PURPOSE Knowledge of an inherited predisposition to myelodysplastic syndrome (MDS) and AML has important clinical implications for treatment decisions, surveillance, and care of at-risk relatives. National Comprehensive Cancer Network (NCCN) guidelines recently incorporated recommendations for germline genetic evaluation of patients with MDS/AML on the basis of personal and family history features, but the practicality of implementing these recommendations has not been studied. METHODS A hereditary hematology quality improvement (QI) committee was formed to implement these guidelines in a prospective cohort of patients diagnosed with MDS/AML. Referral for germline genetic testing was recommended for patients meeting NCCN guideline criteria. Referral patterns and genetic evaluation outcomes were compared with a historical cohort of patients with MDS/AML. Barriers to evaluation were identified. RESULTS Of the 90 patients with MDS/AML evaluated by the QI committee, 59 (66%) met criteria for germline evaluation. Implementation of the QI committee led to more referrals for germline evaluation in accordance with NCCN guidelines (31% v 14%, P = .03). However, the majority of those meeting criteria were never referred due to high medical acuity or being deceased or in hospice at the time of QI committee recommendations. Despite this, two (17%) of the 12 patients undergoing genetic testing were diagnosed with a hereditary myeloid malignancy syndrome. CONCLUSION Current NCCN guidelines resulted in two thirds of patients with MDS/AML meeting criteria for germline evaluation. A hereditary hematology-focused QI committee aided initial implementation and modestly improved NCCN guideline adherence. However, the high morbidity and mortality and prolonged inpatient stays associated with MDS/AML challenged traditional outpatient genetic counseling models. Further improvements in guideline adherence require innovating new models of genetic counseling and testing for this patient population.

Purpose Molecular tumor boards provide precision treatment recommendations based on cancer genomic profile. However, practical barriers limit their benefits. We studied the clinical utility of the precision medicine molecular tumor board (PMMTB) and described challenges with PMMTB implementation. Methods An observational cohort study included patients reviewed by the PMMTB between September 2015 to December 2017. Patients who had consented to the registry study were included. The primary endpoint of this study was time on treatment (ToT) ratio. Clinical utility was established if the primary endpoint had least 15% of patients achieving a ToT ratio of ≥1.3. Results Overall, 278 patients were presented to the PMMTB and 113 cases were included in the final analysis. The PMMTB identified at least one nonstandard of care (SOC) clinically actionable mutation for 69.0% (78/113) of cases. In patients who received non-SOC treatment, 43.8% (7/16) achieved a ToT ratio of 1.3 or more (p < 0.001). Fifty-nine patients did not receive non-SOC recommendations. Reasons for not pursuing treatment included 35.6% having response to current treatment, 20.3% died prior to starting or considering PMMTB recommendations, 13.6% pursued other treatment options based on clinician discretion, another 10.2% pursued other treatment options because clinical trials recommended were not geographically accessible, 8.5% had rapid decline of performance status, 6.8% lacked of financial support for treatment, and 5.1% were excluded from clinical trials due to abnormal laboratory values. Conclusion The regional PMMTB non-SOC recommendations benefitted a majority of patients and additional processes were implemented to assist with non-SOC treatment accessibility.

Introduction: Bcl-2 inhibitor Venetoclax (Ven) in combination with hypomethylating agents (HMA) has improved response rates (RR), and median overall survival (OS) in Acute Myeloid Leukemia (AML) patients who are elderly and/or ineligible for intensive therapies. However, observed outcomes in patients treated in off-trial setting may be inferior (Winters, et al 2019). While disease markers that predict poor RR are well described, patient factors that could impact the inferior outcomes in the real-world setting have not been fully understood. We investigated the impact of incremental age, early hospitalization, comorbidity burden, along with other disease and treatment variables, on survival. Patients and methods: After IRB approval, all consecutive patients with AML and high-risk myelodysplastic syndromes (MDS) who were treated with Ven based regimen between 2017 and 2021 were reviewed. Descriptive statistics are reported. Kaplan-Meir analysis was used to estimate survival, and cox-proportional hazards was used to investigate survival association with variables. Overall survival (OS) was calculated from the time of initiation of venetoclax to the date of last follow up or death. Disease related data, effect of Incremental age, number of medical co-morbid conditions, unplanned early hospitalization (EH) rates within 30 days (EH30) and 90 days (EH90), causes of hospitalization, transfusion needs, and other treatment related adverse events were captured. Factors that impacted EH and overall survival were investigated. Results: Baseline characteristics are outlined in Table 1. A total of 89 subjects with AML and MDS-EB2 who received Ven based therapy were identified. All but 3 received HMA/Ven combination. Forty-nine (55%) received HMA/Ven in first line (FL) and 40(45%) in second line (SL) or later, of whom 12(30%) were treated in post- transplant (ASCT) relapse. Median age was 72 and 64, and median follow up was 21 months (95% CI, 9,27) and 22 months (95% CI, 9,32), respectively, for FL and SL. By ELN criteria high risk patients were 77% and 57% in FL and SL cohorts, respectively. Sixty percent and 40% patients had EH30 and 52%, and 35% patients had EH90 in FL and SL cohorts, respectively. Presence of ≥2 comorbidities significantly predicted EH90 (p=0.04). Most common cause of EH was neutropenic fever and sepsis. In 20 patients where data was available, median pRBC units received were 6(range 1-32), and 10(range 0-50), and median platelet units were 8(range 0-42), and 1 (range 0-73), in FL and SL cohorts, respectively. Table 2 summarizes survival outcomes by important variables. Median OS is 6 months (95% CI, 4,10), and 8 months (95% CI, 4,11) for the entire FL and SL groups. Within the SL group, median OS was significantly worse at 4 months (95% CI 0,8) Vs 11 months (95% CI, 4,13) for those who previously received an ASCT vs those who did not (p=0.02). In FL patients, increasing age (10 vs 5 months, p=0.03) and poor therapy response (11 vs 2 months, p<0.0001) had significant impact on survival, while in SL group TP53mut (13 vs 4 months, p=0.04) and poor response (8 vs 2.5 months p=0.04) were significant predictors of poor OS. On multivariate analysis (MVA), only TP53mut (p=0.04), and response (p=0.003) retained significant impact on OS in both FL and SL cohorts. While EH90 and presence of ≥2 comorbidities also trended towards lower survival, they did not reach statistical significance. Incremental age had no impact on OS in MVA. Following remission, ASCT Vs no-ASCT resulted in an improved survival, with a median OS of 15 months (95%CI 0,19) vs 5 months (95% CI 3,9), p=0.09; and NR (95% CI 3, NR months) Vs 6 months (95% CI 4, 8), p=0.04, In both FL and SL cohorts respectively. Conclusions: We comprehensively evaluated disease and patient factors, and their impact on hospitalization, and on OS in AML patients during Ven based therapy. EH and transfusions were common, without an impact on OS. Age had no impact on EH or OS, but comorbidity burden increased EH risk. High risk disease and poor response to therapy resulted in poor OS. ASCT was crucial for prolonged OS in both FL and SL cohorts. One likely cause of inferior OS noted in FL patients could be the lower rate of ASCT. Our results could provide better understanding to optimize Ven based therapy, and improve early treatment related toxicities in the real-world setting. Quality of life and health care utilization burden associated with this regimen needs to be studied systematically. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Background: Myeloid malignancies such as acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) are traditionally thought of as sporadic disorders. Recently, there has been increasing awareness of hereditary myeloid malignancy syndromes (HMMS) and their impact on MDS/AML treatment decisions, other organ and cancer surveillance, and at-risk family member management. Detection of patients with an HMMS is challenging due to variable expressivity, lack of physical signs, incomplete family history information, and limited provider awareness. In 2021, the National Comprehensive Cancer Network (NCCN) guidelines added recommendations for genetic evaluation of patients with MDS/AML meeting certain clinical or molecular criteria to facilitate identification of patients with an HMMS. The impact of utilizing these criteria on the proportions of patients with MDS/AML needing germline genetic evaluation and their efficacy in detecting the subset with an HMMS have not been studied. We established a quality improvement (QI) committee to implement and test the utility and efficacy of NCCN MDS/AML referral criteria. Methods: A QI committee, including a cancer geneticist, a molecular pathologist, hematology faculty and fellows, clinical pharmacists, research coordinators, and a genetic counselor, was formed to implement NCCN recommendations and evaluate patients with MDS/AML for referral to the UW Hereditary Hematology Clinic. At each monthly meeting, clinical and family history and molecular data are reviewed for patients with MDS/AML who had a next-generation sequencing panel performed in the prior month. Patients meeting criteria for referral are identified, and an HMMS evaluation referral recommendation note is written in the electronic medical record and routed to the patient's primary hematologist. To assess the impact of implementing these guidelines on need for HMMS evaluations in routine MDS/AML care, we compared the proportion of patients meeting criteria and referral rates before (1/2019-8/2021) and after (9/2021-4/2022) our intervention. Results: From 9/1/21 through 4/31/22, 42 patients (20 AML, 22 MDS) were reviewed by the committee. 34 patients had a new diagnosis, whereas eight had an established diagnosis but had molecular data obtained for the first time after 9/1/2021. Overall, 23 patients (55%) met criteria for referral. Six patients met clinical criteria, seven patients met molecular criteria, and 10 patients met both clinical and molecular criteria. Eight patients were ultimately referred for HMMS evaluation, corresponding to a referral rate of 35%. Two patients were found to have a pathogenic variant in DDX41, two patients had at least one variant of unknown significance (VUS), one patient had negative testing, and three patients have pending results. For the 15 patients who were not referred, three were deceased at the time of committee meeting, two were pursuing hospice, one patient declined, and one patient was lost to follow-up; the remaining eight patients were not referred for unknown reasons. In the pre-intervention cohort, 71 of 114 patients met criteria for referral (63%), and 8 were ultimately referred for HMMS evaluation, corresponding to a referral rate of 11%. One patient had a pathogenic variant in ANKRD26, two patients had at least one VUS, four patients had negative testing, and one patient declined genetic evaluation. Conclusion: Implementation of current NCCN germline genetic testing criteria for MDS/AML resulted in ~60% of unselected MDS/AML patients meeting referral criteria for HMMS evaluation. Formalized referral recommendations in the form of a QI committee referral note in the medical record increased provider referrals from 11% to 35% in those meeting criteria. Clinical acuity and patient mortality were the largest barriers to referral for HMMS evaluation in this patient population. Among the small proportion actually referred, 5% of patients in the intervention cohort and 1% of patients in the pre-intervention cohort were found to have an HMMS. This experience demonstrates that implementing current NCCN guidelines via a QI committee will significantly increase the proportion of patients recommended to have HMMS evaluation and increases detection of patients with HMMS. Whether these criteria can be refined to maximize detection while minimizing burden on patient care and the healthcare system warrants further investigation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Introduction Acute promyelocytic leukemia (APL) is a potentially curable malignancy with 4-year overall survival rates >90%. Early complications from the disease or its treatment may result in a loss of oral access and require alternative administration of medications. Tretinoin has been the backbone of APL therapy since the late 1990s and is only available as a liquid filled capsule. Case report Two patients with high-risk APL were unable to safely swallow tretinoin capsules due to complications of their disease. Management & outcome We prepared a tretinoin slurry using tretinoin 10 mg capsules, sterile water, and mineral oil at a ratio of 1 capsule to 2.75 mL sterile water to 1.25 mL mineral oil. This was successfully administered to both patients and no doses of tretinoin slurry were missed by either patient. In the patient who has long-term follow up available, a complete remission was achieved. Discussion Due to tretinoin's known teratogenicity, this capsule should not be crushed, cut, or open, which limits its use in patients without oral access. Alternative routes of administration, such as via a nasogastric tube or sublingually, have not been safe and effective. By preparing a tretinoin slurry in our hazardous extemporaneous compounding area, we were able to safely and effectively prepare a tretinoin slurry that was successfully administered to two patients. This alternative preparation did not alter long-term outcomes and represents a viable option for patients who do not have oral access.

PURPOSE:The goal of this survey was to identify opportunities for health systems to increase implementation and adoption of oncology-focused pharmacogenomics services.METHODS:An online survey assessing respondent demographics, baseline knowledge and training in pharmacogenomics, comfort level with pharmacogenomic data, and challenges of implementing clinical pharmacogenomic platforms was distributed to professional colleagues and over national oncology pharmacy listservs. Pharmacists were grouped based on their comfort level with pharmacogenomic data. Results were analyzed utilizing Pearson chi-square test. A p value of <0.05 was considered significant.RESULTS:A total of 84 participants from 58 cancer centers participated in the survey. Most participants were post-graduate year 2 trained and a majority reported being comfortable assessing oncology pharmacogenomic data. Respondents indicated that pharmacogenomics reported within the electronic medical record was the most common institutional process to support pharmacogenomics for oncology patients. Despite this, poor visibility of pharmacogenomics within the electronic medical record was the most challenging aspect of implementing a pharmacogenomic program. Additional challenges included lack of resources for pharmacogenomic programs, insurance denials for pharmacogenomic-driven testing and medication, and prolonged turnaround time of pharmacogenetic results. Length of practice, post-graduate year 2 residency training, institutions with pharmacist involvement on hematology/oncology molecular tumor board, and institutions where a pharmacist helped create local pharmacogenomic policies were significantly associated with respondents' comfortability in assessing pharmacogenomics.CONCLUSION:Oncology pharmacists reported substantial challenges in implementing a pharmacogenomic program. Future efforts to assist in developing pharmacogenomic efforts should focus on increasing pharmacist involvement, expanding education and training, and improving clinical decision support tools.

We compared the outcomes of salvage chemotherapy in 146 patients with relapsed (57.5%) or refractory (42.5%) AML who received CLAG-M (51%), MEC (39%) or CLAG (10%). Minimal residual disease (MRD) was assessed by flow cytometry. Bivariate, Kaplan-Meier, and Cox regression analyses were conducted. Complete remission (CR) rate of 46% (CLAG-M 54% versus MEC/CLAG 40%,p = .045) was observed with MRD-negative CR of 33% (CLAG-M 39% versus MEC/CLAG 22%,p = .042). Median overall survival (OS) was 9.7 months; the longest OS occurred with CLAG-M (13.3, 95%CI 2.4-24.3) versus MEC (6.9, 95%CI 2.9-10.9) or CLAG (6.2, 95%CI 2.4-12.6) (p = .025). When adjusted for age, gender, relapsed/refractory AML, poor risk AML, MRD, chemotherapy and transplant, CLAG-M (HR 0.63, 95% CI 0.40-0.98,p = .042), MRD-negativity (HR 0.15, 95% CI 0.07-0.30,p < .001) and transplant (HR 0.22, 95% CI 0.13-0.39,p < .001) were associated with higher OS. Our findings confirm that CLAG-M is a reasonable salvage regimen for RR-AML followed by transplant.

Background Posaconazole is approved for invasive fungal infection prophylaxis in patients with hematologic malignancies. Posaconazole suspension is plagued by poor oral absorption and dietary requirements that are difficult for patients to meet. The delayed-release tablet formulation of posaconazole may be taken without regards to meals and has significantly better oral absorption than posaconazole suspension. Objectives We sought to determine if a switch to posaconazole tablets improved steady-state drug level attainment for invasive fungal infection prophylaxis in patients with acute myeloid leukemia. Methods All adult inpatients with acute myeloid leukemia undergoing chemotherapy, who received posaconazole for invasive fungal infection prophylaxis between 2012 and 2015, were included. The primary outcome was proportion of patients with first posaconazole level greater than 700 ng/mL. Secondary outcomes included proportion of patients with first posaconazole level greater than 1000 ng/mL, invasive fungal infection within 100 days, and adverse drug events. Results Forty patients received posaconazole tablets and 34 patients received suspension. Posaconazole levels were significantly higher at first measurement in patients receiving tablet than suspension (1296 ng/mL vs. 788 ng/mL, p < 0.01). Thirty-seven patients receiving tablets had a serum drug level greater than 700 ng/mL on first measurement versus 18 receiving suspension (p < 0.01). Patients receiving tablets were also more likely to have a serum drug level over 1000 ng/mL on first measurement (26 vs. 11, p < 0.01). Rates of invasive fungal infection and adverse events were not statistically different. Conclusions Patients receiving posaconazole tablets attained significantly higher serum drug levels than those receiving suspension.

Abstract Background Induction therapy for acute myeloid leukemia (AML) with a cytarabine-anthracycline regimen (7+3) is well-established; however, there is no standard salvage therapy for patients with relapsed/refractory AML (RR-AML). There is a paucity of data regarding outcomes with salvage regimens in RR-AML that include cladribine, cytarabine, and filgrastim with mitoxantrone (CLAG-M) or without mitoxantrone (CLAG), and mitoxantrone, etoposide, and cytarabine (MEC). We compared outcomes of patients receiving CLAG-M, CLAG or MEC as salvage therapy for RR-AML. Methods A multi-center retrospective study was conducted, including 146 adult RR-AML patients who underwent salvage therapy at the University of Wisconsin and Medical College of Wisconsin from 2009 to 2018. Demographic, clinical and pathologic factors were ascertained at the time of RR-AML diagnosis. The Center for International Blood and Marrow Transplant Research (CIBMTR) response criteria were used. Refractory AML was defined as failure to achieve remission after one or more courses of induction chemotherapy. Minimal residual disease (MRD)-negative was defined by the absence of leukemic cells by morphology and flow cytometry (<0.01%). Data were analyzed using SPSS version 21 (SPSS Inc, Chicago, IL). Bivariate analyses, using chi-square and t-test, and logistic regression analyses were performed for baseline characteristics and response to salvage chemotherapy. Kaplan-Meier analyses, using the log-rank test, were conducted. Cox regression analyses were used to correlate factors with OS. Hazard ratios (HR) with 95% CI were obtained. Statistical significance was considered at P<0.05. Results The study included 146 patients with relapsed (57.5%, n=84) or refractory (42.5%, n=62) AML who received CLAG-M (51%, n=74), MEC (39%, n=57) or CLAG (10%, n=15) salvage chemotherapy. Baseline characteristics were similar between the three groups (all P>0.1). Median age was 60 years (range 22-77 years) and 59% patients were male. AML was classified according to WHO 2016 guidelines as AML with recurrent genetic abnormalities (23%), myelodysplasia (MDS)-related AML (25%), therapy-related AML (8%) and AML not otherwise specified (44%). Cytogenetics were good (5%), intermediate (60%) and poor (36%) with normal (41%), complex (25%), trisomy (8%) and monosomy 5 or 7 (5.5%) being common karyotypes. Among those who had molecular testing (n=119), NPM1 and FLT3-ITD were reported in 21% and 20% patients respectively. AML risk status was good (16%), intermediate (32%) and poor (52%), based on cytogenetic and molecular abnormalities as per ELN 2017 and NCCN 2018 guidelines. Extramedullary disease was present in 13% patients. Prior hematopoietic stem cell transplant (HSCT) was performed in 13% patients. Median lab values prior to salvage regimen were: hemoglobin 9.1 g/dL, platelets 49 K/uL, leukocytes 2.5 K/uL, LDH 231 U/L and bone marrow myeloblasts 28%. Overall response rate was 49% (CLAG-M 55%, n=41/74; MEC 44%, n=25/57, CLAG 40%, n=6/15) with complete remission (CR) rate of 46% (CLAG-M 54%, MEC 37%, CLAG 40%) [P=0.140]. Three percent patients (n=5; CLAG-M=1, MEC=4) had CR with incomplete hematologic recovery (CRi). MRD analysis was available for 83 patients and a trend was seen in MRD-negative CR rates favoring CLAG-M (44%) over MEC (25%) or CLAG (17%) [P=0.128]. Sixty-six patients (45%) received subsequent HSCT (CLAG-M 50%, n=37/74; MEC 44%, 25/57; CLAG 27%, n=4/15) [P=0.245]. At last follow-up, 34% patients were in CR (CLAG-M 42%, MEC 28%, CLAG 20%) [P=0.120]. Fifty (34%) patients were alive at last follow-up (CLAG-M 46%, MEC 23%, CLAG 20%) [P=0.010]. Median OS was 9.7 months (95% CI 6.8-12.6) that was significantly better with CLAG-M (13.3 months, 95% CI 2.4-24.3) compared to MEC (6.9 months, 95% CI 2.9-10.9) or CLAG (6.2 months, 95% CI 2.4-12.6) [P=0.025] Figure 1. In multivariate model adjusted for age, gender and refractory vs relapsed AML, MEC (HR 1.75, 95% CI 1.13-2.71, P=0.013) and CLAG (HR 1.97, 95% CI 1.02-3.79, P=0.043) regimens had worse OS compared to CLAG-M. After adjusting for age, gender, refractory vs relapsed AML and HSCT, CLAG-M remained independent predictor of better OS (HR 0.64, 95% CI 0.42-0.97, P=0.037). Conclusion CLAG-M compared to MEC or CLAG is associated with significantly better OS in RR-AML regardless of age, refractory vs relapsed AML and HSCT. Our findings support the use of CLAG-M as a preferred salvage regimen for RR-AML. Figure 1. Figure 1. Disclosures Atallah: Novartis: Consultancy; BMS: Consultancy; Jazz: Consultancy; Abbvie: Consultancy; Pfizer: Consultancy.

Background: Adult acute lymphoblastic leukemia (ALL) treatment has undergone a significant shift in initial management over the previous decade. While pediatric patients have historically responded well to chemotherapy with cure rates around 90%, adult ALL patients have significantly worse outcomes with long-term cure rates in the mid 40% range. Several studies in the last decade have shown improved overall survival (OS) rates in adolescents and young adults (AYA) being treated with pediatric-type regimens. In 2011, our institution adopted guidelines recommending that all patients under the age of 40 at time of diagnosis undergo treatment with Berlin-Frankfurt-Münster (BFM) based regimen typically containing asparaginase. Patients over the age of 40 typically receive hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) based therapy with option to proceed either to maintenance chemotherapy vs transplantation following complete remission (CR). Prior to 2011, our group's approach to ALL patients was clinician-dependent, with some using BFM-based regimens and some using hyper-CVAD but without a standardized group approach.

Uniformity of evidence-based chemotherapy prescribing using approved, standard, or “core” regimens provides systems-based safety. Noncore chemotherapy regimens are non-standard-of-care regimens requested by physicians on a patient-by-patient basis. Chemotherapy Council, a Pharmacy & Therapeutics subcommittee, assesses all requests and determines approval status based upon submitted evidence and patient-specific factors. This study's purpose is to describe noncore chemotherapy regimens utilization, efficacy, and clinical outcomes in patients receiving noncore chemotherapy regimens. This retrospective chart review includes a two-stage utilization and outcomes evaluation of patients receiving noncore chemotherapy regimens. Stage I, a demographics and utilization assessment of patients receiving noncore chemotherapy regimens, has data collection including patient age, sex, performance score, malignancy, and noncore chemotherapy regimen use justification. Stage II assesses noncore chemotherapy regimen-related, patient-specific outcomes of breast cancer noncore chemotherapy regimen patients. Breast cancer patients were evaluated on regimen and clinical outcomes including disease stage, regimen duration, discontinuation reason, subsequent chemotherapy, survival, and time from noncore chemotherapy regimen until death. Within stage I, 307 patient-specific noncore chemotherapy regimen requests were submitted. The most commonly submitted rationale was modification of a core regimen (33%), followed by patient-specific factors (29%) and salvage therapy (22%). For stage II, 29 breast cancer patients received a noncore chemotherapy regimen and most (54%) received a modified core regimen. The vast majority of noncore chemotherapy regimen discontinuation was due to either regimen completion (42%) or disease progression (42%). Nonelective hospitalizations (35%) and mortality (30%) were found during the median 13.3 months of follow up. Noncore chemotherapy regimen use provides regimen tailoring for patients who are candidates for further therapy, but nonelective hospitalizations, end-of-life chemotherapy, and mortality warrant further investigation to improve patient outcomes.

The University of Wisconsin Chemotherapy Council (UWCC) monitors the uniformity and appropriateness of chemotherapy administration at the University of Wisconsin Hospital and Clinics through a peer-review process. One aspect involves approval of "patient specific requests" (PSRs) that involve treatments not included in the institution's core regimens. Providers are asked to submit published evidence, information regarding pt. comorbidities, and clinical justification to support the application. However there is no current stipulation regarding demonstration of value, although implicit in this review process is to avoid futile, expensive or potentially harmful treatments. Given the ever burgeoning chemotherapeutic choices available for patients with any stage of disease, and the complexity of selecting an optimal therapeutic regimen, we hypothesized that some approved PSRs might have provided limited benefit to the pts who received them. Therefore, we undertook an analysis of PSRs specifically submitted for patients with leukemia and multiple myeloma (MM) between 1/1/2011 and 7/31/2014 to exam reasons for the submission as well as outcomes after the new therapy was initiated.

Stevens–Johnson syndrome/toxic epidermal necrolysis overlap is an acute hypersensitivity reaction that compromises the integrity of mucous membranes and cutaneous tissue. While the pathophysiology of this syndrome has not been fully elucidated, it is commonly associated with the medication use and carries a significant mortality risk of approximately 30%. No commonalities among causative medications have been identified, and determining the offending agent can be challenging. This case report describes fatal Stevens–Johnson syndrome/toxic epidermal necrolysis overlap in a patient after receiving his first cycle of allopurinol, rituximab, and bendamustine treatment for non-Hodgkin’s B-cell lymphoma. An analysis of FDA Medwatch adverse reaction case reports involving allopurinol, rituximab, and bendamustine is also presented.

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) isolates that are susceptible to vancomycin but are tolerant to its killing effect may present a potential challenge for effective treatment. This study compared the microbiologic characteristics of clinical vancomycin-tolerant (VT-MRSA) and vancomycin-susceptible (VS-MRSA) strains using phenotypic and gene regulation studies. MRSA isolates collected from vancomycin-treated patients with bacteremia over a 5-year period were analyzed for vancomycin, daptomycin, and telavancin susceptibility, as well as accessory gene regulator ( agr ) group and function. Vancomycin tolerance was defined by a minimum bactericidal concentration (MBC)/minimum inhibitor concentration (MIC) ratio of ≥32 mg/liter. VT-MRSA isolates were compared to VS-MRSA isolates for differences in antimicrobial susceptibility, time-kill activity, and gene expression of key cell envelope response genes vraSR , dltA , and mprF . All 115 isolates evaluated were susceptible to vancomycin, daptomycin, and telavancin. Seven isolates (6%) were VT-MRSA. agr group II was more prevalent in isolates with vancomycin MBC/MIC ratios of ≥8. In time-kill analyses, VT-MRSA had reduced vancomycin killing, but daptomycin and telavancin activities were maintained. Significantly greater gene expression was observed in VT-MRSA after 72 h of subinhibitory antibiotic exposures. Vancomycin most notably increased vraSR expression ( P = 0.002 versus VS-MRSA strains). Daptomycin and telavancin increased expression of all genes studied, most significantly mprF expression ( P < 0.001). Longer durations of antibiotic exposure (72 h versus 24 h) resulted in substantial increases in gene expression in VT-MRSA. Although the clinical impact of VT-MRSA is not fully recognized, these data suggest that VT-MRSA strains, while still susceptible, have altered gene regulation to adapt to the antimicrobial effects of glyco- and lipopeptides that may emerge during prolonged durations of exposure.

The presence of Fe(II) alpha-ketoglutarate hydroxylases in rat and human pancreatic islets and INS-1 832/13 cells was demonstrated with the reverse transcriptase polymerase chain reaction (PHD1, 2, and 3; lysyl hydroxylases 1, 2, and 3; and phytanoyl-coenzyme A hydroxylase were seen) and/or immunoblotting (high levels of proline hydroxylase P4Halpha1, PHD2, and PHD4 and low levels of PHD2 and PHD3 in human islets, and high levels of PHD2 in rat islets and INS-1 cells were seen). Prolyl hydroxylase enzyme activity in INS-1 832/13 cells was purified with polyproline affinity chromatography. Inhibitors of alpha-ketoglutarate hydroxylases lowered glucose-induced and leucine-plus-glutamine-induced insulin release in rat pancreatic islets, suggesting that there may be acute unknown effects of alpha-ketoglutarate hydroxylases in insulin secretion. It is possible that an increase in mitochondrially generated alpha-ketoglutarate derived from insulin secretagogue carbon and translocated to the cytosol may be part of the signal for insulin secretion.

Oscillations in citric acid cycle intermediates have never been previously reported in any type of cell. Here we show that adding pyruvate to isolated mitochondria from liver, pancreatic islets, and INS-1 insulinoma cells or adding glucose to intact INS-1 cells causes sustained oscillations in citrate levels. Other citric acid cycle intermediates measured either did not oscillate or possibly oscillated with a low amplitude. In INS-1 mitochondria citrate oscillations are in phase with NAD(P) oscillations, and in intact INS-1 cells citrate oscillations parallel oscillations in ATP, suggesting that these processes are co-regulated. Oscillations have been extensively studied in the pancreatic beta cell where oscillations in glycolysis, NAD(P)/NAD(P)H and ATP/ADP ratios, plasma membrane electrical activity, calcium levels, and insulin secretion have been well documented. Because the mitochondrion is the major site of ATP synthesis and NADH oxidation and the only site of citrate synthesis, mitochondria need to be synchronized for these factors to oscillate. In suspensions of mitochondria from various organs, most of the citrate is exported from the mitochondria. In addition, citrate inhibits its own synthesis. We propose that this enables citrate itself to act as one of the cellular messengers that synchronizes mitochondria. Furthermore, because citrate is a potent inhibitor of the glycolytic enzyme phosphofructokinase, the pacemaker of glycolytic oscillations, citrate may act as a metabolic link between mitochondria and glycolysis. Citrate oscillations may coordinate oscillations in mitochondrial energy production and anaplerosis with glycolytic oscillations, which in the beta cell are known to parallel oscillations in insulin secretion.