Hematopoietic stem cell transplantation-associated thrombotic microangiopathy and the role of advanced practice providers and pharmacists.

Hematopoietic stem cell transplantation-associated thrombotic microangiopathy (HSCT-TMA) is a severe and potentially life-threatening complication. HSCT-TMA is often underdiagnosed due to multifactorial pathophysiology and a historic lack of standard diagnostic criteria. Identification of the multi-hit hypothesis and the key role of the complement system, particularly the lectin pathway of complement, has led to development of treatments targeting the underlying pathogenesis of HSCT-TMA. Additional research is ongoing to investigate the efficacy and safety of these targeted therapies in patients with HSCT-TMA. Advanced practice providers (APPs; nurse practitioners and physician assistants) and pharmacists are critical members of the multidisciplinary HSCT team and ensure management of patients throughout the continuum of care. Additionally, pharmacists and APPs can improve patient care through medication management of complex regimens; transplant education for patients, staff, and trainees; evidence-based protocol and clinical guideline development; assessment and reporting of transplant-related outcomes; and quality improvement initiatives to improve outcomes. Understanding the presentation, prognosis, pathophysiology, and treatment options for HSCT-TMA can improve each of these efforts. Collaborative practice model for monitoring and care of HSCT-TMA. Advanced practice providers and pharmacists contribute to many aspects of patient care in transplant centers, including medication management for complex regimens; transplant education for patients, staff, and trainees; evidence-based protocol and clinical guideline development; assessment and reporting of transplant-related outcomes; and quality improvement initiatives. HSCT-TMA is a severe and potentially life-threatening complication that is often underdiagnosed. The collaboration of a multidisciplinary team of advanced practice providers, pharmacists, and physicians can optimize recognition, diagnosis, management, and monitoring of patients with HSCT-TMA, thereby improving outcomes for these patients.

Implementation and results of a standardized process for identifying ambulatory pharmacy clinical outcome measures.

PURPOSE: Given the variation in clinical practice, a clinician-centric, standardized process to implement and validate clinical pharmacy outcome measures was developed. SUMMARY: Four specialty clinics with embedded clinic-based pharmacists underwent an iterative process to define, refine, and implement the build of electronic health record functionality for outcome measure data collection and reporting. Starting with a list of identified measures, clinic workgroups met to discuss each measure and identify gaps in measure implementation. Information technology experts created electronic documentation forms with discrete data and reports based on criteria specified by the clinic workgroups. Of 32 outcome measures identified as priorities for demonstrating pharmacists' impact in previous research, 29 were implemented for routine monitoring through this project. Implementation strategies included identification through existing reporting, development of discrete documentation tools within the electronic health record, and development of new reporting tools from available discrete data fields. Time to implementation decreased from the first to the last pilot clinic implementation, as demonstrated through a 9-day reduction in electronic documentation form development and 31-day reduction in report development turnaround time. CONCLUSION: A standardized and reproducible process was developed for the implementation of clinical pharmacy outcomes measures for 4 specialty clinics. The process was successfully utilized to develop measurable outputs for a variety of oncology and nononcology specialty disease states based upon multidisciplinary stakeholder input.

Development and implementation of a standardized process for identifying ambulatory pharmacy clinical outcomes measures.

PURPOSE: There is minimal available guidance on the process for selection of clinical outcomes measures to demonstrate the impact of clinic-based pharmacists (CBPs) despite an increased need and desire for outcomes data. The overall aims of this project were to (1) develop a standardized process for identifying clinical outcomes measures impacted by CBPs and (2) identify and prioritize potential clinical outcomes measures to track for CBPs within 4 specialty clinic pilot sites. METHODS: To develop a standardized process for identification and prioritization of measures, 4 consecutive Plan-Do-Study-Act (PDSA) cycles were performed with 4 different specialty clinics serving as pilot sites. Following each pilot cycle, rapid cycle improvements were implemented. A modified Delphi methodology served as the framework for measure selection and included gathering expert stakeholder insights regarding importance, feasibility, and validity of potential measures. Measures were identified via environmental scan of existing validated quality metrics, clinical guidelines, and other relevant literature. RESULTS: The primary outcome for this project was the development and refinement of a standardized process for measure identification and prioritization. The secondary outcome was narrowed and ranked lists of stakeholder-prioritized measures for 4 CBP-embedded pilot specialty clinics. These lists included 12 cardiothoracic transplant, 6 breast oncology, 9 neurology, and 7 gynecologic oncology measures. CONCLUSION: The measure identification and prioritization process developed was successfully utilized to identify and prioritize outcomes measures to track for 4 CBP-embedded specialty clinics. Due to the successful use of the process in a variety of specialty clinics, the standardized process has significant potential for expansion.

Plerixafor strategies for autologous hematopoietic cell transplant mobilization: A comparison of efficacy and cost.

Addition of plerixafor (P) to granulocyte colony stimulating factor (G-CSF) during peripheral blood mobilization of hematopoietic stem cells (HSC) increases the number of patients meeting collection goals prior to autologous stem cell transplant (aSCT). However, use of P is not universal among transplant centers due to cost. This study aims to compare clinical and financial impacts of using an algorithm-based P mobilization strategy versus use in all patients. This was a single center, retrospective analysis of adult patients with myeloma or amyloidosis receiving aSCT who received apheresis of their HSC between 3/1/2017 and 3/1/2019. Patients prior to 3/1/2018 were classified as receiving P "per algorithm" and those after this date were classified as "up-front" P. For the per-algorithm group, P was given for a pre-apheresis CD34+ cell count of <20 cells/µL on mobilization day 5 and patients returned on day 6 for apheresis. Of the 129 patients included, 55 received P per-algorithm and 74 received up-front P. There was a reduction in median number of apheresis days (1.5 vs 1 day, p < 0.001) and an increase in median number of CD34+ cells collected (6.6 vs 8.5 × 106 cells/kg, p < 0.001) with up-front P. Up-front P increased drug cost but reduced apheresis costs, which resulted in a net savings of $121 per patient in total mobilization costs. These findings suggest that use of up-front P for mobilization significantly reduces apheresis days and increases HSC collection yield without increasing overall cost per patient.

Evaluation of mobilization efficacy with an extended interval following plerixafor administration.

Plerixafor is a hematopoietic stem cell mobilizing agent used in combination with granulocyte-colony stimulating factor to improve collection for autologous stem cell transplantation. Despite a recommendation for administration 11 h prior to apheresis per package labeling, logistical challenges lead many institutions to administer plerixafor at an extended interval. The purpose of this study was to determine if plerixafor effectively and efficiently mobilizes CD34+ cells when given at an extended interval prior to apheresis. This was a retrospective evaluation of adult patients who received plerixafor based on an algorithm reserving daily plerixafor only for patients with a pre-apheresis CD34+ count of < 20 cells/µL (pre-apheresis plerixafor) or with a low CD34+ yield after the first apheresis session (rescue plerixafor). The primary outcome was achievement of a disease-specific collection goal of ≥ 6 ×106 CD34+ cells/kg for multiple myeloma and ≥ 4 ×106 CD34+ cells/kg for lymphoma. The mean interval between plerixafor administration and apheresis was 17 h in this study. Despite this extended interval, 64% of patients met their disease-specific collection goal. A minimum collection goal of ≥ 2 ×106 CD34+ cells/kg was achieved by 95% of patients. Mobilization remained efficient with a median of two days to complete collection. Based on this data, plerixafor effectively and efficiently mobilizes CD34+ cells when given at an extended interval prior to apheresis.

Influence of Germline Genetics on Tacrolimus Pharmacokinetics and Pharmacodynamics in Allogeneic Hematopoietic Stem Cell Transplant Patients.

Tacrolimus exhibits high inter-patient pharmacokinetics (PK) variability, as well as a narrow therapeutic index, and therefore requires therapeutic drug monitoring. Germline mutations in cytochrome P450 isoforms 4 and 5 genes (CYP3A4/5) and the ATP-binding cassette B1 gene (ABCB1) may contribute to interindividual tacrolimus PK variability, which may impact clinical outcomes among allogeneic hematopoietic stem cell transplantation (HSCT) patients. In this study, 252 adult patients who received tacrolimus for acute graft versus host disease (aGVHD) prophylaxis after allogeneic HSCT were genotyped to evaluate if germline genetic variants associated with tacrolimus PK and pharmacodynamic (PD) variability. Significant associations were detected between germline variants in CYP3A4/5 and ABCB1 and PK endpoints (e.g., median steady-state tacrolimus concentrations and time to goal tacrolimus concentration). However, significant associations were not observed between CYP3A4/5 or ABCB1 germline variants and PD endpoints (e.g., aGVHD and treatment-emergent nephrotoxicity). Decreased age and CYP3A5*1/*1 genotype were independently associated with subtherapeutic tacrolimus trough concentrations while CYP3A5*1*3 or CYP3A5*3/*3 genotypes, myeloablative allogeneic HSCT conditioning regimen (MAC) and increased weight were independently associated with supratherapeutic tacrolimus trough concentrations. Future lines of prospective research inquiry are warranted to use both germline genetic and clinical data to develop precision dosing tools that will optimize both tacrolimus dosing and clinical outcomes among adult HSCT patients.

Drug-Drug Interaction Between Isavuconazole and Tacrolimus: Is Empiric Dose Adjustment Necessary?

A paucity of data currently exists regarding drug-drug interaction (DDI) with tacrolimus and isavuconazole coadministration. Current literature provides conflicting recommendations on whether an empiric tacrolimus dose reduction is necessary when coadministered with isavuconazole. A 47-year-old African American female with acute lymphoblastic leukemia underwent an allogenic stem cell transplant (alloSCT) and was subsequently placed on routine posttransplant therapy including tacrolimus for immunosuppression and posaconazole for antifungal prophylaxis. Tacrolimus was empirically dose reduced due to the expected DDI with posaconazole based on current recommendations. Due to a persistently prolonged QTc interval and need for mold coverage, antifungal prophylaxis was ultimately changed to isavuconazole at standard recommended dosing. Tacrolimus was empirically dose reduced by 40% based on limited available literature at the time; however, tacrolimus trough concentrations subsequently declined, requiring an increase in tacrolimus dose to maintain therapeutic trough concentrations. Adequate isavuconazole absorption was documented through pharmacokinetic and pharmacodynamic data by measuring an isavuconazole trough concentration and directly observing isavuconazole's shortening effect on the QTc interval, respectively. Our experience in an alloSCT patient suggests that an empiric tacrolimus dose reduction is not required when isavuconazole is initiated, but close tacrolimus therapeutic drug monitoring should rather be performed to guide tacrolimus dosing.

Evaluation of a Test Dose Strategy for Pharmacokinetically-Guided Busulfan Dosing for Hematopoietic Stem Cell Transplantation.

Targeted busulfan dosing helps limit chemotherapy-related toxicity and optimize disease outcomes in hematopoietic stem cell transplantation (HCT). The objective of this study was to evaluate busulfan exposure from a pharmacokinetic (PK)-guided dosing strategy using a test dose. This retrospective evaluation included adult patients who underwent HCT at our institution with busulfan-based myeloablative (>9 mg/kg) conditioning between January 2014 and October 2015. A weight-based test dose of 0.8 mg/kg was used with PK assessments to predict area under the curve (AUCpred) achieved with weight-based dosing, with a target AUC of 4800 µM*minute (AUCtarget). PK from the test dose was then used to calculate a PK-guided first myeloablative busulfan dose. PK assessments were also done after the first dose to assess if the goal area under the curve (AUC) had been achieved (AUCfirst). A PK-guided first dose resulted in achievement of target AUC with target ranges of ±10% in 50% of patients, ±15% in 75%, and ±20% in 94%. This was an improved rate of target achievement compared with the 33%, 44%, and 63% of patients who achieved the desired AUC for these respective target ranges when using weight-based dosing (P = .12, .004, and <.001, respectively). The PK-guided strategy also decreased the variability of AUC from 3.6-fold in AUCpred from the weight-based test doses (2700.8 to 9631 µM*minute; SD, 1211.6 µM*minute) to 1.8-fold in AUCfirst from the PK-guided first doses (3672.1 to 6609.8 µM*minute; SD, 574.7 µM*minute). This reflects a 2-fold improvement in AUC variability with a PK-guided dosing strategy. This is also improved from the 3-fold variability in AUC reported in other studies. Weight and body surface area were significantly associated with the likelihood of AUCfirst being within the ±10% target range (P = .04 for both associations). There was no significant association between AUCfirst and death, relapse, or a composite of the two. These results demonstrate a significant improvement in target AUC attainment and less interpatient variability with PK-guided dosing using a test dose strategy compared with weight-based dosing.

Patient perspectives on the barriers associated with medication adherence to oral chemotherapy.

Purpose Appropriate use of oral chemotherapy is a challenge for patients and clinicians. The purpose of this study was to analyze cancer patients' use of oral chemotherapies and identify opportunities to improve adherence. Methods We developed a 30-question survey to address frequency and reasons for reducing/skipping doses; sources of information for oral chemotherapy use; perceived importance of food-drug effects; and ease of understanding labeling directions. Results Ninety-three patients taking oral chemotherapies with chronic myeloid leukemia, renal cell carcinoma, breast cancer, and colorectal cancer completed the survey. This was a well-educated population with 69% (n = 62) having completed some college; 51% (n = 47) female and 59% (n = 54) older than 50 years of age. Thirty percent of patients reported forgetting to take their oral chemotherapy at least "sometimes". Younger patients (<50 vs. ≥50, p = 0.002), shorter treatment duration (<6 vs. ≥6 months p = 0.03), or with chronic myeloid leukemia (vs. other diagnoses, p = 0.015) forget to take their oral chemotherapy at higher rates. Twenty-three percent (n = 21) indicated they intentionally skipped their oral chemotherapies and 38% (n = 8) of those did not inform their physicians. Forty-one percent (n = 28) taking drugs with significant food-drug effects did not think about their last meal before taking their oral chemotherapy and 80% (n = 55) did not understand the potential interactions. Additionally, 39% (n = 36/92) never looked at labeling and 15% (n = 14/91) had difficulty understanding label directions. Conclusion There are three main barriers associated with appropriate use of oral chemotherapies: misunderstanding about the timing of drug with food; stopping drug without informing physicians; and difficulty understanding labeling directions. A multipronged approach is needed to optimize communication of directions for optimal oral chemotherapy use.

Comparison of Weight-Based Dosing Strategies for Intravenous Immunoglobulin in Patients with Hematologic Malignancies.

STUDY OBJECTIVE: Intravenous immunoglobulin (IVIG) is a weight-based therapy used to treat and prevent infections in patients with hematologic malignancies. IVIG doses were calculated traditionally using actual body weight (ABW). However, limited pharmacokinetic data suggest dosing strategies using ideal body weight (IBW) or adjusted body weight (adjBW) may be appropriate given the small volume of distribution of IVIG. Our objective was to compare the effectiveness of using a precision-dosing strategy (IBW or adjBW) with a traditional-dosing strategy (ABW) for IVIG in patients with hematologic malignancies or those undergoing hematopoietic stem cell transplant, as well as to perform an IVIG drug use analysis. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: Between April 2014 and September 2016, 209 IVIG encounters met inclusion criteria for the primary outcome. Of those encounters, 125 were dosed using the traditional-dosing strategy, and 84 used the precision-dosing strategy. MEASUREMENTS AND MAIN RESULTS: The primary outcome was infection rate within 30 days of IVIG administration. Secondary outcomes included 60-day infection rate, immunoglobulin G (IgG)-level response (IgG higher than 400 mg/dl), and realized and potential IVIG savings. No difference in 30-day infection rate between precision- and traditional-dosing strategies was identified (15.5% vs 16%, respectively, p=0.823). Similarly, no difference was identified in the 60-day infection rate between groups (23.2% vs 19.8%, respectively, p=0.568). Levels of IgG obtained after IVIG repletion showed a treatment response rate of 86% in both groups. Use of a precision-dosing strategy achieved $2600/month in institutional savings with the opportunity for an additional $4600/month in savings with complete adherence to this dosing strategy. CONCLUSION: No differences in infection rate and IgG-level response were identified when a precision-dosing strategy was used. Implementation of an IVIG precision-dosing strategy provided institutional cost savings.

ReCAP: Pharmacists' Impact in Hematopoietic Stem-Cell Transplantation: Economic and Humanistic Outcomes.

PURPOSE: This study seeks to evaluate the impact of pharmacists' involvement in the care of patients undergoing bone marrow transplantation (BMT). METHODS: This was a three-phase study. In phase 1, inpatient and outpatient pharmacist encounters were totaled and services provided were translated to revenue generated from prescription revenue and billing charges. In phase 2, pharmacists' activities and interventions were associated with time savings estimated by providers. In phase 3, patients and providers were surveyed to assess their expectations, experiences, and value perceptions of pharmacists.A positive response rate of 80%for each survey item was set as the threshold for high expectations and successful service delivery. RESULTS: In phase 1, after 6 months of data collection, clinical services were provided to 170 inpatients and 290 outpatients. For inpatients, there was an average discharge prescription revenue of $990 per patient through the outpatient pharmacy. In the outpatient clinic, pharmacist visits generated an additional $23,000 in charges (approximately $80 per patient) and an annual prescription revenue of approximately $840,000 through the outpatient pharmacy. In phase 2, pharmacists' activities led to a total time savings of 122 hours. In phase 3, patients and providers met the predetermined 80% positive response rate for most survey items. The item for which patient and provider responses consistently did not meet this threshold related to pharmacists educating patients about their BMT. CONCLUSION: Pharmacists are valuable resources in the care of patients undergoing BMT, as their care translates to increased revenue, provider time savings, and positive perceptions from patients and providers.