bluuebunny/crossref_metadata_2025 huggingface dataset:
The Value of Post-Remission Therapy in Older Adults with Acute Myeloid Leukemia (AML).
Authors: Sekeres Mikkael A. , Fu Alex Z , Earl Marc , Kalaycio Matt , Advani Anjali , Saunthararajah Yogen , Sobecks Ronald , Copelan Edward
Published: October 2019

Abstract 1043

Poster Board I-65

Background:

In older (age 3 60) AML patients (pts) who are induced into complete remission, it is unclear whether post-remission therapy provides additional benefit.

Methods:

We examined all older AML pts treated with cytarabine-based induction chemotherapy at a single institution between 1997 and 2008. Data on known prognostic factors (age, white blood cell count (WBC) at diagnosis, cytogenetic risk groups (as defined by CALGB 8461) and AML etiology (de novo vs. secondary AML)) were collected. Of 240 pts identified, 25 had unknown post-remission status, leaving 215 pts for analyses: 81 receiving cytarabine-based post-remission therapy (PRT) for 1-2 cycles; 134 received no PRT. A cohort study using a propensity score method was conducted in which pts receiving PRT and those not receiving PRT were matched in a 1:1 ratio to address potential sample selection bias and to better balance patient characteristics. A logistic regression was used to predict the propensities of receiving PRT using individual characteristics: age, gender, race, WBC at presentation, AML cytogenetics, secondary AML, re-induction, FAB classification, and complete remission (CR). Overall survival (OS) was measured from the time of diagnosis; disease-free survival (DFS) from the time of CR. Individual characteristics and survival between groups were assessed by the routines of linear, categorical, and survival analyses.

Results:

Median age was 68 years (range, 60-81). Patients receiving PRT were more likely to be younger (67 vs 69 years, P=.003), male (67% vs. 52%, p=.04), have de novo AML (75% vs. 50%, p=.0012), favorable- or intermediate-risk cytogenetics (65% vs. 36%, p<.0001), to have M3 AML (5% vs. 0%), and to have achieved a CR (100% vs. 48%, p<.0001). There were no differences between groups in race, WBC at admission, reinduction rates, or comorbid conditions including renal dysfunction, hepatic dysfunction, and cardiac comorbidity. Median DFS and OS for those receiving PRT vs. no PRT were.45 and.34 years, and 1.13 and.69 years (p=.026 and p<.001, respectively, Figure 1). Only 3 patients underwent a bone marrow transplant after relapse, and there was no correlation between the total amount of chemotherapy received during induction for PRT, or OS. After 1:1 propensity score matching (n=88), there were no differences in baseline characteristics, re-induction, or CR rates, yet DFS and OSl remained significantly greater for pts receiving PRT vs. those who did not (Hazard Ratios.48 and.30, p=.05 and p<.0001, respectively).

Conclusions:

Even after adjusting for patient disease and treatment factors that could influence PRT administration, older AML pts receiving at least one cycle of PRT lived significantly longer than those who did not. PRT should be considered as a standard part of intensive therapy for older AML pts.

Disclosures:

No relevant conflicts of interest to declare.
Oridonin-Generated Cleavage Fragment of AML1-ETO Inhibits Its Oligomerization and Oncogenic Function Leading to Differentiation and Apoptosis of Leukemic Cells.
Authors: Wu Chuanfeng , Zhen Tao , Zhou Guangbiao , Liu Ping , Chen Zhu , Chen Saijuan
Published: October 2019

Abstract 1051

Poster Board I-73

Oligomerization through the NHR2 domain is essential for AML1-ETO's inhibition of granulocytic differentiation and enhanced clonogenic potential of primary bone marrow cells. We show here that Oridonin interferes with AML1-ETO oligomerization through its cleavage fragment DAML1-ETO, which consists of the amino acids (aa) 188-752 of the parental oncoprotein or aa 40-604s of the wild-type ETO. DAML1-ETO interacts with the parental AML1-ETO through NHR2 and exerts dominant negative effects on AML1-ETO with regard to DNA binding, transregulatory activity on target genes and regulation of leukemic cell survival, differentiation and proliferation both in vitro and in vivo. Moreover, Oridonin can activate retinoic acid and cAMP/PKA pathways, and potentiate differentiation induced by all-trans retinoic acid (ATRA) and G-CSF. Consistently, combined use of Oridonin, ATRA and G-CSF significantly prolongs lifespan of t (8;21) leukemic mice and, interestingly, we find that this treatment targets the Lin-/Sca-1+/C-KIT+ and Lin-/Sca-1-/C-KIT+ leukemia initiating cells. These data suggest that Oridonin, and potentially other small molecules, can inhibit AML1-ETO oligomerization and leukemogenic function, thus providing a targeted therapy that activates key regulatory pathways for myelomonocytic cell differentiation and apoptosis.

Disclosures:

No relevant conflicts of interest to declare.
Comparative Clinical and Biological Features of Primary Mediastinal B-Cell Lymphoma (PMBL) and Mediastinal Grey Zone Lymphoma (MGZL).
Authors: Dunleavy Kieron , Pittaluga Stefania , Tay Kevin , Grant Nicole , Chen Clara C , Shovlin Margaret , Steinberg Seth , Staudt Louis M , Jaffe Elaine S , Janik John E , Wilson Wyndham H
Published: October 2019

Abstract 106

Mediastinal B-cell lymphomas (MBCL) are a clinical-pathologically related group, putatively derived from thymic B-cells, and include PMBL, Nodular Sclerosis Hodgkin Lymphoma (NSHL) and MGZL. PMBL and NSHL contain significant molecular overlap, and MGZL has pathological features intermediate between PMBL and NSHL. Overlapping clinical features include young age, female predominance and localized mediastinal presentation. The risk of local failure after anthracycline-based therapy has led to routine mediastinal radiation (RT) in PMBL and bulky NSHL, suggesting relative chemo-resistance. Anecdotal reports also suggest MGZL is relatively resistant to Hodgkin-based chemotherapy. Thus, better systemic therapy is needed to avoid RT and its risk of secondary malignancies and cardiac disease, and to improve cure. Clinical studies suggest PMBL and NSHL are particularly responsive to dose-intense strategies. We prospectively compared untreated PMBL and MGZL for the first time and assessed if the dose-intense DA-EPOCH-R regimen would obviate the need for RT and improve cure. DA-EPOCH-R was administered 6-8 cycles and FDG-PET was used in pts with residual masses to assess need for biopsy and RT (n=31). PMBL and MGZL had similar clinical characteristics shown below. PMBL and MGZL IHC, respectively, had similar CD20+ 100% both; CD10+ 5% and 0%; BCL6+ 86% and 100%; and MUM1+ 58% and 67%; but different CD30+ 71% and 100% (P=0.14) and CD15+ 0% and 60% (P=0.0009). At 4 years median F/U, PFS and OS were 100% for patients with PMBL without RT (table below). Comparison to historical PMBL (n=17) treated with DA-EPOCH (PFS 65% and OS 77% at 10 years) indicated a significant benefit of rituximab (PFS: P=0.0012) and (OS: P=0.013). MGZL outcome with DA-EPOCH-R was significantly worse than PMBL (PFS 30% and OS 83% at 4 years) and 50% required mediastinal RT (figure below). FDG-PET + and - predictive value for relapse were 62% and 95%, respectively. In conclusion, DA-EPOCH-R is highly effective in PMBL and obviates RT whereas MGZL shows greater chemo-resistance. Rituximab adds significant benefit to PMBL. We hypothesize that MGZL and NSHL are more chemo-resistant than PMBL and may share molecular mechanisms of drug resistance. Novel therapeutic strategies, such as targeting the microenvironment, are needed in these diseases. Comparative gene expression profiling is underway.

Disclosures:

No relevant conflicts of interest to declare.
The Administration of Fondaparinux in Strongly Suspected Heparin-Induced Thrombocytopenia (HIT): Further Evidence of Its Safety and Efficacy, and Need for a Controlled Randomized Study.
Authors: Piovella Franco , Barco Stefano , Barone Marisa , Beltrametti Chiara , De Amici Mara
Published: October 2019

Abstract 1072

Poster Board I-94

Introduction:

Heparin-induced thrombocytopenia (HIT), alone or associated with thrombosis (HITT), may develop during anticoagulant treatment with unfractionated heparin (UFH) or low-molecular weight heparin (LWMH). Fondaparinux is a selective inhibitor of coagulation factor Xa which apparently does not react with anti-PF4/heparin antibodies in in vitro testing.

Methods:

From january 2005 to december 2007 we treated 44 patients who had strong suspect of HIT (12 patients) or HITT (32 patients, of whom 12 had both DVT and PE). Of these, 30 patients were previously exposed to unfractionated heparin (UFH) for major cardiac surgery. The remaining patients were admitted to medical or general surgery wards. In the 32 patients who developed HITT, we applied therapeutic dosages of fondaparinux, i.e. 7.5 mg QD or lower, in accordance with their bleeding risk. The remaining patients were treated with prophylactic dosages of fondaparinux, i.e. 2.5 mg QD. Switch to warfarin was performed as soon as possible. The mean of our patients 4T's score was 6.2, corresponding to high risk patients; the mean of anticorpal optical density (GTI Enhanced®) was 1.4; the mean platelet number was 45 × 109/L.

Results:

All patients but four showed sustained normalization of the platelet number. All patients but four showed a significant reduction of their thromboembolic burden. No death related to severe bleeding was recorded. Two episodes of major bleeding were recorded in post-surgical patients (4,5%); 4 episodes of minor bleeding were recorded (9,1%). Four patients underwent dialysis during fondaparinux without bleeding complications. One patient developed acute coronary syndrome during treatment with fondaparinux. Nine patients did not survive (20,5%), with a key role of primitive diseases (i.e. sepsis) causing delay in the diagnostic process of HIT (four of them had a diagnosis of HIT with a mean delay of 7 days). In 16 patients submitted to therapeutic dosages of fondaparinux, anti-PF4/heparin antibody titers were followed over time showing a constant decrease: in one case antibody levels did not decrease up to 6 months after stopping both heparin and fondaparinux. Thirty patients were easily switched from fondaparinux to VKAs without problems in reaching the appropriate INR target.

Conclusions:

This report provides further evidence supporting the safety and efficacy of fondaparinux in the treatment of HIT and underlines the importance of an early diagnosis. However, it shows the need of a randomized controlled study between fondaparinux and a registered comparator drug.

Disclosures:

Piovella: GlaxoSmithKline: Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Boehringer Ingelheim: Honoraria, Speakers Bureau. Off Label Use: fondaparinux in the treatment of heparin-induced thrombocytopenia.
First Line Antiviral Therapy Significantly Improves Survival of Patients with Acute, Chronic and Smoldering ATL: a Worldwide Meta-Analysis.
Authors: Bazarbachi Ali , Plumelle Yves , Ramos Juan Carlos , Tortevoye Patricia , Otrock Zaher , Taylor Graham , Gessain Antoine , Harrington William J , Panelatti Gérard , Hermine Olivier
Published: October 2019

Abstract 108

HTLV-I associated adult T cell leukemia/lymphoma (ATL) is an aggressive T cells malignancy, with poor prognosis due to chemotherapy resistance. Multiple small studies using zidovudine (AZT) and interferon-α (IFN) showed response in ATL patients. However, the global impact of this innovative antiviral treatment strategy on long-term survival of ATL patients in routine practice remains undetermined. We realized a worldwide meta-analysis on the use of AZT/IFN treatment. Charts of 254 ATL patients treated from 1994 to 2008 in the USA (59 patients), the UK (13 patients), Martinique (111 patients) and France metropolitaine (67 patients) were individually reviewed. Collected data included epidemiological, clinical and biological characteristics, ATL subtype, first line treatment, response to first line therapy, and overall survival. In 231 patients with available survival data, first line therapy was recorded in 207 patients only. Median age was 50 years (range 16 to 95). According to Shimoyama classification, there were 116 acute ATL, 18 chronic ATL, 11 smoldering ATL, 100 ATL lymphoma, and 9 patients with an unknown subtype. Hypercalcemia was present in 48% of patients. Five year overall survival rates were 20% for 77 patients who received chemotherapy alone, 46% for 75 patients who received first line antiviral therapy alone (p=0.012), and 12% for 55 patients who received chemotherapy followed by antiviral therapy. Response rate to first line antiviral therapy was 66%, including 35% complete remission (CR). When overall survival analysis was performed by ATL subtype, patients with acute, chronic, and smoldering ATL significantly benefited from first line antiviral therapy, whereas patients with ATL lymphoma had a better outcome with first line chemotherapy. Achievement of CR with first line antiviral therapy resulted in prolonged survival of more than 10 years in 82% of the acute ATL subgroup. Finally, first line antiviral therapy in chronic and smoldering ATL resulted in 100% overall survival at 10 years. Multivariate analysis using Cox regression showed that first line antiviral therapy significantly improves overall survival of ATL patients. In conclusion, these results confirm that treatment of ATL using AZT and IFN results in a high response and CR rates particularly in acute, chronic and smoldering ATL, but not in lymphoma, resulting in impressive prolonged survival and hence should be considered as gold standard first line therapy. Predictive factors of response are currently under investigations in order to improve prognosis of this still uncurable disease.

Disclosures:

No relevant conflicts of interest to declare.
DNA Double-Strand Break Formation Induced by Replication Arrest Depend On Artemis.
Authors: Takagi Masatoshi , Unno Junya , Kiyono Thoru , Honda Fumiko , Teraoka Hirobumi , Maeda Daisuke , Masutani Mitsuko , Morio Tomohiro , Mizutani Shuki
Published: October 2019

Abstract 1097

Poster Board I-119

Hydroxyurea (HU) is an antineoplastic drug used in hematological malignancies, specifically polycythemia vera, essential thrombocytosis or chronic myelogenous leukemia. HU targets cells that are actively replicating DNA by inhibit ing ribonucleotide reductase, which causes an imbalance in the deoxynucleotide triphosphate pool. Stalled replication forks lead to the production of single-stranded DNA (ssDNA), which in some cases is converted to DSBs by unknown mechanisms, an event that is termed replication fork collapse. however, the precise mechanism for DSB induction and the cellular response to persistent replication fork stalling are not fully understood. We show that DSBs are generated in an Artemis nuclease-dependent manner following prolonged stalling caused by exposure to HU, with subsequent activation of the ataxia-telangiectasia mutated (ATM) signaling pathway. DNA-dependent protein kinase (DNA-PK) activity, a prerequisite for the endonuclease activity of Artemis, is also required for DSB generation and subsequent ATM activation. Our findings indicate a novel function of Artemis as a molecular switch that converts single-stranded DNA lesions into DSBs, thereby activating an ATM-dependent fail-safe mechanism following prolonged replication fork stalling.

Disclosures

No relevant conflicts of interest to declare.
Base Excision Repair Deficiency in Acute Myeloid Leukemia.
Authors: Olipitz Werner , Scheer Nicole , Quehenberger Franz , Hiden Karin , Rankl Julia , Schlembach Dietmar , Sill Heinz
Published: October 2019

Abstract 1106

Poster Board I-128

Base excision repair (BER) is the main DNA repair mechanism for single DNA base lesions resulting from oxidative stress, chemical damage or ionizing radiation. We investigated BER in acute myeloid leukemia (AML), a disorder characterized by widespread genomic instability. AML cell lines were treated with H2O2 and DNA damage induction and repair were monitored using the alkaline comet assay. Significantly reduced single strand break (SSB) formation - representing BER intermediates - was observed in 5/10 cell lines. Significantly reduced SSB formation was also demonstrated in 15/30 leukemic samples from patients with therapy-related AML, 13/35 with de novo AML and 14/26 with AML following a myelodysplastic syndrome but only in 1/31 CD34+ hematopoietic stem and progenitor cell specimens isolated from umbilical cord blood (P=.0000056). Reduced SSB formation was not due to differences in intracellular ROS concentrations or selection for a damage resistant subpopulation. To determine whether initial steps of BER were impaired, incision assays with oligonucleotides harboring either 7,8-dihydro-8-oxoguanine or the AP site analog furan were performed. Significantly diminished cleavage for both substrates was observed in cell lines that did not exhibit SSB formation upon H2O2 treatment. These data demonstrate that BER is functionally impaired in a significant proportion of myeloid cell lines and leukemic cells from patients with AML.

Disclosures

No relevant conflicts of interest to declare.
Genetic Variations in GRIA1 On Chromosome 5q33 Related to Asparaginase Hypersensitivity in Childhood Acute Lymphoblastic Leukemia (ALL).
Authors: Chen Shih-Hsiang , Pei Deqing , Yang Wenjian , Cheng Cheng , Jeha Sima , Evans William E. , Pui Ching-Hon , Relling Mary V.
Published: October 2019

Abstract 112

Asparaginase, an important antileukemic agent for ALL, is isolated from bacterial sources, and hence hypersensitivity reactions frequently occur; these reactions may attenuate its enzymatic activity and thus its antileukemic effect. Inherited genomic variations are known to affect the risk of hypersensitivity to some medications, but those that affect the risk of asparaginase allergy are not known. We interrogated 500,000 single nucleotide polymorphisms (SNPs) in 485 children with ALL treated on a single clinical trial to identify SNPs associated with allergy to native E. Coli (Elspar) asparaginase. A total of 204 (41%) patients developed an allergic reaction, most of which were NCI grade 2. We divided the patients into a discovery (n = 322) and a validation (n = 163) cohort, balancing for age, sex, treatment arm, race, and the occurrence of asparaginase allergy. Among the top 100 SNPs significantly associated with allergy in the discovery cohort, SNPs on chromosomes 5 and 19 were overrepresented, hosting 12 SNPs annotated to genes. Among these 12 SNPs, only one SNP (rs4958381 in GRIA1 on chromosome 5q33) replicated in the validation cohort (p = 2.8 ′ 10−5 and 2.0 ′ 10−3 in the discovery and validation cohorts, respectively). This locus has been associated with asthma or atopy. We further found that an additional 11 SNPs annotated to GRIA1 (a glutamate receptor gene) associated with asparaginase allergy at p < 0.05 in the discovery cohort, 4 of which replicated in the validation cohort (rs10070447, rs6890057, rs4958676, and rs6889909) at p < 0.05. Based on GRIA1 SNP rs4958381, the cumulative incidence of asparaginase allergy (Figure) was 74%, 44%, and 32% for those with the AA, AG, and GG genotypes, respectively (n = 485, p = 4.2 ′ 10−8). The 5q33 region hosts several cytokine and immunomodulatory genes, with multiple genome-wide studies implicating this locus in asthma and atopy. An agnostic genome-wide approach implicates genomic variations in GRIA1 on chromosome 5q33 as predisposing to the risk of asparaginase allergy.

Disclosures:

No relevant conflicts of interest to declare.
MICA-129 Genotype, Soluble MICA and Anti-MICA Antibodies as Biomarkers of Chronic Graft Versus Host Disease.
Authors: Boukouaci Wahid , Busson Marc , de Latour Regis Peffault , Rocha Vanderson , Toubert Antoine , Charron Dominique , Socie Gerard P , Tamouza Ryad
Published: October 2019

Abstract 1138

Poster Board I-160

Background

The MHC class I-related chain A (MICA) molecules is of particular in non T-cell receptor (TCR)-mediated immune function. MICA engages NKG2D, a C-type lectin expressed on effector cells including NK, and T cells. Such engagement triggers NK cells and co-simulates T lymphocytes to mount adequate immune response. Further, a soluble isoform of MICA (sMICA) has been implicated in the pathogenesis of a variety of cancers, auto-immune and other organ transplant-related disorders through NKG2D receptor down regulation. Functionally relevant polymorphism of the MICA gene may also contribute to inter-patients variability in allo-immune responses as observed in various clinical settings including organ-transplantation. A methionine (met) to valine (val) change at position 129 of the alpha 2-heavy chain domain categorized the MICA alleles into strong (MICA-129 met) and weak (MICA-129 val) binders of NKG2D receptor. Given the demonstrated importance of MICA in immune pathways, in this study, we explored the MICA-related parameters namely MICA-129 gene polymorphism, pre- and post-transplant serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) in a HLA-matched sibling HSCT setting.

Results

We evaluated whether MICA-129 gene polymorphism, pre- and post-HSCT sMICA and MICA Abs could influence the incidence of chronic graft-versus-host disease (c.GvHD) and relapse of their disease in 211 HLA-identical sibling pairs.

In multivariate analysis on chronic GvHD risk, 3 factors reached significance: recipient MICA-129 val/val genotype (HR = 1.52; 95% confidence interval [95%CI] = 1.02-2.24; P =.04), older recipient age (3 15 years) (HR = 3.36; 95%CI = 1.65-6.84; P =.001) and source of stem cells (PBSC vs BM) (HR = 1.67; 95%CI = 1.10-2.53; P =.017). Since acute GvHD (aGvHD) is a major risk factor of subsequent c.GvHD, we then introduced aGvHD as a time-dependant co-variate in the multivariate analysis model. This analysis confirmed that the risk conferred by the MICA-129 val/val genotype is independent from aGvHD. Elevated post-HSCT sMICA serum levels were also independently associated with c.GvHD (p =.0001) regardless of history of acute GvHD. On the contrary, the presence of pre-transplant MICA Abs confers protection against c.GvHD (p =.04). There was an inverse relationship between MICA Abs and sMICA suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse.

Conclusion

Altogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for c.GvHD monitoring.

Disclosures

No relevant conflicts of interest to declare.
Gene Expression Patterns Associated with Cytarabine Pharmacology and Outcome in Pediatric Acute Myeloid Leukemia.
Authors: Lamba Jatinder K. , Crews Kristine , Pounds Stanley , Cao Xueyuan , Gandhi Varsha , Plunkett William , Baker Sharyn D. , Pui Ching-Hon , Campana Dario , Downing James R. , Rubnitz Jeffrey , Ribeiro Raul C
Published: October 2019

Abstract 114

To identify genes that influence responses to cytarabine (ara-C) treatment, we explored the association of gene expression in leukemic cells at diagnosis with multiple pharmacological and clinical end-points in children with acute myeloid leukemia (AML) treated with ara-C on the St. Jude AML97 clinical trial. We applied a novel statistical procedure, PRojection Onto the Most Interesting Statistical Evidence (PROMISE; PR), to identify genes with expression levels associated with clinical and pharmacological endpoints. To do this, we first defined the following values of the clinical and pharmacological variables as “therapeutically beneficial” :higher leukemic cell ara-C triphosphate levels, lower DNA synthesis values on days 1 and 2 of treatment relative to baseline, decreases in leukocyte counts on day 2 of treatment, improved response and decreased risk of relapse, death, or second malignancy. We considered a gene to show a therapeutically beneficial pattern of association if its expression was positively correlated with ara-CTP levels, negatively correlated with DNA synthesis levels, negatively correlated with decrease in leukocyte counts on day 2, positively correlated with better treatment response, and negativelycorrelated with the risk of relapse or death. A gene showed a therapeutically detrimental pattern of association if its expression had the opposite correlations with the clinical and pharmacological variables. We performed five variable (PR5 using early pharmacologically interesting phenotype measures) or seven variable (PR7 all the above indicated phenotypes) PROMISE analyses. PR5 identified 275 beneficial probe sets and 69 detrimental probe sets (p ≤ 0.005). PR7 analysis identified 112 beneficial probe sets and 115 detrimental probe sets (p ≤ 0.005). To confirm these results, we performed a PROMISE for a cohort of patients treated with ara-C and other agents on the AML02 protocol. Gene expression in leukemic cells at diagnosis was analyzed for a beneficial or detrimental pattern of association with three phenotypes (PR-3); diagnostic blast ara-C cytotoxicity, minimal residual disease (MRD) and event-free survival (EFS). Eighty-one probe sets identified by PR5 or PR7 analyses in the initial cohort were confirmed in the PR-3 analysis of AML02 data. Genes identified in the present study may serve as predictive markers of response and candidates for future drug development.

Disclosures:

No relevant conflicts of interest to declare.
Influence of Genetic Variability of GSTM1 and GSTT1 Null Alleles Between Donor and Recipient in the Development of Acute Graft Versus Host Disease.
Authors: Contento-Gonzalo Alejandro , Alcala-Peña Magdalena , Barrios Manuel , Ortiz-Pareja Macarena , Jiménez-Velasco Antonio , Román-Gómez José , Gomez Antonio P. Torres , Heiniger Ana Isabel
Published: October 2019

Abstract 1154

Poster Board I-176

INTRODUCTION

Glutathione-S-transferase (GST) M1 and T1 are multifunctional enzymes involved in the metabolism of environmental carcinogens and chemotherapeutic drugs. The immunogenic activity of these enzymes and their association with graft rejection has been widely proved in solid organ transplantation. In this study we examined whether genetic variability (absence versus presence of the gene in donor/recipient pairs) could be related to acute graft versus host disease (aGvHD) in patients undergoing myeloablative allogeneic hematopoietic stem cell transplantation (alloHSCT) from related donor (RD).

PATIENTS AND METHODS

We evaluated 64 patients with acute leukemia (34 AML and 30 ALL) undergoing alloSCT and receiving myeloablative conditioning (MAC), with a minimum follow-up of 100 days. Donors were HLA-identical siblings in all cases, except in 2 presenting only a single HLA disparity. As source of HSCs, bone marrow progenitors were used in 25 patients (40%) and peripheral blood progenitors in 39 (60%). Total body irradiation (TBI) was used for conditioning treatment in 18 cases (28%). GvHD prophylaxis consisted of a short-term combination of Cyclosporine and Methotrexate. Presence in homozygous or heterozygous (positivity) or absence (negativity) of GSTM1/T1 genes were determined by real-time PCR. A Chi-square test was used to evaluate qualitative variables and non-parametric tests for quantitative variables. The Cox proportional-hazard model was applied to multivariate analysis.

RESULTS

GSTT1 and GSTM1 positivity was observed in 73 and 47% of patients, respectively, and in 72 and 46% of donors, respectively. Nineteen of 64 patients (30%) presented grade II-IV aGvHD. The incidence of grade II-IV aGVHD in GSTM1-positive patients was 79% versus 21% in GSTM1-negative patients. In univariate analysis, only GSTM1 positive patients developed grade II-IV aGvHD (p=0.001). In multivariate analysis, GSTM1 positivity was the only variable significantly associated with the appearance of grade II-IV aGvHD (p=0.002). No significant association was detected between GSTT1 genetic variability and the incidence of aGvHD. We found no significant difference in patients overall survival in relation to GSTM1 and GSTT1 genetic variability.

CONCLUSIONS

GSTM1-positive recipients develop more likely grade II-IV aGvHD, independently of other known risk factors. GSTM1 gene determination (homozygous or heterozygous) could be used to assess the aGvHD risk in allogeneic hematopoietic stem cell transplantation.

Disclosures

No relevant conflicts of interest to declare.
Influenza A H1N1 Virus Infection in Two Hematopoietic Stem Cell Transplant Recipients.
Authors: Bastos Diogo Assed , Rodrigues Celso Arrais , Patah Poliana , Dias Beatriz Souza , Rocha Vanderson , Novis Yana
Published: October 2019

Abstract 1169

Poster Board I-191

In April 2009, a novel swine-origin influenza A (H1N1) virus (S-OIV) was identified in Mexico. Since then, several cases have been reported, with subsequent cases observed in many other countries. Clinical presentation may range from mild symptomatic patients to cases of severe clinical presentation and death due to pneumonia and respiratory failure. Definition of high risk groups are thought to be similar to those defined for seasonal influenza, including young children and elderly patients, pregnant women and patients with chronic medical conditions, especially immunocompromised hosts. Hematopoietic stem cell transplant (HSCT) recipients are at high risk for infectious complications, including severe viral infections. To our knowledge, there are no reported cases of S-OIV infection in HSCT recipients to date. The clinical features and the possible consequences of this novel influenza virus in this setting remain unknown. We describe two HSCT recipients with confirmed influenza H1N1 virus infection and a benign clinical course after oseltamivir treatment. The first case is a 12 year-old male patient with diagnosis of acute myelogenous leukemia in second complete remission who underwent an unrelated umbilical cord blood transplant with two 4/6 HLA-mismatched cord blood units. Graft-versus-host disease (GVHD) prophylaxis consisted of the association of cyclosporine and mycophenolate mofetil. Additionally, he was also being treated for an invasive aspergillosis with oral voriconazole. On day+3 after transplant, he developed fever, rhinorrhea, and dry cough. A nasal wash and a nasal swab were positive for influenza A by direct immune fluorescence and for influenza A H1N1 by real-time polymerase chain reaction (RT-PCR). Computed tomography of the nasal sinus and thorax were unremarkable. Oseltamivir therapy (75 mg po twice daily for 10 days) was initiated the same day with progressive improvement of symptoms. Oseltamivir was well tolerated and there was no interference with serum levels of cyclosporine. The second case is a 30 year-old female patient with gray zone non-Hodgkin lymphoma in relapse after autologous stem cell transplant that underwent an HLA-matched related HSCT in September 2008. She relapsed 6 months after the transplant. Cyclosporine was withdrawn. Ten days later, she developed fever rhinorrhea, and myalgia. Influenza A H1N1 was confirmed by RT-PCR of a nasal wash specimen. Treatment with a 5-day course of oseltamivir (75 mg po twice daily) was initiated and the patient had a favorable clinical course, with no complications. These two cases of confirmed influenza H1N1 virus infection in HSCT recipients with a benign clinical course highlight the need for a better understanding of the clinical course and management of this novel viral agent in severely immunocompromised hosts.

Disclosures:

No relevant conflicts of interest to declare.
Partially Matched Related Donor Transplantation Can Achieve Outcomes Comparable to Unrelated Donor Transplantation for Patients with Hematologic Malignancies.
Authors: Huang Xiao Jun , Xu Lan-Ping , Liu Kai yan , Liu Dai-Hong , Wang Yu , Chen Huan , Chen Yu-Hong , Han Wei , Wang Jing-Zhi , Chen Yao , Zhang Xiao-Hui , Shi Hongxia , Wang Feng-Rong , Tang Fei-Fei
Published: October 2019

Abstract 1197

Poster Board I-219

Abstract

Purpose:

To compare the outcomes of patients undergoing hematopoietic stem cell transplantation (HSCT) from partially matched related donors (PMRDs) or unrelated donors (URDs) for hematologic malignancies without the use of in vitro T cell depletion (TCD).

Experimental Design:

297 consecutive patients were performed HSCT from URDs (n = 78) or PMRDs (n = 219) during the same time period. Incidences of graft-versus-host disease (GVHD), relapse, non-relapse mortality (NRM), overall survival (OS) and leukemia-free survival (LFS) are compared between the PMRD and URD groups.

Results:

All patients achieved full engraftment. The cumulative incidences of grades II to IV acute GVHD in the PMRD and URD cohorts were 47% (95% CI, 33%-62%) versus 31% (CI, 20%-42%, P = .033), with a relative risk (RR) = 1.72 (1.01-2.94), P = .046. The incidence of chronic GVHD did not differ significantly between the two cohorts (P = .17). Two-year incidences of NRM and relapse were 20% (CI, 15%-26%) versus 18% (CI, 10%-27%), with P = 0.98, and 12% (CI, 8%-16%) versus 18% (CI, 10%-27%), with P = .12, for the PMRD versus URD cohort respectively. Four-year OS and LFS were 74% (CI, 67%-80%) versus 74% (CI, 62%-85%), with P = .98, and 67% (CI, 59%-75%) versus 61% (CI, 47%-74%), with P = .74, respectively.

Conclusions:

Our comparisons demonstrate that every major end point, including relapse, NRM, OS and LFS, was comparable between the PMRD and URD groups.

Disclosures:

No relevant conflicts of interest to declare.
Variation of T-Reg and CD 200+ T- Lymphocytes After in Vitro Treatment with Active Drugs against CLL.
Authors: Parrinello Nunziatina , La Cava Piera , Tibullo Daniele , Giallongo Cesarina , Chiarenza Annalisa , Romano Alessandra , Cavalli Maide , Triolo Anna , Palumbo Giuseppe A , Di Raimondo Francesco
Published: October 2019

Abstract 1239

Poster Board I-261

Background

Purine analogues, in particular fludarabine, are considered the gold standard of treatment of CLL. However, fludarabine therapy is sometimes complicated by autoimmune haemolytic anemia (AHA). The mechanism of this side effect is not clear but it is conceivable that a fludarabine-induced suppression of some regulatory systems, including T-reg, is responsible for this phenomenon. In addition, we have observed that patients affected by autoimmune diseases such as AHA or PTI have a reduced number of T lymphocytes bearing the CD200 antigen that is considered a tolerogenic molecule. In this perspective, we evaluated the variation of T-reg and CD200+ T lymphocytes induced by incubating in vitro peripheral blood mononuclear cells (PBMC) of CLL patients and normal subjects with purine analogues and other drugs active against CLL.

Method

PBMC obtained from patients with chronic lymphocytic leukaemia (CLL) (n=9) and from normal adult (n=6) were isolated by density gradient and cultured in RPMI supplemented with 10% FBS and 1% of penicillin streptomicyn. Cells were then incubated for 24 hours with drugs at two concentrations: bendamustine (1 and 50 μg/ml) campath (1 and 5 μg/ml) prednisone ( 1 and 10 nM), fludarabine (0,25 and 10 μg/ml) pentostatin (3 and 60 μg/ml). The cytotoxicity was evalutated after 24 hours by trypan Blue and flow cytometry. T-reg cells were identified as CD4+/CD25+/FoxP3+ T cells and expressed as a percentage of the CD4+T-cell population.

Results

Although all of these drugs induced lymphocytes cytotoxicity, fludarabine, prednisone, and campath reduced also the percentage of T-reg and CD200+ T –lymphocytes, while bendamustin and especially pentostatin induced the same cytotoxicity but spared T-reg populations and CD200+ T-lymphocytes. Table I indicates results obtained with the highest concentration of drugs.

In conclusion, pentostatin and bendamustine seems to be active drugs against CLL and their usage shouldn't be complicated by autoimmune phenomena.

Disclosures

No relevant conflicts of interest to declare.
CKS1B Mediates SKP2/p27Kip1-Independent Myeloma Cell Survival and Disease Progression through Activation of MEK/ERK and JAK/STAT3 Signaling Pathways.
Authors: Zhan Fenghuang , Shi Lei , Wang Siqing , Xu Hongwei , Cao Thai M. , Xu Chunjiao , Wu Yong , Zangari Maurizio , Li Guiyuan , Tricot Guido J.
Published: October 2019

Abstract 126

We previously reported that CKS1B may influence myeloma (MM) cell growth and survival through SKP2/p27Kip1-dependent and -independent mechanisms. However, there is still no direct evidence to prove that CKS1B has a role in MM cell proliferation and disease progression. The present study was performed to establish its functional role and define CKS1B-mediated SKP2/p27Kip1-independent down-stream signaling pathways. CKS1B was over-expressed in OCI-MY5 and XG1 MM cell lines by lentivirus. Western blots confirmed CKS1B over-expression. Cells were cultured in medium containing 1% fetal bovine serum for 7 days. CKS1B-transfection resulted in increased cell proliferation compared to empty-vector (EV)-transfected controls. We also examined the role of CKS1B in myeloma resistance to the general used chemotherapeutic drugs, such as bortezomib (5nM), doxorubicin (100nM) and etoposide (100nM). Untreated cells and empty-vector (EV)-transfected cells with or without drug treatments served as controls. Significant less inhibition of cell growth and cell death was observed after drug treatment in CKS1B-transfected cells compared with controls (P < .05). To screen down-stream signaling pathways associated with cell growth and survival in OCI-MY5, MS28PE and XG-1 cells were transfected with specific CKS1B-shRNA, which resulted in decreased phosphorylation of MEK1/2, ERK1/2, STAT3, MCL1 and BCL2 compared to wild-type and control cells, transfected with scrambled CKS1B-shRNA. To confirm these results, we examined the alteration of STAT3, MEK/ERK and BCL2 signaling pathways in OCI-MY5 and XG1 cells after forced over-expression of CKS1B. Increased levels of p-MEK1/2, p-ERK1/2, p-STAT3, MCL1 and p-BCL2 were observed compared to the EV-transfected controls, confirming that CKS1B activates STAT3, MEK/ERK and BCL2 signaling pathways. In Contrast, SKP2 over-expression or p27Kip1 inhibition resulted in inhibition of STAT3 and MEK/ERK pathways with no remarkable changes inBCL2. Further investigation showed that BCL2 is a downstream target of MEK/ERK signaling. Stimulation of STAT3, MEK/ERK and BCL2 signaling pathways only partially abrogated MM cell death and growth inhibition induced by CKS1B knockdown. Targeting either the STAT3, MEK/ERK or BCL2 signaling pathway with specific inhibitors induced significant MM cell death and growth inhibition in CKS1B-over-expressing MM cells; their combination had a synergistic effect on cell death and growth inhibition. Our findings provide a rationale for targeting STAT3 and MEK/ERK/BCL2 signaling in the therapy of aggressive CKS1B-overexpressing MM, which shows increased proliferation and drug-resistance

Disclosures:

No relevant conflicts of interest to declare.
A Stratified Metaanalysis of Desmopressin (DDAVP) for Minimising Perioperative Allogeneic Blood Transfusion.
Authors: Zotz Rainer B.
Published: October 2019

Abstract 1306

Poster Board I-328

Background

DDAVP has been evaluated in post-operative surgery patients without inherited bleeding disorders to determine whether it decreases blood loss and can minimise exposure to allogeneic transfusion. Previous reviews with overall negative results have not discriminated between prophylactic and therapeutic indications for DDAVP (Carless et al. 2006). The aim of this analysis was to create a systematic metaanalysis stratified for prophylactic administration of DDAVP to all patients as compared to a therapeutic indication, defined as blood loss >1l in the control group or prior aspirin medication.

Methods

Studies were evaluated in the metaanalysis when they were controlled trials in which adult patients, scheduled for non-urgent surgery, were randomised to DDAVP, or to a control group, who did not receive the intervention.

Results

Eighteen trials of DDAVP (n=1295) reported data on the number of patients transfused with allogeneic RBC transfusion. In subjects treated with DDAVP for therapeutic reasons, the pooled relative risk of exposure to perioperative allogeneic RBC transfusion was 0.36 (95%CI = 0.19 to 0.66). The use of DDAVP did significantly reduce blood loss; weighted mean difference (WMD) =-386 ml: 95% confidence interval (95%CI) =-542 to -231ml per patient) or the volume of RBC transfused (WMD = -340 ml: 95%CI = -547 to -134 ml per patient). In contrast, in subjects treated with DDAVP for prophylactic reasons, no significant benefit from using DDAVP was found.

Conclusions

Desmopressin administered for therapeutic indications significantly minimises perioperative allogeneic RBC transfusion in patients who do not have congenital bleeding disorders.

Disclosures

Zotz: CSL Behring: Research Funding. Off Label Use: DDAVP is a widely used drug for increasing coagulation factor VIII and von Willebrand Factor activities.
Platelet Dense Granule Deficiency is Associated with Menorrhagia.
Authors: Sham Josh , Gunning William T. , Braggins Laura , Sham Ronald L. , Kouides Peter
Published: October 2019

Abstract 1327

Poster Board I-349

Outpatient evaluation of hemostasis for women with menorrhagia and/or other bleeding symptoms can be unrevealing. A candidate etiology in some of these patients may be platelet (PL) dense granule (DG) deficiency, a heterogeneous bleeding diathesis characterized by variable abnormalities in platelet aggregation and decreased DG number and/or decreased DG volume by electron microscopy (EM) and image analysis.

Objective

To determine the correlation between menorrhagia and the number and volume of platelet DGs in a cohort of women participating in a multi-center menorrhagia treatment study (British J Haem 145(2):212-220, 2009).

Patients and Methods

The diagnosis of menorrhagia was determined using a semi-objective pictorial blood assessment chart (PBAC) necessitating a score of >100. The menorrhagia patients were compared to control subjects, evaluated as paired subjects on the same day. A total of 29 pairs were studied. Patients were eligible only if gynecological exam was normal. All patients were tested for other underlying hemostatic defects. Hemostatic disorders included: a platelet function disorder in 7/29 (24%), a coagulation factor deficiency 2/29 (7%) and von Willebrand disease 1/29 (3%).

Results

The mean age of the menorrhagia group was 35 ± 6.07 years. These patients had an average PBAC score of 454 ± 302.6 Patients were found to have a mean of 2.910 ± 1.207 DG/PL compared to 4.617 ± 1.13 DG/PL for the control group (p-value <0.001 by t test). The mean difference between the two groups was found to be 1.707, and the 95% confidence interval on the difference was found to be [1.096, 2.318]. DG volume was also determined using image analysis. The mean volume for the menorrhagia group was found to be 5.93 ± 3.68 × 106 fL. The mean volume for the control group was 10.04 ± 3.31 × 106 fL (p-value <0.001 by t test). The difference between the two values was found to be 4.11 with a 95% confidence interval on the difference of [2.266, 5.947].

Conclusions

Patients with menorrhagia with and without other hemostatic defects, had fewer platelet DGs than the control group. In addition, the aggregate DG volume/PL was significantly reduced in menorrhagia patients compared to the control group. These findings suggest that the menorrhagia experienced by some women is associated with platelet DG deficiency. Further study is needed in determining the significance of these findings.

Disclosures

No relevant conflicts of interest to declare.
Diagnostic Delays and Survival for Medicare Patients with Chronic Myeloid Leukemia in the Pre-Imatinib Era.
Authors: Friese Christopher R , Magazu Lysa S , Neville Bridget A , Richardson Lisa C , Earle Craig C , Abel Gregory A
Published: October 2019

Abstract 1369

Poster Board I-391

Background:

Timeliness of diagnosis is a quality of care measure endorsed by the Institute of Medicine. Clinical outcomes for patients with chronic myelogenous leukemia (CML) are better when tyrosine kinase inhibitors, such as imatinib, are initiated in the early stages of disease. However, the patterns of care surrounding the CML diagnosis period, as well as the relationship between diagnosis delay and overall survival in the pre-imatinib era, are unknown.

Methods:

The Surveillance, Epidemiology and End Results (SEER)-Medicare linked database was used to identify traditional Medicare enrollees diagnosed with CML during 1991 through May 2001 (prior to the FDA approval of imatinib). Both inpatient and outpatient claims were analyzed from one year before, through six months following, the SEER diagnosis date. Signs, symptoms, and diagnostic studies commonly encountered in CML diagnoses were identified by CPT procedure and ICD-9 diagnosis and procedure codes. We calculated the time between the first visit for a sign or symptom and the SEER diagnosis date, and defined this time period as ‘diagnostic delay’ if it met or exceeded the median number of days for the sample. An accelerated failure time model examined variables associated with diagnostic delay. Overall survival was examined using a Cox proportional hazards model. Analyses were adjusted to account for a possible lag time in SEER cancer diagnosis dates, as well as year of diagnosis.

Results:

We studied 768 patients who met eligibility criteria. The most frequent signs and symptoms prior to CML diagnosis were infection (29.4%), anemia (22.4%), leukocytosis (13.4%) and fatigue (11.9%). The median time between any sign or symptom and CML diagnosis date in SEER was 90 days (interquartile range = 270). The median survival time was 3.5 years. The time between sign or symptom and CML diagnosis was increased for patients with at least one comorbidity (β=0.83, p < .001), and for those diagnosed at age 75 or greater (β=0.30, p < .05). Males had shortened times to diagnosis (β=-0.41, p < .01). Diagnostic delay was not a significant predictor of overall survival (HR = 1.04, 95% CI = 0.88-1.23).

Conclusions:

The most common signs and symptoms older patients experience prior to CML diagnosis are nonspecific, which may impair diagnostic efforts. Prior to the approval and general availability of imatinib, differences in timeliness of diagnosis were observed by age, gender, and presence of comorbidities. Examination of patient-provider interactions stratified by these variables may aid efforts to standardize the diagnostic process, although diagnostic delay was not significantly associated with overall survival in the pre-imatinib era.

Disclosures:

No relevant conflicts of interest to declare.