Busulfan clearance does not predict the development of hepatic veno-occlusive disease in patients undergoing hematopoietic stem cell transplantation
International journal of hematology. 2020
Hepatic veno-occlusive disease (VOD) is a life-threatening complication following hematopoietic stem cell transplant (HSCT). Busulfan has a narrow therapeutic index and its concentration was found to correlate with VOD. Our primary objective was to assess the association between busulfan clearance and VOD in HSCT patients. In this retrospective analysis, we included patients who received their HSCT between 2003 and 2014 and followed at Sultan Qaboos University Hospital. All patients who received dose-targeted busulfan-containing conditioning were included. Target steady-state concentration (Css) was 800-900 ng/ml. VOD was assessed using modified Seattle criteria. The impact of busulfan clearance on VOD was analyzed using univariable logistic regression model. Seventy-three patients were included with a mean age of 15 years. Of those, 47% were transplanted for hematological malignancies and 53% for inherited hemoglobinopathies. Target Css was achieved in 85% of patients. The rate of VOD was 17%. There was no significant impact of busulfan clearance (p = 0.919) or area-under-the-concentration-time-curve (p = 0.275) on VOD. Targeting busulfan Css into narrow therapeutic range may have accounted for the findings. The risk of VOD might be related to other factors such as the genetic background, and more studies are required to investigate these factors.
Acute toxicity and outcome among pediatric allogeneic hematopoietic transplant patients conditioned with treosulfan-based regimens
Pediatric hematology and oncology. 2020;:1-10
Treosulfan-based regimens constitute a feasible and increasingly used, but still myeloablative, conditioning in pediatric allogeneic hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed the acute toxicity and outcome of all consecutive (2004-2015) pediatric HSCT patients prepared for HSCT with treosulfan in a single-center setting. We included HSCTs performed for both nonmalignant (n = 23) and malignant diseases (n = 11). The controls were patients with nonmalignant diseases or hematological malignancies conditioned with cyclophosphamide (Cy)-total body irradiation (TBI)-based (39 patients) or busulfan-based regimens (11 patients). The major toxicities of the treosulfan-based regimens were limited to oral mucosa and skin. 50% of the patients needed IV morphine for severe mucositis compared to 31% in patients conditioned with Cy-TBI (P = 0.02). Other toxicities were rare. The disease-free survival (DFS) of patients transplanted for nonmalignant disorders was 88.9 +/- 7.5% at 2 years. The event-free survival (EFS) at 2 years in this small cohort for those with a malignant disease and a treosulfan-based conditioning was 54.5 +/- 1.5%. We conclude that a treosulfan-based conditioning regimen gives excellent DFS in pediatric HSCT performed for a nonmalignant disorder but with substantial mucosal toxicity. In a malignant disorder a treosulfan-based regimen looks promising but larger, preferably randomized, studies are needed to prove efficacy.
Oral levetiracetam for prevention of busulfan-induced seizures in adult hematopoietic cell transplant
International journal of clinical pharmacy. 2020
Background Antiseizure prophylaxis is recommended when high-dose of busulfan is given as part of the conditioning regimens in the allogenic hematopoietic stem cell transplant. Phenytoin has been widely used but its pharmacokinetics and pharmacodynamics profile makes its use complicated. Levetiracetam is a safe, effective and well tolerated antiseizure drug with good results in epileptic patients. Objective To describe our experience using oral (p.o) levetiracetam 1000 mg every 12 h (q12h) as an antiseizure prophylaxis, evaluating its preventive effects and adverse event rates after a high-dose of intravenous (i.v.) busulfan, as part of the conditioning regimen Methods Retrospective study of patients who underwent an allogenic hematopoietic stem cell transplant with a conditioning regimen based on high-dose of busulfan between January and November 2017. Results The study population comprised 36 patients, of whom 18 (50%) had acute myeloid leukemia as diagnosis. No seizures occurred in any patient. Levetiracetam was well tolerated and no serious adverse events were reported. Conclusions Our results suggest that giving levetiracetam at 1000 mg q12h p.o starting 12 h before the administration of i.v. busulfan until 48 h after the last dose, can be used as an alternative in the prevention of busulfan-induced seizures in adults.
The use of low doses of methotrexate during peri-cell infusion period may be a risk factor for acute kidney injury in patients subjected to hematopoietic stem cell transplantation
Annals of hematology. 2020
Acute kidney injury (AKI) after hematopoietic stem cell transplantation (HSCT) is associated with high mortality rates. To determine the incidence and risk factors associated with AKI in patients undergoing HSCT during the infusion period, patients admitted for HSCT from 2012 to 2015 were studied. AKI was classified according to the KDIGO (Kidney Disease Improving Global Outcomes) criteria. We analyzed the main comorbidities, underlying conditions, types of transplant, preparative regimens, and use of potentially nephrotoxic drugs as risk factors for AKI. Among the 180 patients (median age 53 years), 69 (36.5%) developed AKI (23 KDIGO 1, 28 KDIGO 2, and 18 KDIGO 3), 49 (50.0%) undergoing allogeneic and 20 (22.3%) autologous transplantation, and 18 (9.4%) required dialysis. The main comorbidities were hypertension (38; 19.8%), and diabetes (19; 9.9%). The median pre-transplant creatinine was 0.7 mg/dl. Twenty-one patients died (10.9%). The risk factors for AKI in allogeneic HSCT were as follows: baseline estimated glomerular filtration rate (eGFR) (RR 1.12 (1.02-1.22), p = 0.019), use of vasopressors (RR 3.72 (2.20-6.29), p < 0.001), and use of methotrexate (RR 1.83 (1.08-3.11), p = 0.025). Male gender (RR 5.91 (1.65-21.16), p = 0.006), baseline eGFR (RR 1.22 (1.04-1.43), p = 0.011), and use of aminoglycosides (RR 3.92 (1.06-14.44), p = 0.041) were the risk factors for AKI associated with autologous HSCT. During hospitalization for HSCT, AKI was a common problem. The use of a low dose of methotrexate to prevent graft versus host disease was associated with its occurrence.
Less mucositis toxicity after 6 versus 3 fractions of high-dose total body irradiation before allogeneic stem cell transplantation
Bone marrow transplantation. 2019
Radiation Related Toxicities Using Organ Sparing Total Marrow Irradiation Transplant Conditioning Regimens
International journal of radiation oncology, biology, physics. 2019
PURPOSE Toxicities after organ sparing myeloablative total marrow irradiation (TMI) conditioning regimens have not been well characterized. The purpose of this study is to report pulmonary, renal, thyroid, and cataract toxicities from a prospective trial monitoring patients up to 8 years after TMI. METHODS A total of 142 patients with primarily multiple myeloma or acute leukemia undergoing hematopoietic cell transplantation (HCT) were evaluated. Follow-up included pulmonary function tests, serum creatinine, GFR, thyroid panel, and ophthalmologic exams performed at 100 days, 6 months, and annually. Median TMI dose was 14 Gy (10-19 Gy) delivered at 1.5-2.0 Gy twice a day at a dose-rate of 200 cGy/minute. RESULTS Median age was 52 years (range 9-70). Median follow-up (range) for all patients was 2 years (0-8) and for patients alive at the time of last follow-up (n=50) 5.5 years (0-8). Mean organ doses in Gy were lung 7.0, kidneys 7.1, thyroid 6.7 and lens 2.8. The crude incidence of radiation pneumonitis (RP) was 1/142 (0.7%). The cumulative incidence (CI) of infection and RP (I/RP) was 22.7% at 2 years post TMI. Mean lung dose (MLD) < 8 Gy predicted for significantly lower rates of I/RP (2-year CI 20.8% vs 31.8%, p=0.012). No radiation induced renal toxicity was noted. Hypothyroidism (HT) occurred in 6.0% and cataract formation (CF) in 7.0% of patients. CONCLUSION TMI delivered with IMRT results in lower organ doses and was associated with fewer toxicities compared to historical cohorts treated with conventional TBI. Keeping the mean lung dose to 8 Gy or less was associated with lower pulmonary complications. Further evaluation in clinical trials of IMRT to deliver TMI, TMLI and organ sparing conformal TBI is warranted.
Incidence, predictors, and outcomes of veno-occlusive disease/sinusoidal obstruction syndrome after reduced intensity allogeneic hematopoietic cell transplantation
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Hepatic veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication of hematopoietic stem cell transplantation (HCT) that is felt to be triggered, at least in part, by damage to the liver sinusoidal endothelium from cytotoxic conditioning regimens. Accordingly, the incidence of VOD/SOS after reduced intensity conditioning (RIC) HCT is low compared to myeloablative transplantation, and the natural history, risk factors, and outcomes of VOD/SOS after RIC have not been well characterized. We retrospectively reviewed 1583 consecutive patients receiving RIC HCT at the Dana-Farber Cancer Institute between 2007-2017 and ascertained 26 cases of VOD/SOS. The median day of VOD/SOS onset was 26 days (range 5, 48) and the cumulative incidence at day 50 was 1.6% (95% confidence interval 1.1%, 2.4%). Day 100 non-relapse mortality rate was 23% in the VOD/SOS cohort compared to 6.4% in patients without VOD/SOS (p=0.006). Cumulative incidence of VOD/SOS at day 50 was 3.1% after RIC regimen with Flu/Bu2+/-ATG (busulfan dose 6.4 mg/kg), compared to 0.15% after Flu/Bu1+/-ATG (busulfan dose 3.2 mg/kg) (p=0.0002); the incidence rate was 2.1% after RIC HCT with sirolimus containing GVHD prophylaxis, compared to 0.8% for RIC without sirolimus (p=0.06). Significant risk factors identified in multivariable analysis for the development of VOD/SOS were sirolimus use (hazard ratio (HR) 5.1, 95% CI 1.8-14.2, p=0.002) and RIC regimen with Flu/Bu2+/-ATG (HR 34, 95% CI 4.5 - 252, p<0.001) or other (HR 32, 95% CI 3.9 - 257, p=0.001) compared to Flu/Bu1+/-ATG. Rising serum tacrolimus or sirolimus levels, new acute kidney injury, and increasing platelet transfusion requirements were significant early predictors of onset in the week preceding prior VOD/SOS diagnosis. When compared to a previously published cohort of 76 VOD/SOS pts who developed VOD/SOS after myeloablative HCT in the same time period, VOD/SOS after RIC occurred later and was associated with a lower peak bilirubin level and better overall survival. The variability in presenting features for RIC VOD/SOS highlights the importance of maintaining a high index of suspicion for this entity in RIC HCT.
Reduced risk of sinusoidal obstruction syndrome of the liver after Busulfan-Cyclophosphamide conditioning prior to allogeneic hematopoietic stem cell transplantation
Clinical and translational science. 2019
The aim of this study is to evaluate the incidence of sinusoidal obstruction syndrome (SOS) of the liver and the clinical outcome after hematopoietic stem cell transplantation (HSCT) based on several modifications in our protocols. We retrospectively investigated 372 patients undergoing myeloablative conditioning with oral busulfan and cyclophosphamide before allogeneic HSCT during 1990-2015. Patients' supportive care was changed in order to reduce the regimen-related toxicities. Norethisterone use was terminated in 1998, therapeutic drug monitoring of busulfan was initiated in 2000 and the use of liver supportive drugs, such as ursodeoxycholic acid (UDCA) and N-acetyl-L-cysteine (NAC), were started in 2002 and 2009, respectively. In total, 26 patients (7.0%) developed SOS at a median of 19 days after transplantation. Of these 26 patients, 20 died at a median of 119 days after HSCT and 102 days after the diagnosis of SOS. The incidence of SOS decreased over time in accordance with the improvements in supportive care. The highest incidence of SOS was during 1995-99 (16.2%) compared to 2.3% during 2010-2015. Overall survival for patients with SOS was 62%, 46% and 27% at 100 days, 1 year and 5 years after HSCT respectively compared to 92%, 77% and 66% for those who did not develop SOS (P<0.001). In conclusion; the incidence of SOS and related deaths were significantly decreased over the last years. Our institution pursues massive preventative and personalized measures for SOS. This strategy may also be applicable in other conditioning protocols in order to reduce the incidence of SOS and hence, improve the clinical outcome.
Veno-occlusive disease after high-dose busulfan-melphalan in neuroblastoma
Bone marrow transplantation. 2018
Survival for high-risk neuroblastoma patients is still suboptimal. Although stem cell transplantation (SCT) is used, there is no consensus as to which conditioning regimen has the greatest efficacy and fewest toxicities. We assessed the incidence of and risk for hepatic veno-occlusive disease (VOD) for neuroblastoma patients who underwent autologous SCT with busulfan and melphalan (BuMel) at eight centers following Children's Oncology Group (COG)-based induction chemotherapy. Data regarding the patients, SCT characteristics, busulfan steady-state concentrations, incidence of VOD, and survival were evaluated. VOD was defined using the modified Seattle criteria. Possible factors associated with VOD (age, busulfan-pharmacokinetic parameters, history of hepatic dysfunction, and day of neutrophil engraftment) were evaluated. Seventy five patients were included and 23 children (31%) developed VOD at a median of 19 days after SCT (range 14-27 days). VOD was the cause of death in 4 patients (5%). In a multivariable analysis, young age (OR 1.7 (95% CI: 1.16-2.56; p = 0.012)) and early day of neutrophil engraftment (OR 1.4 (95% CI: 1.08-2.14; p = 0.041) were associated with the development of VOD. Initial or cumulative busulfan steady-state concentration were not associated with VOD. We found that despite the use of intravenous busulfan with adjusted serum levels, the incidence of VOD remains high in pediatric neuroblastoma patients.
Maximal concentration of intravenous busulfan as a determinant of veno-occlusive disease: a pharmacokinetic-pharmacodynamic analysis in 293 hematopoietic stem cell transplanted children
Bone marrow transplantation. 2018
Veno-occlusive disease (VOD) is a severe adverse reaction to busulfan-containing regimens used in the preparation of children for hematopoietic stem cell transplantation (HSCT). We conducted a retrospective analysis of data to examine determinants of VOD in children who received IV busulfan for HSCT conditioning. Busulfan PK parameters as well as various indices (maximal concentration-Cmax, area under the concentration-time curve-AUC) were estimated using a validated Bayesian approach. The influence of available PK, demographic, and clinical variables on the incidence of VOD was evaluated by using logistic regression and classification and regression tree (CART) analyses. Among the 293 patients included, the mean age was 6.5 years and the mean actual body weight was 26.3 kg. The incidence of VOD was 25.6%. Busulfan Cmax as well as weight <9 kg or age <3 years were identified as independent predictors of VOD in logistic regression analysis. CART analysis identified busulfan Cmax over the entire regimen as the strongest predictor of VOD. This study suggests that busulfan-associated VOD is in part a concentration-dependent reaction. In addition, the youngest children showed the highest risk of VOD. These findings may have important implications for busulfan dosing and therapeutic drug monitoring practice in HSCT children.