Remimazolam for Sedation During Fiberoptic Intubation in an Adolescent.

In specific clinical scenarios, fiberoptic intubation (FOI) may be the preferred technique for airway management and endotracheal intubation. In addition to topical anesthesia of the airway, sedation is frequently necessary, especially in younger patients, to facilitate the procedure. The goal is to facilitate the procedure by providing sedation, anxiolysis, and analgesia with maintenance of spontaneous ventilation. Remimazolam is a novel benzodiazepine with a short half-life and limited context sensitive half-life that can be titrated by continuous infusion. These novel properties may make it a suitable agent for sedation during FOI of the trachea. We report the novel use of a combination of remimazolam and remifentanil infusions to provide sedation during FOI in an adolescent. The basic pharmacology of remimazolam is presented and previous reports of its use for sedation during FOI are reviewed.

Brentuximab vedotin plus AVD for Hodgkin lymphoma: incidence and management of peripheral neuropathy in a multisite cohort.

Brentuximab vedotin (BV) in combination with doxorubicin, vinblastine, and dacarbazine (AVD) is increasingly used for frontline treatment of stage III/IV classical Hodgkin lymphoma (cHL). Peripheral neuropathy (PN) was the most common and treatment-limiting side effect seen in clinical trials but has not been studied in a nontrial setting, in which clinicians may have different strategies for managing it. We conducted a multisite retrospective study to characterize PN in patients who received BV + AVD for newly diagnosed cHL. One hundred fifty-three patients from 10 US institutions were eligible. Thirty-four patients (22%) had at least 1 ineligibility criteria for ECHELON-1, including stage, performance status, and comorbidities. PN was reported by 80% of patients during treatment; 39% experienced grade (G) 1, 31% G2, and 10% G3. In total, BV was modified in 44% of patients because of PN leading to BV discontinuation in 23%, dose reduction in 17%, and temporary hold in 4%. With a median follow-up of 24 months, PN resolution was documented in 36% and improvement in 33% at the last follow-up. Two-year progression-free survival (PFS) for the advanced-stage patients was 82.7% (95% confidence interval [CI], 0.76-0.90) and overall survival was 97.4% (95% CI, 0.94-1.00). Patients who discontinued BV because of PN did not have inferior PFS. In the nontrial setting, BV + AVD was associated with a high incidence of PN. In our cohort, which includes patients who would not have been eligible for the pivotal ECHELON-1 trial, BV discontinuation rates were higher than previously reported, but 2-year outcomes remain comparable.

High-grade B-cell lymphoma, not otherwise specified: a multi-institutional retrospective study.

In this multi-institutional retrospective study, we examined the characteristics and outcomes of 160 patients with high-grade B-cell lymphoma, not otherwise specified (HGBL-NOS)-a rare category defined by high-grade morphologic features and lack of MYC rearrangements with BCL2 and/or BCL6 rearrangements ("double hit"). Our results show that HGBL-NOS tumors are heterogeneous: 83% of patients had a germinal center B-cell immunophenotype, 37% a dual-expressor immunophenotype (MYC and BCL2 expression), 28% MYC rearrangement, 13% BCL2 rearrangement, and 11% BCL6 rearrangement. Most patients presented with stage IV disease, a high serum lactate dehydrogenase, and other high-risk clinical factors. Most frequent first-line regimens included dose-adjusted cyclophosphamide, doxorubicin, vincristine, and etoposide, with rituximab and prednisone (DA-EPOCH-R; 43%); rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP; 33%); or other intensive chemotherapy programs. We found no significant differences in the rates of complete response (CR), progression-free survival (PFS), or overall survival (OS) between these chemotherapy regimens. CR was attained by 69% of patients. PFS at 2 years was 55.2% and OS was 68.1%. In a multivariable model, the main prognostic factors for PFS and OS were poor performance status, lactate dehydrogenase >3 × upper limit of normal, and a dual-expressor immunophenotype. Age >60 years or presence of MYC rearrangement were not prognostic, but patients with TP53 alterations had a dismal PFS. Presence of MYC rearrangement was not predictive of better PFS in patients treated with DA-EPOCH-R vs R-CHOP. Improvements in the diagnostic criteria and therapeutic approaches beyond dose-intense chemotherapy are needed to overcome the unfavorable prognosis of patients with HGBL-NOS.

Pemigatinib for the treatment of myeloid/lymphoid neoplasms with FGFR1 rearrangement.

INTRODUCTION: Myeloid/lymphoid neoplasms with fibroblast growth factor receptor-1 (FGFR1) rearrangements (MLNFGFR1) are rare entities with aggressive features and poor prognosis. Presentation is heterogeneous, ranging from myeloproliferative neoplasms (with or without eosinophilia) to T-cell lymphoma and acute leukemia. Historical treatments have been guided by the presenting phenotype with induction chemotherapy frequently used. Pemigatinib is a FGFR1-3 tyrosine kinase inhibitor that has demonstrated high complete hematologic and cytogenetic response rates in MLNFGFR1. AREAS COVERED: We discuss the pathogenesis, presentation, and historical treatments for MLNFGFR1, in addition to clinical data using pemigatinib and other targeted therapies. Discussion of the mechanism of action and adverse events is also included. EXPERT OPINION: Pemigatinib represents a significant advance in the management of MLNFGFR1. High rates of complete hematologic and cytogenetic response have been observed. While direct comparative data are unavailable, outcomes appear favorable compared to conventional approaches. Long-term efficacy and tolerability are not yet known, and allogeneic hematopoietic stem cell transplant (alloHSCT) continues to be the treatment with the highest chance of long-term disease free survival in responding patients. Combinations of pemigatinib and chemotherapy, particularly for more aggressive phenotypes, warrant future investigation as does the use of pemigatinib maintenance following alloHSCT.

A multi-center analysis of the impact of DA-EPOCH-R dose-adjustment on clinical outcomes of patients with double/triple-hit lymphoma.

Patients with double- and triple-hit lymphomas (DHL/THL) have inferior outcomes with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP), and higher-intensity regimens such as dose-adjusted (DA)-EPOCH-R are standard. Dose-intensification of DA-EPOCH-R is guided by hematologic toxicity, without conclusive benefit for DHL/THL patients. To determine if cumulative doses of DA-EPOCH-R or compliance with dose adjustment impacts survival, we retrospectively evaluated detailed clinical data from 109 adult (age ≥18 years) patients with DHL/THL treated with ≥4 cycles of induction DA-EPOCH-R from 2014 to 2019 at six centers. A comprehensive multivariate analysis was performed. Survival outcomes for the entire cohort were comparable to historical estimates for DHL/THL treated with this regimen (median follow-up 27.9 months). Overall survival (OS) and progression-free survival (PFS) were not significantly associated with cumulative chemotherapy dose, dose escalation, or compliance with dose adjustment. Heterogeneous dosing practices were observed. Prospective investigation is warranted to evaluate the practice of dose adjustment of R-EPOCH for patients with DHL/THL.

Outcomes of Tisagenlecleucel in Lymphoma Patients With Predominant Management in an Ambulatory Setting.

INTRODUCTION: Chimeric antigen receptor T-cell therapy (CAR T) is a revolutionary adoptive immunotherapy approach in lymphoma; however, substantial resources are necessary for administration and care of these patients. Our institution has administered tisagenlecleucel primarily in an outpatient setting, and here we report our clinical outcomes. PATIENTS AND METHODS: We conducted a single institution, retrospective study investigating outcomes of adult lymphoma patients treated with commercial tisagenlecleucel between 10/2017 and 12/2020. We analyzed patient characteristics and outcomes of efficacy and safety including overall response rate, progression-free survival, overall survival and cytokine-release syndrome, neurotoxicity, and hospitalizations. RESULTS: Seventy-two patients with relapsed or refractory non-Hodgkin lymphoma (NHL) who received commercial tisagenlecleucel were identified; 68 (94.4%) patients received outpatient tisagenlecleucel. The overall response rate was 43% with a complete response observed in 25 patients (34.7%). At a median follow-up of 9.1 months, the median progression-free survival was 3.3 months. Grade 3-4 cytokine release syndrome was not observed in the study group and two patients had grade 3-4 neurotoxicity. Twenty-six patients (36.1%) were admitted within 30 days after infusion with a median length of stay of 5 days. Fourteen patients (19.4%) were admitted within 72 hours of infusion. No patient died of CAR T cell-related toxicity. CONCLUSION: Our experience affirms treatment with tisagenlecleucel in the outpatient setting is safe and feasible with close supervision and adequate institutional experience. After infusion, adverse events were manageable and the majority of patients did not require hospitalization.

New and emerging therapies for the treatment of relapsed/refractory diffuse large B-cell lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of aggressive non-Hodgkin lymphoma. Approximately 40% of patients with DLBCL will experience disease relapse or will be refractory to first line chemoimmunotherapy, necessitating second-line salvage therapy. This has historically consisted of platinum-based chemotherapy regimens followed by autologous hematopoietic stem cell transplantation with curative intent for transplant-eligible patients or palliative chemotherapy for transplant-ineligible patients. In recent years there have been several new therapeutic agents approved for the treatment of relapsed/refractory DLBCL, thereby expanding the therapeutic landscape. These agents include polatuzumab vedotin, tafasitamab, loncastuximab tesirine, selinexor, and anti-CD19 chimeric antigen receptor T-cell therapies such as axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel. This review summarizes the pharmacology, efficacy, safety, dosing, and administration of new agents recently approved for the treatment of relapsed/refractory DLBCL.

Addressing the Challenges of Novel Oncology and Hematology Treatments Across Sites of Care: Specialty Pharmacy Solutions.

Background: The number of Food and Drug Administration (FDA) approvals for anticancer therapies has significantly increased in recent years, but these novel therapies are costly and present challenges to patients and providers. Many institutions have implemented health systems specialty pharmacies (HSSPs) to help patients and providers navigate financial and logistical barriers to treatment with oral anticancer therapies. Patients on oral anticancer therapy are often treated across multiple sites of care which can complicate the inpatient specialty medication initiation process. Health systems often limit inclusion of oral anticancer therapies for inpatient administration due to costs, however several new therapies necessitate admission for treatment initiation. Health systems are then faced with the challenge of starting costly oral anticancer therapy inpatient and ensuring continued access to therapy upon discharge. We describe the integrated HSSP multidisciplinary approach to this MUP including providers, inpatient and outpatient pharmacists, specialty and inpatient pharmacies, institutional procurement team, and the institutional pharmacy and therapeutics (P&T) committee to streamline this process.The HSSP multidisciplinary processes addresses a growing need for cancer patients to receive timely and affordable treatments across different sites of care. The healthcare team and P&T committee ensure the patient receives the most appropriate therapy while being conscious of health-system costs. The HSSP and procurement team ensure the patient can obtain and afford the medication. The implemented processes allows for direct communication and collaboration between different sites of care and this collaborative approach leads to optimal patient care.

18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography Following Chimeric Antigen Receptor T-cell Therapy in Large B-cell Lymphoma.

PURPOSE: 18F-Fluorodeoxyglucose positron emission tomography/computed tomography (FDG PET/CT) is a well-established imaging modality to assess responses in patients with B-cell neoplasms. However, there is limited information about the utility of FDG PET/CT after chimeric antigen receptor T-cell (CART) therapies for large B-cell lymphomas. In this retrospective analysis, we aimed to evaluate how FDG PET/CT performs in patients receiving commercially available anti-CD19 CART therapies for relapsed/refractory (r/r) large B-cell lymphomas. In addition, we examined the time to repeat scan and the rate of pseudoprogression within this population. Lastly, the rates of radiographic response to CART therapy using FDG PET/CT are reported. PROCEDURES: The pre-treatment and post-treatment scans were analyzed from a selected cohort of 43 patients from a single institution. Patients were stratified by diagnosis of either a first occurrence of diffuse large B-cell lymphoma: de novo diffuse large B-cell lymphoma (DLBCL); or a transformed diffuse large B-cell lymphoma arising from indolent non-Hodgkin lymphoma (t-iNHL). RESULTS: More patients received CART therapy for DLBCL than t-iNHL (65 % vs 35 %). FDG PET/CT had a 99 % sensitivity and 100 % specificity for detecting recurrent disease in this group. The median time to initial response assessment was 86 days (IQR 79-91; full range 24-146) after infusion. There were no biopsy-proven cases of pseudoprogression identified. In this selected group of patients, the overall response rate by Lugano 2014 criteria was 56 %. All patients with a partial response (N = 6) eventually progressed despite additional therapy. CONCLUSIONS: Due to its excellent test characteristics and ability to detect asymptomatic disease, routine surveillance with PET/CT at 3 months after CART infusion is supported by our data. Earlier PET/CT may be of value in select situations as we did not find any cases of pseudoprogression.

Quantifying Radiation Exposure From Intraoperative Computed Tomography in Traditionally Safe Operating Room Zones.

OBJECTIVES: To quantify the amount of radiation exposure from a commercially available computed tomography surgical imaging system that occurs in areas of the operating room that are generally believed to be safe and to correlate these amounts with established safety recommendations. DESIGN: Experimental in vitro study. SETTING: Standard hospital operating room at a Level 1 trauma center. PARTICIPANTS: Radiation survey instruments at specified distances from an intraoperative computed tomography scanner. Represented positions were the location of the anesthesiologist (80 cm), the radiation technologist (180 cm), the substerile room (500 cm), the operating room door (600 cm), the next-room nursing station (960 cm), and the hallway (1000 cm). INTERVENTION: Radiation survey instruments were systematically exposed by a protocol intended to imitate expected radiation scatter during operative room use. MAIN OUTCOME MEASUREMENTS: Radiation exposure readings from radiation survey instruments. RESULTS: The mean radiation exposure rates are reported. The mean exposure rate was highest at the anesthesiologist (2200 mrem/h), followed by the door (25.33 mrem/h), the technologist (21.0 mrem/h), the substerile room (8.2 mrem/h), the hallway (2.633 mrem/h), and then the next-room nursing station (1.557 mrem/h). The mean integrated doses per scan were 15.03 mrem for the anesthesiologist, 0.170 mrem for the technologist, 0.136 mrem at the door, 0.033 mrem in the substerile room, 0.014 mrem in the hallway, and 0.005 mrem at the next-door nursing station. The exposure was related both to distance from the machine and to orientation from the machine. CONCLUSIONS: These results indicate that although there is measurable radiation exposure outside of the operating room, the magnitude is low enough to be clinically insignificant. This study provides data that reinforce the need to wear a protective gear or leave the room during the use of intraoperative computed tomography but unsuspecting surrounding staff need not worry about uninformed exposure.

Venous thromboembolism following pegaspargase in adults receiving antithrombin supplementation.

Pegaspargase (PEG) increases venous thromboembolism (VTE) in acute lymphoblastic leukemia (ALL) potentially due to depletion of anticoagulation factors, including antithrombin (AT). The benefit and cost of AT supplementation in adults is unclear. We aimed to characterize VTE incidence and risk factors following AT and determine the characteristics and costs of supplementation. Fifty-three adults received PEG and AT. VTE occurred in 21% (grade ≥3 8%). T cell ALL and patients receiving prednisone during induction were at highest risk. Repeat AT levels post supplementation were subtherapeutic forty-four percent of the time. A median of 18 days elapsed between PEG and two sequential therapeutic AT levels despite supplementation. Patients received a median of 2 AT doses per PEG dose at a median cost of $11,145. VTE remains common in adults despite AT supplementation. More aggressive AT supplementation may reduce VTE but warrant prospective evaluation given the significant cost.

Student engagement using multiple-attempt 'Weekly Participation Task' quizzes with undergraduate nursing students.

BACKGROUND: Student engagement is essential to quality learning. Regular formative assessment tasks can support positive student engagement attitudes and behaviours towards learning. OBJECTIVES: This study aimed to evaluate the relationships of regular, recurrent delivery of online quizzes in promoting student engagement and academic performance. DESIGN: Concurrent exploratory mixed-method design. SETTING: A large metropolitan university in Western Sydney. PARTICIPANTS: Data from 1037 final-year undergraduate nursing students enrolled in a core theoretical unit related to palliative nursing. METHOD: A series of new Weekly Participation Task (WPT), consisting of multiple online quizzes was embedded into the unit. Administrative data, including data retrieved from the learning analytics, was used for quantitative data analysis. Qualitative data were retrieved from open-ended questions within the institutional Student Feedback on Unit survey. RESULTS: Each student's overall mean number of attempts was 4.6, achieving a mean quiz score of 97.6%. Students with high quiz attempts were more likely to also had high tutorial attendance (AOR: 1.42, 95% CI: 1.05 to 1.90), achieved maximum quizzes scores (AOR: 1.78, 95% CI: 1.26 to 2.51), but interestingly, lower grade point average (AOR: 1.73, 95% CI: 1.28 to 2.35). The WPT received 111 (26%) positive comments in students' open-ended responses, and all three (behavioural, emotional and cognitive) student engagement dimensions were evident as students' sources of satisfaction. CONCLUSIONS: The WPTs are a successful formative assessment task that supports student engagement across all three dimensions, and contributes significantly to reducing student stress and increasing preparedness for and participation in face-to-face tutorial sessions.

Management and outcomes of sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease).

Sinus histiocytosis with massive lymphadenopathy (Rosai Dorfman Disease [RDD]), is a rare, benign but clinically heterogeneous histiocytic disorder. Our aims were to analyze the clinical characteristics of the disease and explore the outcomes of patients with RDD followed at our institution. Between January 2000 and February 2019, there were 15 patients with a pathologically confirmed diagnosis of RDD. Median age at diagnosis was 48 years old (range 26-78). The majority (87%, n = 13) of the patients had extranodal disease. Frontline approaches included surgical intervention/complete excision (n = 5, 33%), rituximab monotherapy (n = 5, 33%), observation (n = 3, 20%), and radiation (n = 2, 13%). Two of the five patients underwent surgical excision and were subsequently treated with rituximab. Of the 7 patients who were given rituximab, 64% remained progression free 24 months after the initial rituximab administration. Our review parallels previous reports and highlights rituximab as a favorable option for therapy if ineligible for surgery or radiation.

Treatment of Patients With Relapsed/Refractory Non-Hodgkin Lymphoma With Venetoclax: A Single-Center Evaluation of Off-Label Use.

INTRODUCTION: Venetoclax is a highly effective agent in chronic lymphocytic leukemia and acute myeloid leukemia. Phase I/II clinical trials have shown it to be safe and effective in non-Hodgkin lymphoma (NHL). Adverse events were consistent with package labeling despite escalation to high doses. To the best of our knowledge, venetoclax use outside the setting of a clinical trial of NHL has not been reported. PATIENTS AND METHODS: We conducted a single-center, retrospective study of 34 adult patients who had been treated off-label with venetoclax-containing regimens from 2016 to 2018. RESULTS: Of the 34 patients with NHL treated with venetoclax therapy, 13 had had high-grade B-cell lymphoma/diffuse large B-cell lymphoma, 10 mantle cell lymphoma, 5 transformed follicular lymphoma, 2 Richter transformation, 2 marginal zone lymphoma, 1 follicular lymphoma, and 1 post-transplant lymphoproliferative disorder. The patients had received a median of 4 previous therapies. The overall response rate was 26% (3% with a complete response and 35% with stable disease). The median venetoclax dose achieved was 400 mg. Of those receiving combination therapy, 18% had undergone radiation and 62% had received other systemic antineoplastic therapy. The median progression-free and overall survival for the cohort was 2 and 4.5 months, respectively. Adverse events occurred in 76% of the patients during venetoclax therapy. The adverse events included neutropenia, thrombocytopenia, tumor lysis syndrome, infection, neutropenic fever, diarrhea, and 1 opportunistic infection. CONCLUSION: Venetoclax therapy in a real-world cohort offered modest benefits in heavily pretreated patients. Adverse events were observed at a greater incidence than in the clinical trials. A wide heterogeneity of venetoclax dose escalation, multiagent combinations, and timing of initiation were identified and require investigation in subsequent clinical trials.

Oral Vancomycin Prophylaxis Is Highly Effective in Preventing Clostridium difficile Infection in Allogeneic Hematopoietic Cell Transplant Recipients.

BACKGROUND: Clostridium difficile infection (CDI) is a leading cause of infectious complications in allogeneic hematopoietic cell transplant recipients (alloHCT). We sought to evaluate whether prophylactic oral vancomycin reduces the incidence of CDI in alloHCT recipients. METHODS: We conducted a retrospective cohort study to examine the effectiveness of CDI prophylaxis with oral vancomycin, as compared to no prophylaxis, in 145 consecutive adult alloHCT recipients at the University of Pennsylvania between April 2015 and November 2016. Patients received oral vancomycin 125 mg twice daily, starting on admission and continuing until discharge. The primary outcome of interest was the association between oral vancomycin prophylaxis and CDI diagnosis. Secondary outcomes included graft-versus-host disease (GVHD) and relapse. RESULTS: There were no cases of CDI in patients that received prophylaxis (0/90, 0%), whereas 11/55 (20%) patients who did not receive prophylaxis developed CDI (P < .001). Oral vancomycin prophylaxis was not associated with a higher risk of acute, grades 2-4 GVHD (subhazard ratio [sHR] 1.59; 95% confidence interval [CI] 0.88-2.89; P = .12), acute, grades 3-4 GVHD (sHR 0.65; 95% CI 0.25-1.66; P = .36), or acute, grades 2-4 gastrointestinal GVHD (sHR 1.95; 95% CI 0.93-4.07; P = .08) at day 180 post-transplant. No associations between oral vancomycin and relapse or survival were observed. CONCLUSIONS: Prophylaxis with oral vancomycin is highly effective in preventing CDI in alloHCT recipients without increasing the risk of graft-versus-host disease or disease relapse. Further evaluation via a prospective study is warranted.

Left atrial abnormality (LAA) as a predictor of ibrutinib-associated atrial fibrillation in patients with chronic lymphocytic leukemia.

Results from several recent studies in chronic lymphocytic leukemia (CLL) have demonstrated an association between ibrutinib exposure and the development of atrial fibrillation, estimated incidence of 11% with long-term follow up. This is a common cause of ibrutinib discontinuation. Risk factors for atrial fibrillation include advanced age, hypertension (HTN), mitral valve disease (MVD), left atrial remodeling, coronary artery disease (CAD) and risk factors for cardiovascular dysfunction We conducted a retrospective case control study using the presence of left atrial abnormality identified on pre-ibrutinib EKGs, defined as either (1) Lead II-bifed p wave, with 40 mcsec between peaks for ≥ 2.5 mm wide ≥ 100 msec in duration, (2) Lead V1-biphasic P wave with terminal portion ≥ 40 msec in duration or terminal portion ≥ 1 mm deep or (3) PR interval ≥ 200 msec (intra-atrial conduction delay) as a predictor for development of atrial fibrillation. 183 consecutively CLL patients treated with ibrutinib were identified. 44 patients met inclusion criteria (20 cases, 24 controls). 20 (11.3%) of patients developed atrial fibrillation. Left atrial enlargement was identified as a significant predictor of development of atrial fibrillation (OR 9.1, 95% CI 2.2-37.3, p=0.02). Age, baseline HTN, CAD, diabetes, age and sex were not significant predictors. Area under the ROC curve for the model was estimated to be 75%. LAA identified by EKG is a moderately specific and sensitive finding that can identify patients at increased risk for this toxicity.

Systemic Treatments for Lung Cancer Patients Receiving Hemodialysis.

Chemotherapy, and now targeted therapies and immunotherapies, are widely used for the management of patients with all stages of lung cancer. Some challenges present when patients are receiving concomitant hemodialysis for various comorbid conditions. However, this should not immediately rule out a patient for treatment. Many drugs may be safely given to patients who are receiving hemodialysis with the proper dosing schedule and careful monitoring. This article will outline the current literature surrounding the use of these drugs in patients undergoing active hemodialysis while being treated for lung cancer.

Lack of a significant pharmacokinetic interaction between maraviroc and tacrolimus in allogeneic HSCT recipients.

OBJECTIVES: Emerging data suggest that the combination of tacrolimus and the CCR5 antagonist maraviroc, both cytochrome P450-3A4 substrates, may be effective in preventing graft-versus-host disease in patients undergoing allogeneic HSCT. This study evaluated whether a pharmacokinetic interaction exists between these agents. METHODS: The study included 36 allogeneic HSCT recipients who received maraviroc + tacrolimus and 43 recipients of tacrolimus alone. We used a difference-in-differences analysis to examine the change in the concentration/dose ratios of tacrolimus after the discontinuation of maraviroc. In addition, we analysed the concentrations and dose requirements of tacrolimus in the two groups. RESULTS: There was no significant difference in tacrolimus concentration/dose ratios in patients receiving maraviroc + tacrolimus compared with tacrolimus alone. Upon discontinuation of maraviroc, the change in concentration/dose ratio was small and not significant relative to the control group, and the effect estimate was further attenuated after adjustment for confounders [-0.35 (ng/mL)/(mg/day); P = 0.46]. In addition, the change in mean tacrolimus dose after discontinuation of maraviroc was similar between the groups (0.12 mg/day; P = 0.56), as was the change in mean tacrolimus concentration (0.02 ng/mL; P = 0.97). CONCLUSIONS: Our findings do not support a significant inhibitory effect of maraviroc on the metabolism of tacrolimus. These data demonstrate that this drug combination is safe and imply that the protective effect of maraviroc against graft-versus-host disease was not mediated through an increase in tacrolimus concentrations. These findings are important for the design of clinical trials that evaluate maraviroc in combination with cytochrome P450-3A4 substrates.