulable environment of pregnancy increases this risk. The most frequent gestational complications consist of spontaneous abortion, thrombosis, bleeding, and hypertensive disease of pregnancy. Treatment depends on thrombotic risk, gestational trimester, and myeloproliferative neoplasm.

Las neoplasias mieloproliferativas (NMP) están asociadas a un riesgo notable de trombosis y el entorno de hipercoagulabilidad propio del embarazo aumenta este riesgo. Las complicaciones gestacionales más frecuentes consisten en: aborto espontáneo, trombosis, sangrado y enfermedad hipertensiva del embarazo. El tratamiento depende del riesgo trombótico, trimestre gestacional y neoplasia mieloproliferativa.

Polycythemia vera.

Polycythemia vera (PV) is mainly characterized by erythrocytosis, thrombotic and hemorrhagic predisposition, a variety of symptoms, and cumulative risks of fibrotic progression and/or leukemic evolution over time. The diagnosis is made based on the 2016 WHO criteria. The treatment of PV focuses on rapidly reducing the erythrocyte mass, either by means of phlebotomies or with cytoreductive treatment, and the reduction of thrombotic risk by correcting cardiovascular risk factors and the use of platelet antiaggregants.

La policitemia vera (PV) se caracteriza principalmente por eritrocitosis, predisposición trombótica y hemorrágica, una variedad de síntomas y riesgos acumulativos de progresión fibrótica y/o evolución leucémica a lo largo del tiempo. El diagnóstico se realiza con base en los criterios de la Organización Mundial de la Salud del 2016. El tratamiento de la PV se centra en reducir rápidamente la masa eritrocitaria, ya sea por medio de flebotomías o con tratamiento citorreductor, y la disminución del riesgo trombótico mediante la corrección de factores de riesgo cardiovascular y el uso de antiagregantes plaquetarios.

Risks in invasive procedures.

Patients with myeloproliferative neoplasms have an increased risk of thrombosis and bleeding. This risk must be identified, as well as individualizing the therapeutic strategy before invasive procedures; adequate cytoreduction reduces the risk of complications.

Los pacientes con neoplasias mieloproliferativas tienen un riesgo incrementado de trombosis y sangrado. Se debe identificar dicho riesgo, así como individualizar la estrategia terapéutica previo a los procedimientos invasivos; una adecuada citorreducción disminuye el riesgo de complicaciones.

Symptom control.

In addition to symptoms secondary to splenomegaly, microvascular abnormalities, and thrombohemorrhagic complications, patients with MPN may experience a significant symptom burden attributed to an increase in circulating inflammatory cytokines. These symptoms can be severe and limit quality of life. Therefore, in addition to the prevention of complications, one of the objectives of the treatment of MPN is the control of symptoms.

Además de la sintomatología secundaria a la esplenomegalia, a las alteraciones microvasculares y a las complicaciones trombohemorrágicas, los pacientes con neoplasias mieloproliferativas (NMP) pueden experimentar una importante carga sintomática atribuida a un aumento de citocinas inflamatorias circulantes. Estos síntomas pueden ser severos y limitar la calidad de vida. Por ello, además de la prevención de las complicaciones, uno de los objetivos del tratamiento de las NMP es el control de los síntomas.

Thrombotic events.

Major thrombotic complications in myeloproliferative neoplasms (MPNs) represent an important clinical problem due to their high morbidity, the complexity of their management, and their associated mortality. The appearance of a thrombosis implies a high thrombotic risk stratification of the MPN and determines the initiation or optimization of cytoreductive treatment and the use of antiplatelet or anticoagulant therapy as secondary prophylaxis. The incidence of thrombosis at the time of diagnosis is higher than during the course of the disease, being located in the arterial territory in 60-70% of cases. Once thrombosis has occurred, up to 20-33% of patients experience thrombotic recurrence in the same initial vascular territory.

Las complicaciones trombóticas mayores en las neoplasias mieloproliferativas (NMP) representan un importante problema clínico debido a su elevada morbilidad, la complejidad de su manejo y su mortalidad asociada. La aparición de una trombosis comporta una estratificación de alto riesgo trombótico de la NMP y determina el inicio o la optimización del tratamiento citorreductor y el uso de terapia antiplaquetaria o anticoagulante como profilaxis secundaria. La incidencia de trombosis en el momento del diagnóstico es mayor que durante la evolución de la enfermedad, localizándose en territorio arterial en el 60-70% casos. Una vez se ha producido una trombosis, hasta el 20-33% de los pacientes sufre una recurrencia trombótica en el mismo territorio vascular inicial.

Myelofibrosis: diagnosis and treatment.

Myelofibrosis (MF) is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal myeloproliferation, dysregulated kinase signaling, and release of abnormal cytokines. In recent years, important progress has been made in the knowledge of the molecular biology and the prognostic assessment of MF. Conventional treatment has limited impact on the patients' survival; it includes a wait-and-see approach for asymptomatic patients, erythropoiesis-stimulating agents, androgens, or immunomodulatory agents for anemia, cytoreductive drugs such as hydroxyurea for the splenomegaly and constitutional symptoms, and splenectomy or radiotherapy in selected patients. The discovery of the Janus kinase (JAK) 2 mutation triggered the development of molecular targeted therapy of MF. The JAK inhibitors are effective in both JAK2-positive and JAK2-negative MF; one of them, ruxolitinib, is the current best available therapy for MF splenomegaly and constitutional symptoms. Although ruxolitinib has changed the therapeutic scenario of MF, there is no clear indication of a disease-modifying effect. Allogeneic stem cell transplantation remains the only curative therapy of MF, but due to its associated morbidity and mortality, it is usually restricted to eligible high- and intermediate-2-risk MF patients. To improve current therapeutic results, the combination of JAK inhibitors with other agents is currently being tested, and newer drugs are being investigated.

La mielofibrosis (MF) es una neoplasia mieloproliferativa negativa para BCR-ABL1 caracterizada por mieloproliferación clonal, señalización de cinasa desregulada y liberación de citocinas anormales. En los últimos años se han realizado importantes avances en el conocimiento de la biología molecular y la valoración pronóstica de la MF. El tratamiento convencional tiene un impacto limitado en la supervivencia de los pacientes; incluye un enfoque de espera para pacientes asintomáticos, agentes estimulantes de la eritropoyesis, andrógenos o agentes inmunomoduladores para la anemia, fármacos citorreductores como la hidroxiurea para la esplenomegalia y los síntomas constitucionales, y esplenectomía o radioterapia en pacientes seleccionados. El descubrimiento de la mutación Janus cinasa (JAK) 2 desencadenó el desarrollo de la terapia dirigida molecular de la MF. Los inhibidores de JAK son efectivos tanto en MF con JAK2 positivo como con JAK2 negativo; uno de ellos, el ruxolitinib, es la mejor terapia disponible actualmente para la esplenomegalia y los síntomas constitucionales de la MF. Sin embargo, aunque el ruxolitinib ha cambiado el escenario terapéutico de la MF, no hay indicios claros de un efecto modificador de la enfermedad. El alotrasplante de células madre sigue siendo la única terapia curativa de la MF, pero debido a su morbilidad y mortalidad asociadas, generalmente se restringe a pacientes elegibles con MF de riesgo alto e intermedio 2. Para mejorar los resultados terapéuticos actuales, actualmente se está probando la combinación de inhibidores de JAK con otros agentes y se están investigando fármacos más nuevos.

Infection as Trigger for Congenital Thrombotic Thrombocytopenic Purpura in an Adult Patient.

Congenital thrombotic thrombocytopenic purpura (cTTP) is an inherited disease that is sometimes fatal in early childhood. cTTP is similar to idiopathic thrombotic thrombocytopenic purpura (iTTP); both are characterized by varying levels of thrombocytopenia, microangiopathic hemolytic anemia (MAHA), and end-organ damage secondary to occlusion of the microvasculature. cTTP is caused by a partial or total deficiency or loss of function of ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13). We report the case of a 33-year-old woman who was mistakenly diagnosed with primary immune thrombocytopenia (ITP) during childhood. The patient was referred to our center with dyspnea, fatigue, fever, and jaundice with no clinical bleeding. Laboratory features were compatible with MAHA; ADAMTS-13 activity was at 0%, with negativity for ADAMTS-13 antibodies. We concluded the final diagnosis was cTTP. The triggering factor identified for MAHA was a double infection: central venous catheter bacterial infection and atypical pneumonia. After 7 days of treatment with antibiotics and ongoing total plasma exchange (TPE), the patient responded favorably. Our patient received fresh frozen plasma (FFP) infusion once every 2 weeks, and prophylactic voriconazole remained under control at the time of writing. As demonstrated in this case, effective treatment of the trigger cause helps reduce the need for continuous FFP exposure and controls the MAHA.