Background: Intravenous busulfan (BU) is widely used in conditioning chemotherapy prior to stem cell transplantation at an initial dose of .8 mg/kg and is then adjusted to achieve a pre-defined goal drug exposure. A variety of dosing weights have been described in the literature. The primary objective of this study was to determine the impact on steady-state concentrations when ideal body weight (IBW) was used to dose BU in obese transplant recipients compared to non-obese patients. The secondary objectives were to determine the impact on survival and to describe the use of alternative dosing weights. Methods: This was a retrospective, IRB-approved, single-center analysis of all adult stem cell transplant recipients who received BU between August 1, 2007 and October 31, 2014. The obese and non-obese cohorts were based on a cutoff of 130% IBW. P values <.05 were considered statistically significant. Results: There were 63 patients included in the obese cohort and 82 patients included in the non-obese cohort. The mean steady-state concentration after the first dose of BU was 673.7 ng/mL in the obese cohort and 779.3 ng/mL in the non-obese cohort (P < .001). When the obese cohort was compared to the non-obese cohort, a larger proportion of concentrations were subtherapeutic (41.3% vs 9.8%, P < .001), a smaller proportion were therapeutic (50.8% vs 74.4%, P = .003), and there was no difference in the proportion of supratherapeutic concentrations (7.9% vs 15.8%, P = .14). There was no difference in overall survival between the two groups (P = .18). The Day +100 progression-free survival was 81.4% vs 89.0% (P = .14) and the Day +365 progression-free survival was 54.2% vs 71.2% (P = .04) in the obese compared to non-obese cohorts, respectively. Alternative dosing weights are presented in Table 1. Adjusted body weights with a 25% (ABW25) and 40% (ABW40) correction factor are appropriate to dose BU in obese patients while IBW, ABW25, and ABW40 are appropriate in non-obese patients. Actual body weight (ABW) was not appropriate in either group.Table 1Alternative Dosing WeightsCohortAverage Final Dose, IBW(mg/kg, SD)Average Final Dose, ABW(mg/kg, SD)Average Final Dose, ABW25(mg/kg, SD)Average Final Dose, ABW40(mg/kg, SD)P value≥130% IBW (n = 63).91 (.17).58 (.12).79 (.14).74 (.14)<.001100 to <130% IBW (n = 82).79 (.12).69 (.10).76 (.11).75 (.11)<.001 Open table in a new tab Conclusion: The use of IBW to dose BU resulted in lower steady-state concentrations and a larger proportion of subtherapeutic concentrations in obese patients. While there was no difference in overall survival, there was a decrease in progression-free survival in the obese cohort suggesting that IBW should not be used to dose BU in these patients. This retrospective study is the largest to evaluate the dosing of BU in obese patients; however, prospective, multicenter studies are needed to validate these findings. (Figure 1)
Nirmatrelvir/ritonavir (NIM/r) inhibits tacrolimus metabolism resulting in a profound drug-drug interaction that is further complicated by the use of azole antifungals.We describe three strategies, in 4 patient cases, for the initiation of NIM/r in allogeneic hematopoietic stem cell transplant (alloHSCT) recipients on tacrolimus at the time of diagnosis. Patients 1 and 2 (strategy 1) experienced prolonged, elevated tacrolimus concentrations after an empiric 33% reduction in tacrolimus dose and adjustment of azole antifungal at NIM/r initiation (strategy 1) and with complete discontinuation of tacrolimus and azole antifungal at NIM/r initiation (strategy 2). Patients 3 and 4 (strategy 3) did not experience elevated tacrolimus concentrations on NIM/r treatment with complete discontinuation of tacrolimus and azole antifungal and a 12-24-h delay in NIM/r initiation. Reinitiation of tacrolimus after NIM/r completion resulted in variable tacrolimus concentrations.NIM/r-tacrolimus is a serious drug-drug interaction which can be mitigated by early discontinuation of tacrolimus and azole antifungals, close monitoring, and reinitiation of tacrolimus and antifungal 48-72 h after completion of therapy.
Abstract Despite significant advances in deciphering the molecular landscape of acute myeloid leukaemia (AML), therapeutic outcomes of this haematological malignancy have only modestly improved over the past decades. Drug resistance and disease recurrence almost invariably occur, highlighting the need for a deeper understanding of these processes. While low O 2 compartments, such as bone marrow (BM) niches, are well‐recognized hosts of drug‐resistant leukaemic cells, standard in vitro studies are routinely performed under supra‐physiologic (21% O 2 , ambient air) conditions, which limits clinical translatability. We hereby identify molecular pathways enriched in AML cells that survive acute challenges with classic or targeted therapeutic agents. Experiments took into account variations in O 2 tension encountered by leukaemic cells in clinical settings. Integrated RNA and protein profiles revealed that lipid biosynthesis, and particularly the cholesterol biogenesis branch, is a particularly therapy‐induced vulnerability in AML cells under low O 2 states. We also demonstrate that the impact of the cytotoxic agent cytarabine is selectively enhanced by a high‐potency statin. The cholesterol biosynthesis programme is amenable to additional translational opportunities within the expanding AML therapeutic landscape. Our findings support the further investigation of higher‐potency statin (eg rosuvastatin)–based combination therapies to enhance targeting residual AML cells that reside in low O 2 environments.
Oral budesonide exerts local effects with negligible systemic glucocorticoid activity, due to rapid first-pass metabolism, therefore, could potentially be efficacious in preventing gastrointestinal (GI) acute GVHD (aGVHD). We explored the use of budesonide, added to posttransplant cyclophosphamide (PTCy), tacrolimus, and mycophenolate mofetil, for prevention of GI aGVHD after allogeneic hematopoietic stem cell transplantation (AHSCT) in a prospective observational study and treated 80 patients with a median age of 53 years (range 19-74). Results were compared with a publicly available CIBMTR dataset of 646 patients who received PTCy-based GVHD prophylaxis (CIBMTR Study # GV17-02) (control). Cumulative incidence (CI) of 3-month grade 2-4 and grade 3-4 aGVHD in the budesonide and control groups were 3.8% vs. 34.4% (p < 0.001) and 1.3% vs. 9.8% (p = 0.029), respectively. One-year GRFS (70.5% vs. 31.5%, p < 0.001), PFS (73.4% vs. 52.8%, p = 0.003), and OS (80.1% vs. 64.2%, p = 0.038) were significantly higher in the budesonide group compared with control group. Propensity score-adjusted analyses showed that the addition of budesonide significantly decreased risk of aGVHD grade 2-4 (HR 0.29, p < 0.001), grade 3-4 (HR 0.12, p = 0.045), and cGVHD (HR 0.22, p < 0.001), which resulted in better GRFS (HR 0.38, p < 0.001), PFS (HR 0.58, p = 0.012), and OS (HR 0.72, p = 0.044). Similar results were found when using propensity score-matched analysis restricted to recipients of haploidentical transplantation. In conclusion, addition of budesonide to PTCy-based GVHD prophylaxis is safe and effective in preventing severe acute GI GVHD with significantly improved GRFS. These results could facilitate transition to peripheral blood grafts for all allogeneic transplant recipients.
Blinatumomab is a bispecific CD19/CD3-directed T-cell engager that plays an important role in the management of acute lymphoblastic leukemia (ALL). Despite its ability to produce high response rates with minimal myelotoxicity compared to conventional chemotherapy, blinatumomab use can be associated with significant neurotoxicity. Intrathecal (IT) chemotherapy plays a vital role in the prevention and treatment of central nervous system (CNS)-involved ALL and is often intercalated with systemic CNS-targeting therapies. Although the current evidence regarding blinatumomab's ability to exert clinical activity in the CNS space remains controversial, there is limited data on the safety of concurrent IT chemotherapy use. In this report, we describe our experience with the safety and timing of concurrent IT chemotherapy and blinatumomab. We retrospectively reviewed adult (≥18-years old) ALL patients treated with blinatumomab between February 2016 and August 2022 at our institution. Patients with low-burden disease (i.e., <1% in the bone marrow) received blinatumomab 28 mcg/day for 28 days per cycle while all others received a lower dose of 9 mcg/day for the first seven days during cycle 1. Premedication with dexamethasone 16 mg in the former and 20 mg in the latter, was administered prior to blinatumomab initiation, with dose escalation to the full dose, or when interruptions exceeded 4 h. Concurrent IT chemotherapy was defined as administration within 24 h of initiation or during blinatumomab infusion. History of CNS disorder was defined by previous seizures, aphasia, cerebrovascular ischemia/hemorrhage, severe brain injury, dementia, Parkinson's disease, cerebellar disease, psychosis, or movement disorder. Neurotoxicity was graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE, version 5.0), and included confusion/encephalopathy, persistent headaches, visual disturbances, paresthesia, hemiparesis, muscular weakness, aphasia, tremors, dysgraphia, and memory impairment. The University of California Irvine Health Institutional Review Board approved this study and informed consent was waived. The Chi-square or Fisher's exact test was used to assess categorical data, while the Wilcoxon rank-sum or Student's t-test was used to analyze continuous variables, respectively. Multivariable logistic regression analysis (MVA) was performed in a forward stepwise fashion utilizing variables significant with a p < .20 to identify predictors for neurotoxicity. The final model selection was based on the lowest Bayesian information criteria score and was validated via the likelihood-ratio test. All analyses were performed using Intercooled Stata, version 17 (StataCorp, College Station, TX). Of 49 patients assessed ([mean ± SD] age, 47 ± 19 years; 23 men [46.9%]), 18 (36.7%) received concurrent IT chemotherapy with blinatumomab, and 31 (63.3%) did not (control). Baseline characteristics were comparable between the concurrent IT and control cohorts, with the exception of higher lactate dehydrogenase (p = .046) and a lower number of prior IT chemotherapies (p = .045) in the former. Most patients (75.5%) had good functional status with an Eastern Cooperative Oncology Group (ECOG) score of 0 (18.4%; n = 9) or 1 (57.1%; n = 28) and none of the included patients had positive cerebrospinal fluid (CSF) samples or abnormal brain MRI at the start of blinatumomab. Patient details and outcomes are available in Table S1. Overall, 17 (34.7%) patients experienced neurotoxicity in this study, with a significantly higher incidence seen in the concurrent IT cohort (55.6% vs. 22.6%; p = .019). Three of 18 patients (16.7%) in the concurrent IT cohort experienced grade 3–4 neurotoxicity compared to one of 31 (3.3%) in the control. Patients most commonly experienced a headache at the onset of neurotoxicity (70.6%, n = 12), which was often concurrent with one or more neurologic symptoms (83.3%). These included diminished cognition (60%; n = 6/10) (i.e., confusion, encephalopathy, memory impairment) or impaired motor function, such as unilateral extremity weakness or tremors (30%; n = 3/10). Eight of the 17 (47.1%) neurotoxicity events occurred during blinatumomab step-up dosing (9 mcg/day) while the remaining nine events were with a full dose (28 mcg/day) blinatumomab. Additional information on symptom onset and outcomes are available in Table S2. All patients with neurotoxicity in the concurrent IT chemotherapy cohort had received IT within 14 days of blinatumomab initiation and symptoms occurred after IT administration with a median (IQR) onset of (3.5 [2–4] days). Assessment by point-biserial correlation demonstrated later IT administration was moderately associated with decreased neurotoxicity (correlation coefficient [rpb] = −.55; p = .018). Median (IQR) time from blinatumomab initiation to onset of neurotoxicity was 5 (3–8) days, with a non-significant difference noted between the concurrent IT (5 [3–5] days) and control (8 [2–22] days) groups (p = .46). The timing of IT chemotherapy and blinatumomab dose in relation to the onset of neurotoxicity is depicted in Figure S1. Methotrexate 15 mg was the most common preparation given preceding neurotoxicity events (90%) followed by triple (methotrexate, cytarabine, and hydrocortisone) IT chemotherapy (10%). Increased risk with one chemotherapy agent over another could not be evaluated as 94.4% (n = 17/18) of patients received methotrexate via the IT route during blinatumomab (methotrexate alone [77.8%], triple IT [11.1%], cytarabine alone [5.6%], and alternating methotrexate with cytarabine [11.1%]). In MVA, we found that concurrent IT chemotherapy (adjusted Odds Ratio, [aOR] = 4.32; 95% CI:1.15–16.30; p = .031) and hypoalbuminemia ([aOR] = 4.04; 95% CI:1.05–15.44; p = .042) were significantly associated with neurotoxicity (Table 1). In a recently published retrospective analysis, Ngo, et al. described lower rates of neurotoxicity with concurrent IT chemotherapy (5.3% vs. 27.2%; p = .004), leading the authors to speculate on a potential neuroprotective effect from IT chemotherapy.1 In comparison, where most patients received IT chemotherapy on the last day of blinatumomab, we observed a higher incidence of neurotoxicity when IT chemotherapy was administered at the beginning or early during blinatumomab administration (the majority of our patients received IT chemotherapy during the first 14 days of blinatumomab). Other evidence for the safety of concurrent IT chemotherapy with blinatumomab is limited, with only a few published papers available.2, 3 In a case series of eleven patients with active or history of CNS-positive ALL receiving blinatumomab, a higher rate of grade ≥3 blinatumomab-induced neurotoxicities was seen with concurrent IT chemotherapy (33.3% vs. 0%).2 Incidence of grade 1–2 neurotoxicity was not described. Another case report by Chen, et al. describes a 26-year-old male who received triple IT chemotherapy on days 4, 8, and 11 of blinatumomab infusion with subsequent neurotoxicity noted on day 12.3 Several studies have evaluated the combination of dasatinib or ponatinib with blinatumomab, intercalating IT chemotherapy during blinatumomab infusions but none address this potential interaction. While the exact mechanism remains unclear, the pathogenesis of blinatumomab-associated neurotoxicity has been suggested to follow a stepwise model with the increased endothelial adhesiveness of activated T-cells, endothelium activation by these T-cells, followed by extravasation of T-cells and further attraction of circulating leukocytes, and finally cytokine release by extravasated T-cells in the brain.4 Theoretically, administration of chemotherapy would halt T-cell activation and potentially limit T-cell mediated neurotoxicity. In fact, the utilization of IT chemotherapy for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS) has recently been described in the management of chimeric antigen receptor T-cell therapy patients.5, 6 Interestingly, a case report describing secondary prophylaxis with IT chemotherapy in a patient receiving blinatumomab has also been described and a prospective clinical trial to evaluate this utility is underway (NCT 05519579).7, 8 This may also explain why Ngo, et al. saw a neuroprotective effect when IT chemotherapy was administered later in blinatumomab treatment, as compared with an increase in neurotoxicity when administered upfront or early during blinatumomab infusion. In these cases, systemic inflammation and circulating cytokines induced by blinatumomab therapy may have already been present and susceptible to the cytotoxic effects of IT chemotherapy. We, therefore, hypothesize that additive neurotoxicity may occur when IT chemotherapy is administered early during a 28-day blinatumomab cycle, prior to the onset of T-cell mediated neurotoxicity. There are several limitations to this single-center study that should be acknowledged. Our ability to make definitive conclusions about causality is constrained given the study's retrospective design and limited sample size. Nevertheless, our findings were consistent with the available literature and after controlling for these known variables, the signal for concurrent IT chemotherapy persisted.9 The incidence of neurotoxicity found in our study was also consistent with the reported literature. We report a total of 34.7% of patients who experienced neurotoxicity events (22.6% in the control) while Ngo, et al. and Stein, et al. described rates of 24.6% (27.2% in their control) and 52%, respectively.1, 9 Lastly, the implications of cytarabine or methotrexate could not be assessed as the majority of patients in the concurrent IT cohort received methotrexate-containing preparations. In conclusion, we have found that concomitant administration of IT chemotherapy in patients receiving treatment with blinatumomab is associated with a higher incidence of neurotoxicity. As a result, we believe that concurrent IT chemotherapy (specifically those containing methotrexate) during the first 14 days of blinatumomab treatment should be avoided. Further studies are needed to clarify the best timing of IT chemotherapy administration during treatment with blinatumomab for patients with ALL. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Dr. Piyanuch Kongtim has consulting relationships with CareDx. Dr. Alexandre Chan has consulting relationships with Eli Lilly and Company and Blueprint Medicines. Dr. Susan O'Brien has consulting relationships with Amgen, Celgene, GlaxoSmithKline, AstraZeneca, Autolus, GlaxoSmithKline, Nova Research Company, Bristol Myers Squibb, DynaMed, Eli Lilly, and Company, Janssen Oncology, Johnson and Johnson, Juno Therapeutics, MEI Pharma, Inc., Merck, Aptose Biosciences, Vaniam Group, AbbVie/Genentech, Sunesis Pharmaceuticals, Alexion Pharmaceuticals, Astellas Pharma, Gilead Sciences, Pharmacyclics, TG Therapeutics, Vida Ventures, and Pfizer and has received honoraria/research funding from Alliance, Janssen, Eisai, Amgen, Loxo Oncology, Inc., Mustang Bio, Inc., Nurix Therapeutics, Inc., Astellas Pharma, Aptose Biosciences, Beigene, Ltd., Caribou Biosciences, Inc., Acerta Pharma, Regeneron, Gilead Sciences, Pfizer, AbbVie, Alexion Pharmaceuticals, TG Therapeutics, Pharmacyclics, and Kite, a Gilead company. Dr. Deepa Jeyakumar has received research funding through Pfizer and Jazz Pharmaceuticals. The remaining authors report no potential conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. TABLE S1. Patient demographics and clinical outcomes. Table S2. Summary of patients who experienced neurotoxicity. FIGURE S1. Timing of intrathecal chemotherapy and onset of neurotoxicity. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) characterized by responsiveness to chemotherapy and differentiating agents [1]. The current standard of care for the ...
Tacrolimus requires close therapeutic drug monitoring (TDM) to ensure efficacy and minimize adverse effects. Pharmacists are uniquely positioned on transplant teams to interpret levels and recommend therapy modifications. Their impact in the immediate postoperative setting has not been described previously.To evaluate the impact of a clinical solid organ transplant pharmacist on nephrotoxicity, TDM, and revenue generation in adult kidney transplant recipients on tacrolimus.Retrospective assessment of adult kidney transplant recipients at University of Florida Health Shands Hospital.A transplant pharmacist rounded 5 days a week and made medication recommendations on transplant recipients-including tacrolimus dose modifications based on levels. Pharmacy services were expanded to include medication reconciliation, medication counseling, and delivery of discharge medications to bedside.Incidence of nephrotoxicity during tacrolimus exposure.Of the 70 kidney transplant recipients in the postpharmacist cohort, 18 (25.7%) experienced nephrotoxicity while on tacrolimus, compared to 18 (25%) of the 72 in the prepharmacist cohort ( P = .922). A significantly greater proportion of recipients who experienced nephrotoxicity were male, had hypertension, or experienced delayed or slow graft function. The rate of appropriately drawn tacrolimus troughs significantly increased from 23.4% to 30.3% in the postpharmacist cohort ( P < .001). The median outpatient pharmacy revenue generated per recipient significantly increased from US$345.49 (interquartile range [IQR]: 0-4727.56) to US$4834.95 per recipient (IQR: 3592.78-6224.60; P < .001). The length of stay (7 days, IQR: 6-9, vs 8 days, IQR: 6-9; P = .107) and the 30-day readmission rate were similar between groups (20.8% vs 21.4%; P = .931).
7048 Background: It is unknown if HyperCVAD is more favorable than pediatric-inspired regimens (PIRs) among adult Hispanic patients with newly diagnosed B-cell acute lymphoblastic leukemia. This analysis aims to determine the interaction of Hispanic ethnicity and treatment regimen on outcomes. Methods: Records of adults (≥ 18 years) treated with a PIR or HyperCVAD from January 2011 to November 2022 at our institution were reviewed. Patients were excluded if they received treatment modifications in a clinical trial or were lost to follow-up prior to 6 months. The primary endpoint was event-free survival (EFS) comprised of relapse, death, secondary malignancy, or failure to achieve complete remission. Secondary endpoints included overall survival (OS). Ph+ disease was not grouped into the poor-risk category. Results: 100 patients were included. Median age was 39 years, 57% were male, and 61% self-identified as Hispanic. 48 were included in the PIR and 52 in the HyperCVAD groups. 37 in the PIR group received CALGB 10403. There was no difference in race, ethnicity, rituximab use, WBC, LDH, bone marrow blast %, presence of CNS disease at diagnosis, or poor-risk genetics (Table) between the PIR and HyperCVAD groups. However, a lower rate of Ph+ disease (8.3% vs 58%) and younger median age (31 years vs 49 years) was observed in the PIR group. Allogeneic stem cell transplantation (ASCT) was pursued in 48% of PIR and 37% of HyperCVAD-treated patients. EFS at 5-years was lower among patients receiving a PIR compared to HyperCVAD (28% vs 41%; hazard ratio [HR], 1.89; P = .022). After censoring for ASCT there was no change (P = .03). Treatment group was the only significant predictor for EFS although a treatment-by-subgroup interaction (P < .10) with Hispanic ethnicity was found. OS at 5-years was 61% in PIR and 64% in HyperCVAD-treated patients (HR, 1.54; P = .25). In multivariable Cox regression analysis, Hispanic ethnicity (HR, 2.56; P = .041) and male sex (HR, 2.62; P = .027) were predictors for worse OS. Hispanic patients demonstrated worse EFS with a PIR compared to HyperCVAD (HR, 2.52; P = .008), which remained significant when evaluating only Ph- patients (HR, 2.20; P=.048). Non-Hispanics did not experience the same difference in EFS (HR, 0.88; P=.81). Conclusions: Treatment with a PIR resulted in worse EFS over HyperCVAD in adult Hispanic ALL patients. Future studies focusing on regimen intensity, adherence, and toxicities are needed to explore potential causes for this disparity. [Table: see text]
