RESUMEN
PURPOSE: Adavosertib may alter exposure to substrates of the cytochrome P450 (CYP) family of enzymes. This study assessed its effect on the pharmacokinetics of a cocktail of probe substrates for CYP3A (midazolam), CYP2C19 (omeprazole), and CYP1A2 (caffeine). METHODS: Period 1: patients with locally advanced or metastatic solid tumors received 'cocktail': caffeine 200 mg, omeprazole 20 mg, and midazolam 2 mg (single dose); period 2: after 7- to 14-day washout, patients received adavosertib 225 mg twice daily on days 1-3 (five doses), with cocktail on day 3. After cocktail alone or in combination with adavosertib administration, 24-h pharmacokinetic sampling occurred for probe substrates and their respective metabolites paraxanthine, 5-hydroxyomeprazole (5-HO), and 1'-hydroxymidazolam (1'-HM). Safety was assessed throughout. RESULTS: Of 33 patients (median age 60.0 years, range 41-83) receiving cocktail, 30 received adavosertib. Adavosertib co-administration increased caffeine, omeprazole, and midazolam exposure by 49%, 80%, and 55% (AUC0-12), respectively; AUC0-t increased by 61%, 98%, and 55%. Maximum plasma drug concentration (Cmax) increased by 4%, 46%, and 39%. Adavosertib co-administration increased 5-HO and 1'-HM exposure by 43% and 54% (AUC0-12) and 49% and 58% (AUC0-t), respectively; paraxanthine exposure was unchanged. Adavosertib co-administration decreased Cmax for paraxanthine and 5-HO by 19% and 7%; Cmax increased by 33% for 1'-HM. After receiving adavosertib, 19 (63%) patients had treatment-related adverse events (six [20%] grade ≥ 3). CONCLUSION: Adavosertib (225 mg bid) is a weak inhibitor of CYP1A2, CYP2C19, and CYP3A. CLINICALTRIALS: GOV: NCT03333824.
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Citocromo P-450 CYP1A2 , Neoplasias , Humanos , Adulto , Persona de Mediana Edad , Anciano , Anciano de 80 o más Años , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP3A/metabolismo , Midazolam , Cafeína/metabolismo , Citocromo P-450 CYP2C19 , Interacciones Farmacológicas , Sistema Enzimático del Citocromo P-450/metabolismo , OmeprazolRESUMEN
PURPOSE: Adavosertib is a small-molecule, ATP-competitive inhibitor of Wee1 kinase. Molecularly targeted oncology agents have the potential to increase the risk of cardiovascular events, including prolongation of QT interval and associated cardiac arrhythmias. This study investigated the effect of adavosertib on the QTc interval in patients with advanced solid tumors. METHODS: Eligible patients were ≥ 18 years of age with advanced solid tumors for which no standard therapy existed. Patients received adavosertib 225 mg twice daily on days 1-2 at 12-h intervals and once on day 3. Patients underwent digital 12-lead electrocardiogram and pharmacokinetic assessments pre-administration and time-matched assessments during the drug administration period. The relationship between maximum plasma drug concentration (Cmax) and baseline-adjusted corrected QT interval by Fridericia (QTcF) was estimated using a prespecified linear mixed-effects model. RESULTS: Twenty-one patients received adavosertib. Concentration-QT modeling of ΔQTcF and the upper limit of the 90% confidence interval corresponding to the geometric mean of Cmax observed on days 1 and 3 were below the threshold for regulatory concern (not > 10 ms). No significant relationship between ΔQTcF (vs baseline) and adavosertib concentration was identified (P = 0.27). Pharmacokinetics and the adverse event (AE) profile were consistent with previous studies at this dose. Eleven (52.4%) patients experienced 17 treatment-related AEs in total, including diarrhea and nausea (both reported in six [28.6%] patients), vomiting (reported in two [9.5%] patients), anemia, decreased appetite, and constipation (all reported in one [4.8%] patient). CONCLUSION: Adavosertib does not have a clinically important effect on QTc prolongation. CLINICALTRIALS: GOV: NCT03333824.
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Antineoplásicos , Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Pirimidinonas/uso terapéutico , Electrocardiografía , Pirazoles/uso terapéutico , Antineoplásicos/efectos adversosRESUMEN
Tumor lysis syndrome (TLS) is an oncology emergency that occurs as a result of rapid tumor cell breakdown and the consequent release of massive amounts of intracellular contents, including potassium, phosphate, and uric acid, into the systemic circulation. These metabolic disturbances lead to life-threatening conditions and may cause sudden death if not treated. TLS commonly occurs following initiation of cytotoxic treatment in patients with high-grade lymphomas or acute lymphoblastic leukemia. Spontaneous cases involving both solid and hematologic tumors have also been reported. Rarely, TLS occurs following treatment with irradiation, corticosteroids, hormonal therapy, or biologic therapy. It is necessary to identify patients at risk for TLS early in order to initiate preventive measures. In the event that preventive measures fail, the clinical parameters and signs of TLS must be understood and recognized so that treatment can begin as soon as possible, as this condition is a significant cause of morbidity and mortality.
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Síndrome de Lisis Tumoral , Humanos , Diálisis Renal , Insuficiencia Renal , Factores de Riesgo , Síndrome de Lisis Tumoral/diagnóstico , Síndrome de Lisis Tumoral/fisiopatología , Síndrome de Lisis Tumoral/terapiaRESUMEN
BACKGROUND: The purpose of the study was to determine outcomes for patients treated with accelerated partial breast irradiation (APBI) on the basis of breast cancer subtype (BCST). PATIENTS AND METHODS: Our single-institution, institutional review board-approved APBI database was queried for patients who had complete testing results for the estrogen (ER), progesterone (PR), and HER2/neu receptors to determine outcomes for each BCST. Women were assigned as luminal A (LA), luminal B (LB), HER2, and basal BCST using their ER, PR, and HER2/neu receptor status. Degree of ER expression supplemented the receptor-based luminal BCST assignment. Two hundred seventy-eight patients had results for all 3 receptors (LA = 164 [59%], LB = 81 [29%], HER2 = 5 [2%], basal = 28 [10%]), which were submitted for analysis (ipsilateral breast tumor recurrence [IBTR], regional nodal failure, distant metastasis [DM], disease-free survival [DFS], cause-specific survival [CSS], and overall survival [OS]). RESULTS: Median follow-up was 5.4 years (range, 0.1-12.4 years). Basal and HER2 subtype patients had higher histologic grades (Grade 3 = 75% vs. 10% LA/LB; P < .001), larger tumors (13.0 mm basal vs. 10.7 mm LA/LB; P = .059), and were more likely to receive chemotherapy (68% vs. 15% LA/LB; P < .001). Margin and nodal status were similar among BCSTs. At 5 years, IBTR rates were similar (1.8%, 2.9%, 0%, and 4.8%) for LA, LB, HER2, and basal subtypes, respectively (P = .62). DM was only seen in LA (2.9%) and LB (1.3%) (P = .83). DFS (95%-100%), CSS (97%-100%), and OS (80%-100%) were not statistically different (P = .97, .87, .46, respectively). CONCLUSION: Five-year local control rates after breast-conserving surgery, APBI, and appropriate systemic therapy are excellent for luminal, HER2, and basal phenotypes of early-stage breast cancer; however, further study of receptor subtype effect on risk stratification in early-stage breast cancer is needed.
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Neoplasias de la Mama/patología , Neoplasias de la Mama/radioterapia , Radioterapia Conformacional , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Estadificación de Neoplasias , Pronóstico , Dosificación Radioterapéutica , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tasa de Supervivencia , Carga TumoralRESUMEN
BACKGROUND: During induction treatment, acute myeloid leukemia patients may develop pulmonary infiltrates due to infectious or noninfectious etiologies. The risk association and the clinical outcome of such pulmonary infiltrates are poorly characterized in the literature. METHODS: We retrospectively reviewed 363 cases of acute myeloid leukemia patients who received induction therapy as inpatients over a period of 11 years at William Beaumont Health System. Of these 363 patients, 120 developed pulmonary infiltrates during induction therapy, those patients were divided into 2 groups based on distribution of the infiltrate presenting as localized or diffuse in nature. Data on patients characteristics, leukemia subtype, cytogenetic risk, microorganism type, white blood cell count at diagnosis, neutrophil count at the time the infiltrate was reported, response to antibiotic and/or antifungal therapy, using respiratory support, and mortality rate were retrieved through chart review. RESULTS: Thirty-three percent of patients developed pulmonary infiltrates during their induction therapy. Sixty-three patients (52.5%) had a localized infiltrates and 57 patients (47.5%) had diffuse infiltrates. Of the 120 patients with pulmonary infiltrates, 48 (40%) had at least 1 pathogenic microorganism identified, and 58 (48.7%) required intubation and ventilatory support. Patients with localized pulmonary infiltrates were more likely to have positive pathogenic microorganisms (68.3% vs. 8.8%, P<0.001), to be neutropenic (96.8% vs. 21%, P<0.001), and tended to have potentially reversible infiltrates after treatment (87.3% vs. 21%, P<0.001). Whereas patients with diffuse infiltrates were more like to require intubation (78.9% vs. 21%, P<0.001), to have leukocytosis (white blood cell >100 billions/L) at diagnosis (54.4% vs. 0%, P<0.001), and had a higher mortality rate (70.2% vs. 9.5%, P<0.001). CONCLUSIONS: The radiologic patterns of pulmonary infiltrates showed specific etiological and prognostic associations. Diffuse infiltrates are an unfavorable characteristic with overall dismal outcome.
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Quimioterapia de Inducción/efectos adversos , Leucemia Mieloide Aguda/tratamiento farmacológico , Leucemia Mieloide Aguda/patología , Enfermedades Pulmonares/etiología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Intubación , Enfermedades Pulmonares/inducido químicamente , Enfermedades Pulmonares/microbiología , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Respiración Artificial , Estudios Retrospectivos , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
PURPOSE: To identify dosimetric predictors for the development of gastrointestinal (GI) toxicity in patients with locally advanced pancreatic adenocarcinoma (LAPC) treated with concurrent full-dose gemcitabine and radiotherapy (GemRT). METHODS AND MATERIALS: From June 2002 to June 2009, 46 LAPC patients treated with definitive GemRT were retrospectively analyzed. The stomach and duodenum were retrospectively contoured separately to determine their dose-volume histogram (DVH) parameters. GI toxicity was defined as Grade 3 or higher GI toxicity. The follow-up time was calculated from the start of RT to the date of death or last contact. Univariate analysis (UVA) and multivariate analysis (MVA) using Kaplan-Meier and Cox regression models were performed to identify risk factors associated with GI toxicity. The receiver operating characteristic curve and the area under the receiver operating characteristic curve (AUC) were used to determine the best DVH parameter to predict for GI toxicity. RESULTS: Of the patients, 28 (61%) received concurrent gemcitabine alone, and 18 (39%) had concurrent gemcitabine with daily erlotinib. On UVA, only the V(20Gy) to V(35Gy) of duodenum were significantly associated with GI toxicity (all p ≤ 0.05). On MVA, the V(25Gy) of duodenum and the use of erlotinib were independent risk factors for GI toxicity (p = 0.006 and 0.02, respectively). For the entire cohort, the V(25Gy) of duodenum is the best predictor for GI toxicity (AUC = 0.717), and the 12-month GI toxicity rate was 8% vs. 48% for V(25Gy) ≤ 45% and V(25Gy) > 45%, respectively (p = 0.03). However, excluding the erlotinib group, the V(35Gy) is the best predictor (AUC = 0.725), and the 12-month GI toxicity rate was 0% vs. 41% for V(35Gy) ≤ 20% and V(35Gy) > 20%, respectively (p = 0.04). CONCLUSIONS: DVH parameters of duodenum may predict Grade 3 GI toxicity after GemRT for LAPC. Concurrent use of erlotinib during GemRT may increase GI toxicity.
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Adenocarcinoma/radioterapia , Antimetabolitos Antineoplásicos/administración & dosificación , Desoxicitidina/análogos & derivados , Duodeno/efectos de la radiación , Neoplasias Pancreáticas/radioterapia , Traumatismos por Radiación/complicaciones , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Adenocarcinoma/tratamiento farmacológico , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Análisis de Varianza , Antimetabolitos Antineoplásicos/efectos adversos , Área Bajo la Curva , Terapia Combinada/efectos adversos , Terapia Combinada/métodos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Duodeno/efectos de los fármacos , Clorhidrato de Erlotinib , Femenino , Tracto Gastrointestinal/efectos de los fármacos , Tracto Gastrointestinal/efectos de la radiación , Humanos , Masculino , Persona de Mediana Edad , Órganos en Riesgo/efectos de la radiación , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/patología , Quinazolinas/administración & dosificación , Quinazolinas/efectos adversos , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Dosificación Radioterapéutica , Estudios Retrospectivos , Factores de Riesgo , GemcitabinaRESUMEN
PURPOSE: To evaluate survival in patients with resected pancreatic cancer treated with concurrent chemoradiation with or without adjuvant gemcitabine (Gem). METHODS AND MATERIALS: From 1998 to 2010, 86 patients with pancreatic adenocarcinoma who underwent resection were treated with adjuvant concurrent chemoradiation. Thirty-four patients received concurrent 5-fluorouracil-based chemoradiation (5-FU/RT) with traditional field radiation (range, 45-61.2 Gy; median, 50.4 Gy) without further adjuvant therapy. Thirty patients received traditional field 5-FU/RT (range, 45-60.4 Gy; median, 50.4 Gy) with Gem (1,000 mg/m(2) weekly) either before and after radiotherapy or only after radiotherapy. Twenty-two patients received concurrent full-dose Gem (1,000 mg/m(2) weekly)-based chemoradiation (Gem/RT), consisting of involved-field radiation (range, 27-38 Gy; median, 36 Gy) followed by further adjuvant Gem. RESULTS: The median age of the cohort was 65 years (range, 40-80 years). Of the patients, 58 had T3 tumors (67%), 22 had T2 tumors (26%), and 6 had T1 tumors (7%). N1 disease was present in 61 patients (71%), whereas 18 patients (21%) had R1 resections. Performance status, lymph node status, and margin status were all similar among the treatment groups. Median follow-up was 19.0 months. Median overall survival (OS) (19.2 months, 19.0 months, and 21.0 months) and 3-year OS rates (26.5%, 27.2%, and 32.1%) were similar among patients with 5-FU/RT with no adjuvant Gem, those with 5-FU/RT with adjuvant Gem, and those with Gem/RT with adjuvant Gem, respectively (p = 0.88). Patients who received adjuvant Gem had a similar median OS (22.1 months) and 3-year OS rate (29%) compared to patients who did not (19.2 months and 26.5%, respectively) (p = 0.62). There was a trend for improved 3-year OS rates in patients with R0 vs. R1 resections (28.1% vs. 14.2%, p = 0.06) and in patients with T1 and T2 vs. T3 tumors (38% vs. 20%, p = 0.09). Node-negative patients had an improved 3-year OS rate (30.1%) when compared with patients with N1 disease (16.2%) (p = 0.02). CONCLUSION: In our cohort of patients with resected pancreatic cancer, Gem chemotherapy did not improve OS after chemoradiotherapy.
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Quimioradioterapia/mortalidad , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/terapia , Fármacos Sensibilizantes a Radiaciones/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/uso terapéutico , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/mortalidad , Desoxicitidina/uso terapéutico , Esquema de Medicación , Fluorouracilo/uso terapéutico , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Neoplasias Pancreáticas/patología , Dosificación Radioterapéutica , Radioterapia Conformacional/métodos , Radioterapia Conformacional/mortalidad , Análisis de Supervivencia , GemcitabinaRESUMEN
PURPOSE: To determine the recommended dose of radiotherapy when combined with full-dose gemcitabine and erlotinib for unresected pancreas cancer. METHODS AND MATERIALS: Patients with unresected pancreatic cancer (Zubrod performance status 0-2) were eligible for the present study. Gemcitabine was given weekly for 7 weeks (1,000 mg/m(2)) with erlotinib daily for 8 weeks (100 mg). A final toxicity assessment was performed in Week 9. Radiotherapy (starting at 30 Gy in 2-Gy fractions, 5 d/wk) was given to the gross tumor plus a 1-cm margin starting with the first dose of gemcitabine. A standard 3 plus 3 dose escalation (an additional 4 Gy within 2 days for each dose level) was used, except for the starting dose level, which was scheduled to contain 6 patients. In general, Grade 3 or greater gastrointestinal toxicity was considered a dose-limiting toxicity, except for Grade 3 anorexia or Grade 3 fatigue alone. RESULTS: A total of 20 patients were treated (10 men and 10 women). Nausea, vomiting, and infection were significantly associated with the radiation dose (p = .01, p = .03, and p = .03, respectively). Of the 20 patients, 5 did not complete treatment and were not evaluable for dose-escalation purposes (3 who developed progressive disease during treatment and 2 who electively discontinued it). Dose-limiting toxicity occurred in none of 6 patients at 30 Gy, 2 of 6 at 34 Gy, and 1 of 3 patients at 38 Gy. CONCLUSION: The results of the present study have indicated that the recommended Phase II dose is 30 Gy in 15 fractions.
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Antimetabolitos Antineoplásicos/administración & dosificación , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Quinazolinas/administración & dosificación , Fármacos Sensibilizantes a Radiaciones/administración & dosificación , Radioterapia Conformacional/métodos , Anciano , Anciano de 80 o más Años , Antimetabolitos Antineoplásicos/efectos adversos , Desoxicitidina/administración & dosificación , Desoxicitidina/efectos adversos , Esquema de Medicación , Quimioterapia Combinada/métodos , Clorhidrato de Erlotinib , Femenino , Humanos , Infecciones/etiología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Náusea/etiología , Neoplasias Pancreáticas/patología , Quinazolinas/efectos adversos , Fármacos Sensibilizantes a Radiaciones/efectos adversos , Dosificación Radioterapéutica , Radioterapia Conformacional/efectos adversos , Factores de Tiempo , Carga Tumoral/efectos de la radiación , Vómitos/etiología , GemcitabinaRESUMEN
PURPOSE: To retrospectively compare the efficacy and toxicity of full-dose gemcitabine based chemoradiotherapy (GemRT) versus 5-fluorouracil (5-FU) based chemoradiotherapy (5FURT) for locally advanced pancreas cancer (LAPC). METHODS: From January 1998 to December 2008, 93 patients with LAPC were treated either with 5FURT (n=38) or GemRT (n=55). 5FURT consisted of standard-field radiotherapy given concurrently with infusional 5-FU or capecitabine. GemRT consisted of involved-field radiotherapy given concurrently with full-dose gemcitabine (1000mg/m(2) weekly) with or without erlotinib. The follow-up time was calculated from the time of diagnosis to the date of death or last contact. RESULTS: Patient characteristics were not significantly different between treatment groups. The overall survival (OS) was significantly better for GemRT compared to 5FURT (median 12.5months versus 10.2months; 51% versus 34% at 1year; 12% versus 0% at 3years; 7% versus 0% at 5years, respectively; all P=0.04). The OS benefit of GemRT was maintained on subset analysis without concurrent erlotinib or with sequential gemcitabine (all P<0.05). The rates of distant metastasis, subsequent hospitalization, acute and late grade 3-5 gastrointestinal toxicities were not significantly different between the GemRT and 5FURT groups. CONCLUSIONS: GemRT was associated with an improved OS compared to standard 5FURT. This approach yielded long-term survivors and was not associated with increased hospitalization or severe gastrointestinal toxicity.
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Antimetabolitos Antineoplásicos/uso terapéutico , Desoxicitidina/análogos & derivados , Fluorouracilo/uso terapéutico , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/radioterapia , Radioterapia Conformacional , Antimetabolitos Antineoplásicos/administración & dosificación , Distribución de Chi-Cuadrado , Terapia Combinada , Medios de Contraste/administración & dosificación , Desoxicitidina/administración & dosificación , Desoxicitidina/uso terapéutico , Fraccionamiento de la Dosis de Radiación , Clorhidrato de Erlotinib , Fluorouracilo/administración & dosificación , Humanos , Neoplasias Pancreáticas/patología , Inhibidores de Proteínas Quinasas/administración & dosificación , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/administración & dosificación , Quinazolinas/uso terapéutico , Radiografía Intervencional , Estudios Retrospectivos , Tasa de Supervivencia , Tomografía Computarizada por Rayos X , GemcitabinaRESUMEN
With the acquisition of emerging technologies in the treatment of primary and metastatic hepatic malignancy by interventional radiology, a multidisciplinary tumor board was created by the authors to improve treatment planning for these diseases.
RESUMEN
Acquired pure red cell aplasia (PRCA) may be the result of a cellular or humoral autoimmune process. One proposed mechanism is the destruction of erythroid progenitors by self-reactive, cytotoxic T cells or natural killer (NK) cells. These cells normally express MHC class I receptors (KIR) which inhibit cytotoxicity when the target cell expresses the HLA class I antigen(s) they bind. Therefore, loss of these antigens on maturing erythroid progenitors may render them susceptible to destruction by the pathogenic cells. Interferon-alpha (INF-alpha) increases HLA class I expression on hematopoietic precursor cells. Therefore, we initiated a trial of INF-alpha in a patient with refractory PRCA. Following treatment, he developed transfusion independence, and a sustained normal hematocrit. Analysis of bone marrow erythroid cells revealed an increase in expression of HLA class I molecules. INF-alpha should be used in a controlled trial in patients with PRCA to determine its activity and mechanism of action.
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Interferón-alfa/uso terapéutico , Aplasia Pura de Células Rojas/tratamiento farmacológico , Adulto , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Masculino , Aplasia Pura de Células Rojas/inmunologíaRESUMEN
Sources for allogeneic stem cells for patients with haematological disorders lacking a histocompatible sibling donor include matched unrelated donor (MUD) and umbilical cord blood (UCB). A total of 51 patients with haematological disorders, treated with myeloablation and transplantation with either unrelated human leucocyte antigen (HLA) partially matched UCB (28 patients) or HLA-matched MUD grafts (23 patients) during 1997-2003, were evaluated for life-threatening infections, haematological reconstitution, graft versus host disease, relapse and event-free survival (EFS). The median duration of neutropenia after transplantation was longer (29 d vs. 14 d) in the UCB group. The probability of donor-derived neutrophil engraftment by day 42 was 0.86 [95% confidence interval (CI) 0.71-1.0] in UCB recipients versus 0.96 (95% CI 0.87-1.0) in MUD recipients surviving >28 d. Overall infection rates were higher in UCB recipients, particularly at the early time points (before day +50) after transplantation. Graft failure occurred in five UCB recipients and two MUD recipients and was associated with the occurrence of bacteraemia during neutropenia. The EFS at 3-year follow-up was 0.25 in UCB and 0.35 in MUD recipients. UCB transplantation in adults is associated with delayed neutrophil and lymphocyte recovery compared with MUD grafting, and higher rates of bacteraemia at early time points after transplantation.