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The Swiss Blood Stem Cell Transplantation and Cellular Therapy Group (SBST) leads a mandatory national registry for all hematopoietic stem cell transplants (HCT) and cellular therapies. After 25 years, information was available for 11,226 patients receiving an HCT (4031 allogeneic and 7195 autologous), including 925 pediatric patients. We compared patient characteristics and outcome by quinquennia 1997-2001, 2002-2006, 2007-2011, 2012-2016, and 2017-2021. There were numerous changes over time. Allogeneic transplant recipients became older (median age 33.7 vs. 54.3) and had more frequently unrelated donors and reduced intensity conditioning in later quinquennia. Similarly, age increased for recipients of autologous HCT (median 48.3 vs. 59.9). We did not see a significant drop in transplant activity during the SARS-CoV-2 pandemic. Analysis of outcome showed overall survival (relative risk (RR) of death 0.664 (0.529-0.832) and progression free survival (RR 0.708 (0.577-0.870) being improved over time comparing the latest to the first quinquennium adjusting for risk factors. Non-relapse mortality decreased in recipients of allogeneic HCT (RR: 0.371 (0.270-0.509)) over time but relapse risks did not. Outcome of autologous HCT improved as well across quinquennia, this improvement was mainly due to decreased relapse risks (RR 0.681 (0.597-0.777)), possibly related to maintenance treatment or rescue treatment for relapse mainly in myeloma patients. Cellular therapies other than allogeneic or autologous HCT, particularly chimeric antigen receptor T-cells (CAR-T) treatment have started to increase after 2019, year of approval of the first commercial CAR-T product in Switzerland. Data on chimeric antigen receptor T-cell treatment are too early for comparative analyses. Detailed analyses of changes over time are presented. This study includes all HCTs, and cellular therapies, data useful for quality assurance programs, health care cost estimation and benchmarking. Between 50% and 60% of patients are long-term survivors after both types of HCT, indicating growing populations of surviving patients requiring long-term care.
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Trasplante de Células Madre Hematopoyéticas , Receptores Quiméricos de Antígenos , Adulto , Niño , Humanos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Recurrencia Local de Neoplasia/etiología , Recurrencia , Suiza , Acondicionamiento Pretrasplante , Trasplante Homólogo , Persona de Mediana EdadRESUMEN
Allogeneic haematopoietic cell transplantation (allo-HCT) recipients show impaired antibody (Ab) response to a standard two-dose vaccination against severe acute respiratory syndrome coronavirus-2 and currently a third dose is recommended as part of the primary vaccination regimen. By assessing Ab titres 1 month after a third mRNA vaccine dose in 74 allo-HCT recipients we show sufficient neutralisation activity in 77% of the patients. Discontinuation of immunosuppression before the third vaccine led to serological responses in 50% of low responders to two vaccinations. Identifying factors that might contribute to better vaccine responses in allo-HCT recipients is critical to optimise current vaccination strategies.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Humanos , Vacunas contra la COVID-19 , Formación de Anticuerpos , COVID-19/prevención & control , SARS-CoV-2 , Receptores de Trasplantes , Vacunación , Anticuerpos AntiviralesRESUMEN
Elderly patients (EP) of 60 years and above with acute lymphoblastic leukemia (ALL) have a dismal prognosis, but pediatric-inspired chemotherapy and allogeneic stem cell transplantation (allo HCT) are used reluctantly due to limited data and historical reports of high treatment-related mortality in EP. We analyzed 130 adult ALL patients treated at our center between 2009 and 2019, of which 26 were EP (range 60-76 years). Induction with pediatric-inspired protocols was feasible in 65.2% of EP and resulted in complete remission in 86.7% compared to 88.0% in younger patients (YP) of less than 60 years. Early death occurred in 6.7% of EP. Three-year overall survival (OS) for Ph - B-ALL was significantly worse for EP (n = 16) than YP (n = 64) with 30.0% vs 78.1% (p ≤ 0.001). Forty-nine patients received allo HCT including 8 EP, for which improved 3-year OS of 87.5% was observed, whereas EP without allo HCT died after a median of 9.5 months. In Ph + B-ALL, 3-year OS did not differ between EP (60.0%, n = 7) and YP (70.8%, n = 19). Non-relapse mortality and infection rate were low in EP (14.3% and 12.5%, respectively). Our data indicate that selected EP can be treated effectively and safely with pediatric regimens and might benefit from intensified therapy including allo HCT.
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Trasplante de Células Madre Hematopoyéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Adulto , Anciano , Niño , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , Pronóstico , Inducción de Remisión , Estudios RetrospectivosRESUMEN
Busulfan and cyclophosphamide (BuCy) is a frequently used myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). Theoretical considerations and pharmacological data indicate that application of busulfan prior to subsequent cyclophosphamide (BuCy) may trigger liver toxicity. Reversing the order of application to cyclophosphamide-busulfan (CyBu) might be preferable, a hypothesis supported by animal data and retrospective studies. We performed a prospective randomized trial to determine impact of order of application of Bu and Cy before allo-HCT in 70 patients with hematological malignancy, 33 patients received BuCy and 37 CyBu for conditioning. In the short term, there were minimal differences in liver toxicity favoring CyBu over BuCy, significant only for alanine amino transferase at day 30 (p = 0.03). With longer follow-up at 4 years, non-relapse mortality (6% versus 27%, p = 0.05) was lower and survival (63% versus 43%, p = 0.06) was higher with CyBu compared to BuCy. Other outcomes, such as engraftment (p = 0.21), acute and chronic graft-versus-host disease (p = 0.40; 0.36), and relapse (p = 0.79), were similar in both groups. We prospectively show evidence that the order of application of Cy and Bu in myeloablative conditioning in allo-HCT patients has impact on outcome.
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Busulfano/administración & dosificación , Ciclofosfamida/administración & dosificación , Neoplasias Hematológicas/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Inmunosupresores/administración & dosificación , Acondicionamiento Pretrasplante/métodos , Adulto , Anciano , Busulfano/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Enfermedad Hepática Inducida por Sustancias y Drogas/mortalidad , Ciclofosfamida/efectos adversos , Quimioterapia Combinada , Femenino , Neoplasias Hematológicas/tratamiento farmacológico , Neoplasias Hematológicas/mortalidad , Trasplante de Células Madre Hematopoyéticas/mortalidad , Humanos , Inmunosupresores/efectos adversos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Acondicionamiento Pretrasplante/mortalidad , Trasplante Homólogo/métodos , Trasplante Homólogo/mortalidad , Adulto JovenRESUMEN
Recently, an immunodeficiency syndrome caused by guanine-adenine-thymine-adenine 2 (GATA2) deficiency has been described. The syndrome is characterized by (i) typical onset in early adulthood, (ii) profound peripheral blood cytopenias of monocytes, B lymphocytes, and NK cells, (iii) distinct susceptibility to disseminated non-tuberculous mycobacterial (NTM) and other opportunistic infections (particularly human papillomavirus), and (iv) a high risk of developing hematologic malignancies (myelodysplastic syndromes (MDS); acute myeloid leukemias (AML)). Considerable clinical heterogeneity exists among patients with GATA2 deficiency, but once infectious symptoms occur or MDS/AML arises, survival declines significantly. Allogeneic hematopoietic cell transplantation (HCT) currently provides the only curative treatment option for both MDS/AML and dysfunctional immunity with life-threatening opportunistic infections. Strategies regarding timing of allogeneic HCT, antimicrobial prophylaxis and treatment, intensity of the preparative regimen, and optimal donor and graft source have not been clearly defined due to the rarity of the disease. Here, we provide a comprehensive analysis of the available literature and published case reports on the use of allogeneic HCT in patients with GATA2 deficiency. In addition, a case of a young woman with GATA2 deficiency, who developed an immune reconstitution inflammatory syndrome in her mycobacterial skin lesions post allogeneic HCT is presented and illustrates distinct problems encountered in this disease context.
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Factor de Transcripción GATA2/deficiencia , Trasplante de Células Madre Hematopoyéticas , Síndrome Inflamatorio de Reconstitución Inmune/etiología , Síndromes de Inmunodeficiencia/terapia , Infecciones por Mycobacterium no Tuberculosas/etiología , Adolescente , Adulto , Aloinjertos , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Humanos , Síndromes de Inmunodeficiencia/genética , Masculino , Persona de Mediana Edad , Infecciones por Mycobacterium no Tuberculosas/inmunología , Infecciones por Mycobacterium no Tuberculosas/patología , Mycobacterium abscessus/aislamiento & purificación , Síndromes Mielodisplásicos/etiología , Trasplante de Células Madre de Sangre Periférica , Embolia Pulmonar/etiología , Úlcera Cutánea/etiología , Verrugas/etiología , Adulto JovenRESUMEN
Biosimilars are increasingly being licensed as equipotent drugs, although efficacy and safety data are not available for all clinical indications. Accordingly, the efficacy of the biosimilar filgrastim Zarzio® combined with vinorelbine for chemo-mobilization of CD34+ hematopoietic progenitor cells (HPC) in patients with multiple myeloma has not been evaluated yet. We compared the efficacy of vinorelbine combined with this biosimilar filgrastim for HPC mobilization to vinorelbine plus original filgrastim (Neupogen®). Overall, 105 multiple myeloma patients received vinorelbine 35 mg/m2 intravenously on day 1 and either original filgrastim (n = 61;58%) or biosimilar filgrastim (n = 44;42%) at a dose of 5 µg per kg body weight (BW) twice daily subcutaneously starting day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and performed for a maximum of three consecutive days until at least 4 × 106 HPC/kg BW were collected. All patients proceeded to leukapheresis. In 102 (97%) patients the leukapheresis sessions were started as planned at day 8. The median number of collected HPC was 7.3 × 106 /kg BW (0.2-18.3) with original filgrastim compared to 9 × 106 /kg BW (4.2-23.8) with the biosimilar filgrastim (P = 0.16). HPC collection was successful in 57 (93%) of 61 patients of the original group and in all 44 (100%) patients of the biosimilar group (P = 0.14). No differences were observed regarding side effects. Duration of neutrophil engraftment after autologous HPC transplantation was similar between the two groups (P = 0.17). Biosimilar and original filgrastim achieve comparable results in combination with vinorelbine regarding HPC mobilization and transplantation outcome in multiple myeloma patients. J. Clin. Apheresis 32:21-26, 2017. © 2016 Wiley Periodicals, Inc.
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Biosimilares Farmacéuticos/farmacología , Filgrastim/farmacología , Movilización de Célula Madre Hematopoyética/métodos , Mieloma Múltiple/terapia , Vinblastina/análogos & derivados , Biosimilares Farmacéuticos/administración & dosificación , Recuento de Células , Protocolos Clínicos , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada/métodos , Filgrastim/administración & dosificación , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Estudios Retrospectivos , Vinblastina/administración & dosificación , Vinblastina/farmacología , VinorelbinaRESUMEN
We aimed to assess the efficacy of vinorelbine plus granulocyte colony-stimulating factor (G-CSF) for chemo-mobilization of CD34(+) hematopoietic progenitor cells (HPC) in patients with multiple myeloma and to identify adverse risk factors for successful mobilization. Vinorelbine 35 mg/m(2) was administered intravenously on day 1 in an outpatient setting. Filgrastim 5 µg/kg body weight (BW) was given twice daily subcutaneously from day 4 until the end of the collection procedure. Leukapheresis was scheduled to start on day 8 and be performed for a maximum of 3 consecutive days until at least 4 × 10(6) CD34(+) cells per kg BW were collected. Overall, 223 patients were mobilized and 221 (99%) patients proceeded to leukapheresis. Three (1.5%) patients required an unscheduled hospitalization after chemo-mobilization because of neutropenic fever and renal failure (n = 1), severe bone pain (n = 1), and abdominal pain with constipation (n = 1). In 211 (95%) patients, the leukaphereses were started as planned at day 8, whereas in 8 (3%) patients the procedure was postponed to day 9 and in 2 (1%) patients to day 10. In the great majority of patients (77%), the predefined amount of HPC could be collected with 1 leukapheresis. Forty-four (20%) patients needed a second leukapheresis, whereas only 6 (3%) patients required a third leukapheresis procedure. The median number of CD34(+) cells collected was 6.56 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW at the first day of leukapheresis and 7.65 × 10(6) (range, .18 to 25.9 × 10(6)) per kg BW in total. HPC collection was successful in 212 (95%) patients after a maximum of 3 leukaphereses. Patient age (P = .02) and prior exposition to lenalidomide (P < .001) were independent risk factors for a lower HPC amount collected in multiple regression analysis. Vinorelbine plus G-CSF enables a very reliable prediction of the timing of leukapheresis and results in successful HPC collection in 95% of the patients.
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Antineoplásicos Fitogénicos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos/uso terapéutico , Movilización de Célula Madre Hematopoyética/métodos , Trasplante de Células Madre Hematopoyéticas , Células Madre Hematopoyéticas/inmunología , Mieloma Múltiple/terapia , Vinblastina/análogos & derivados , Adulto , Factores de Edad , Anciano , Antígenos CD34/genética , Antígenos CD34/inmunología , Recuento de Células , Quimioterapia Combinada , Femenino , Filgrastim , Expresión Génica , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/efectos de los fármacos , Humanos , Lenalidomida , Leucaféresis , Masculino , Persona de Mediana Edad , Mieloma Múltiple/inmunología , Mieloma Múltiple/patología , Proteínas Recombinantes/uso terapéutico , Estudios Retrospectivos , Factores de Riesgo , Talidomida/efectos adversos , Talidomida/análogos & derivados , Trasplante Autólogo , Resultado del Tratamiento , Vinblastina/uso terapéutico , VinorelbinaRESUMEN
We here investigate the occurrence of fluoride intake-associated alterations in patients with hematologic disease on triazol antifungal medication. Clinical, laboratory, and radiology data of overall 43 patients with hematologic malignancies taking voriconazole (n = 20), posaconazole (n = 8), and itraconazole (n = 4), and a hematologic patient control group (n = 11) are described. Bone pain and radiologic evidence of periostitis were exclusively observed in patients receiving long-term voriconazole. Cessation of treatment led to clinical improvement in all cases. In line with clinical evidence, fluoride serum concentration was elevated in patients receiving voriconazole (median, 156.5 µg/L; interquartile range, 96.8 µg/L; normal < 30 µg/L) but not in the other treatment groups (P < .001 for all comparisons vs voriconazole). We conclude that serum fluoride levels were elevated on average 5-fold above normal levels in hematologic patients receiving voriconazole. Clinically relevant skeletal disease was associated with renal insufficiency and above 10-fold elevated fluoride levels, and was reversible on termination of voriconazole treatment.
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Antifúngicos/uso terapéutico , Enfermedades Óseas/inducido químicamente , Enfermedades Óseas/prevención & control , Fluoruros/sangre , Neoplasias Hematológicas/terapia , Músculo Esquelético/fisiopatología , Adulto , Femenino , Neoplasias Hematológicas/complicaciones , Neoplasias Hematológicas/microbiología , Humanos , Itraconazol/uso terapéutico , Persona de Mediana Edad , Periostitis/inducido químicamente , Pirimidinas/uso terapéutico , Estudios Retrospectivos , Trasplante de Células Madre , Trasplante Homólogo , Triazoles/uso terapéutico , VoriconazolRESUMEN
AIM: Until the year 2000, allogeneic haematopoietic cell transplantation (HCT) was the standard treatment for young and fit chronic myeloid leukaemia (CML) patients. CML was the main indication for allogeneic HCT. The introduction of tyrosine kinase inhibitors changed the treatment of CML patients dramatically. Allogeneic HCT was rapidly replaced by tyrosine kinase inhibitors as first-line treatment for CML, and the indication shifted to the treatment of non-responders, patients intolerant to tyrosine kinase inhibitors and patients whose CML is transforming to the accelerated phase and blast crisis. This paper describes changes in the use of transplantation technology for CML patients in the face of rapid drug development. METHODS: All patients receiving a transplant for CML between 1997 and 2021 in Switzerland were included in the study. For the purpose of this analysis, time periods were analysed in quinquennia, 1997-2001 (Q1), 2002-2006 (Q2), 2007-2011 (Q3), 2012-2016 (Q4) and 2017-2021 (Q5), as the observation period spanned 25 years. RESULTS: Overall, 239 patients received a transplant. These included 96 in Q1, 56 in Q2, 25 in Q3, 34 in Q4 and 28 in Q5. Patient characteristics changed over time: recent patients were older and had a longer interval from diagnosis to transplantation because of tyrosine kinase inhibitor treatment. However, the proportions of patients receiving transplants during an early versus advanced disease stage differed little. Transplant technology changed, as well. Patients received intensive conditioning regimens less often due to higher age and more commonly had peripheral blood as opposed to bone marrow transplants. However, the type of stem cell donor selected did not differ. In a univariable analysis, there were no significant differences in survival, progression-free survival, non-relapse mortality, relapse incidence or incidences of acute and chronic graft-versus-host disease among the five quinquennia. In a multivariable analysis, older age, donors other than HLA-identical siblings and more advanced disease stage, but not the quinquennium, were associated with higher risk of death. CONCLUSION: Since the introduction of tyrosine kinase inhibitors haematopoietic cell transplantation has been used less frequently to treat CML. Patients in recent cohorts received transplants at an older age and later in the disease course; despite these higher risks, the outcome of allogeneic HCT has not worsened over time but has not improved, either. As the outcome is worse in advanced phases, it is important to conduct transplants before disease progression. Therefore, patients with advanced disease should be monitored closely and receive transplants in time.
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Trasplante de Células Madre Hematopoyéticas , Leucemia Mielógena Crónica BCR-ABL Positiva , Inhibidores de Proteínas Quinasas , Trasplante Homólogo , Humanos , Trasplante de Células Madre Hematopoyéticas/métodos , Leucemia Mielógena Crónica BCR-ABL Positiva/terapia , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Suiza , Masculino , Femenino , Adulto , Persona de Mediana Edad , Trasplante Homólogo/métodos , Inhibidores de Proteínas Quinasas/uso terapéutico , Adolescente , Acondicionamiento Pretrasplante/métodosRESUMEN
Therapeutic drug monitoring (TDM) of busulfan (Bu) is well-established in pediatric hematopoietic stem cell transplantation (HSCT), but its use in adults is limited due to a lack of clear recommendations and scarcity of evidence regarding its utility. GSTA1 promoter variants are reported to affect Bu clearance in both adults and pediatric patients. This study aimed to evaluate the value of preemptive genotyping GSTA1 and body composition (obesity) in individualizing Bu dosing in adults, through pharmacokinetic (PK) modeling and simulations. A population pharmacokinetic (PopPK) model was developed and validated with data from 60 adults who underwent HSCT. Simulations assessed different dosing scenarios based on body size metrics and GSTA1 genotypes. Due to the limited number of obese patients in the cohort, the effect of obesity on Bu pharmacokinetics (PK) was evaluated in silico using a physiologically-based pharmacokinetic (PBPK) model and relevant virtual populations from Simcyp software. Patients with at least 1 GSTA1*B haplotype had 17% lower clearance on average. PopPK simulations indicated that adjusting doses based on genotype increased the probability of achieving the target exposure (3.7 to 5.5 mg.h/L) from 53% to 60 % in GSTA1*A homozygous patients, and from 50% to 61% in *B carriers. Still, Approximately 40% of patients would not achieve this therapeutic window without TDM. A 2-sample optimal design was validated for routine model-based Bu first dose AUC0-∞ estimation, and the model was implemented in the Tucuxi user-friendly TDM software. PBPK simulations confirmed body surface area-based doses of 29 to 31 mg/m2/6h as the most appropriate, regardless of obesity status. This study emphasizes the importance of individualized Bu dosing strategies in adults to achieve therapeutic targets. Preemptive genotyping alone may not have a significant clinical impact, and routine TDM may be necessary for optimal transplantation outcomes.
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Busulfano , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Niño , Busulfano/uso terapéutico , Farmacogenética , Monitoreo de Drogas , ObesidadRESUMEN
Hematopoietic cell transplantation (HCT) was developed more than 65 years ago to treat malignant blood disorders and irreversible bone marrow failures, with the aim of replacing a diseased hematopoietic system with a healthy one (allogeneic HCT). Decades later, the procedure was adapted to apply maximal chemotherapy or radiotherapy, which would result in bone marrow failure, but could be remedied by an infusion of a patient's own cryopreserved bone marrow (autologous HCT). Both treatments are high-risk and complex, especially during the initial phases. However, concerted efforts, vision, and collaboration between physicians and centers worldwide have resulted in HCT becoming a standard of care for many hematological disorders with progressive improvements in outcomes. Registries and the collaboration of societies worldwide have enabled the delivery of this curative therapy to many patients with fatal hematological diseases. More than 1.5 million HCT were performed between 1957 and 2019, and activity is continuously increasing worldwide.
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Enfermedades Hematológicas , Trasplante de Células Madre Hematopoyéticas , Sistema de Registros , Humanos , Enfermedades Hematológicas/terapiaRESUMEN
Despite the high cure rate with initial therapy, approximately 10% of Hodgkin lymphoma (HL) patients are refractory to initial treatment, and up to 30% of patients will relapse after achieving initial complete remission. Despite promising initial results of treatment by immune checkpoint inhibitors, most patients will eventually progress. We analyzed 62 adult patients with relapsed or refractory HL (rrHL) treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) in one of three University Hospitals of Switzerland (Zurich, Basel, and Geneva) between May 2001 and January 2020. The primary endpoint was overall survival (OS). Secondary endpoints were relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence, which were assessed in univariate analysis. The median follow-up was 61 months (interquartile range 59-139). The 2- and 5-year OS was 54% (standard error (SE) ±12) and 50.2% (SE ±13.3), respectively, and the 2- and 5-year RFS was 40.7% (SE ±16.3) and 34.4% (SE ±19.0), respectively. NRM was 23.1% (SE ±2.2) and 27.4% (SE ±2.5) at 2 and 5 years, respectively. The cumulative incidence of relapse was 36.1% (SE ±5.6) at 2 years and 38.2% (SE ±6.6) at 5 years. Our analysis of allo-HSCT outcomes in the context of rrHL shows encouraging OS and RFS rates, with the mortality rate reaching plateau at 50% at 2 years after allo-HSCT. This confirms that allo-HSCT still remains as a potentially curative option for half of patients with rrHL.
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Hematopoietic cell transplantation from haploidentical donors (haploHCT) has facilitated treatment of AML and MDS by increasing donor availability and became more feasible since the introduction of post-transplant cyclophosphamide (ptCY). In our single-center retrospective analysis including 213 patients with AML or MDS, we compare the outcome of haploHCT (n = 40) with ptCY with HCT from HLA-identical MRD (n = 105) and MUD (n = 68). At 2 years after transplantation, overall survival (OS) after haploHCT was not significantly different (0.59; 95% confidence interval 0.44-0.79) compared to MRD (0.77; 0.67-0.88) and MUD transplantation (0.72; 0.64-0.82, p = 0.51). While progression-free survival (PFS) was also not significantly different (haploHCT: 0.60; 0.46-0.78, MRD: 0.55; 0.44-0.69, MUD: 0.64; 0.55-0.74, p = 0.64), non-relapse mortality (NRM) was significantly higher after haploHCT (0.18; 0.08-0.33) vs. MRD (0.029; 0.005-0.09) and MUD (0.06; 0.02-0.12, p < 0.05). Higher NRM was mainly caused by a higher rate of fatal infections, while deaths related to GvHD or other non-relapse reasons were rare in all groups. As most fatal infections occurred early and were bacterial related, one potential risk factor among many was identified in the significantly longer time to neutrophil engraftment after haploHCT with a median of 16 days (interquartile range; 14.8-20.0) vs. 12 days (10.0-13.0) for MRD and 11 days (10.0-13.0) for MUD (p = 0.01).
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Due to relatively high nonrelapse mortality (NRM), allogeneic hematopoietic stem cell transplantation (allo-HSCT) in non-Hodgkin's lymphoma (NHL) remains the ultimate line of treatment but the only curable approach in a setting of relapse/refractory disease. Here, we conducted a retrospective, multicenter, registry-based analysis on patients who underwent allo-HSCT for NHL in Switzerland, over 30-year (1985-2020) period. The study included 301 allo-HSCTs performed for NHL patients in three University Hospitals of Switzerland (Zurich, Basel and Geneva) 09/1985 to 05/2020. We assessed in univariate and multivariable analysis the impact on survivals (overall survival [OS], relapse free survival [RFS], relapse incidence [RI], and non-treatment related mortality [NRM]). The maximum follow-up was 25 years with median follow-up for alive patients of 61 months. The median age at allo-HSCT was 51 years. Three- and -year OS was - 59.5% and 55.4%; 3- and 5-year PFS was 50% and 44%; 3- and 5-year NRM was 21.7% and 23.6%. RI at 3 and 5 years was 27.4% and 34.9%. In conclusion, our analysis of the entire Swiss experience of allo-HSCT in patients with NHL shows promising 5- and possibly 10-year OS and relatively acceptable NRM rates for such population, the majority being not in complete remission (CR) at the time of transplantation.
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Busulfan (Bu) combined with cyclophosphamide (Cy) is commonly used as a myeloablative conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT). There is inter-individual variability of Bu pharmacokinetics (PK) and hence in toxicity and efficacy. The introduction of therapeutic drug monitoring (TDM) of Bu has decreased toxicity of the regimen. Hepatic metabolism of Bu is mediated through Glutathione-S-Transferases (GSTs), mainly GSTA1. Patients with GSTA1*A variants are considered normal metabolizers and GSTA1*B corresponds to poor metabolism, defined by nucleotide changes at -52 or -69 locus in GSTA1 promoter region. The aim of the study was to explore the correlation between GSTA1 polymorphisms and Bu-PK in 60 adult patients receiving an allo-HCT in the BuCyBu clinical study (ClinicalTrials.gov I, ID NCT01779882) comparing the sequence BuCy to CyBu. DNA samples prior to conditioning were genotyped for candidate variants at -52 (rs3957356) and -69 (rs3957357) loci in the GSTA1 promoter. Thirty-three % of patients were GSTA1*A*A, 49% GSTA1*A*B and 18% GSTA1*B*B. In GSTA1*A*A patients, median Bu-AUC was 3.6 ± 0.7 mg*h/L, in GSTA1*A*B 4.5 ± 1.6 and in GSTA1*B*B 4.9 ± 1.4 (AUC 35% higher than GSTA1*A*A, p = 0.03), with a similar significant correlation with Bu-clearance (p = 0.04). The correlation between GSTA1 polymorphism and AUC remained significant in multivariate linear regression analysis. There was a trend for lower non-relapse mortality (NRM) in patients with low AUC. We could not demonstrate a correlation between GSTA1 polymorphisms and NRM, acute graft-versus-host disease (aGvHD) in this small cohort, but there is a trend of higher aGvHD incidence in GSTA1*B*B patients.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Adulto , Humanos , Busulfano/uso terapéutico , Busulfano/farmacocinética , Farmacogenética , Ciclofosfamida/uso terapéutico , Polimorfismo Genético , Acondicionamiento Pretrasplante , Enfermedad Injerto contra Huésped/tratamiento farmacológicoRESUMEN
Aim and Objective: Our study was an observational and evolutional to analyze the significance of orbital volume calculation in predicting the probability or tendency of developing late enopthalmous on patients with unilateral orbital fracture with or without associated midface injury reported to our hospital. Materials and Methods: The subjects in our study included fifteen patients between18 and 60years. They were treated surgically and conservatively. Patients were exposed to series of examination from the day of injury or reporting for a consecutive period of up to six months following injury. CT was taken prior to treatment following management to evaluate the volume change in orbit. Its correlation and significance to treatment outcome were analyzed using MIMICS software by Materialise by comparing injured orbit to opposite side normal eye. Result: Conclusive of clinical examination and summary of statistical analysis patients were categorized into three groups: Low (with volume change of less than 2%), Medium (volume change between 2 to 20%) and High (volume change more than 20%) by comparing fractured orbit to uninjured orbit and a statistically significant mean value of 27.7 ± 2.6 cu. mm for fractures eye and 25.9 ± 2.6 cu. mm for normal eye was found (P ≤ 0.05). Conclusion: Orbital volume can be considered as useful criteria in evaluation of patients with orbital fracture. Evaluation and follow up in correlation with resultant volume assessment provide a better indicator for assessment of prognosis and enopthalmous. Unlike other methods for volume assessment MIMICS software by Materialise provide a better method and it can be incorporated to working station in hospital. Every CT assessment in orbital trauma should include orbital volume as a parameter and this software is easy and user-friendly software that does not require its technical knowledge for application.
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OBJECTIVES: This study aimed to uncover the strategies that junior doctors implement to maintain their mental, physical and social well-being, and the barriers they experience in practising these strategies. PARTICIPANTS: Fifteen junior doctors in their postgraduate year 1 or 2 currently practising in Australia were recruited. OUTCOME MEASURES: Semistructured interviews were conducted, and the transcripts underwent thematic analysis. RESULTS: Three key themes emerged from thematic analysis, namely: well-being strategies, barriers to well-being and and future interventions. Exercise, a healthy and balanced diet, quality sleep, and workplace organisations were frequently reported well-being strategies. High workload, unpredictable routines, lack of familiarity with the healthcare system and ongoing stigma surrounding mental health were seen as barriers to well-being. Suggested interventions included increased control over rosters, subsidised access to facilities such as gyms and increased internship preparedness programmes organised by the medical schools. CONCLUSIONS: The findings from this study may assist in developing more personalised and targeted methods to help junior doctors maintain their mental, physical and social well-being. Future studies may address the structural and systemic changes required to develop a workforce that fosters the well-being of junior doctors and reduces the institutional barriers to practising well-being strategies.
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Salud Mental , Lugar de Trabajo , Humanos , Australia , Lugar de Trabajo/psicología , Investigación Cualitativa , Cuerpo Médico de Hospitales/psicologíaRESUMEN
Vaccines against SARS-CoV-2 have been rapidly approved. Although pivotal studies were conducted in healthy volunteers, little information is available on the safety and efficacy of mRNA vaccines in immunocompromised patients, including recipients of allogeneic hematopoietic cell transplantation (allo-HCT). Here we used a novel assay to analyze patient- and transplantation-related factors and their influence on immune responses to SARS-CoV-2 vaccination over an extended period (up to 6 months) in a large and homogenous group of allo-HCT recipients at a single center in Switzerland. We examined longitudinal antibody responses to SARS-CoV-2 vaccination with BNT162b2 (BioNTech/Pfizer) and mRNA-1273 (Moderna) in 110 allo-HCT recipients and 86 healthy controls. Seroprofiling recording IgG, IgA, and IgM reactivity against SARS-CoV-2 antigens (receptor-binding domain, spike glycoprotein subunits S1 and S2, and nucleocapsid protein) was performed before vaccination, before the second dose, and at 1, 3, and 6 months after the second dose. Patients were stratified to 3 groups: 3 to 6 months post-allo-HCT, 6 to 12 months post-allo-HCT, and >12 months post-allo-HCT. Patients in the 3 to 6 months and 6 to 12 months post-allo-HCT groups developed significantly lower antibody titers after vaccination compared with patients in the >12 months post-allo-HCT group and healthy controls (P < .001). Within the cohort of allo-HCT recipients, patients age >65 years (P = .030), those receiving immunosuppression for prevention or treatment of graft-versus-host disease (GVHD) (P = .033), and patients with relapsed disease (P = .014) displayed low humoral immune responses to the vaccine. In contrast, the intensity of the conditioning regimen, underlying disease (myeloid/lymphoid/other), and presence of chronic GVHD had no impact on antibody levels. Antibody titers achieved the highest levels at 1 month after the second dose of the vaccine but waned substantially in all transplantation groups and healthy controls over time. This analysis of long-term vaccine antibody response is of critical importance to allo-HCT recipients and transplant physicians to guide treatment decisions regarding revaccination and social behavior during the SARS-CoV-2 pandemic.
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COVID-19 , Trasplante de Células Madre Hematopoyéticas , Anciano , Formación de Anticuerpos , Vacuna BNT162 , COVID-19/prevención & control , Vacunas contra la COVID-19 , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Humanos , SARS-CoV-2 , VacunaciónRESUMEN
HLA compatibility is a key factor for survival after unrelated hematopoietic stem cell transplantation (HSCT). HLA-A, -B, -C, -DRB1, and -DQB1 are usually matched between donor and recipient. By contrast, HLA-DPB1 mismatches are frequent, although it is feasible to optimize donor selection and DPB1 matching with prospective typing. Because classical DPB1 allele mismatches are often unavoidable, however, several biological models have been developed to predict the optimal DPB1 mismatch combination for less graft-versus-host disease (GVHD) and better overall survival. In 909 recipient/donor pairs, we analyzed the role of 3 biological models: T-cell epitopes (TCEs) based on the immunogenicity of DPB1, cell surface expression of DPB1 molecules based on a single-nucleotide polymorphism located in the 3' untranslated region, and the Predicted Indirectly ReCognizable HLA Epitopes (PIRCHE) model based on the presentation of allogeneic peptides derived from mismatched HLA, compared with the classical allele mismatch. Matching for both DPB1 alleles remains the best option to prevent acute GVHD. In the situation of one DPB1 allele mismatch, the donor associated with the lowest acute GVHD risks is mismatched for an allele with a low expression profile in the recipient, followed by a permissive TCE3/4 mismatch and/or the absence of PIRCHE II potential against the recipient. In the context of 2 DPB1 mismatches, the same considerations apply for a permissive TCE3/4 mismatch and no PIRCHE II. By combining the biological models, the most favorable DPB1 constellation can be defined. This approach will help optimize donor selection and improve post-HSCT complications and patient prognosis.