Two novel assays demonstrate persistent daratumumab exposure in a pediatric patient with delayed engraftment following allogeneic hematopoietic stem cell transplantation.

BACKGROUND AIMS: Daratumumab, a human IgG monoclonal antibody targeting CD38, is a promising treatment for pediatric patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL). We describe a case of delayed engraftment following a mismatched, unrelated donor hematopoietic stem cell transplant (HSCT) in a 14-year-old female with relapsed T-ALL, treated with daratumumab and chemotherapy. By Day 28 post-HSCT, the patient had no neutrophil engraftment but full donor myeloid chimerism. METHODS: We developed two novel, semi-quantitative, antibody-based assays to measure the patient's bound and plasma daratumumab levels to determine if prolonged drug exposure may have contributed to her slow engraftment. RESULTS: Daratumumab levels were significantly elevated more than 30 days after the patient's final infusion, and levels inversely correlated with her white blood cell counts. To clear daratumumab, the patient underwent several rounds of plasmapheresis and subsequently engrafted. CONCLUSIONS: This is the first report of both delayed daratumumab clearance and delayed stem cell engraftment following daratumumab treatment in a pediatric patient. Further investigation is needed to elucidate the optimal dosing of daratumumab for treatment of acute leukemias in pediatric populations as well as daratumumab's potential effects on hematopoietic stem cells and stem cell engraftment following allogenic HSCT.

The MAGIC algorithm probability is a validated response biomarker of treatment of acute graft-versus-host disease.

The Mount Sinai Acute GVHD International Consortium (MAGIC) algorithm probability (MAP), derived from 2 serum biomarkers, measures damage to crypts in the gastrointestinal tract during graft-versus-host disease (GVHD). We hypothesized that changes in MAP after treatment could validate it as a response biomarker. We prospectively collected serum samples and clinical stages of acute GVHD from 615 patients receiving hematopoietic cell transplantation in 20 centers at initiation of first-line systemic treatment and 4 weeks later. We computed MAPs and clinical responses and compared their abilities to predict 6-month nonrelapse mortality (NRM) in the validation cohort (n = 367). After 4 weeks of treatment, MAPs predicted NRM better than the change in clinical symptoms in all patients and identified 2 groups with significantly different NRM in both clinical responders (40% vs 12%, P < .0001) and nonresponders (65% vs 25%, P < .0001). MAPs successfully reclassified patients for NRM risk within every clinical grade of acute GVHD after 4 weeks of treatment. At the beginning of treatment, patients with a low MAP that rose above the threshold of 0.290 after 4 weeks of treatment had a significant increase in NRM, whereas patients with a high MAP at onset that fell below that threshold after treatment had a striking decrease in NRM that translated into clear differences in overall survival. We conclude that a MAP measured before and after treatment of acute GVHD is a response biomarker that predicts long-term outcomes more accurately than change in clinical symptoms. MAPs have the potential to guide therapy for acute GVHD and may function as a useful end point in clinical trials.

Managing Pain in Chronically Ill Homebound Patients Through Home-Based Primary and Palliative Care.

BACKGROUND:: Many older adults are homebound due to chronic illness and suffer from significant symptoms, including pain. Home-based primary and palliative care (HBPC), which provides interdisciplinary medical and psychosocial care for this population, has been shown to significantly reduce symptom burden. However, little is known about how pain is managed in the homebound. OBJECTIVE:: This article describes pain management for chronically, ill homebound adults in a model, urban HBPC program. DESIGN/MEASUREMENTS:: This was a prospective observational cohort study of newly enrolled HBPC patients, who completed a baseline Edmonton Symptom Assessment System (ESAS) survey during the initial HBPC visit (N = 86). Baseline pain burden was captured by ESAS and pain severity was categorized as none, mild, or moderate-severe. All pain-related assessments and treatments over a 6-month period were categorized by medication type and titration, referrals to outside providers, procedures, and equipment. RESULTS:: At baseline, 55% of the study population had no pain, 18% had mild pain, and 27% had moderate-severe pain. For those with moderate-severe pain at baseline (n = 23), prescriptions for pharmacological treatments for pain, such as opiates and acetaminophen, increased during the study period from 48% to 57% and 52% to 91%, respectively. Nonpharmacological interventions, including referrals to outside providers such as physical therapy, procedures, and equipment for pain management, were also common and 67% of the study population received a service referral during the follow-up period. CONCLUSIONS:: Pharmacological and nonpharmacological treatments are widely used in the setting of HBPC to treat the pain of homebound, older adults.

MAGIC biomarkers predict long-term outcomes for steroid-resistant acute GVHD.

Acute graft-versus-host disease (GVHD) is treated with systemic corticosteroid immunosuppression. Clinical response after 1 week of therapy often guides further treatment decisions, but long-term outcomes vary widely among centers, and more accurate predictive tests are urgently needed. We analyzed clinical data and blood samples taken 1 week after systemic treatment of GVHD from 507 patients from 17 centers of the Mount Sinai Acute GVHD International Consortium (MAGIC), dividing them into a test cohort (n = 236) and 2 validation cohorts separated in time (n = 142 and n = 129). Initial response to systemic steroids correlated with response at 4 weeks, 1-year nonrelapse mortality (NRM), and overall survival (OS). A previously validated algorithm of 2 MAGIC biomarkers (ST2 and REG3α) consistently separated steroid-resistant patients into 2 groups with dramatically different NRM and OS (P < .001 for all 3 cohorts). High biomarker probability, resistance to steroids, and GVHD severity (Minnesota risk) were all significant predictors of NRM in multivariate analysis. A direct comparison of receiver operating characteristic curves showed that the area under the curve for biomarker probability (0.82) was significantly greater than that for steroid response (0.68, P = .004) and for Minnesota risk (0.72, P = .005). In conclusion, MAGIC biomarker probabilities generated after 1 week of systemic treatment of GVHD predict long-term outcomes in steroid-resistant GVHD better than clinical criteria and should prove useful in developing better treatment strategies.

An early-biomarker algorithm predicts lethal graft-versus-host disease and survival.

BACKGROUND. No laboratory test can predict the risk of nonrelapse mortality (NRM) or severe graft-versus-host disease (GVHD) after hematopoietic cellular transplantation (HCT) prior to the onset of GVHD symptoms. METHODS. Patient blood samples on day 7 after HCT were obtained from a multicenter set of 1,287 patients, and 620 samples were assigned to a training set. We measured the concentrations of 4 GVHD biomarkers (ST2, REG3α, TNFR1, and IL-2Rα) and used them to model 6-month NRM using rigorous cross-validation strategies to identify the best algorithm that defined 2 distinct risk groups. We then applied the final algorithm in an independent test set (n = 309) and validation set (n = 358). RESULTS. A 2-biomarker model using ST2 and REG3α concentrations identified patients with a cumulative incidence of 6-month NRM of 28% in the high-risk group and 7% in the low-risk group (P < 0.001). The algorithm performed equally well in the test set (33% vs. 7%, P < 0.001) and the multicenter validation set (26% vs. 10%, P < 0.001). Sixteen percent, 17%, and 20% of patients were at high risk in the training, test, and validation sets, respectively. GVHD-related mortality was greater in high-risk patients (18% vs. 4%, P < 0.001), as was severe gastrointestinal GVHD (17% vs. 8%, P < 0.001). The same algorithm can be successfully adapted to define 3 distinct risk groups at GVHD onset. CONCLUSION. A biomarker algorithm based on a blood sample taken 7 days after HCT can consistently identify a group of patients at high risk for lethal GVHD and NRM. FUNDING. The National Cancer Institute, American Cancer Society, and the Doris Duke Charitable Foundation.

The Association Between Medicolegal and Professional Concerns and Chest Pain Admission Rates.

OBJECTIVES: For patients in whom acute coronary syndrome (ACS) is a concern, disposition decisions are complex and multifactorial and have traditionally been a source of considerable variation. An important factor in disposition decisions for these patients may be physician-perceived medicolegal risk and related professional concerns. The study aim was to determine, at the point of care, how much less frequently physicians report that they would admit possible ACS patients if there was either zero or a defined medicolegal risk. METHODS: This was a point-of-care emergency physician survey. Research assistants approached physicians at or immediately following the moment of disposition decisions for patients who were being admitted for ACS. The primary outcome measures were the proportion of physicians reporting that patients would not have been admitted if medicolegal issues were of no concern and the proportion of physicians reporting that patients would not have been admitted if there was an "acceptable miss rate" of 1% to 2% for ACS patients. RESULTS: During the 3-month study period, 576 patients were admitted to an inpatient unit or to the ED observation protocol. Physicians were approached in 271 cases, and 259 surveys were completed. When presented with hypothetical zero medicolegal risk, physicians answered that they would not have admitted the patients in 30% of cases. With a hypothetical 1% to 2% acceptable miss rate, physicians indicated that they would not have admitted the patients in 29% of the cases. CONCLUSIONS: ED medicolegal and professional concerns may substantially increase admissions for possible ACS. An acceptable miss rate or a zero medicolegal risk environment could potentially lead to a major reduction in admissions that physicians feel to be clinically unnecessary.

Hospital administrators' views on barriers and opportunities to delivering palliative care in the emergency department.

STUDY OBJECTIVE: We identify hospital-level factors from the administrative perspective that affect the availability and delivery of palliative care services in the emergency department (ED). METHODS: Semistructured interviews were conducted with 14 key informants, including hospital executives, ED directors, and palliative care directors at a tertiary care center, a public hospital, and a community hospital. The discussions were digitally recorded and transcribed to conduct a thematic analysis using grounded theory. A coding scheme was iteratively developed to subsequently identify themes and subthemes that emerged from the interviews. RESULTS: Barriers to integrating palliative care and emergency medicine from the administrative perspective include the ED culture of aggressive care, limited knowledge, palliative care staffing, and medicolegal concerns. Incentives to the delivery of palliative care in the ED from these key informants' perspective include improved patient and family satisfaction, opportunities to provide meaningful care to patients, decreased costs of care for admitted patients, and avoidance of unnecessary admissions to more intensive hospital settings, such as the ICU, for patients who have little likelihood of benefit. CONCLUSION: Though hospital administration at 3 urban hospitals on the East coast has great interest in integrating palliative care and emergency medicine to improve quality of care, patient and family satisfaction, and decrease length of stay for admitted patients, palliative care staffing, medicolegal concerns, and logistic issues need to be addressed.