RESUMEN
Viral infections, including those caused by COVID-19, can produce striking morphologic changes in peripheral blood. Distinguishing between reactive changes and abnormal morphology of monocytes remains particularly difficult, with low consensus rates reported amongst hematopathologists. Here, we report a patient who developed transient monocytosis of 11.06 × 109/L with 32% promonocytes and 1% blasts during hospitalization that was secondary to severe COVID-19 infection. Three days later, the clinical status of the patient improved and the WBC had decreased to 8.47 × 109/L with 2.2 × 109/L monocytes. Flow cytometry studies did not reveal immunophenotypic findings specific for an overt malignant population. At no time during admission did the patient develop cytopenia(s), and she was discharged upon clinical improvement. However, the peripheral blood sample containing promonocytes was sent for molecular testing with an extended next-generation sequencing myeloid panel and was positive for pathogenic NPM1 Type A and DNMT3A R882H mutations. Subsequently, despite an essentially normal complete blood count, the patient underwent a bone marrow assessment that showed acute myeloid leukemia with 77% promonocytes. This case emphasizes the critical importance of a full work up to exclude acute leukemia when classical promonocyte morphology is encountered in the peripheral blood. Promonocytes are not a part of the reactive changes associated with COVID-19 and remain specific to myeloid neoplasia.
RESUMEN
This is a consensus-based Canadian guideline whose primary purpose is to standardize and facilitate the management of chronic graft-versus-host disease (cGvHD) across the country. Creating uniform healthcare guidance in Canada is a challenge for a number of reasons including the differences in healthcare authority structure, funding and access to healthcare resources between provinces and territories, as well as the geographic size. These differences can lead to variable and unequal access to effective therapies for GvHD. This document will provide comprehensive and practical guidance that can be applied across Canada by healthcare professionals caring for patients with cGvHD. Hopefully, this guideline, based on input from GvHD treaters across the country, will aid in standardizing cGvHD care and facilitate access to much-needed novel therapies. This consensus paper aims to discuss the optimal approach to the initial assessment of cGvHD, review the severity scoring and global grading system, discuss systemic and topical treatments, as well as supportive therapies, and propose a therapeutic algorithm for frontline and subsequent lines of cGvHD treatment in adults and pediatric patients. Finally, we will make suggestions about the future direction of cGvHD treatment development such as (1) a mode-of-action-based cGvHD drug selection, according to the pathogenesis of cGvHD, (2) a combination strategy with the introduction of newer targeted drugs, (3) a steroid-free regimen, particularly for front line therapy for cGvHD treatment, and (4) a pre-emptive approach which can prevent the progression of cGvHD in high-risk patients destined to develop severe and highly morbid forms of cGvHD.
Asunto(s)
Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Consenso , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/patología , Enfermedad Crónica , CanadáRESUMEN
Acute graft versus host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplant (HCT) and is associated with significant morbidity and mortality. Steroid refractory aGVHD (SR-aGVHD) carries a particularly grim prognosis. Ruxolitinib has shown promise for treatment of SR-aGVHD in a phase 3 trial; however, safety and efficacy data outside of the clinical trial setting is lacking. We performed a multicenter retrospective study to examine the response to ruxolitinib and its efficacy in patients with SR-aGVHD. We included 59 patients treated with ruxolitinib for SR-aGVHD between 2015 and 2022. Of these 59 patients, 36 patients (61.0%) achieved a complete (CR) or partial response (PR) at 28 days, while 31 patients (52.5%) obtained a CR/PR at day 56. Patients that achieved a CR or PR at day 28 had a higher rate of overall survival (OS; 69.2%), compared with patients that did not (31.6%; p = 0.037). OS at 12 months was 41.5%, with a median OS duration of 5.3 months. Failure free survival (FFS) at 12 months was 29.1%, with a median FFS of 2.6 months. Overall, this real-world experience data support ruxolitinib as the standard of care for SR-aGVHD in a non-controlled trial population.
Asunto(s)
Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Nitrilos , Pirazoles , Pirimidinas , Humanos , Nitrilos/uso terapéutico , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Trasplante de Células Madre Hematopoyéticas/métodos , Anciano , Enfermedad Aguda , Esteroides/uso terapéutico , Adolescente , Adulto Joven , Tasa de SupervivenciaRESUMEN
As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the volume of HCT performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long-term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pre-, peri- and post-transplant exposures and other underlying risk-factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and updated in 2012. To review contemporary literature and update the recommendations while considering the changing practice of HCT and cellular therapy, an international group of experts was again convened. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed but cGVHD management is not covered in detail. These guidelines emphasize special needs of patients with distinct underlying HCT indications or comorbidities (e.g., hemoglobinopathies, older adults) but do not replace more detailed group, disease, or condition specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Trasplante de Células Madre Hematopoyéticas/métodos , Enfermedad Injerto contra Huésped/prevención & control , Enfermedad Injerto contra Huésped/etiología , Sobrevivientes , Adulto , Guías de Práctica Clínica como Asunto , Masculino , NiñoRESUMEN
As hematopoietic cell transplantation (HCT) and cellular therapy expand to new indications and international access improves, the number of HCTs performed annually continues to rise. Parallel improvements in HCT techniques and supportive care entails more patients surviving long term, creating further emphasis on survivorship needs. Survivors are at risk for developing late complications secondary to pretransplantation, peritransplantation, and post-transplantation exposures and other underlying risk factors. Guidelines for screening and preventive practices for HCT survivors were originally published in 2006 and then updated in 2012. An international group of experts was convened to review the contemporary literature and update the recommendations while considering the changing practices of HCT and cellular therapy. This review provides updated pediatric and adult survivorship guidelines for HCT and cellular therapy. The contributory role of chronic graft-versus-host disease (cGVHD) to the development of late effects is discussed, but cGVHD management is not covered in detail. These guidelines emphasize the special needs of patients with distinct underlying HCT indications or comorbidities (eg, hemoglobinopathies, older adults) but do not replace more detailed group-, disease-, or condition-specific guidelines. Although these recommendations should be applicable to the vast majority of HCT recipients, resource constraints may limit their implementation in some settings.
Asunto(s)
Trasplante de Células Madre Hematopoyéticas , Sobrevivientes , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Factores de Riesgo , Sobrevida , SupervivenciaRESUMEN
Allogenic hematopoietic stem cell transplantation (allo-HSCT) is a life-saving treatment for various hematological disorders. The success of allo-HSCT depends on the engraftment of donor cells and the elimination of recipient cells monitored through chimerism testing. We aimed to validate a next-generation sequencing (NGS)-based chimerism assay for engraftment monitoring and to emphasize the importance of including the most prevalent cell subsets in proficiency testing (PT) programs. We evaluated the analytical performance of NGS-based chimerism testing (AlloSeq-HCT and CareDx) with a panel of targeted 202 informative single-nucleotide polymorphisms (SNPs) (i.e., linearity and precision, analytical sensitivity and specificity, system accuracy, and reproducibility). We further compared the performance of our NGS panel with conventional short tandem repeat (STR) analysis in unfractionated whole blood and cell-subset-enriched CD3 and CD66. Our NGS-based chimerism monitoring assay has an impressive detection limit (0.3% host DNA) for minor alleles and analytical specificity (99.9%). Pearson's correlation between NGS- and STR-based chimerism monitoring showed a linear relationship with a slope of 0.8 and r = 0.973. The concordance of allo-HSCT patients using unfractionated whole blood, CD3, and CD66 was 0.95, 0.96, and 0.54, respectively. Utilization of CD3+ cell subsets for mixed chimerism detection yielded an average of 7.3 ± 7-fold higher donor percentage detection compared to their corresponding unfractionated whole blood samples. The accuracy of the NGS assay achieved a concordance of 98.6% on blinded external quality control STR samples. The reproducibility series showed near 100% concordance with respect to inter-assay, inter-tech, inter-instrument, cell flow kits, and AlloSeq-HCT software versions. Our study provided robust validation of NGS-based chimerism testing for accurate detection and monitoring of engraftment in allo-HSCT patients. By incorporating the cell subsets (CD3 and CD66), the sensitivity and accuracy of engraftment monitoring are significantly improved, making them an essential component of any PT program. Furthermore, the implementation of NGS-based chimerism testing shows potential to streamline high-volume transplant services and improve clinical outcomes by enabling early relapse detection and guiding timely interventions.
RESUMEN
Established first-line therapy for chronic graft-versus-host disease (cGvHD) comprises corticosteroids with/without calcineurin inhibitors, but about half of cGvHD patients are refractory to corticosteroid therapy. The present study retrospectively analyzed treatment outcomes in 426 patients and undertook a propensity-score matching (PSM) analysis between ruxolitinib (RUX) treated group and a historical group of cGvHD patients treated with best available treatment (BAT). PSM process adjusted unbalanced risk factors between the 2 groups, including GvHD severity, HCT-CI score, and treatment line, extracting 88 patients (44 in BAT/RUX groups each) for final analysis. In PSM subgroup, RUX group showed 74.7% 12 months' FFS rate vs 19.1% for BAT group (p < 0.001), whereas 12 months' OS rates were 89.2% and 77.7%, respectively. Multivariate analysis for FFS confirmed RUX superiority over BAT together with HCT-CI score 0-2 vs ≥3. For OS, RUX was superior to BAT, while age ≥60 years and severe grade cGvHD adversely impacted OS. In PSM subgroup, at months 0, 3, and 6, 4.5%, 12.2% and 22.2% more patients in RUX group could discontinue prednisone compared to BAT group, respectively. In conclusion, the current study showed that for FFS, RUX was superior to BAT as second-line therapy or beyond in cGvHD patients after therapy failure.
Asunto(s)
Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Persona de Mediana Edad , Enfermedad Injerto contra Huésped/etiología , Estudios Retrospectivos , Puntaje de Propensión , Prednisona , Trasplante de Células Madre Hematopoyéticas/efectos adversosRESUMEN
Although ruxolitinib is emerging as the treatment of choice for steroid-refractory or -dependent chronic graft versus host disease (cGVHD) based on randomized control trial data, there is relatively little real-world data published on ruxolitinib for this indication. We wanted to evaluate the real-world efficacy and safety of ruxolitinib in cGVHD patients who have failed any previous systemic therapy for cGVHD. We retrospectively evaluated the efficacy of ruxolitinib in 115 heavily pretreated patients with steroid-refractory or -dependent chronic GVHD across 5 transplantation centers. The majority of the study population had severe cGVHD (60%) and received ruxolitinib at the fourth treatment line or beyond (82%, n = 96). The median duration of follow-up in this study population was 13 months. The overall response rate (ORR) was 48.6%, 54.9%, and 48.5% at 3, 6, and 12 months, respectively. Clinical benefit (an outcome metric combining ORR with steroid reduction) was observed in 58.7%, 64.8%, and 60.6% of patients at 3, 6, and 12 months, respectively. Approximately one third of patients (37.9%) were able to discontinue prednisone at 12 months, and 63.8% were able to taper prednisone to a daily dose <0.1 mg/kg at 12 months. Failure-free survival at 12 months was 64.6% (54.1%-73.2%). Multivariate analysis identified that patients with severe cGVHD were at a higher risk of failure because of a therapy switch, whereas a pretransplantation hematopoietic stem cell transplantation-comorbidity index score ≥ 3 was associated with a high risk of failure because of increasing risk of non-relapse mortality. Overall, this study demonstrates the therapeutic efficacy of ruxolitinib for cGVHD in a heavily pretreated real-world population.
Asunto(s)
Síndrome de Bronquiolitis Obliterante , Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Humanos , Estudios Retrospectivos , Prednisona/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/tratamiento farmacológico , Enfermedad Injerto contra Huésped/etiología , Terapia Recuperativa/efectos adversosRESUMEN
Iron overload (IO) reflected by elevated ferritin is associated with increased mortality in myelodysplastic syndromes (MDS), however, ferritin is an imperfect metric. Elevated labile plasma iron correlates with clinical outcomes and transferrin saturation (TSAT) >80%, but is not readily measurable. The trajectory of TSAT, and its association with clinical outcomes remain undefined. Canadian MDS registry patients were evaluated. Mean TSAT, mean ferritin and transfusion dose density (TDD) were determined. Survival was evaluated by TSAT and ferritin (<50%, 50-80%, >80%), (≤500 µg/L, 501-800 µg/L, >800 µg/L). In 718 patients, median age was 74 years; 12%, 31%, 29%, 15% and 13% were IPSS-R very low, low, intermediate, high and very high. TSAT and ferritin were moderately correlated (r=0.63, P<0.0001). TSAT increased over time in transfusion- dependent patients (P=0.006). Higher TSAT and ferritin were associated with inferior 5-year overall (OS), progression- free (PFS), and leukemia-free survival (LFS) (P≤0.008) and higher TDD with inferior 5-year OS. TSAT >80% trended with inferior cardiac death-free survival (P=0.053). In univariate analysis, age, IPSS-R, blast percentage by Eastern Cooperative Oncology Group Performance Status, frailty, Charlson Comorbidity Index, iron chelation (Y/N), TDD, TSAT and ferritin were significantly associated with inferior OS. By multivariable analysis, TSAT >80% (P=0.007) remained significant for OS (R2 30.3%). In MDS, TSAT >80% and ferritin >800 µg/L portended inferior OS, PFS and LFS. TSAT may indicate the presence of oxidative stress, and is readily measurable in a clinical setting. The relationship between TSAT and cardiac death-free survival warrants further study.
Asunto(s)
Hierro , Síndromes Mielodisplásicos , Humanos , Anciano , Canadá , Ferritinas , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/terapia , Transferrinas , TransferrinaRESUMEN
In many stem cell transplant centres, BCNU, etoposide, cytarabine and melphalan (BEAM) high-dose chemotherapy (HDCT) has been replaced by the more economic and available bendamustine, etoposide, cytarabine, melphalan (BeEAM) regimen. However, there is a paucity of information on the efficacy and safety of BeEAM HDCT. We describe our experience with BeEAM HDCT in terms of safety, efficacy and cost-savings. We compare overall and progression-free survival to a cohort of patients previously transplanted at our institution with the older BEAM regimen. We performed a retrospective chart review of 41 lymphoma patients undergoing BeEAM HDCT at the Royal University Hospital in Saskatoon, Saskatchewan between 2015 and 2019 to elicit regimen safety in the first 100 days post-transplant. Furthermore, we calculated overall and progression-free survival and constructed corresponding Kaplan-Meier curves, comparing the results to a historical cohort of BEAM patients (n = 86). Finally, we conducted an economic analysis using the financials available at our centre's pharmacy. With regards to BeEAM HDCT, we report a 100-day transplant-related mortality of 2.4%. Additionally, we report acceptable rates of typhlitis (27%), grade III-IV mucositis (4.9%) and grade III-IV nephrotoxicity (2.4%). In terms of overall and progression-free survival, we found no statistical difference between BeEAM and BEAM (p = 0.296; 0.762, respectively). Finally, our economic analysis revealed a net savings of $21,200 CAD per transplant when BeEAM is used in replacement of BEAM. The acceptable safety profile of BeEAM and its comparable efficacy to BEAM are encouraging for the perseverance of this cost-effective HDCT regimen.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Trasplante de Células Madre Hematopoyéticas/métodos , Neoplasias/terapia , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Carmustina , Citarabina , Etopósido , Femenino , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Masculino , Melfalán , Persona de Mediana Edad , Neoplasias/diagnóstico , Neoplasias/mortalidad , Evaluación de Resultado en la Atención de Salud , Podofilotoxina , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
The incorporation of patient-reported outcomes with traditional disease risk classification was found to strengthen survival prediction in patients with myelodysplastic syndromes (MDS). In the present Canadian MDS registry analysis, we validate a recently reported prognostic model, the Fatigue-International Prognostic Scoring System among higher-risk patients [FA-IPSS(h)], which incorporates patients' reported fatigue, assessed by the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30), with a threshold of ≥45 points, in higher IPSS score, stratifying them into distinct subgroups with different survival outcomes. We further validated this concept, using the Revised IPSS >3·5 as cut-off for the definition of higher-risk MDS, and patients' reported fatigue according to Edmonton Symptom Self-Assessment Scale (ESAS) Global Fatigue Scale (GFS), a single-item fatigue rating scale, which is easier to deploy. This emphasises the power of self-reported fatigue at refining overall survival predictions in higher-risk MDS and further bolsters the importance of considering patient-related outcomes in global assessments.
Asunto(s)
Fatiga/complicaciones , Síndromes Mielodisplásicos/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Canadá/epidemiología , Fatiga/diagnóstico , Fatiga/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/epidemiología , Medición de Resultados Informados por el Paciente , Pronóstico , Calidad de Vida , Sistema de RegistrosRESUMEN
Introduction: Granulocyte colony-stimulating factor (G-CSF) is the first line treatment for mobilization, most commonly using a regimen of daily filgrastim. The use of biosimilars can provide substantial cost savings to the health care system while delivering comparable efficacy outcomes. In 2016, the Saskatchewan Cancer Agency was a leader in Canada, instituting formulary changed from a G-CSF originator product to a cost savings alternative biosimilar for stem cell mobilization prior to autologous stem cell transplant (ASCT) and for engraftment. The purpose of this study was to investigate the clinical comparability of biosimilar G-CSF to its reference product in a real-world clinical setting and to validate use of the biosimilar in mobilization and engraftment-an indication which had been granted by extrapolation. METHODS: A retrospective chart review was completed including all patients diagnosed with a hematological malignancy between 2012 and 2018 who underwent ASCT. To assess real-world outcomes across a diverse population, successful CD34+ stem cell collection was compared between patients mobilized with originator filgrastim, Neupogen, and biosimilar filgrastim, Grastofil. Additional comparisons included the number of apheresis required, time to absolute neutrophil count (ANC) engraftment, platelet engraftment, length of hospital stay, and Plerixafor use. RESULTS: 217 patients were mobilized and transplanted during the study period. There was no statistically significant difference in success rate between patients mobilized with biosimilar filgrastim and those who had received originator G-CSF (100% vs. 92.4%, p = 0.075). Neither disease type, nor concurrent chemomobilization regimen resulted in a detectable difference between the two G-CSF products in successful stem cell harvest. Engraftment was highly similar between groups, as demonstrated by ANC recovery (11.6 days Neupogen vs. 11.6 days Grastofil), platelet recovery (14.0 days Neupogen vs. 14.2 days Grastofil), and total length of hospital stay (22.4 days Neupogen vs. 22.3 days Grastofil). No statistically significant difference in adjunctive use of Plerixafor® was observed between Neupogen and Grastofil patients (25.9% vs. 23.4%, p = 0.72). CONCLUSION: Extrapolation of indications for biosimilars is justified. This real-world evidence builds upon registrational studies to confirm that no clinically meaningful differences were detected between originator Neupogen and biosimilar Grastofil in the setting of PBSC mobilization and engraftment post ASCT. Biosimilars are as safe and effective as originator products. Implementation across all approved indications without hesitation maximizes cost savings to the provincial system, allowing for more optimal allocation of health care resources.
Asunto(s)
Biosimilares Farmacéuticos , Compuestos Heterocíclicos , Mieloma Múltiple , Células Madre de Sangre Periférica , Factor Estimulante de Colonias de Granulocitos , Movilización de Célula Madre Hematopoyética , Humanos , Mieloma Múltiple/terapia , Estudios Retrospectivos , SaskatchewanRESUMEN
PURPOSE: Evidence regarding red blood cell (RBC) transfusion practices and their impact on hematopoietic cell transplantation (HCT) outcomes are poorly understood. PATIENTS AND METHODS: We performed a noninferiority randomized controlled trial in four different centers that evaluated patients with hematologic malignancies requiring HCT who were randomly assigned to either a restrictive (hemoglobin [Hb] threshold < 70 g/L) or liberal (Hb threshold < 90 g/L) RBC transfusion strategy between day 0 and day 100. The noninferiority margin corresponds to a 12% absolute difference between groups in Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) score relative to baseline. The primary outcome was health-related quality of life (HRQOL) measured by FACT-BMT score at day 100. Additional end points were collected: HRQOL by FACT-BMT score at baseline and at days 7, 14, 28, 60, and 100; transplantation-related mortality; length of hospital stay; intensive care unit admissions; acute graft-versus-host disease; Bearman toxicity score; sinusoidal obstruction syndrome; serious infections; WHO Bleeding Scale; transfusion requirements; and reactions to therapy. RESULTS: A total of 300 patients were randomly assigned to either restrictive-strategy or liberal-strategy treatment groups between 2011 and 2016 at four Canadian adult HCT centers. After HCT, mean pre-transfusion Hb levels were 70.9 g/L in the restrictive-strategy group and 84.6 g/L in the liberal-strategy group (P < .0001). The number of RBC units transfused was lower in the restrictive-strategy group than in the liberal-strategy group (mean, 2.73 units [standard deviation, 4.81 units] v 5.02 units [standard deviation, 6.13 units]; P = .0004). After adjusting for transfusion type and baseline FACT-BMT score, the restrictive-strategy group had a higher FACT-BMT score at day 100 (difference of 1.6 points; 95% CI, -2.5 to 5.6 points), which was noninferior compared with that of the liberal-strategy group. There were no significant differences in clinical outcomes between the transfusion strategies. CONCLUSION: In patients undergoing HCT, the use of a restrictive RBC transfusion strategy threshold of 70 g/L was as effective as a threshold of 90 g/L and resulted in similar HRQOL and HCT outcomes with fewer transfusions.
Asunto(s)
Transfusión de Eritrocitos/métodos , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Adulto , Canadá , Transfusión de Eritrocitos/efectos adversos , Femenino , Enfermedad Injerto contra Huésped/diagnóstico , Enfermedad Injerto contra Huésped/etiología , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Tiempo de Internación/estadística & datos numéricos , Masculino , Persona de Mediana Edad , Calidad de Vida , Resultado del TratamientoRESUMEN
Thrombotic microangiopathies (TMA) are characterized by microangiopathic hemolytic anemia, thrombocytopenia and organ damage resulting from mechanical factors, accumulation of the ultra-large von Willebrand factor multimers or complement-mediated abnormalities. Severe acquired vitamin B12 (Cobalamin - Cbl) deficiency or congenital defective Cbl metabolism could lead to a picture that mimics TMA. The later has been termed metabolism-mediated TMA (MM- TMA). This confusing picture is mediated partly by the large red cell fragmentation coupled with reduced platelet production in the absence of vitamin B12 and partly by the accumulated byproducts and metabolites that induce endothelial injury and hence organ damage. Expensive and complicated treatment for TMA is often initiated on an empiric basis, pending the results of confirmatory tests. In contrast, vitamin B12 Pseudo-TMA and MM-TMA could be treated with proper vitamin B12 supplementation. It is therefore important to identify these disorders promptly. The recent availability of a validated scoring system such as the PLASMIC score uses simple clinical and laboratory parameters. As it incorporates the mean corpuscular volume in its laboratory parameters, this helps in the identification of pseudo and MM-TMA. Perhaps some minor modification of this scoring system by changing the parameters of hemolysis to include reticulocytosis and rather than and/or other hemolytic parameters could even help refine this identification.
Asunto(s)
Microangiopatías Trombóticas/sangre , Deficiencia de Vitamina B 12/complicaciones , Humanos , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/patologíaRESUMEN
BACKGROUND: Previous trials testing prevention strategies for chronic graft versus host disease (GVHD) have measured its cumulative incidence. In this trial of anti-thymocyte globulin, we measured treatment-independence at a long-term timepoint as the primary endpoint. METHODS: This was a randomised, open-label, multicentre, phase 3 trial done at ten centres in Canada and one in Australia. Eligible patients had a haematological malignancy (leukaemia, myelodysplastic syndrome, or lymphoma), were between 16 and 70 years of age, eligible for transplantation with a Karnofsky score of at least 60, and received an unrelated donor (fully matched or one-locus mismatched at HLA-A, HLA-B, HLA-C, or DRB1 loci) graft following myeloablative or non-myeloablative-reduced intensity conditioning. Patients were randomly assigned to receive anti-thymocyte globulin 4·5 mg/kg plus standard GVHD prophylaxis (cyclosporine or tacrolimus plus methotrexate or mycophenolate) or standard GVHD prophylaxis alone. The primary endpoint, freedom from immunosuppressive therapy without resumption at 12 months, was previously reported. Here we report on the prespecified 24-month analysis. Analyses were per-protocol, excluding those patients who did not proceed to transplantation. This trial is registered as ISRCTN 29899028 and NCT01217723, status completed. FINDINGS: Between June 9, 2010, and July 8, 2013, we recruited and randomly assigned 203 eligible patients to receive anti-thymocyte globulin (n=101) or no additional treatment (n=102) along with standard GVHD prophylaxis. 7 (3%) patients did not receive a transplant and were excluded from the analysis. 38 (38%) of 99 evaluable patients in the anti-thymocyte globulin plus GVHD prophylaxis group were free from immunosuppressive therapy at 24 months compared with 18 (19%) of 97 patients in the standard GVHD prophylaxis group (adjusted odds ratio [OR] 3·49 [95% CI 1·607·60]; p=0·0016). At 24 months, the cumulative incidence of relapse was 16·3% (95% CI 8·923·7) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 17·5 (9·925·1) in the standard GVHD prophylaxis group (p=0·73) and non-relapse mortality was 21·2% (95% CI 13·229·2) versus 31·3% (21·940·7; p=0·15). The cumulative incidence of chronic GVHD at 24 months was 26·3% (95% CI 17·535·1) in the anti-thymocyte globulin group and 41·3% (31·351·3) in the standard GVHD prophylaxis group (p=0·032). Overall survival at 24 months was 70·6% (95% CI 60·678·6) in the anti-thymocyte globulin plus GVHD prophylaxis group compared with 53·3% (42·862·8) in the standard GVHD prophylaxis group (adjusted hazard ratio [HR] 0·56, 95% CI [0·350·90]; p=0·017). Symptoms of chronic GVHD by the Lee Scale were more prevalent in the standard GVHD prophylaxis group, with scores of 13·27 (SD 10·94) in the anti-thymocyte globulin plus GVHD prophylaxis group and 20·38 (SD 14·68) in the standard GVHD prophylaxis group (p=0·040). Depressive symptoms were more prominent in the standard GVHD prophylaxis group, the mean Center for Epidemiological Studies Depression scale (CES-D) scores were 10·40 (SD 9·88) in the anti-thymocyte globulin group and 14·62 (SD 12·26) in the standard GVHD prophylaxis group (p=0·034). Serious adverse events (CTCAE grade 4 or 5) occurred in 38 (38%) patients in the anti-thymocyte globulin group and in 49 (51%) in the standard GVHD prophylaxis group, the most common being infection and GVHD. One patient in the anti-thymocyte globulin plus GVHD prophylaxis group died of Epstein-Barr virus hepatitis, but no deaths were attributable to anti-thymocyte globulin. INTERPRETATION: The results of this prespecified 24-month analysis suggest that pretreatment with anti-thymocyte globulin provides clinically meaningful benefits when added to standard GVHD prophylaxis in patients undergoing unrelated donor transplantation, including decreases in use of immunosuppressive therapy, chronic GVHD and its symptoms, depressive symptoms, and improved overall survival. Anti-thymocyte globulin should be included in the preparative regimens of patients with haematological malignancies selected for unrelated donor transplantation. FUNDING: Canadian Institutes of Health Research and Sanofi.
Asunto(s)
Suero Antilinfocítico/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Enfermedad Injerto contra Huésped/prevención & control , Neoplasias Hematológicas/terapia , Inmunosupresores/uso terapéutico , Trasplante de Células Madre de Sangre Periférica/efectos adversos , Adolescente , Adulto , Anciano , Ciclosporina/administración & dosificación , Ciclosporina/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Enfermedad Injerto contra Huésped/etiología , Humanos , Inmunosupresores/administración & dosificación , Estimación de Kaplan-Meier , Masculino , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Persona de Mediana Edad , Ácido Micofenólico/administración & dosificación , Ácido Micofenólico/uso terapéutico , Medición de Resultados Informados por el Paciente , Linfocitos T/inmunología , Tacrolimus/administración & dosificación , Tacrolimus/uso terapéutico , Trasplante Homólogo/efectos adversos , Resultado del Tratamiento , Donante no Emparentado , Adulto JovenRESUMEN
Transplant-associated thrombotic microangiopathy (TA-TMA) is one of the early endothelial complications post Hematopoietic Stem Cell Transplant (HSCT). Several mechanisms during HSCT can contribute to systemic capillary endothelial damage which can lead to TA-TMA among other complications as capillary leak syndrome or engraftment syndrome. Early diagnosis of TA-TMA contributes a challenge due to overlapping clinical manifestations and the absence of specific diagnostic criteria. Incidence is greatly variable between 1-76% according to risk factors of patients and the definition used to confirm the diagnosis. The mortality rates in patients who develop severe TA-TMA are in excess of 80%. Early treatment improves the outcome. This review outlines the diagnostic challenges and therapeutic options for TA-TMA.
Asunto(s)
Síndrome de Fuga Capilar , Trasplante de Células Madre Hematopoyéticas , Microangiopatías Trombóticas , Aloinjertos , Síndrome de Fuga Capilar/diagnóstico , Síndrome de Fuga Capilar/etiología , Síndrome de Fuga Capilar/metabolismo , Síndrome de Fuga Capilar/terapia , Humanos , Microangiopatías Trombóticas/diagnóstico , Microangiopatías Trombóticas/etiología , Microangiopatías Trombóticas/metabolismo , Microangiopatías Trombóticas/terapiaRESUMEN
In 2008 the first evidence-based Canadian consensus guideline addressing the diagnosis, monitoring and management of transfusional iron overload in patients with myelodysplastic syndromes (MDS) was published. The Canadian Consortium on MDS, comprised of hematologists from across Canada with a clinical and academic interest in MDS, reconvened to update these guidelines. A literature search was updated in 2017; topics reviewed include mechanisms of iron overload induced cellular damage, evidence for clinical endpoints impacted by iron overload including organ dysfunction, infections, marrow failure, overall survival, acute myeloid leukemia progression, and endpoints around hematopoietic stem-cell transplant. Evidence for an impact of iron reduction on the same endpoints is discussed, guidelines are updated, and areas identified where evidence is suboptimal. The guidelines address common questions around the diagnosis, workup and management of iron overload in clinical practice, and take the approach of who, when, why and how to treat iron overload in MDS. Practical recommendations for treatment and monitoring are made. Evidence levels and grading of recommendations are provided for all clinical endpoints examined.
Asunto(s)
Sobrecarga de Hierro , Síndromes Mielodisplásicos , Canadá , Femenino , Humanos , Sobrecarga de Hierro/diagnóstico , Sobrecarga de Hierro/metabolismo , Sobrecarga de Hierro/patología , Sobrecarga de Hierro/terapia , Masculino , Estudios Multicéntricos como Asunto , Síndromes Mielodisplásicos/diagnóstico , Síndromes Mielodisplásicos/metabolismo , Síndromes Mielodisplásicos/patología , Síndromes Mielodisplásicos/terapia , Guías de Práctica Clínica como AsuntoRESUMEN
Prediction of response to erythropoietin stimulating agents (ESAs) in anemic MDS patients is often based on the Nordic score. We wished to validate the Nordic score (IWG 2006 response criteria) in a larger cohort and determine if other variables such as IPSS/IPSS-R, ferritin, LDH, and a novel European ESA response score (Santini 2013) were of prognostic importance. We analyzed 208 ESA-treated MDS patients (WHO 2008 criteria) from a prospective registry. Ninety-four and 93% had lower risk scores by IPSS (low/int - 1) and IPSS-R (low/very low), respectively. Erythroid response was achieved in 94 patients (47%); responses were similar with erythropoietin (50%) and darbepoetin (39%; p = 0.2). The Nordic and European scores were both validated on univariate analysis. Variables independently predictive of response in multivariate analysis were low-risk IPSS score (OR 0.1, p = 0.0016) and serum EPO level < 100 mIU/mL (OR 8.7, p < 0.0001). We propose a new ESA response score, consisting of (a) IPSS low score (1 point) and (b) serum EPO levels < 100 mIU/ml (2 points), yielding scores ranging from 0 to 3, with response rates varying from 17 to 81%. The Nordic score has validity but we observed lower than the expected response rates in the best risk group. Our proposed scoring system appears more discriminating but needs validation.
Asunto(s)
Eritropoyetina/sangre , Hematínicos/administración & dosificación , Modelos Biológicos , Síndromes Mielodisplásicos , Sistema de Registros , Canadá , Femenino , Ferritinas/sangre , Humanos , Lactante , Recién Nacido , L-Lactato Deshidrogenasa/sangre , Masculino , Síndromes Mielodisplásicos/sangre , Síndromes Mielodisplásicos/tratamiento farmacológico , Síndromes Mielodisplásicos/mortalidad , Estudios ProspectivosRESUMEN
The treatment of acute myeloid leukemia (AML) in older patients is undergoing rapid changes, with a number of important publications in the past five years. Because of this, a group of Canadian leukemia experts has produced an update to the Canadian Consensus Guidelines that were published in 2013, with several new agents recommended, subject to availability. Recent studies have supported the survival benefit of induction chemotherapy for patients under age 80, except those with major co-morbidities or those with adverse risk cytogenetics who are not candidates for allogeneic hematopoietic stem cell transplantation (HSCT). Midostaurin should be added to induction therapy for patients up to age 70 with a FLT3 mutation, and gemtuzumab ozogamicin for de novo AML up to age 70 with favorable or intermediate risk cytogenetics. Daunorubicin 60 mg/m2 is the recommended dose for 3+7 induction therapy. Acute promyelocytic leukemia should be treated with arsenic trioxide plus all-trans retinoic acid, regardless of age, with cytotoxic therapy added upfront only for those with initial white blood count > 10. HSCT may be considered for selected suitable patients up to age 70-75. Haploidentical donor transplants may be considered for older patients. For non-induction candidates, azacitidine is recommended for those with adverse risk cytogenetics, while either a hypomethylating agent (HMA) or low-dose cytarabine can be used for others. HMA may also be used for relapsed/refractory disease after chemotherapy. For patients with secondary AML, CPX-351 is recommended for fit patients age 60-75.