Community-engaged basic science in an NCI-designated comprehensive cancer center: antioxidants and chemotherapeutic efficacy.

PURPOSE: While community engagement has been a longstanding aspect of cancer-relevant research in social and behavioral sciences, it is far less common in basic/translational/clinical research. With the National Cancer Institute's incorporation of Community Outreach and Engagement into the Cancer Center Support Grant guidelines, successful models are desirable. We report on a pilot study supported by the University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC), that used a community-engaged, data-driven process to inform a pre-clinical study of the impact of antioxidants on the efficacy of platinum-based chemotherapeutics. METHODS: We conducted a survey of UMGCCC catchment area residents (n = 120) to identify commonly used antioxidants. We then evaluated the effect of individually combining commonly used antioxidants from the survey (vitamin C, green tea, and melatonin) with platinum agents in models of non-small cell lung cancer (A549), colon adenocarcinoma (SW620) and head and neck squamous cell carcinoma (FaDu). RESULTS: In vitro, the anti-neoplastic activity of each chemotherapy was not potentiated by any of the antioxidants. Instead, when combined at fixed ratios, most antioxidant-chemotherapy combinations were antagonistic. In vivo, addition of antioxidants did not improve chemotherapeutic efficacy and in a FaDu-tumor bearing model, cisplatin-mediated tumor growth inhibition was significantly impeded by the addition of epigallocatechin gallate, the main antioxidant in green tea. CONCLUSION: These initial findings do not support addition of antioxidant supplementation to improve platinum-based chemotherapeutic efficacy. This study's approach can serve as a model of how to bring together the two seemingly discordant areas of basic research and community engagement.

Biologic and Clinical Characteristics of Isochromosome der(17)(q10)t(15;17) in Acute Promyelocytic Leukemia.

INTRODUCTION: Acute promyelocytic leukemia (APL) is genetically characterized by the fusion of promyelocytic leukemia (PML) gene with retinoic acid receptor alpha (RARα) resulting from a t(15;17)(q24;q21) chromosomal translocation. An infrequent but recurrent finding in APL is the formation of an isochromosome of the derivative chromosome 17; ider(17)(q10)t(15;17) or ider(17q). This rearrangement in APL results in an additional copy of the PML-RARα fusion gene as well as loss of 17p/TP53. Due to the infrequent occurrence of the ider(17q), the prognostic impact of this genetic finding is not well known. Case Presentation(s): Here, we describe the clinical characteristics and outcomes of our case series of 5 patients with ider(17q) APL treated at the University of Maryland and Johns Hopkins University. CONCLUSION: In our series, patients with APL with ider(17q) did not have a worse prognosis.

Mesothelioma cancer cells are glutamine addicted and glutamine restriction reduces YAP1 signaling to attenuate tumor formation.

Glutamine addiction is an important phenotype displayed in some types of cancer. In these cells, glutamine depletion results in a marked reduction in the aggressive cancer phenotype. Mesothelioma is an extremely aggressive disease that lacks effective therapy. In this study, we show that mesothelioma tumors are glutamine addicted suggesting that glutamine depletion may be a potential therapeutic strategy. We show that glutamine restriction, by removing glutamine from the medium or treatment with inhibitors that attenuate glutamine uptake (V-9302) or conversion to glutamate (CB-839), markedly reduces mesothelioma cell proliferation, spheroid formation, invasion, and migration. Inhibition of the SLC1A5 glutamine importer, by knockout or treatment with V-9302, an SLC1A5 inhibitor, also markedly reduces mesothelioma cell tumor growth. A relationship between glutamine utilization and YAP1/TEAD signaling has been demonstrated in other tumor types, and the YAP1/TEAD signaling cascade is active in mesothelioma cells and drives cell survival and proliferation. We therefore assessed the impact of glutamine depletion on YAP1/TEAD signaling. We show that glutamine restriction, SLC1A5 knockdown/knockout, or treatment with V-9302 or CB-839, reduces YAP1 level, YAP1/TEAD-dependent transcription, and YAP1/TEAD target protein (e.g., CTGF, cyclin D1, COL1A2, COL3A1, etc.) levels. These changes are observed in both cells and tumors. These findings indicate that mesothelioma is a glutamine addicted cancer, show that glutamine depletion attenuates YAP1/TEAD signaling and tumor growth, and suggest that glutamine restriction may be useful as a mesothelioma treatment strategy.

Flotetuzumab as salvage immunotherapy for refractory acute myeloid leukemia.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after <6 months (early relapse [ER]). We have recently shown an association between an immune-infiltrated tumor microenvironment (TME) and resistance to cytarabine-based chemotherapy but responsiveness to flotetuzumab, a bispecific DART antibody-based molecule to CD3ε and CD123. This paper reports the results of a multicenter, open-label, phase 1/2 study of flotetuzumab in 88 adults with relapsed/refractory AML: 42 in a dose-finding segment and 46 at the recommended phase 2 dose (RP2D) of 500 ng/kg per day. The most frequent adverse events were infusion-related reactions (IRRs)/cytokine release syndrome (CRS), largely grade 1-2. Stepwise dosing during week 1, pretreatment dexamethasone, prompt use of tocilizumab, and temporary dose reductions/interruptions successfully prevented severe IRR/CRS. Clinical benefit accrued to PIF/ER patients showing an immune-infiltrated TME. Among 30 PIF/ER patients treated at the RP2D, the complete remission (CR)/CR with partial hematological recovery (CRh) rate was 26.7%, with an overall response rate (CR/CRh/CR with incomplete hematological recovery) of 30.0%. In PIF/ER patients who achieved CR/CRh, median overall survival was 10.2 months (range, 1.87-27.27), with 6- and 12-month survival rates of 75% (95% confidence interval [CI], 0.450-1.05) and 50% (95% CI, 0.154-0.846). Bone marrow transcriptomic analysis showed that a parsimonious 10-gene signature predicted CRs to flotetuzumab (area under the receiver operating characteristic curve = 0.904 vs 0.672 for the European LeukemiaNet classifier). Flotetuzumab represents an innovative experimental approach associated with acceptable safety and encouraging evidence of activity in PIF/ER patients. This trial was registered at www.clinicaltrials.gov as #NCT02152956.

Impact of pegaspargase dose capping on incidence of pegaspargase-related adverse events in adults.

INTRODUCTION: Asparaginase derivatives are essential components of the treatment of acute lymphoblastic leukemia in adolescent and young adult patients. However, their associated toxicities limit wider use in older populations. This study seeks to determine if the practice of capping the pegaspargase dose at 3750 units reduces the risk of related adverse events in adults. METHODS: Adverse event data were retrospectively collected 28 days following each administration of pegaspargase in a single center. Doses were categorized as either capped (≤3750 units) (n = 57, 47.5%) or non-capped (>3750 units) (n = 63, 52.5%). The primary endpoint of this study was the composite incidence of serious pegaspargase-related adverse events, defined as grade 3 or higher. RESULTS: Of the 120 doses administered, 47 (39.2%) were administered to patients > 39 years. For the primary endpoint, 26 doses (45.6%) in the dose capped group versus 22 doses (34.9%) in the non-dose capped group were associated with serious pegaspargase-related adverse events (p = 0.23). Isolated laboratory abnormalities accounted for all hepatotoxicity and pancreatic toxicity events, while venous thromboembolism and bleeding occurred after 8.3% and 13.3% of doses, respectively. Multivariate analysis of the primary outcome to adjust for differences in baseline characteristics found no difference between groups (OR 2.56 (0.84, 7.77, p = 0.098)). CONCLUSIONS: The incidence of serious clinical toxicities was low in this study, particularly pegaspargase-related venous thromboembolism. This suggests that the practice of capping pegaspargase doses at 3750 units, coupled with vigilant monitoring and prophylaxis for pegaspargase-related adverse events, can allow for the inclusion of this drug in the treatment of older individuals.

Olanzapine within steroid-sparing antiemetic regimen to prevent chemotherapy-induced nausea and vomiting in patients with acute leukemia receiving multi-day intensive chemotherapy.

INTRODUCTION: Olanzapine use for chemotherapy-induced nausea and vomiting (CINV) in hematological malignancies, for multi-day chemotherapy, and with a steroid-sparing antiemetic strategy is poorly understood. This study investigated if olanzapine is associated with improved prevention of CINV when added to a steroid-sparing antiemetic regimen in patients with acute leukemia receiving intensive, moderately emetogenic, multi-day chemotherapy. METHODS: This was a single-center, retrospective cohort study in patients with acute leukemia. Patients who received olanzapine for CINV prevention were compared to those who did not. All patients received a 5-HT3 antagonist. Adult patients receiving moderately emetogenic, multi-day, intensive chemotherapy for acute leukemia were included. Patients were excluded if they received steroids greater than physiological doses during the study period. The primary endpoint was the complete response of CINV (no emesis or rescue antiemetic usage). RESULTS: This study included 58 patients, 12 patients received olanzapine and 46 patients were in the control group. Baseline demographics were similar. In the study population, 89.7% had acute myeloid leukemia, median age was 54 (interquartile range 42-63) years, 34.5% were female, 27.6% had prior CINV. Complete response of CINV was similar between groups, 4 (33.3%) and 15 (32.6%) patients in the olanzapine and control groups, respectively. Safety events were similar between groups. CONCLUSION: Patients with acute leukemia receiving multi-day intensive chemotherapy are at high risk for CINV. The limited data in this study suggests that olanzapine use within a steroid-sparing antiemetic regimen was well tolerated and associated with similar incidence and severity of CINV compared to the control group.

Arsenic trioxide dose capping to decrease toxicity in the treatment of acute promyelocytic leukemia.

Arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) combination therapy yields high complete remission and disease-free survival rates in acute promyelocytic leukemia (APL). ATO is dosed on actual body weight and high ATO doses in overweight patients may contribute to increased toxicity. We performed a retrospective, two-center study comparing toxicities in patients who received the Lo-Coco et al ATRA/ATO regimen with capped ATO, ≤10 mg/dose, and non-capped ATO, >10 mg/dose. A total of 44 patients were included; 15 received doses ≤10 mg and 29 received >10 mg. During induction, there was no difference in the incidence of grade ≥3 hepatotoxicity, grade ≥3 QTc prolongation, neurotoxicity, and cardiac toxicity between groups. In consolidation, patients receiving >10 mg/dose experienced a greater incidence of neurotoxicity (66.7% vs 22.2%; p = 0.046). Capping doses saved $24634.37/patient and reduced waste of partially-used vials. At a median follow-up of 27 months, no disease relapses occurred in either group. This represents an opportunity to improve the safety profile of this highly effective regimen.

A Prospective Study of Peritransplant Sorafenib for Patients with FLT3-ITD Acute Myeloid Leukemia Undergoing Allogeneic Transplantation.

FLT3-ITD-mutated acute myeloid leukemia (AML) remains a therapeutic challenge. FLT3 inhibition in the setting of minimal residual disease and a new immune system via allogeneic transplantation offers a promise of improved survival for these patients. We performed a prospective study of patients with FLT3-ITD AML undergoing allogeneic transplant that was conducted to evaluate the safety, tolerability, and outcome of sorafenib administered peritransplant. Sorafenib dosing was individualized, starting at 200 mg twice a day (BID), and titrated based on tolerability or toxicities until a tolerable dose was identified. Forty-four patients, with a median age of 52 years, undergoing allogeneic transplant were started on sorafenib in the peritransplant period (21 pretransplant). The median duration of post-transplant follow-up was 27.6 months (range, 5.2 to 60.4). Overall survival was 76% at both 24 and 36 months. Event-free survival at 24 and 36 months was 74% and 64%, respectively. Ten patients died in the post-transplant period, with 6 deaths due to relapsed leukemia and 4 from transplant-associated toxicity. Tolerable doses ranged from 200 mg every other day to 400 mg BID with similar exposure. Correlative studies evaluating FLT3 inhibition via a plasma inhibitory activity assay showed consistent inhibition of FLT3 at all tolerability-determined dosing levels. Sorafenib is well tolerated in the peritransplant setting irrespective of the conditioning intensity or the donor source. Our findings indicate that sorafenib dosing can be individualized in the post-transplantation setting according to patient tolerability. This approach results in effective in vivo FLT3 inhibition and yields encouraging survival results.

A phase 1 study of the antibody-drug conjugate brentuximab vedotin with re-induction chemotherapy in patients with CD30-expressing relapsed/refractory acute myeloid leukemia.

BACKGROUND: Outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) remain poor. Novel therapies specifically targeting AML are of high interest. Brentuximab vedotin (BV) is an antibody-drug conjugate that is specific for human CD30. In this phase 1 dose escalation study, the authors evaluated the safety of BV combined with mitoxantrone, etoposide, and cytarabine (MEC) re-induction chemotherapy for patients with CD30-expressing R/R AML. METHODS: Using a standard dose escalation design, the authors evaluated 3 dose levels of BV (0.9 mg/kg, 1.2 mg/kg, and 1.8 mg/kg) administered once on day 1 followed by MEC on days 3 through 7. RESULTS: There were no dose-limiting toxicities noted and the maximum tolerated dose was not reached. The recommended phase 2 dose of BV was determined to be 1.8 mg/kg when combined with MEC. The side effect profile was similar to that expected from MEC chemotherapy alone, with the most common grade ≥3 toxicities being febrile neutropenia, thrombocytopenia, and anemia (toxicities were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]). Among the 22 patients enrolled on the trial, the composite response rate was 36%, with a composite response rate of 42% noted among those who received the highest dose of BV. The median overall survival was 9.5 months, with a median disease-free survival of 6.8 months observed among responders. Approximately 55% of patients were able to proceed with either allogeneic hematopoietic stem cell transplantation or donor lymphocyte infusion. CONCLUSIONS: The combination of BV with MEC was found to be safe in patients with CD30-expressing R/R AML and warrants further study comparing this combination with the use of MEC alone in this population (ClinicalTrials.gov identifier NCT01830777). LAY SUMMARY: The outcomes for patients with relapsed/refractory acute myeloid leukemia (R/R AML) are exceptionally poor. New and emerging treatment combinations are actively being studied in an effort to improve outcomes. The authors examined the combination of brentuximab vedotin, an antibody product that recognizes a marker called CD30, with mitoxantrone, etoposide, and cytarabine (MEC), a common chemotherapy regimen, in patients with R/R AML that expressed the CD30 marker. The authors found that the combination was safe and well tolerated. Future studies comparing this new combination with the use of MEC alone can help to inform its effectiveness for this patient population.

Peripheral blood blast rate of clearance is an independent predictor of clinical response and outcomes in acute myeloid leukaemia.

The day 14 bone marrow aspirate and biopsy (D14BM) is regularly used to predict achievement of complete remission (CR) with induction chemotherapy in acute myeloid leukemia (AML), however its utility has been questioned. Clearance of peripheral blood blasts (PBB) may serve as an early measure of chemosensitivity. PBB rate of clearance (PBB-RC) was calculated for treatment-naive AML patients (n = 164) undergoing induction with an anthracycline and cytarabine (7+3) and with detectable PBB at diagnosis. PBB-RC was defined as the percentage of the absolute PBB count on the day of diagnosis that was cleared with each day of therapy, on average, until D14 or day of PBB clearance. Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR = 1·81; 95% CI: 1·24-2·64, P < 0·005). PBB-RC was also associated with improved CR rates (OR per 5% = 1·97; 95% CI: 1·27-3·01, P < 0·005) and overall survival (OS) [hazard ratio (HR) per 5% = 0·67; 95% CI: 0·52-0·87]. African American patients had poorer OS adjusted for PBB-RC (HR = 2·18; 95% CI: 1·13-4·23), while race was not associated with D14BM or CR rate. PBB-RC during induction chemotherapy is predictive of D14BM clearance, CR, and OS, and can therefore serve as a prognostic marker for clinical outcomes in AML.

Real-world experience managing blinatumomab toxicities in adults with relapsed/refractory acute lymphoblastic leukemia.

PURPOSE: The purpose of this study was to determine the effect of blinatumomab toxicities on drug therapy modifications in an intended 28-day course of blinatumomab therapy. METHODS: Patients with acute lymphoblastic leukemia who received blinatumomab at the University of Maryland Marlene & Stewart Greenebaum Comprehensive Cancer Center from March 1, 2015 to April 30, 2018 were included. The primary objective of this study was to identify the frequency and severity of blinatumomab toxicities that led to drug therapy modifications; secondary objectives were to identify the frequency and duration of modifications and the total dose and duration of therapy received. RESULTS: This study included 23 patients. Seventy-eight percent of patients experienced cytokine release syndrome and/or neurotoxicity. Eighteen drug therapy modifications occurred due to toxicity with a median interruption time of nine hours. Drug therapy was continued for the majority of grade 1 or 2 events and discontinued during grade 3 or 4 neurotoxicity. The median number of days of therapy delivered was 28 days (range, 27-35). A median of 2 h (range, 0-16) of therapy or 0.2% (range, 0-2.4) of a total 28-day cycle was lost due to transition of care. CONCLUSION: This retrospective study demonstrates a single center experience with blinatumomab toxicity management and appropriate delivery of drug during transitions of care. Overall, these results support to the importance of institutional guidelines in place to facilitate safe and effective delivery of blinatumomab.

Optimizing pegylated asparaginase use: An institutional guideline for dosing, monitoring, and management.

The incorporation of L-asparaginase and pegylated asparaginase into pediatric-inspired regimens has conferred a survival advantage in treatment of adults with acute lymphoblastic leukemia. Use of asparaginase products requires careful prevention, monitoring, and management of adverse effects including hypersensitivity, hepatotoxicity, pancreatitis, coagulopathy, and thrombosis. Currently, there is limited published literature to offer guidance on management of these toxicities. At the University of Maryland Marlene and Stewart Greenebaum Comprehensive Cancer Center, a standard of practice guideline was created to prevent and manage asparaginase-related adverse events. By sharing our long-term experience with asparaginase products and clinical management of asparaginase-induced toxicities, this article aims to improve patient safety and optimize treatment outcomes.

Relapsed Philadelphia Chromosome-Positive Pre-B-ALL after CD19-Directed CAR-T Cell Therapy Successfully Treated with Combination of Blinatumomab and Ponatinib.

Adults with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL) treated with conventional chemotherapy have dismal outcomes. Novel immunotherapies targeting CD19, including the bispecific T-cell engager blinatumomab and chimeric antigen-receptor T (CAR-T) cells, have revolutionized the treatment of R/R B-ALL. Robust response rates to CAR-T cell therapy after blinatumomab have recently been reported, but it is unknown whether blinatumomab can be effective following failure of anti-CD19 CAR-T cell therapy. Herein, we describe a patient with Philadelphia chromosome-positive B-ALL who relapsed after CD19-directed CAR-T therapy, but subsequently responded to the combination of blinatumomab and the tyrosine kinase inhibitor ponatinib, with the achievement of a complete remission lasting 12 months.

Analysis of the Mechanisms of Action of Naphthoquinone-Based Anti-Acute Myeloid Leukemia Chemotherapeutics.

Acute myeloid leukemia (AML) is a neoplastic disorder resulting from clonal proliferation of poorly differentiated immature myeloid cells. Distinct genetic and epigenetic aberrations are key features of AML that account for its variable response to standard therapy. Irrespective of their oncogenic mutations, AML cells produce elevated levels of reactive oxygen species (ROS). They also alter expression and activity of antioxidant enzymes to promote cell proliferation and survival. Subsequently, selective targeting of redox homeostasis in a molecularly heterogeneous disease, such as AML, has been an appealing approach in the development of novel anti-leukemic chemotherapeutics. Naphthoquinones are able to undergo redox cycling and generate ROS in cancer cells, which have made them excellent candidates for testing against AML cells. In addition to inducing oxidative imbalance in AML cells, depending on their structure, naphthoquinones negatively affect other cellular apparatus causing neoplastic cell death. Here we provide an overview of the anti-AML activities of naphthoquinone derivatives, as well as analysis of their mechanism of action, including induction of reduction-oxidation imbalance, alteration in mitochondrial transmembrane potential, Bcl-2 modulation, initiation of DNA damage, and modulation of MAPK and STAT3 activity, alterations in the unfolded protein response and translocation of FOX-related transcription factors to the nucleus.

Synthesis, characterization and antineoplastic activity of bis-aziridinyl dimeric naphthoquinone - A novel class of compounds with potent activity against acute myeloid leukemia cells.

The synthesis, characterization and antileukemic activity of rationally designed amino dimeric naphthoquinone (BiQ) possessing aziridine as alkylating moiety is described. Bis-aziridinyl BiQ decreased proliferation of acute myeloid leukemia (AML) cell lines and primary cells from patients, and exhibited potent (nanomolar) inhibition of colony formation and overall cell survival in AML cells. Effective production of reactive oxygen species (ROS) and double stranded DNA breaks (DSB) induced by bis-aziridinyl BiQ is reported. Bis-dimethylamine BiQ, as the isostere of bis-aziridinyl BiQ but without the alkylating moiety did not show as potent anti-AML activity. Systemic administration of bis-aziridinyl BiQ was well tolerated in NSG mice.

A direct interaction between NQO1 and a chemotherapeutic dimeric naphthoquinone.

BACKGROUND: Multimeric naphthoquinones are redox-active compounds that exhibit antineoplastic, antiprotozoal, and antiviral activities. Due to their multimodal effect on perturbation of cellular oxidative state, these compounds hold great potential as therapeutic agents against highly proliferative neoplastic cells. In our previous work, we developed a series of novel dimeric naphthoquinones and showed that they were selectively cytotoxic to human acute myeloid leukemia (AML), breast and prostate cancer cell lines. We subsequently identified the oxidoreductase NAD(P)H dehydrogenase, quinone 1 (NQO1) as the major target of dimeric naphthoquinones and proposed a mechanism of action that entailed induction of a futile redox cycling. RESULTS: Here, for the first time, we describe a direct physical interaction between the bromohydroxy dimeric naphthoquinone E6a and NQO1. Moreover, our studies reveal an extensive binding interface between E6a and the isoalloxazine ring of the flavin adenine dinucleotide (FAD) cofactor of NQO1 in addition to interactions with protein side chains in the active site. We also present biochemical evidence that dimeric naphthoquinones affect the redox state of the FAD cofactor of NQO1. Comparison of the mode of binding of E6a with those of other chemotherapeutics reveals unique characteristics of the interaction that can be leveraged in future drug optimization efforts. CONCLUSION: The first structure of a dimeric naphthoquinone-NQO1 complex was reported, which can be used for design and synthesis of more potent next generation dimeric naphthoquinones to target NQO1 with higher affinity and specificity.

Molecular Pathogenesis and Clinical Significance of Driver Mutations in Primary Myelofibrosis: A Review.

Primary myelofibrosis (PMF) is a rare chronic BCR-ABL1-negative myeloproliferative neoplasm characterized by progressive bone marrow fibrosis, inefficient hematopoiesis, and shortened survival. The clinical manifestations of PMF include splenomegaly, consequent to extramedullary hematopoiesis, pancytopenias, and an array of potentially debilitating constitutional symptoms. The diagnosis is based on bone marrow morphology and clinical criteria. Mutations in the JAK2 (V617F), MPL (W515), and CALR (exon 9 indel) genes are found in approximately 90% of patients whereas the remaining 10% are so-called triple negatives. Activation of the JAK/STAT pathway results in overproduction of abnormal megakaryocytes leading to bone marrow fibrosis. These mutations might be accompanied by other mutations, such as ASXL1. The commonly used prognostication scoring for PMF is based on the International Prognostic Scoring System. The subsequently developed Dynamic International Prognostic Scoring System-plus employs clinical as well as cytogenetic variables. In PMF, CALR mutation is associated with superior survival and ASXL1 with inferior outcome. Patients with triple-negative PMF have a higher incidence of leukemic transformation and lower overall survival compared with CALR- or JAK2-mutant patients. The impact of genetic lesions on survival is independent of current prognostic scoring systems. These observations indicate that driver and passenger mutations define distinct disease entities within PMF. Accounting for them is not only relevant to clinical decision-making, but should also be considered in designing clinical trials.

Mortality and cancer in relation to ABO blood group phenotypes in the Golestan Cohort Study.

BACKGROUND: A few studies have shown an association between blood group alleles and vascular disease, including atherosclerosis, which is thought to be due to the higher level of von Willebrand factor in these individuals and the association of blood group locus variants with plasma lipid levels. No large population-based study has explored this association with overall and cause-specific mortality. METHODS: We aimed to study the association between ABO blood groups and overall and cause-specific mortality in the Golestan Cohort Study. In this cohort, 50,045 people 40- to 70-years old were recruited between 2004 and 2008, and followed annually to capture all incident cancers and deaths due to any cause. We used Cox regression models adjusted for age, sex, smoking, socioeconomic status, ethnicity, place of residence, education and opium use. RESULTS: During a total of 346,708 person-years of follow-up (mean duration 6.9 years), 3,623 cohort participants died. Non-O blood groups were associated with significantly increased total mortality (hazard ratio (HR) = 1.09; 95% confidence interval (CI): 1.01 to 1.17) and cardiovascular disease mortality (HR = 1.15; 95% CI: 1.03 to 1.27). Blood group was not significantly associated with overall cancer mortality, but people with group A, group B, and all non-O blood groups combined had increased risk of incident gastric cancer. In a subgroup of cohort participants, we also showed higher plasma total cholesterol and low-density lipoprotein (LDL) in those with blood group A. CONCLUSIONS: Non-O blood groups have an increased mortality, particularly due to cardiovascular diseases, which may be due to the effect of blood group alleles on blood biochemistry or their effect on von Willebrand factor and factor VIII levels.

Presence of isocitrate dehydrogenase mutations may predict clinical response to hypomethylating agents in patients with acute myeloid leukemia.

Mutations in IDH1 and IDH2 occur in 15-20% of AML cases, resulting in the production of 2-hydroxyglutarate, which promotes aberrant hypermethylation of DNA in leukemic cells. Although these mutations have been shown to have prognostic implications for patients with AML, optimal treatment strategies have yet to be defined. We retrospectively identified forty-two patients with AML treated with DNA methyltransferase inhibitors (DNMTIs) decitabine (n = 36) or azacitidine (n = 6) and performed analysis of stored samples for the presence of IDH1 and IDH2 mutations. Of the forty-two samples analyzed, seven (16.7%) had IDH mutations. Thirteen patients (31%) achieved remission [(complete remission (CR)/complete remission with incomplete count recovery (CRi)/partial response (PR)] after treatment with a DNMTI, five of seven (71.4%) with IDH mutations and eight of thirty-five (22.9%) without IDH mutations (P = 0.01). When adjusted for age at diagnosis, sex, bone marrow blast percentage and cytogenetic, the odds of achieving response after administration of a DNMTI among patients with an IDH mutation was 14.2 when compared to patients without an IDH mutation (95%CI: 1.3-150.4). IDH1 and IDH2 mutations may predict a favorable response to DNMTI in patients with AML.

Prospective serial evaluation of 2-hydroxyglutarate, during treatment of newly diagnosed acute myeloid leukemia, to assess disease activity and therapeutic response.

Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.