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Chimeric antigen receptor T cell (CAR T) therapy has been integrated into treatment algorithms for acute leukemia, lymphoma, and, most recently, multiple myeloma. The number of clinical trials in both hematologic and solid tumor malignancies for new products and potential indications continues to grow. The clinical toxicities of CAR T therapy include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, which often warrant inpatient admission for close monitoring and treatment. Consequently, many centers have built processes around the administration of these cells in the inpatient setting. As new products gain Food and Drug Administration approval with more manageable toxicity profiles, and as institutions gain experience with the management of these toxicities, outpatient administration and monitoring should be expected. In addition, payor reimbursements for inpatient treatment have put the sustainability of inpatient CAR T therapy in jeopardy, especially for centers with a payor mix that includes a high proportion of Medicare patients. This has the serious potential to limit access to care. As the use of CAR T therapy continues to expand, changes in payment models, care settings, or both are needed to ensure the sustainability of safe, efficient, and cost-effective treatment. This review outlines the efficacy and toxicity of currently approved products, as well as best practices to optimize the management of CAR T cell therapy in the outpatient setting.

Hematopoietic cell transplantation (HCT) is an essential component of potentially curative therapy for patients with hematologic malignancies. High-dose chemotherapy with autologous (auto) stem cell rescue is used to overcome chemoresistance in multiple myeloma, non-Hodgkin lymphoma, and Hodgkin lymphoma. Alternatively, poor-risk acute leukemias rely on the graft versus leukemia effect of allogeneic (allo) products. Long-term remissions are feasible with both auto- and allo-HCT; however, disease relapse is the leading cause of death after HCT for many patients. In recognition of this, novel therapies are being investigated in the upfront, relapsed/refractory, and post-HCT maintenance settings to deepen response and maintain disease control. To date, the most robust data to support this approach are in multiple myeloma, where post-transplant maintenance therapy has improved clinical outcomes. In Hodgkin lymphoma, patients with high-risk features may benefit from post-auto-HCT vedotin (BV) regardless of pre-HCT BV exposure. Apart from mantle cell lymphoma, where rituximab maintenance is generally accepted, post-auto-HCT maintenance in other forms of NHL is less established. In patients who undergo allo-HCT, the utilization of maintenance therapy is an important component of improving post-HCT outcomes, however, an individualized approach that considers patient factors such as residual toxicity from HCT, an immature graft with poor graft function, infection, and graft-versus-host disease create a complex environment for aggressive interventions. Initiation of directed agents in patients with identified mutations prior to allo-HCT, including FLT3 in acute myeloid leukemia and Philadelphia chromosome in acute lymphoid leukemia have generally improved post-HCT outcomes. Ongoing studies are exploring the safety and efficacy of additional maintenance strategies post-allo-HCT in an effort to further improve post-HCT outcomes.

Curative therapy for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor has been frustratingly elusive. In with the goal of improving engraftment while minimizing transplantation-related morbidity, a multi-institutional learning collaborative was developed in the context of a Phase II clinical trial of nonmyeloablative, related HLA-haploidentical (haplo) bone marrow transplantation (BMT) with post-transplantation cyclophosphamide. All eligible participants had hemoglobin SS, and 89% (16 of 18) had an identifiable donor. The median patient age was 20.9 years (IQR, 12.1 to 26.0 years), and the most common indication for transplantation was overt stroke (in 69%; 11 of 16). In the first 3 patients, the conditioning regimen consisted of antithymocyte globulin, fludarabine, cyclophosphamide, and low-dose total body irradiation. Graft-versus-host disease (GVHD) prophylaxis included post-transplantation cyclophosphamide, mycophenolate mofetil, and sirolimus. Primary graft rejection occurred in 2 of the 3 patients (67%), which triggered the study-stopping rule. To reduce graft rejection risk, thiotepa was added to the conditioning regimen, and then 15 patients (including 2 with previous graft rejection) underwent haplo-BMT with this thiotepa-augmented conditioning regimen. At a median follow-up of 13.3 months (interquartile range [IQR], 3.8 to 23.1 months), 93% (14 of 15) had >95% stable donor engraftment at 6 months, with 100% overall survival. The median time to neutrophil engraftment (>500) was 22 days (IQR, 19 to 27 days), and that for platelet engraftment (>50 x 109/L) was 28 days (IQR, 27 days to not reached). Two patients had grade III-IV acute GVHD, 1 patient had mild chronic GVHD, and 86% of patients (6 of 7) were off immunosuppression therapy by 1-year post-transplantation. Our data suggest that haplo-BMT with post-transplantation cyclophosphamide and thiotepa improves donor engraftment without significantly increasing morbidity or mortality and could dramatically expand curative options for individuals with SCD.

Haploidentical hematopoietic cell transplant (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is utilized for patients with hematological disorders but without conventional donors. The effects of new-onset post-transplant diabetes mellitus (PTDM) following haplo-HCT are unknown. We examined PTDM incidence and outcomes after haplo-HCT with PTCY. Patients without diabetes receiving haplo-HCT (n=64) were analyzed for PTDM diagnosis (defined as blood glucose≥ 200 mg/dL). By day 100, 14 (22%) patients developed PTDM (median, 18 days). Hyperglycemia (blood glucose ≥ 200 mg/dL) preceded corticosteroids in 11 (79%) individuals. PTDM patients had increased death/relapse (p=0.029). PTDM occurs frequently, precedes corticosteroids, and leads to inferior outcomes following haplo-HCT. PTDM prophylaxis/treatment may improve HCT survival.

There is no standard therapy for refractory acute myeloid leukemia (AML), but several salvage therapies are available (National Comprehensive Cancer Network [NCCN], 2018). Recently, there have been major developments in the treatment of AML focusing on the development of targeted and novel therapies. Ivosidenib is the first approved oral, targeted, small-molecule inhibitor of the isocitrate dehydrogenase 1 (IDH1) mutation seen in AML. IDH1 mutations have been associated with significantly worse outcomes in disease-free survival, relapse-free survival, and overall survival (NCCN, 2018). This article reviews the clinical trials and dose escalation studies that led to the U.S. Food & Drug Administration approval for ivosidenib in patients with relapsed or refractory AML with a susceptible IDH1 mutation. Patient counseling and monitoring, including dosing and administration, are important steps that advanced practitioners should be aware of. The mechanism of action and pharmacokinetic information for ivosidenib is discussed, as well as recommendations for drug-drug interaction management. Adverse events and monitoring parameters are addressed in detail, as well as how to interrupt and resume treatment due to adverse events.

Introduction: HLA-Haploidentical bone marrow transplant (haplo-BMT) is a curative approach for individuals with severe sickle cell disease (SCD) who lack an HLA-identical sibling donor. Haplo-BMT expands the donor pool among adults and children with SCD to > 90% and is a less toxic treatment option than myeloablative matched related donor transplant, gene therapy or gene editing. In 2013, our research team developed a multi-institution learning collaborative with the main objective of optimizing haplo-BMT. In a Phase II clinical trial, to improve engraftment rates, we augmented the original Hopkins haplo-BMT protocol (Bolaños-Meade et al. Blood 2012) with thiotepa (10 mg/kg). The trial was conducted at 3 sites and showed durable engraftment in 93% (14/15) of participants (including 2 with previous graft rejection), and a 100% overall survival after a median follow-up of 13.3 months (de la Fuente et al. BBMT 2019). We present results of extension of this ongoing trial comprising additional sites and participants. Material and methods: The trial was approved by the Institutional Review Board (IRB) at each participating site and opened in October 2013 (ClinicalTrials.gov identifier NCT01850108). The global learning collaborative includes 22 sites, in 10 countries, meets weekly via conference calls for sharing of SCD Haplo-BMT knowledge and patient related questions. Each site has a standalone institutionally IRB protocol, with similar eligibility criteria, and data sharing agreement with Vanderbilt University Medical Center. The agreements for aggregate REDCap data sharing and DSMB assessment of the outcomes with stopping rules. Common conditioning regimen included: rabbit ATG 4.5 mg/kg, thiotepa (10 mg/kg), fludarabine 150 mg/m2, cyclophosphamide 29 mg/kg and TBI 2Gy. GVHD prophylaxis included posttransplant cyclophosphamide (PTCy) 100 mg/kg, mycophenolate mofetil and sirolimus. Bone marrow mobilized with filgrastim (5-10 μg/kg/d x5 days) was initially used, 27% (11/41), but later stopped at several sites. Primary graft failure was defined as 5% donor (myeloid) cells by day +42. The primary endpoint was 1-year EFS. Primary or secondary graft rejection, stroke, and death were considered events. Safety stopping rules were implemented, independent of age, using graft failure, death, grade III or IV acute GVHD or moderate or severe chronic GVHD. Results: We enrolled 41 consecutive participants from 8/14/2014 - 6/30/2020. Participant genotype included 39 patients with HbSS, 1 patient each with HbSC and Sβ0 thalassemia. Median age was 16.9 years (range 1.3 to 43), and 51% (21/41) of participants were 500/mcL) and platelet (>50 x 109/L) counts were 20 days (17.0, 24.2) and 32 days (27.0, 36.8) respectively. Incidence of grades III-IV acute and moderate chronic GVHD were 9.7% (4/41) and 12.1% (5/41), respectively. No participant had severe GVHD. Among durably engrafted participants, 81.8% (27/33) were off immunosuppression at 1-year posttransplant. Kaplan-Meier probabilities of EFS and OS were 75.5% (95% CI 61.3%, 92.9%) and 87.9% (95% CI 75.5%, 100.0%) at one year, respectively (Figure). Mortality was 7.3% (3/41). Graft failure was 12% (5/41; 3-primary and 2-secondary). All graft failures were in participants Conclusion: Our novel global learning collaborative effort for haplo-BMT for SCD is a scalable and efficient approach to sharing knowledge and implementing curative therapy for SCD. Importantly all haplo-BMT candidate had donors. An unexpected outcome in this trial, not likely to occur by chance, is that all graft rejections occurred in young participants (< 18 years), and all older participants (> 18 years) engrafted. The trial will add new stopping rules by age strata ( or = to 18 years) and will modify the conditioning regimen in pediatric stratum. Disclosures Black: HRSA: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; Micelle BioPharma: Research Funding; NHLBI: Research Funding. DeBaun:Novartis: Membership on an entity's Board of Directors or advisory committees; Global Blood Therapeutics (GBT): Membership on an entity's Board of Directors or advisory committees.

Cancer survivors are at increased risk for insulin resistance, which can lead to diabetes mellitus, dyslipidemia, and cardiovascular disease. Whether susceptibility to insulin resistance is due to shared onco-metabolic risk factors, like obesity and older age, or if it originates from malignancy and its treatment is unknown. We investigated metabolic and malignancy-associated risk factors and their effect on insulin sensitivity in patients with treated hematological malignancies. Due to previous glucocorticoid exposure, we hypothesized that patients with lymphoid malignancies would be less insulin sensitive. Nineteen adult patients with treated hematological malignancies but without diabetes mellitus were evaluated with a 2-hour, 75-gram, oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp. Hyperinsulinemic-euglycemic clamps were performed to measure steady-state glucose infusion rate (M-value) as an indicator of whole-body glucose utilization during high-dose insulin stimulation. Decreasing M-values reflect increasing insulin resistance. Patient characteristics were analyzed and compared with OGTT and clamp results. The majority of individuals had myeloid malignancies [MDS/AML (n=7) and CML/MPN (n = 4)]. The remainder were diagnosed with NHL (n=7) and CML lymphoid blast crisis (n=1). All patients were treated before metabolic testing. Sixteen individuals (84%) received cytotoxic chemotherapy and 3 (16%) were administered only tyrosine kinase inhibitors. Median lines of systemic treatment were 2 (range, 1-6), and median time from cancer diagnosis to metabolic testing was 10 months (range, 3-132). Immediately before OGTTs and clamps, 10 (53%) patients were in a complete response, and 9 (47%) had persistent/stable disease. During OGTTs, impaired fasting glucose (plasma glucose 100-125 mg/dL) and impaired glucose tolerance (2-hour plasma glucose 140-199 mg/dL) were respectively observed in 5 (26%) and 6 (32%) patients. M-values were decreased in patients with impaired glucose tolerance. Overweight and obese cancer patients also had lower M-values than individuals with normal body mass indices (BMI) (Table 1). There were otherwise no differences in insulin resistance per age, sex, performance status, ethnicity, or diabetes family history. Differences in insulin resistance were not observed based on exposure to cytotoxic chemotherapy, non-cranial irradiation, numbers of lines of treatment, response, or malignancy duration. Previous glucocorticoid exposure did not impact insulin sensitivity. Surprisingly, patients with myeloid malignancies demonstrated lower M-values (6.92 + 0.54 vs. 12.11 + 1.89; p=0.026) than did those with lymphoid cancers. Acquired mutations involved with myeloid malignancies and clonal hematopoiesis (CH) can increase the risk for atherosclerosis and cardiovascular disease, which are sequelae of insulin resistance. Accordingly, insulin resistance was increased in patients with both a myeloid malignancy and mutations involving either DNMT3A, TET2, ASXL1, or JAK2 compared to myeloid malignancies with unknown/absent CH mutations or lymphoid cancers (6.71 + 0.77 vs. 7.28 + 0.72 vs. 12.11 + 1.89; p=0.031). After adjustment for interaction effect in linear regression modeling, both myeloid malignancy and elevated BMI continued to predict lower insulin sensitivity (Table 2). Pre-diabetes was diagnosed by fasting glucose or OGTT in 26-32% of patients with treated hematological cancers, more than double the prevalence of impaired fasting glucose or impaired glucose tolerance reported by the National Health and Nutrition Examination Survey III. Contrary to our hypothesis, lymphoid cancers and short-term steroids did not contribute to insulin resistance. Instead, myeloid malignancies and CH mutations were associated with reduced insulin sensitivity. Interventions targeting energy balance and obesity will be needed to prevent the harmful sequelae of insulin resistance in long-term cancer survivors. Alternatively, elimination of CH mutations could prove to be a novel treatment of insulin resistance. Disclosures Dholaria: bms: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J&J: Research Funding.

The mortality rate triples for the 50% of patients diagnosed with new-onset post-transplant diabetes mellitus (PTDM) after HLA-identical allogeneic hematopoietic cell transplant (HCT) (Griffith, BBMT 2011). Haploidentical HCT (haplo-HCT) with post-transplant cyclophosphamide (PTCY) is increasingly utilized for patients with hematological disorders but without a conventional HLA-matched donor; however, the effects of PTDM after haplo-HCT is unknown. We examined the incidence, outcomes, and risk factors for PTDM in patients undergoing haplo-HCT. Patients receiving haplo-HCT with PTCY at Vanderbilt-Ingram Cancer Center (n= 65) were retrospectively analyzed for PTDM diagnosis (defined as a random blood glucose ≥200 mg/dL). Exclusion criteria included non-haplo-HCTs, second HCT, or pre-existing diabetes mellitus. The primary outcome was the incidence of new-onset PTDM by day 100. Secondary outcomes included: cumulative incidence (CI) of grades 2-4 graft-versus-host disease (GVHD), time to systemic steroids, PTDM risk factors, overall survival (OS), disease free survival (DFS), and non-relapse mortality (NRM). PTDM was diagnosed in 14 (21.5%) patients at a median of 18 days after haplo-HCT (range, 8-72 days). Hyperglycemia preceded grade 2-4 GVHD and steroids in 12 (85.7%) patents. Clinical characteristics including ablative conditioning and GVHD did not predict PTDM development (Table 1). OS was decreased in the PTDM group (Figure 1). Among haplo-HCT recipients with cancer (n= 41) DFS was lower and the CI of relapse was increased in PTDM patients (Figure 1). Similar to HLA-identical transplants, PTDM occurs frequently, precedes alloreactivity, and leads to inferior survival following haplo-HCT. Interestingly, glucose metabolism appears to be associated with relapse risk. Prophylaxis/treatment of PTDM may improve outcomes after conventional and haplo-HCT.

Background: Venous thromboembolism (VTE) is a recognized complication of sickle cell disease (SCD). SCD confers a life-time risk of development of VTE, with a cumulative incidence of 11.3% by age of 40 years based on Cooperative group studies. Patients with SCD and VTE have a higher mortality rate (HR, 2.32; 95% CI, 1.20-4.46) compared to those without VTE (Naik et al, Am J Med. 2013;126(5):443-449). However, it remains unclear if this thrombotic pre-disposition improves after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: This is a retrospective single institution cohort study of SCD patients with history of VTE and/or cerebrovascular accident (CVA) who underwent allo-HSCT for indications of CVA, recurrent acute chest, or organ dysfunction related to SCD. Inclusion criteria included SCD genotype, VTE of any location, or CVA confirmed on ultrasound, V/Q scan, or CT/MRI angiography/venography. The number and proportion of VTE and CVA events were recorded before and after allo-HSCT. Patients who had VTE events prior to transplant did not have their anticoagulation or aspirin continued post-transplant. Statistical and clinically significant differences were identified using non-parametric analysis using McNemar's method with exact probability and binomial distribution. Multivariate analysis was done to identify potential explanatory variables within results. Results: 26 patients with SCD met inclusion criteria, all had HbSS genotype. 23 patients (88%) underwent HLA-haploidentical bone marrow transplant (haplo-BMT) with reduced intensity conditioning and 3 (12%) patients had myeloablative matched sibling donor transplants (MSD). Graft-versus-Host Disease (GVHD) prophylaxis included posttransplant cyclophosphamide/sirolimus/mycophenolate and cyclosporine/methotrexate in haplo-BMT and MSD, respectively. All patients had standard infection prophylaxis. The median age was 25 years (range: 8-54) at transplant and 17 patients were male (62%). 18 patients were taking hydroxyurea and 9 were on chronic transfusion therapy. Two patients had a second transplant for prior graft failure following haplo-BMT, all achieved 100% donor chimerism on days 30 and 100. Median follow up for the cohort was 74.5 (range:10-212) months total and 28.5 (range: 9-111) post allo-HSCT. Prior to allo-HSCT, 10 patients developed 7 deep vein thrombosis (DVT) and 3 pulmonary emboli. Seven of these (70%) were unprovoked events. 11 patients (40%) had ischemic CVA. Post-transplant, there were two provoked DVTs and one embolic stroke events in three patients, of which two had a history of provoked VTE (Figure). One DVT and the embolic stroke were associated with venous catheter use in a patient with PFO (patent foramen ovale). Only one patient had grade two acute GVHD after development of DVT. All events occurred within 30 days post transplantation and during acute hospitalization. No further VTE occurred after 3 months of anticoagulation in all patients. There was an absolute difference of 25% [95% CI=4.87- 26.9, p=0.015] in the prevalence of VTE events before and after allo-HSCT. In addition, there was an absolute 38.5% [95% CI=10.63-45.96, p=0.006] difference in the number of ischemic CVA before and after allo-HSCT. GVHD status, infection rates, age, history of pulmonary hypertension, and gender did not reach significance in explaining variation in results on logistic multivariate analysis (p > 0.05). Conclusion : In patients with SCD with a history of thrombosis, there is an observed reduction in prevalence of VTE and stroke events post transplantation. Allogeneic stem cell transplantation may attenuate the ongoing activation of the coagulation cascade and hypercoagulable state in SCD. This needs to be validated in a larger prospective cohort study. Disclosures Green: Scripps: Honoraria, Other: travel; North American Thrombosis: Honoraria; CSL: Research Funding; Baxter,: Research Funding; Baxalta: Research Funding; Shire US Inc: Other: clinical trial support. Dholaria:bms: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J&J: Research Funding.

Introduction: Haploidentical bone marrow transplant (haplo-BMT) with post-transplant cyclophosphamide (PTCy) provides near universal donor availability and curative potential for individuals with severe sickle cell disease (SCD). However, a recently recognized late-effect following allogeneic hematopoietic cell transplant is new-onset post-transplant diabetes mellitus type II (PTDM), which occurs in up to 50% of patients and is associated with a three-fold increase in mortality (Griffith et al BBMT 2011, Engelhardt et al BBMT 2019). Known risk factors for PTDM include older age, total body irradiation, and non-Caucasian ethnicity. Studies have shown that pre-transplant insulin resistance and enhanced immune cell alloreactivity are other important contributing factors (Engelhardt et al Blood 2011). To our knowledge, the incidence of PTDM following haplo-BMT with PTCy for SCD has not been characterized, in a population which is predominantly African-American, with a crude prevalence of diabetes mellitus type II of 16.4 (14.7-18.2), and thus represents an unmet need. We hypothesized that the ethnicity and chronic inflammatory state that exists in individuals with SCD contributes to an increased risk of PTDM and may be associated with worse transplant-related outcomes. Methods: We analyzed a multi-center cohort of 33 patients with SCD who underwent haplo-BMT with PTCy. All patients received the reduced-intensity conditioning as shown in Figure 1. Ten patients (31%) had preconditioning with hydroxyurea, azathioprine and hyper-transfusion. Patients with existing diabetes mellitus or follow-up time less than one year were excluded. PTDM was defined as any random single blood glucose level of > 200 mg/dL between D0 and D+100 of transplant. Baseline patient and transplant-related variables were analyzed. Immune subsets were analyzed by flow cytometry at one, two, three, six, and twelve months post-haplo-BMT. Results: The median age at transplant was 11.5 years. Median at age last follow up was 16 years. Baseline and transplant-related data are summarized in Table 1. No patients experienced primary graft failure, while three patients had secondary graft failure at a median of 87 days (range 60-604 days) following haplo-BMT (Table 1). Donor chimerism at 6 months and 1 year was >95% for myeloid and lymphoid lineages for all patients. Fourteen patients (44%) developed PTDM at a median time of 18 days (range 3-40 days), though only three (21%) were treated with corticosteroids prior to the development of PTDM (Table 1). In the PTDM cohort, the median time to corticosteroid use was 22 days. Sixteen patients required corticosteroids for any indication (13 PTDM, 3 non-PTDM), with a median time of administration of 32 days. The starting dose in prednisone equivalents in both groups was 1 mg/kg. All four deaths occurred in the PTDM cohort. The cumulative incidence of grade II-IV acute GVHD was 6/33 (18%). One patient (3%) developed grade IV acute GvHD of the skin and gut, while moderate-severe chronic GvHD developed in six patients (18%). The median time to acute GvHD was 36 days for the entire cohort (36 days for PTDM group, 37.5 days for non-PTDM group). Quantitative reconstitution of CD8 T-cells was significantly lower at one and two months post-haplo-BMT for PTDM compared to non-PTDM patients. CD4 subsets tended to be lower in the PTDM cohort. No significant difference was seen for CD56 cellular subsets at any time period. Conclusion: PTDM is a frequent occurrence following haplo-BMT for SCD and developed prior to corticosteroid exposure. Early T-cell reconstitution may impact glucose homeostasis. Prospective studies with longer follow up are needed to determine the clinical implications in transplant survivors following allogeneic hematopoietic cell transplant for SCD. Disclosures Dholaria: bms: Research Funding; Poseida: Research Funding; Angiocrine: Research Funding; Takeda: Research Funding; J&J: Research Funding.

Administration of immune effector cell (IEC) therapy is a complex endeavor requiring extensive coordination and communication of various healthcare and administrative teams. Chimeric antigen receptor (CAR) T cells are the most established IEC therapy available. As of July 2018 two commercial gene therapy products, tisagenlecleucel and axicabtagene ciloleucel, have been approved by the US Food and Drug Administration. To gain insight into the infrastructure and practices across the country, the American Society for Blood and Marrow Transplantation Pharmacy Special Interest Group conducted an electronic survey on the current administrative, logistic, and toxicity management practices of CAR T cell therapy across the United States. This survey consists of 52 responses from institutions of varying sizes, most of which (∼80%) had previous investigational experience with CAR T cell therapy. Absorbing the energy of this exciting new treatment has challenged hematopoietic cell transplant programs across the country to strengthen department infrastructure, develop new committees and policies, and implement significant education to ensure safe administration. With the variety of experience with CAR T cell therapy, we hope this survey can contribute to the existing published literature and provide support and consensus to established and developing IEC programs and practice guidelines.

Allogeneic hematopoietic cell transplantation (HCT) patients are at an increased risk of developing central line-associated bloodstream infections (CLABSIs) due to prolonged periods of myelosuppression, immunosuppression, and indwelling catheter days. CLABSIs are among the most serious complications in HCT recipients and can lead to prolonged hospitalizations, intensive care unit admissions, lengthy antimicrobial therapies, and increased mortality. There is a lack of data regarding the incidence and risk factors associated with the development of CLABSIs in the HCT population undergoing outpatient transplantation. This was a single-center, retrospective analysis of adult patients who underwent allogeneic HCT between July 2012 and July 2016 in an outpatient transplant unit at a tertiary academic medical center. The primary outcome was the cumulative incidence of CLABSIs from the date of central line placement through the first 100 days post-transplantation. Secondary outcomes included risk factors for CLABSI, number of hospitalizations due to CLABSI, mortality rate at 6 months post-transplantation, and the cumulative incidence, speciation, and presence of multidrug resistance in identified microorganisms. Three hundred fifty-nine patients underwent allogeneic HCT at Vanderbilt University Medical Center and 352 were included for analysis. The cumulative incidence of CLABSIs was 9%, with the majority occurring within the first 30 days post HCT (67%). The use of a matched unrelated donor (MUD) and/or haploidentical donor (odds ratio, 3.993; 95% confidence interval [CI], 1.329 to 12.001; P = .0136) and use of an ablative conditioning regimen (odds ratio, 2.394; 95% CI, 1.052 to 5.446; P = .0374) were independently associated with development of a CLABSI on multivariate analysis. The most common organism implicated in CLABSI was Staphylococcus epidermidis (34%). Patients who developed a CLABSI had an almost 5 times higher risk of mortality at 6 months post-transplantation compared with patients who did not develop a CLABSI (hazard ratio, 4.932; 95% CI, 2.463 to 9.878; P .001). There is a low incidence of CLABSIs in patients undergoing HCT in the outpatient setting. Patients who underwent HCT using a MUD or haploidentical donor and received ablative conditioning were at higher risk for developing CLABSIs. Overall mortality at 6 months post-transplantation was higher in patients who developed a CLABSI. Additional prospective studies are needed to confirm these observations.

The mortality rate triples for the 50% of allogeneic hematopoietic cell transplant (HCT) recipients diagnosed new-onset post-transplant diabetes mellitus (PTDM). Calcineurin inhibitors and corticosteroids are assumed the cause for hyperglycemia, however patients developing PTDM have elevated fasting C-peptide levels before HCT. We tested the hypotheses that an oral glucose tolerance test (OGTT) would predict new-onset PTDM and that PTDM progresses from established insulin resistance present before HCT. Glucose tolerance and insulin sensitivity were quantified with OGTTs and euglycemic hyperinsulinemic clamps before and 90 days after matched related donor peripheral blood HCT in 20 patients without diabetes. PTDM was diagnosed by a weekly fasting BG ≥126mg/dL or random BG ≥200mg/dL from day 0 to day+100. PTDM was diagnosed in 11 (55%) patients at a median of 22 days post-HCT (range, 0-88 days). Table 1 outlines patient characteristics and OGTT results. PTDM preceded grade 2-4 acute GVHD or corticosteroids in 9 (82%) and 11 (100%) patients, respectively. Pre-transplant 2-hour, post-prandial OGTT plasma glucose values did not discriminate between patients developing PTDM and those maintaining euglycemia after HCT. However, fasting pre-transplant glucose and C-peptide levels were elevated in patients developing PTDM. All 5 patients with impaired fasting glucose (100-125mg/dl) compared to 6 out of 15 individuals with normal fasting glucose levels ( PTDM risk is dependent on pre-transplant insulin resistance and independent of immunosuppression. Impaired fasting glucose levels identified PTDM susceptibility. Peripheral insulin resistance could be targeted for the prevention/treatment of PTDM.

Introduction Haploidentical bone marrow transplant (haplo-BMT) with post-transplant cyclophosphamide (PTCy) has increased curative options for patients with sickle cell disease (SCD), with near universal donor availability. However, this approach is associated with increased risk of graft failure, delayed engraftment, and early viral reactivation. Limited knowledge exists regarding immune reconstitution (IR) following haplo-BMT. We hypothesized that the immunomodulatory properties of the pre-transplant conditioning and PTCy contribute to increased early infectious risk and late effects. Objective To characterize IR and impact on infection and late effects post haplo-BMT for SCD. Methods We examined clinical outcomes and IR in 23 patients with severe SCD who received haplo-BMT in the context of a collaborative consortium involving three centers (France, London, U.S.). Common conditioning included fludarabine 150 mg/m2 total, cyclophosphamide 14.5 mg/kg x2, thiotepa 10 mg/kg x1, and thymoglobulin 4.5 mg/kg total, and total body irradiation 200 cGy x1. 18/23 received pre-conditioning with azathioprine 3 mg/kg/day, hydroxyurea 30 mg/kg/day, and hyper-transfusion. Graft source was bone marrow, and 20/23 donors were mobilized with filgrastim 10 mcg/kg/day x 5 days. PTCy (50 mg/kg/day x2), MMF, and sirolimus were given for GvHD prophylaxis. Cellular subsets analyzed included CD4, CD8, NK, and B cells. Patients deceased or without IR data were excluded. Results Table 1 shows patient and donor characteristics. Median total nucleated and CD34 cell doses were 4.9 × 10(9)/kg and 4.69 × 10(6)/kg, respectively. Among engrafted patients, those who received preconditioning had delayed platelet recovery (mean 35 days vs 27, p = 0.002), but higher median CD4 absolute cell count (cells/mL) at D+30 (43 vs 41), D+60 (190 vs 98), D+90 (229 vs 191), D+180 (304 vs 308), D+360 (1255 vs 394) compared to those without, respectively. While not statistically significant either, similar patterns were seen for CD8 and CD19 cells. Post-transplant infections were mostly viral, and occurred in the majority of patients 69.6% (16/23), Figure 2. Conclusion Delayed early IR and viral reactivation/infections were observed following haplo-BMT with PTCy for SCD. Further prospective studies are needed to better characterize IR following this approach to optimize immune-prophylaxis.

Introduction: AML pts who relapse after allogeneic hematopoietic cell transplantation (HCT) face poor clinical outcomes and short overall survival (OS) (Schmid et al, Blood2012). The delivery of optimal salvage therapy is challenging as some pts do not tolerate high intensity regimens, and lower intensity therapies may not yield sufficient disease control. Favorable responses in older, treatment naïve AML pts with venetoclax (VEN) in combination with low-dose cytarabine (LDAC) or DNA methyltransferase inhibitor (DNMTi) led to its approval. Off-label use in relapsed/refractory AML is increasing (DiNardo et al, Am J Hematol2018; Aldoss et al, Haematologica2018). We retrospectively evaluated the overall response rate (ORR = CR+CRi+PR+MLFS) and report our clinical experience with VEN-based salvage in post-HCT relapsed AML. Methods: After IRB approval, consecutive pts with post-HCT relapsed AML treated with VEN+LDAC or VEN+DNMTi from May 2018 to July 2019 were retrospectively analyzed. Selection of VEN partner and dosing were at the discretion of the treating physician based on institutional guidelines and published prescribing information. Responses were assigned based on the AML IWG criteria. The Kaplan-Meier method was used to describe OS. ORR and treatment complications were summarized via descriptive statistics. Results: 18 pts with post-HCT relapsed AML who received at least 1 cycle of VEN-based salvage chemotherapy were included. Median age at HCT was 64.5 years (range 34.5-73.7 years). Most pts were poor risk: 6/18 pts had an antecedent hematologic malignancy, 12/18 had an abnormal or complex karyotype (CK) prior to HCT, and 4/12 pts with CK also were TP53mut. 15/18 (83.3%) received reduced intensity conditioning and MUD was the predominant graft type (50%). All pts received PBSCs. Additional disease and response characteristics are reported in Fig 1A. Median time from HCT to relapse was 5.5 mos (range: 0.9 to 44.9 mos); 27.8% of pts relapsed within 100 days and 55.6% relapsed within 6 mos of HCT. At relapse, 1 patient had grade 2 aGVHD and 1 had severe, extensive cGVHD. No pts experienced a GVHD flare or progression during treatment. 14/18 (77.8%) of pts were receiving immunosuppressive therapy (IST) at relapse and received VEN concurrently with IST. VEN-based salvage chemotherapy began shortly after confirmed relapse (range: 4-46 days); 4/18 pts received VEN with LDAC and 14/18 were treated with a DNMTi partner. 15/18 pts were evaluable for response. IWG responses were seen in 8 pts with an ORR of 53%. There were 0 CR, 6 CRi, 0 PR, 2 MLFS, 7 pts had progressive disease (4 by BM, 3 by PB, Fig 1B). 3/18 additional pts had a ≥50% reduction in circulating blasts indicating treatment effect but were non-evaluable given lack of surveillance BM biopsy. Pts received a median of 2.5 cycles (range 1-9). 15/18 pts had treatment held or delayed due to fever/infection (7), PB cytopenias (4), combination (3), or non-hematologic toxicity (1). 6/8 pts who achieved a CRi/MLFS had VEN dosing reduced or administered as a single-agent. One patient achieved CRi with dose interruptions lasting ≥3 mos, maintained this response, and subsequently cleared a TP53 mutation. The majority of pts 13/18 (72.2%) experienced infectious complications during treatment: 7 developed bacterial pneumonia (4 associated with sepsis), 4 fungal penumonia, and 2 oral infections (both associated with sepsis). 8/18 pts had active infections at the time of death. Time from HCT or IST status did not appear to impact the frequency or severity of infectious complications. After a median of 2.7 mos of follow up (range 0.6-8.9 mos), the mOS after the start of VEN was 130 days. Consolidation with donor lymphocyte infusion or second HCT is planned for several pts. Conclusions: Transplant related- and disease related-mortality are difficult to disentangle in post-HCT AML relapse making it challenging to ascertain the benefit of therapy. In this cohort, the majority of pts relapsed within 6 mos of HCT and were receving IST at the start of salvage therapy. In spite of this, VEN-based salvage induced meaningful responses. To convert these responses to long term survival benefit, as VEN-based salvage is more widely used in this setting, consideration of immunosuppression and previous marrow injury should inform alternative dosing regimens, careful monitoring for infectious complications in close follow-up, and broad spectrum antimicrobial prophylaxis. Disclosures Byrne: Karyopharm: Research Funding. Dholaria:Celgene: Honoraria. Ferrell:Incyte: Research Funding; Agios: Consultancy; Forma Therapeutics: Research Funding; Astex Pharmaceuticals: Research Funding. Jagasia:Kadmon: Consultancy; Incyte: Consultancy; Janssen: Research Funding. Strickland:Astellas Pharma: Consultancy; Sunesis Pharmaceuticals: Research Funding; AbbVie: Consultancy; Jazz: Consultancy; Kite: Consultancy; Pfizer: Consultancy. Savona:Sunesis: Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Patents & Royalties; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Incyte Corporation: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Selvita: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Venetoclax use in relapsed/refractory AML

Cytomegalovirus (CMV) seropositivity and early CMV reactivation after hematopoietic-cell transplantation (HCT) remain associated with increased mortality. Those at high risk include CMV seropositive recipient/donor pairs (CMV R+ or D+) and those on escalated immunosuppression (prednisone ≥ 20mg/kg) for graft versus host disease (GVHD). Historically, our institutional CMV reactivation rate (RR) was 63% in our high risk cohort, similar to national average. Prophylaxis with letermovir, a new CMV-antiviral therapy, significantly reduced the incidence of CMV reactivation and viremia in a prospective trial (Marty FM, et al. NEJM 2017). The purpose of this study was to assess CMV reactivation, defined as CMV viral load > 500 IU/mL, with letermovir prophylaxis and its pharmacoeconomic impact in an outpatient transplant program. This was a retrospective review of adult HCT patients receiving letermovir from December 2017-August 2018 at Vanderbilt University Medical Center. Use of letermovir was standardized at a program level. Therapy was used in high risk patients, undergoing HCT with matched-unrelated donor (MUD), cord blood donor or haploidentical donor transplants with no active CMV reactivation prior to initiation and no anti-CMV treatment post-HCT. Primary endpoint compared CMV RR to historical controls utilizing a two-sided t-test. Secondary outcomes evaluated logistics and cost impact. 30 patients met entry criteria (26 CMV R+, 21 D+), RR was significantly lower than our historical control (20% vs 63%; p = 0.0003). Median time to reactivation was 38 days post-HCT (29-58). 4 of the 6 patients with reactivation received induction therapy with ganciclovir (50%), valganciclovir (25%), or letermovir (25%, peak viral load 740 IU/mL) for ∼40 days (31-52). All were CMV R-/D+ with AML and received HCT from MUD (75%) or haploidentical donors (25%). The remaining 2 patients (CMV R+/D+) had low level reactivation (137-500 IU/mL) and continued letermovir through day 100 without additional CMV treatment. Patients started letermovir by day 14 post-HCT (5-65) with a median 83 days (7-158) of prophylaxis. 3 patients received letermovir as secondary prophylaxis due to prior CMV reactivation or escalated immunosuppression for GVHD. Of those patients, reactivation occurred in 1 patient (AML MUD transplant; CMV D-/R+) who had 2 reactivations while on foscarnet therapy. No letermovir resistance was observed. Letermovir copay was between $10 and $360/month. 76% of prescriptions required prior authorization, 19% monetary grant, 18% patient assistance. Majority had private insurance (49%) and Medicare/Medicaid (36%) with a median of 3 days for approval and 5 days from prescription submission to patient medication pick-up. Primary prophylaxis with letermovir is associated with significantly lower RR compared to historical controls and is financially feasible with dedicated pharmacy services.

The FDA approval of the anti-CD19 chimeric antigen receptor (CAR) T-cell product axicabtagene ciloleucel (axi-cel, YESCARTA®) was based on ZUMA-1 (NCT 02348216), a multi-center phase 2 trial of 111 patients with relapsed/refractory large cell lymphoma (Neelapu et al. NEJM 2017). Without a standardized reimbursement pathway, the complex workflow of "commercial" axi-cel may increase delays in care for patients who are otherwise eligible for treatment. We hypothesized that the time to treatment, and probability of receiving treatment with commercial axi-cel, would be inferior to our experience on ZUMA-1 and lead to adverse patient outcomes. From Jan 2016 to Feb 2017, we enrolled 5 patients on ZUMA-1. Using similar eligibility criteria, we intended to treat 25 patients with commercial axi-cel from Nov 2017 to Aug 2018. Time-to-treatment was calculated from date of informed consent (ZUMA-1) or from insurance verification (non-trial patients) and ended at infusion. Time-to-treatment was significantly shorter for ZUMA-1 compared to non-trial patients (mean 31.8 days vs 77.5 days, P:0.003). ZUMA-1 patients were older (mean 64.8 vs. 56.0 years, P:ns), received more lines of chemotherapy prior to initiating the approval process (4.4 vs. 3.3 lines, P:ns), and had a larger volume of disease (largest lesion 36 cm2vs 16.4cm2, P:ns). The majority of non-trial patients (6/8) received bridging chemotherapy (0-2 lines), and there were 5 hospitalizations totaling 27 days. Steroid use was similar between groups (40.0% vs 37.5%) and more non-trial patients received tocilizumab (40.0% vs 62.5%, P=ns), possibly due to updated toxicity guidelines. In the non-trial group, 10 patients became ineligible due to death (6), transfer to another institution (2), clinical decline (1), and loss of follow-up (1) with a mean time to ineligibility of 54.8 days (range 9-91 days). Seven eligible patients are awaiting reimbursement approval (mean 47.3 days, range 5-166 days). ZUMA-1 outcomes were superior to commercial patients with all 5 patients achieving a response by day 30 and all 3 initial partial responses (PRs) deepening to a complete response (CR). In the non-trial group, there were 3 CRs, 2 PRs, 1 stable disease, and 2 patients with disease progression at/before day 30. All ZUMA-1 patients are alive after a median of 721 days vs 7/8 axi-cel patients (median follow-up 78.5 days). In our non-trial experience, treatment with axi-cel resulted in a superior overall survival compared to being untreated (not reached vs 61 days, P:0.01). This single-center experience highlights the ongoing challenges with axi-cel in the real world setting compared with the experience on ZUMA-1, including delays in insurance approval, use of bridging chemotherapy, added chemotherapy toxicity, and increased mortality while awaiting treatment. Standardized reimbursement pathways are needed to ensure timely access to these therapies.

Resistant gram-positive infections, specifically methicillin-resistant Staphylococcus aureus (MRSA), carry an increased risk for morbidity and mortality. Historically, MRSA has been a cause of nosocomial infections, although recent reports have noted an increased prevalence in community-acquired MRSA infections. Vancomycin is the preferred agent to treat MRSA. However, cases of S. aureus with reduced susceptibility to vancomycin have been reported, prompting the need for alternative treatment options. In this review, we discuss the currently available agents with MRSA activity and those in development. Linezolid and quinupristin/dalfopristin have been demonstrated as effective although potential toxicities must be taken into consideration before their use. Daptomycin, tigecycline, telavancin, and ceftaroline are well tolerated but lack the clinical data to support a superior place in treatment over vancomycin. Several new agents in various stages of development have also demonstrated MRSA activity. Currently, vancomycin remains the gold-standard treatment option for MRSA infections. In situations that limit its use, consideration of patient-specific parameters, cost, and relevant clinical data demonstrating drug safety and efficacy should be employed for the selection of the appropriate alternative agent.

OBJECTIVE To discuss the clinical efficacy and safety of ipilimumab, vemurafenib, and investigational agents for the treatment of unresectable stage III and stage IV melanoma and define current strategies of first-line treatment selection. DATA SOURCES Literature was accessed through MEDLINE and International Pharmaceutical Abstracts (1970–November 2012) using the terms melanoma, metastatic melanoma, ipilimumab, vemurafenib, dabrafenib, and trametinib. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION All articles published in English identified from the data sources were evaluated. Studies and abstracts including more than 10 adult patients were included in the review. DATA SYNTHESIS Treatment options for unresectable stage III and IV melanoma are poor and have remained largely unchanged for the past 40 years. Two randomized Phase 3 clinical trials have demonstrated a significant survival benefit with the use of ipilimumab compared to a melanoma vaccine (10.1 vs 6.4 months; p = 0.003) and compared to dacarbazine (11.2 months, 95% CI 9.4–13.6 vs 9.1 months, 95% CI 7.8–10.5). Additionally, long-term follow-up has revealed cases of durable responses of greater than 3 years. Response rates of 50% and greater have been described in vemurafenib-treated patients (1 Phase 1, 1 Phase 2, and 1 Phase 3 randomized trial), although duration of response has not been fully determined. Both new agents possess unique toxicity profiles including immune-related adverse events with ipilimumab and secondary cutaneous cancers reported with vemurafenib use. CONCLUSIONS Treatment strategies have changed for patients with advanced melanoma with the use of ipilimumab and vemurafenib as first-line agents. Increased clinical experience and further published data with these and investigational agents will guide the development of treatment algorithms outlining optimal drug selection and sequencing as well as improve management of their novel adverse events.