Guidelines for the diagnosis and management of adult aplastic anaemia: A British Society for Haematology Guideline.

Pancytopenia with hypocellular bone marrow is the hallmark of aplastic anaemia (AA) and the diagnosis is confirmed after careful evaluation, following exclusion of alternate diagnosis including hypoplastic myelodysplastic syndromes. Emerging use of molecular cyto-genomics is helpful in delineating immune mediated AA from inherited bone marrow failures (IBMF). Camitta criteria is used to assess disease severity, which along with age and availability of human leucocyte antigen compatible donor are determinants for therapeutic decisions. Supportive care with blood and platelet transfusion support, along with anti-microbial prophylaxis and prompt management of opportunistic infections remain key throughout the disease course. The standard first-line treatment for newly diagnosed acquired severe/very severe AA patients is horse anti-thymocyte globulin and ciclosporin-based immunosuppressive therapy (IST) with eltrombopag or allogeneic haemopoietic stem cell transplant (HSCT) from a matched sibling donor. Unrelated donor HSCT in adults should be considered after lack of response to IST, and up front for young adults with severe infections and a readily available matched unrelated donor. Management of IBMF, AA in pregnancy and in elderly require special attention. In view of the rarity of AA and complexity of management, appropriate discussion in multidisciplinary meetings and involvement of expert centres is strongly recommended to improve patient outcomes.

Haploidentical transplant for paediatric patients with severe thalassaemia using post-transplant cyclophosphamide and methotrexate: A prospectively registered multicentre trial from the Bone Marrow Failure Working Group of Hunan Province, China.

Haploidentical transplantation strategies for patients with transfusion-dependent thalassaemia (TD-TM) remain to be investigated. In this study, 54 paediatric patients with TD-TM were treated with a novel approach using post-transplant cyclophosphamide (PTCy) and low-dose methotrexate (LD-MTX), following a myeloablative regimen. The incidence of neutrophil and platelet engraftment was 96.3% ± 2.6% and 94.4% ± 3.1% respectively. The cumulative incidence of grades II-III acute graft-versus-host disease (GVHD) was 13.8% ± 4.8% at 100 days. At three years, the cumulative incidence of chronic GVHD was 28.5% ± 8.5%. With a median follow-up of 520 days (132-1325 days), the overall survival (OS) and event-free survival (EFS) were 98.1% ± 1.8% and 90.7% ± 3.9% respectively. Compared with the low-dose cyclophosphamide (CTX) conditioning regimen (120 mg/kg), the high-CTX regimen (200 mg/kg) achieved a higher incidence of stable engraftment (100% vs 66.7% ± 15.7%, p = 0.003), a comparable incidence of grades II-III acute GVHD, a lower incidence of chronic GVHD (20.2% ± 8.3% vs 66.6% ± 19.2%, p = 0.011), and better overall survival (100% vs 88.9% ± 10.5%, p = 0.025) as well as EFS (95.6% ± 3.1% vs 66.7% ± 15.7%, p = 0.008). Our results using unmanipulated haploidentical grafts and PTCy with LD-MTX in TD-TM are encouraging. (chictr.org.cn ChiCTR1800017969).

Eficacia y seguridad de Azacitidina en pacientes con Síndrome Mielodisplásico de alto riesgo / Efficacy and safety of Azacitidine in patients with high-risk Myelodysplastic Syndrome

ANTECECENTES: Los síndromes mielodisplásicos (SMD) son un grupo heterogéneo de trastornos clonales de la medula ósea (MO) asociada a hematopoyesis ineficaz, manifestándose como displasia morfológica de los elementos hematopoyéticos y citopenias periféricas. El tratamiento curativo es el trasplante de células hematopoyéticas, sin embargo, debido a la edad, comorbilidades y aspectos administrativos, no todos los pacientes pueden acceder a este. Esta población de pacientes presentara anemia, infecciones a repetición y sangrados recurrentes. Los pacientes con alto riesgo tienen una sobrevida corta (0.8 meses). TECNOLOGÍA: Azacitidina está aprobado por las agencias reguladoras internacionales. La FDA aprobó el uso de azacitidina desde el 2004, mientras que EMA aprobó su uso desde el 2008. Este fármaco está disponible en nuestro país, y es distribuido por laboratorio TECNOFARMA SAC. DISCUSIÓN: El síndrome mielodisplásico es un grupo heterogéneo de enfermedades que puede tener una corta sobrevida. El tratamiento curativo es el trasplante de células hematopoyéticas, sin embargo, debido a la edad, comorbilidades y aspectos administrativos, no todos los pacientes pueden acceder a este. Esta población de pacientes presentara anemia, infecciones a repetición y sangrados recurrentes que ponen en peligro su vida. Las guías de práctica clínica (GPC) internacionales como la NCCN (2022), British Society for Haematology (BSH) (2021), European Society of Medical Oncology (ESMO) (2020), recomiendan el empleo de azacitidina en pacientes con SMD con IPSS-R intermedio, alto y muy alto; no candidatos para trasplante (todos con nivel de evidencia II-A). Una revisión sistemática/metaanálisis (2020) determino que azacitidina aumento significativamente TRO (RR = 1.48, 95% IC 1.05­2.1) y remisión completa con recuperación hematológica incompleta (HR = 2.52, IC 95% 1.27­5), con respecto al tratamiento convencional. Azacitidina prolongo significativamente la SG (HR = 0.64, IC 95% 0.50­0.82) con respecto al tratamiento convencional. Sin embargo, azacitidina aumento significativamente el riesgo de NTP grado ≥ 3 (RR = 1.23, IC 95% 1.13­1.35) y trombocitopenia (RR = 1.14, IC 95% 1.04­1.24). Azacitidina está aprobado por las agencias reguladoras internacionales. La FDA aprobó el uso de azacitidina desde el 2004, mientras que EMA aprobó su uso desde el 2008. Este fármaco está disponible en nuestro país, y es distribuido por laboratorio TECNOFARMA SAC. El reporte de uso de medicamentos de alto costo registro a 03 pacientes que recibieron azacitidina durante los ocho primeros meses del año 2021. Los tres pacientes tuvieron un rango de edad entre 51-73 años y la mayoría de ellos recibió solo 01 curso hasta el momento de la publicación del reporte. Con respecto a la toxicidad, 02 pacientes presentaron plaquetopenia grado Posteriormente, se buscaron todos los pacientes con SMD que había recibido tratamiento con azacitidina durante todo el 2021. Cinco pacientes fueron reportados. Uno de los pacientes tenía 1 año con 7 meses, no pudo trasplantarse por no tener hermanos compatibles para procedimiento, por lo que recibió 8 cursos de azacitidina, alcanzando respuesta parcial. Tres de los pacientes presentaron un rango de edad entre 20-50 años, presentaron diagnóstico de SMD con alto riesgo (IPSS-R) y recibieron azacitidina como "puente a trasplante". Uno de ellos recibió solo 01 curso de terapia, mientras que los otros dos recibieron 04 cursos en total. Finalmente, uno de los pacientes, de 47 años de edad, fue diagnosticado con SMD de alto riesgo y recibió solo un curso de azacitidina en setiembre del 2021. La toxicidad reportada fue: plaquetopenia grado 2-4, leucopenia grado 1, neutropenia grado 3. Se presento la evidencia científica disponible en una reunión multidisciplinaria y se discutió la aplicación de la tecnología en el INEN. El área usuaria valida la eficacia y seguridad del uso de azacitidina en los pacientes con síndrome mielodisplásico con IPSS intermedio-2 o de alto riesgo y IPSS-R intermedio, alto o muy alto no candidatos a trasplante o quimioterapia de alta intensidad. También mencionan que su uso puede considerarse como "puente a trasplante", donde también se demostró eficacia y seguridad. Se determinó que el beneficio de la aplicación de azacitidina es moderadamente significativo sobre la supervivencia, con limitada toxicidad, en comparación con tratamiento de soporte, en la población de interés. El balance de efectos favorables entre la intervención y el comparador favorece al uso de azacitidina. Además, se determina que el uso de azacitidina aumentaría la equidad en salud y su aplicación es factible en el INEN. Luego de la emisión de los votos correspondientes, se concluye aprobar el empleo de azacitidina en SMD IPSS-R intermedio, alto y muy alto no candidatos a trasplante ni terapia con intensa. CONCLUSIONES: Síndrome mielodisplásico (SMD) es un grupo heterogéneo de alteraciones caracterizadas por insuficiencia medular ósea. La sobrevida en pacientes con SMD de riesgo intermedio-2 y riesgo alto es de aproximadamente 0.4-1.2 años. Las guías de práctica clínica internacionales (NCCN, BJH y ESMO) recomiendan el uso de azacitidina en pacientes con SMD IPSS-R intermedio, alto y muy alto no candidatos a trasplante ni terapia con intensa. Una RS/MA reciente determino que la terapia con azacitidina es segura y eficaz en pacientes con SMD riesgo IPSS intermedio-2 y alto, demostrando mejorar TR, RCi y SG de forma significativa. La experiencia de tratamiento con azacitidina como tratamiento de pacientes con síndrome mielodisplásico en el INEN es segura y eficaz. Se discutió la evidencia científica disponible en una reunión multidisciplinaria y se concluyó aprobar el empleo de azacitidina en SMD IPSS intermedio-2 o de alto riesgo o IPSS-R intermedio, alto y muy alto no candidatos a trasplante ni terapia con intensa y podría considerarse como puente a trasplante.

When does a PNH clone have clinical significance?

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired blood disease caused by somatic mutations in the phosphatidylinositol glycan class A (PIGA) gene required to produce glycophosphatidyl inositol (GPI) anchors. Although PNH cells are readily identified by flow cytometry due to their deficiency of GPI-anchored proteins, the assessment of the clinical significance of a PNH clone is more nuanced. The interpretation of results requires an understanding of PNH pathogenesis and its relationship to immune-mediated bone marrow failure. Only about one-third of patients with PNH clones have classical PNH disease with overt hemolysis, its associated symptoms, and the highly prothrombotic state characteristic of PNH. Patients with classical PNH benefit the most from complement inhibitors. In contrast, two-thirds of PNH clones occur in patients whose clinical presentation is that of bone marrow failure with few, if any, PNH-related symptoms. The clinical presentations are closely associated with PNH clone size. Although exceptions occur, bone marrow failure patients usually have smaller, subclinical PNH clones. This review addresses the common scenarios that arise in evaluating the clinical significance of PNH clones and provides practical guidelines for approaching a patient with a positive PNH result.

Anti Thymocyte Globulin-Based Treatment for Acquired Bone Marrow Failure in Adults.

Idiopathic acquired aplastic anemia can be successfully treated with Anti Thymocyte Globulin (ATG)-based immune suppressive therapy and is therefore considered a T cell-mediated auto immune disease. Based on this finding, several other forms of idiopathic acquired bone marrow failure are treated with ATG as well. For this review, we extensively searched the present literature for evidence that ATG can lead to enduring remissions in different forms of acquired multi- or single-lineage bone marrow failure. We conclude that ATG-based therapy can lead to an enduring hematopoietic response and increased overall survival (OS) in patients with acquired aplastic aplasia. In patients with hypocellular myelodysplastic syndrome, ATG can lead to a hematological improvement without changing the OS. ATG seems less effective in acquired single-lineage failure diseases like Pure Red Cell Aplasia, Amegakaryocytic Thrombocytopenia and Pure White Cell Aplasia, suggesting a different pathogenesis in these bone marrow failure states compared to aplastic anemia. T cell depletion is hypothesized to play an important role in the beneficial effect of ATG but, as ATG is a mixture of polyclonal antibodies binding to different antigens, other anti-inflammatory or immunomodulatory effects could play a role as well.

Bone Marrow Failure Syndromes, Overlapping Diseases with a Common Cytokine Signature.

Bone marrow failure (BMF) syndromes are a heterogenous group of non-malignant hematologic diseases characterized by single- or multi-lineage cytopenia(s) with either inherited or acquired pathogenesis. Aberrant T or B cells or innate immune responses are variously involved in the pathophysiology of BMF, and hematological improvement after standard immunosuppressive or anti-complement therapies is the main indirect evidence of the central role of the immune system in BMF development. As part of this immune derangement, pro-inflammatory cytokines play an important role in shaping the immune responses and in sustaining inflammation during marrow failure. In this review, we summarize current knowledge of cytokine signatures in BMF syndromes.

Sargramostim (rhu GM-CSF) Improves Survival of Non-Human Primates with Severe Bone Marrow Suppression after Acute, High-Dose, Whole-Body Irradiation.

Exposure to acute, high-dose, whole-body ionizing radiation results in bone marrow failure (hematopoietic acute radiation syndrome with resultant infection, bleeding, anemia, and increased risk of death). Sargramostim (yeast-derived rhu GM-CSF), a yeast-derived, molecularly cloned, hematopoietic growth factor and pleiotropic cytokine supports proliferation, differentiation, maturation and survival of cells of several myeloid lineages. We evaluated the efficacy of sargramostim in non-human primates (rhesus macaques) exposed to whole-body ionizing radiation at a 50-60% lethal dose. The primary end point was day 60 survival. Non-human primates received daily subcutaneous sargramostim (7 mcg/kg/day) or control. To reflect the anticipated setting of a nuclear or radiologic event, treatment began 48 h postirradiation, and non-human primates received only moderate supportive care (no whole blood transfusions or individualized antibiotics). Sargramostim significantly increased day 60 survival to 78% (95% confidence interval, 61-90%) vs. 42% (26-59%; P = 0.0018) in controls. Neutrophil, platelet and lymphocyte recovery rates were accelerated and infection rates decreased. Improved survival when sargramostim was started 48 h postirradiation, without use of intensive supportive care, suggests sargramostim may be effective in treating humans exposed to acute, high-dose whole-body, ionizing radiation in a scenario such as a mass casualty event.

Reduced Intensity Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Pediatric Inherited Immune Deficiencies and Bone Marrow Failure Syndromes.

PURPOSE: Allogeneic bone marrow transplantation (alloBMT) is the only cure for many primary immune deficiency disorders (PIDD), primary immune regulatory disorders (PIRD), and inherited bone marrow failure syndromes (IBMFS). METHODS: We report the results of 25 patients who underwent alloBMT using reduced intensity conditioning (RIC), alternative donors, and post-transplantation cyclophosphamide (PTCy). In an attempt to reduce regimen-related toxicities, we removed low-dose TBI from the prep and added mycophenolate mofetil and tacrolimus for graft-versus-host disease (GVHD) prophylaxis for all donor types in the latter 14 patients. Donors were haploidentical related (n = 14), matched unrelated (n = 9), or mismatched unrelated (n = 2). The median age was 9 years (range 5 months-21 years). RESULTS: With a median follow-up of 26 months (range 7 months-9 years), the 2-year overall survival is 92%. There were two deaths, one from infection, and one from complications after a second myeloablative BMT. Three patients developed secondary graft failure, one at 2 years and two at >3 years, successfully treated with CD34 cell boost in one or second BMT in two. The remaining 20 patients have full or stable mixed donor chimerism and are disease-free. The incidence of mixed chimerism is increased since removing TBI from the prep. The 6-month cumulative incidence of grade II acute GVHD is 17%, with no grade III-IV. The 1-year cumulative incidence of chronic GVHD is 14%, with severe of 5%. CONCLUSION: This alloBMT platform using alternative donors, RIC, and PTCy is associated with excellent rates of engraftment and low rates of GVHD and non-relapse mortality, and offers a curative option for patients with PIDD, PIRD, and IBMFS. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04232085.

The Effectiveness of Rapamycin Combined with Eltrombopag in Murine Models of Immune-Mediated Bone Marrow Failure.

Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Most patients with AA respond to immunosuppressive therapy (IST), usually as antithymocyte globulin (ATG) and cyclosporine (CsA), but some relapse on CsA withdrawal or require long-term administration of CsA to maintain blood counts. Recent research has found that rapamycin (Rapa) was an effective therapy in mouse models of immune-mediated bone marrow failure. However, it has not achieved a satisfactory effect in clinical application. At present, many studies have confirmed that eltrombopag (ELT) combined with IST can improve the curative effect of AA patients. Then, whether Rapa combined Elt in the treatment of AA will acquire better efficacy than a single drug application remains unclear. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation (TBI) and allo-lymphocyte infusion. In our study, we tested the efficacy of Rapa combined with Elt as a new treatment in mouse models of immune-mediated bone marrow failure. It showed that treatment with Rapa in combination Elt in the AA mouse model ameliorated pancytopenia and extended animal survival in a manner comparable to the standard dose of CsA and Rapa alone. However, there was no significant improvement effect on the number and function of NK cells and their subsets, mDCs, and CD4+/CD8+ ratio in AA mice after the therapy of Rapa combined with Elt compared with Rapa alone. Furthermore, the secretion of IL-10 of Tregs in AA mice increased significantly after the therapy of Rapa combined with Elt, but there was no significant difference in the number of Treg cells. We did not observe the difference in the curative effect of the Rapa group and CsA group, but for IL-10/Tregs ratio, the Rapa group was superior to the CsA group. And the IFN-r secretion of CD8+T cells in AA mice decreased significantly after the combination therapy of Rapa and Elt than Rapa alone. Compared with the AA group, the level of plasma IFN-γ, IL-2, and TNF-α decreased significantly (P < 0.05), but IL-10, IL-4, IL-5, and IL-1ß increased significantly in the Rapa group (P < 0.05). As for IL-10, IL-12p70, IL-2, IL-6, KC/GRO, and TNF-α, the therapy of Rapa combined with Elt showed a more significant effect than Rapa alone in AA mice. To some extent, this study had shown a relatively better synergistic effect in murine models of immune-mediated bone marrow failure after the combination therapy of Rapa and Elt, which was a promising clinical utility in SAA treatment.

COVID-19 rapid guideline: rheumatological autoimmune, inflammatory and metabolic bone disorders

The purpose of this guideline is to maximise the safety of children and adults with rheumatological autoimmune, inflammatory and metabolic bone disorders during the COVID-19 pandemic, while protecting staff from infection. It also enables services to make the best use of NHS resources.

Androgen therapy in inherited bone marrow failure syndromes: analysis from the Canadian Inherited Marrow Failure Registry.

Progressive cytopenia is a serious complication among paediatric patients with inherited bone marrow failure syndromes (IBMFS). Androgens have been used to improve blood counts in different bone marrow failure conditions. Little is known about efficacy and toxicity with new androgens (i.e., danazol) in different types of IBMFS. We identified 29 patients from the Canadian Inherited Marrow Failure Registry, who received oxymetholone or danazol. Sixteen (55%) had haematological response including patients with unclassified IBMFS (45%). Danazol showed a better toxicity profile and similar efficacy compared to oxymetholone. Androgens are an effective and safe option to ameliorate bone marrow failure in IBMFS.

Epimedium polysaccharides attenuates hematotoxicity by reducing oxidative stress and enhancing immune function in mice model of benzene-induced bone marrow failure.

Chronic benzene (BZ) exposure is associated with multiple adverse health effects and leads to progressive bone marrow failure (BMF). BZ-induced BMF is an acquired aplastic anemia characterized by severe anemia, neutropenia and thrombocytopenia, which is likely caused by immunotoxicity and oxidative stress. Previous studies showed that Epimedium polysaccharides (EPS), a natural and major herbal compound derived from Epimedium, has immunomodulatory and antioxidant potential. The purpose of this study was to evaluate the potential efficacy of EPS against BZ-induced BMF. BMF mouse model was established by subcutaneous injection of 2 ml/kg BZ in CD1 mice. Mice received daily oral treatment with 100 mg/kg high-dose EPS and 20 mg/kg low-dose EPS for four weeks. Our data showed that EPS treatment alleviated BZ-associated weight loss and increased the number of whole blood cells in peripheral blood and nucleated cells in bone marrow. Furthermore, EPS treatment decreased apoptotic rate and reactive oxygen species production, S-phase arrest in bone marrow cells. Finally, EPS treatment improved T cell-mediated immune suppression by increasing CD3+, CD4 + T-cell counts, and CD4+/CD8+ ratio. and modulated hematopoietic cytokines including EPO, IL-11, and IL-2 in peripheral blood. Our study suggests that EPS is a potential therapeutic target to attenuate hematotoxicity induced by BZ.