Comparison of Outcomes of Allogeneic Hematopoietic Cell Transplantation for Multiple Myeloma Using Three Different Conditioning Regimens.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for patients with multiple myeloma, as it provides a graft-versus-myeloma effect alongside a myeloma-free graft. Although reduced-intensity conditioning regimens decrease nonrelapse mortality (NRM), there is a paucity of data with regard to the ideal conditioning regimen in myeloma. We conducted a retrospective comparison of 3 different preparative regimens used for allo-HCT for multiple myeloma at our institution in recent clinical trials: busulfan/fludarabine (BuFlu), fludarabine/melphalan 100 mg/m2 (FM100), and fludarabine/melphalan 140 mg/m2 (FM140). NRM, progression-free survival (PFS) at 3 years, and overall survival (OS) at 3 years were the primary endpoints. Secondary endpoints included time to engraftment, and the incidence of grades II through IV acute graft-versus-host disease and chronic graft-versus-host disease. A total of 73 patients received allo-HCT with these regimens. NRM at 3 years was seen in 3 (21%), 5 (28%), and 6 (24%) patients in the BuFlu, FM100, and FM140 groups, respectively. Three-year PFS in the BuFlu, FM100, and FM140 groups was 16% (hazard ratio [HR], 1.2; 95% confidence interval [CI], 0.6 to 2.1), 26% (HR, 0.6; 95% CI, 0.3 to 1.2), and 11% (reference), respectively. Three-year OS in the BuFlu, FM100, and FM140 groups was 39% (HR, 1.1; 95% CI, 0.5 to 2.2), 43% (HR, 0.7; 95% CI, 0.3 to 1.4), and 32% (reference), respectively. High-risk cytogenetics and relapsed disease prior to allo-HCT were found to be independent predictors of inferior OS on multivariate analysis, with a HR of 2.1 (P = .02) and 2.6 (P = .004), respectively. In contrast, the preparative regimen did not emerge as a predictor of PFS or OS. Durable clinical remission can be achieved in 11% to 25% of patients with multiple myeloma with the use of allo-HCT without any significant difference in the safety or efficacy of the conditioning regimen. High-risk cytogenetics and relapsed disease prior to transplant were associated with inferior PFS and OS.

Autoimmune hemolytic anemia and thrombocytopenia attributed to an intrauterine contraceptive device.

BACKGROUND: Evans syndrome is a rare condition manifested by combined autoimmune hemolytic anemia (AIHA) and thrombocytopenia or neutropenia. It is often associated with other autoimmune disorders, immunodeficiencies, and non-Hodgkin's lymphoma. CASE REPORT: We describe a patient with Evans syndrome that may have been related to exposure to a polyethylene-based intrauterine contraceptive device (IUD). A 26-year-old white female presented with severe, symptomatic AIHA and subsequently developed severe thrombocytopenia. She had a refractory course resistant to multiple treatments including corticosteroids, intravenous immune globulin, rituximab, splenectomy, cyclophosphamide, cyclosporine, eculizumab, and plasma exchange. It was then noticed that her serum autoantibody agglutinated red blood cells (RBCs) in the presence of polyethylene glycol (PEG) but not in the absence of PEG nor when an alternative agglutination enhancing technique, low-ionic-strength solution, was used. Therefore, her polyethylene-containing IUD, which was a polyethylene frame with a levonorgestrel-releasing device, was removed. Norgestrel-dependent, platelet (PLT)-reactive antibodies were not identified by either flow cytometry or in vivo in a NOD/SCID mouse. Testing for PEG-dependent antibodies was not possible. Remission, with no requirement for RBC or PLT transfusions and return of her hemoglobin and PLT counts to normal, followed removal of the IUD. CONCLUSION: The patient's recovery after removal of the IUD and the PEG dependence of RBC agglutination suggested a possibility that the IUD may have been a contributing factor to the etiology of Evans syndrome in this patient.

Patient-physician agreement on the content of CHD prevention discussions.

BACKGROUND: Little is known about agreement between patients and physicians on content and outcomes of clinical discussions. A common perception of content and outcomes may be desirable to optimize decision making and clinical care. OBJECTIVE: To determine patient-physician agreement on content and outcomes of coronary heart disease (CHD) prevention discussions. DESIGN: Cross-sectional survey nested within a randomized CHD prevention study. SETTING AND PARTICIPANTS: University internal medicine clinic; 24 physicians and 157 patients. METHODS: Following one clinic visit, we surveyed patients and physicians on discussion content, decision making and final decisions about CHD prevention. For comparison, we audio-recorded, transcribed and coded 20 patient-physician visits. We calculated percent agreement between patient/physician reports, patient/transcription reports and physician/transcription reports. We calculated Cohen's kappas to compare patient/physician perspectives. RESULTS: Patients and physicians agreed on whether CHD was discussed in 130 visits (83%; kappa = 0.55; 95% CI 0.40-0.70). When discussions occurred, they agreed about discussion content (pros versus cons) in 53% of visits (kappa = 0.15; 95% CI -0.01-0.30) and physicians' recommendations in 73% (kappa = 0.44; 95% CI 0.28-0.66). Patients and physicians agreed on final decisions to take medication in 78% (kappa = 0.58; 95% CI 0.45-0.71) and change lifestyle in 69% (kappa = 0.38; 95% CI 0.24-0.53). They agreed less often, 43% (kappa = 0.13; 95% CI -0.11-0.37) about degree of involvement in decision making. Audio-recorded results were similar, but showed very low agreement between transcripts and patients' and physicians' self-report on discussion content and decision making. CONCLUSIONS: Disagreements about clinical discussions and decision making may be common. Future work is needed to determine: how widespread such agreements are; whether they impact clinical outcomes; and the relative importance of the subjective experience versus objective steps of shared decision making.

Predicting outcomes in patients with advanced non-small cell lung cancer enrolled in early phase immunotherapy trials.

OBJECTIVES: Immunotherapy (IO) has altered the non-small cell lung cancer (NSCLC) therapeutic landscape. However, the majority of patients do not respond to immune-checkpoint blockade, and subsequently either receive further chemotherapy or are referred for clinical trials. Here we examined the outcomes and predictors of response to IO in early phase clinical trials. MATERIALS AND METHODS: We analyzed the records of 74 patients with metastatic NSCLC that were enrolled on phase 1 IO trials within MD Anderson Cancer Center from 1/2010 to 7/2017. RESULTS: The median age was 68, with a median follow-up of 12.3 months. The median lines of prior therapy was three. There were 53 patients who did not receive any IO as a prior line of treatment with a mOS of 8.2 months and mPFS of 3.4 months. There were 21 patients who progressed on a prior IO agent and subsequently went on an IO study with a mOS of 10.5 months and mPFS of 4.3 months, which was similar to patients who did not receive IO OS HR 0.81 (P = .51) and PFS HR 0.85 (P = .59). Royal Marsden Hospital (RMH) prognostic score >1 was predictive of decreased OS HR 3.59 (P = .014) although PFS was not statistically different. MDACC prognostic score was predictive of both OS HR 3.39 (P = .0002) and PFS HR 1.9 (P = .030). ANC/ALC ratio (NLR) of >6 was predictive of decreased survival mOS 3.2 months compared to NLR <6 mOS 11 months; HR 3.0 (P = .0023). CONCLUSIONS: In our heavily pretreated patient population with NSCLC, early phase clinical trials with IO demonstrated similar outcomes to those seen in larger clinical studies that also used immune checkpoint inhibitors. The addition of NLR to RMH and MDACC prognostic scores can identify patients with poor overall outcomes treated with early phase IO studies.

Harnessing the immune system through programmed death-1 blockade in the management of Hodgkin lymphoma.

Immunotherapy is a rapidly evolving therapeutic option in the treatment of lymphoma. Neoplastic cells evade immune recognition through the programmed death (PD)-1/PD-ligand immune checkpoint pathway. Several novel agents have been developed to restore the immune system's ability to recognize and destroy cancer cells. Nivolumab and pembrolizumab are two anti-PD-1 antibodies that have demonstrated success in the treatment of refractory Hodgkin lymphoma. Harnessing the immune system's ability to target neoplastic cells, ideally without the use of cytotoxic chemotherapeutic agents, is one way in which these novel agents are changing the therapeutic landscape in the treatment of lymphomas. Here, we review the emerging data regarding checkpoint inhibitors in the management of Hodgkin lymphoma, the unique adverse effects encountered with the use of these agents, and a practical approach to the management of these adverse effects. Additionally, we discuss upcoming trials that will further assess the promising future developments of checkpoint inhibition in the treatment of not only Hodgkin lymphoma but also other B cell lymphomas and myeloma. These agents offer immense promise of a future where many lymphomas can be treated without the toxic effects of chemotherapeutic agents.

Hemolytic uremic syndrome associated with Escherichia coli O157:H7 infection in older adults: a case report and review of the literature.

BACKGROUND: Hemolytic uremic syndrome associated with Shiga toxin-producing Escherichia coli O157:H7 has been widely known as a common cause of acute renal failure in children. There are only a few reports of sporadic Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome in adults in the USA. Analyses from the 2011 outbreak of hemolytic uremic syndrome associated with Escherichia coli O104:H4 reported that mortality rates are highest in those patients with age >60-years old. Therefore, recognizing Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome in older people can help early introduction of the appropriate therapy. CASE PRESENTATION: We describe an 86-year-old Caucasian woman, initially treated as suspected thrombotic thrombocytopenic purpura, with worsening neurological and renal functions despite plasmapheresis (plasma exchange). A subsequent normal ADAMTS13 activity level and positive stool sample for Escherichia coli O157:H7 confirmed the diagnosis of Shiga toxin-associated hemolytic uremic syndrome. We shifted our management towards aggressive supportive care. Despite conventional treatment, hemolytic uremic syndrome unfortunately led to her death. CONCLUSIONS: Our case demonstrates the importance of recognizing Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome as an etiology of microangiopathic hemolytic anemia in older people. According to the current literature, supportive care is the best approach for Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome. Therapies such as plasma exchange and eculizumab (a complement inhibitor) are not shown to be effective in Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome. There is a dire need to continue research to find better treatment options in this disease entity with a high mortality, particularly in older people.

Evidence of ball-and-chain transport of ferric enterobactin through FepA.

The Escherichia coli iron transporter, FepA, has a globular N terminus that resides within a transmembrane beta-barrel formed by its C terminus. We engineered 25 cysteine substitution mutations at different locations in FepA and modified their sulfhydryl side chains with fluorescein maleimide in live cells. The reactivity of the Cys residues changed, sometimes dramatically, during the transport of ferric enterobactin, the natural ligand of FepA. Patterns of Cys susceptibility reflected energy- and TonB-dependent motion in the receptor protein. During transport, a residue on the normally buried surface of the N-domain was labeled by fluorescein maleimide in the periplasm, providing evidence that the transport process involves expulsion of the globular domain from the beta-barrel. Porin deficiency much reduced the fluoresceination of this site, confirming the periplasmic labeling route. These data support the previously proposed, but never demonstrated, ball-and-chain theory of membrane transport. Functional complementation between a separately expressed N terminus and C-terminal beta-barrel domain confirmed the feasibility of this mechanism.