bluuebunny/crossref_metadata_2025 huggingface dataset:
Early 18fluorodeoxyglucose PET Scan as a Prognostic Tool in Diffuse Large B-Cell Lymphoma Patients Treated with An Anthracycline-Based Chemotherapy Plus Rituximab.
Authors: Safar Violaine , Dupuis Jehan , Jardin Fabrice , Fruchart Christophe , Bardet Stéphane , Vera Pierre , Tilly Herve , Meignan Michel , Itti Emmanuel , Haioun Corinne
Published: October 2019

Abstract 98

Background:

18Fluorodeoxyglucose PET has been quickly integrated to the diagnostic and therapeutic armamentarium in diffuse large-B cell lymphoma (DLBCL). Moreover, early PET appears a promising prognostic tool for tailoring treatment strategies. We evaluated the predictive value of early PET in a large prospective cohort of patients treated with immunochemotherapy.

Patients and methods:

112 previously untreated patients from three institutions were treated between January 2000 and October 2008 for DLBCL using an anthracycline-based regimen plus Rituximab. Chemotherapy was either an R-CHOP21 regimen (n=57) or a dose-dense regimen (R-ACVBP, n=31 or R-CHOP14, n= 24). PET was performed at diagnosis and after two cycles of treatment. Early PET results were interpreted visually as positive (PET2p) or negative (PET2n), as previously described1, but did not modify the scheduled therapy.

Results:

Median age at diagnosis was 59 years (range 20–79 years) and 67% of patients were males, 44% were over 60 years, 81% presented with an advanced Ann Arbor stage (III–IV), 29% had a poor performance status (ECOG 2-4), 36% had more than one extra-nodal site involved and LDH were elevated in 68%. The repartition on the basis of the International Prognosis Index was the following: low=5%, low-intermediate =35%, intermediate-high=37% and high risk=23%. After two cycles, 70 patients (63%) were PET2n and 42 (38%) were PET2p (38 patients in partial response and 4 with stable disease). Median follow-up was 38 months for living patients. Ten of 70 (14%) PET2n patients showed progression versus 22 of 42 (52%) PET2p patients. The estimated 5-year progression free survival (PFS) was 81% for PET2n and 47% for PET2p patients (log rank test, p<0.0001). Prognostic value of early PET was significant in terms of PFS whether patients were treated with R-CHOP21 (p=0.0006) or with dose-dense regimens (p=0.0056). Nine of 70 (13%) PET2n and 15 of 42 (36%) PET2p patients died. The estimated 5-year overall survival (OS) was 88% for PET2n and 62% for PET2p patients (log rank test, p<0.0034). Prognostic value of early PET was significant in terms of OS for patients treated with R-CHOP21 (p=0. 0225) but not for those treated with dose-dense regimens (p=0.133).

Conclusion:

Early PET after 2 cycles of treatment is a powerful tool to predict outcome in DLBCL patients treated with Rituximab combined with an anthracycline-based chemotherapy. It brings promising opportunities in the designing of new treatment strategies for DLBCL.

Reference : 1 Haioun et al. Blood 2005; 106(4):1376–81.

Disclosures:

No relevant conflicts of interest to declare.
Loss of Non-Inherited Maternal MHC and Materno-Fetal Transmission of p190 Type BCR-ABL Leukemia.
Authors: Isoda Takeshi , Ford Anthony , Tomizawa Daisuke , Delft Frederik W van , Castro David Gonzalez de , Mitsuiki Noriko , Score Joannah , Taki Tomohiko , Morio Tomohiro , Takagi Masatoshi , Saji Hiroh , Mizutani Shuki , Greaves Mel
Published: October 2019

Abstract 980

Poster Board I-2

Introduction:

Materno-fetal transmission of malignant clone is one of the rare causes of leukemia in infants. It has been recorded some 20 times over the past 100 years but definitive, genetic evidence for a maternal origin has been lacking. Here we present a detailed genetic analysis of materno-fetal transmission in a case with p190 type BCR-ABL leukemia.

Patients course:

A mother was found to have p190 type BCR-ABL positive acute lymphoblastic leukemia (ALL) one month after delivery of a baby, and died during induction therapy by uncontrolled bacillus cereus encephalitis. Her baby developed p190 type BCR-ABL positive B-precursor lymphoblastic lymphoma (B-LBL stage3 jaw tumor and pleural effusion) at 11-month old. Non-Hodgkin's lymphoma type chemotherapy according to Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) ALB-NHL03, followed by Hyper-CVAD imatinib therapy without stem cell transplantation were given to her, leading to complete remission for more than 31 months.

Material and methods:

We first cloned the BCR-ABL genomic breakpoint region from the infant's pleural effusion (PE). The breakpoint was designated as a fusion between BCR intron 1 and ABL intron1. Then, We conducted Q-PCR by using BCR-ABL genomic breakpoint specific primer and sequencing. Fifteen polymorphic STR markers were amplified in the paternal blood DNA and Patient's PE and PB DNA samples using the Powerplex-16 system. HLA serotyping was by microdroplet lymphocyte cytotoxity. Genotyping was carried out using a reversed SSO HLA DNA typing method. The infant jaw tumor was further analyzed by Affymetrix high resolusion (250K) SNP arrays.

Results:

Short tandem repeat profiles indicated that the infant jaw tumor was, unambiguously, of maternal origin. Amplification of BCR-ABL genomic breakpoints on maternal leukemic cells and infant lymphoma cells revealed that these leukemia clones shared the same unique BCR-ABL genomic sequence, indicating a shared, single cell origin. Positivity of BCR-ABL specific PCR on Guthrie card blood spot also indicated that the leukemic clone was present in the blood at birth. Additionally the infant, maternal-derived leukemic cells had uniparental disomy of chromosome 6p with a deletion of non-inherited maternal MHC allele (NIMA), suggesting a mechanism for immune evasion in the baby.

Conclusions:

This is the first case with definite evidence of in utero materno-fetal transmission of mother's leukemic cells. This case also suggests that materno-feto transfer of leukemic cells is more common than as reflected in the frequency of clinically diagnosed cases, where the immuno-surveillance, predominantly directed against major HLA locus antigens, may be the principal constraint.

Disclosures:

No relevant conflicts of interest to declare.
Testing the BCL-2 Family to Direct Therapy and Predict Response.
Authors: Letai Anthony
Published: October 2019

Abstract SCI-14

Many, if not most, chemotherapeutic agents kill cancer cells via the mitochondrial apoptotic pathway. A simple model of this pathway breaks the killing into three steps. In Step 1, drug contacts target. In Step 2, prodeath signaling is generated. In Step 3, this pro-death signaling is interpreted by the BCL-2 family proteins at the mitochondrion, and when sufficient, the cancer cell is committed to the fate of death. Despite prominent exceptions, it is generally poorly understood why some cells are killed by chemotherapy and others are not. This is particularly perplexing in the case of most conventional chemotherapeutics which target ubiquitous elements such as DNA or microtubules. Most studies of determinants of chemotherapy induced cell death are focused on Steps 1 and 2. Relatively little is known about how mitochondrial preconditions affect chemosensitivity in cancer cells. We have developed a tool called BH3 profiling which exposes mitochondria to measured doses of BH3 domains, pro-death molecules of the BCL-2 family that ultimately carry pro-death signaling from Step 2 to the mitochondrion. By comparing mitochondrial dysfunction between different cells exposed to identical doses of BH3 domains, we can compare readiness of different cell types to undergo apoptosis. We have shown that this mitochondrial preset predicts response to conventional therapies of disparate mechanism, including etoposide, vincristine, and doxorubicin. Furthermore, BH3 profiling can predict response to agents such as ABT-737 which selectively kill cells dependent on anti-apoptotic proteins BCL-2, BCL-XL, and BCL-w. We have found BH3 profiling to be useful in many hematologic malignancies, including CLL, AML, ALL, lymphoma and myeloma. We have recently improved the BH3 profiling tool so that now it can be performed in a fluorescence activated cell sorting (FACS) format. The FACS format allows us to deconvolute complex, heterogeneous samples such are typically provided by clinical material. Our results suggest that heterogeneity of response to therapies, either within heterogeneous samples or between different tumors, relies to a very great extent on the mitochondrial preset measured by BH3 profiling.

Disclosures

Letai: Abbott Laboratories: Served as advisor for clinical development meeting.; Eutropics Pharmaceuticals: Equity Ownership.
Mitochondria in Neuroplasticity, Neurologic Disease and Aging.
Authors: Mattson Mark P.
Published: October 2019

Abstract SCI-2

Brain cells are influenced in health and disease by several types of bone marrow-derived cells (BMDC) that either reside in, or are recruited to, the brain. Microglia are macrophage-like cells that continuously surveil the brain, and respond to injury, infection or disease by endocytosing damaged/dead cells and microorganisms, and by producing pro-inflammatory cytokines. Lymphocytes of various phenotypes enter the brain in large numbers in response to acute injury (stroke, severe epileptic seizures, trauma) or chronic disease (multiple sclerosis, Alzheimer's disease). While microglia and lymphocytes are best known for their adverse effects on neuronal function and survival in injury or disease (Arumugam et al., Nat Med. 2006; 12:621-3), recent findings suggest that these cells may also serve important beneficial roles in processes such as learning and memory (Ziv et al. Nat Neurosci. 2006; 9:268-75). Here I describe how BMDC can affect neuronal excitability and mitochondrial function in normal physiological settings and in disease states. We have found that low concentrations of tumor necrosis factor (TNF), which is produced by microglia/macrophages and lymphocytes, can promote neuronal survival and synaptic plasticity by activating the transcription factor NF-kB to induce the expression of glutamate receptor subunits, mitochondrial SOD2 and Bcl2 (Mattson and Meffert, Cell Death Differ. 2006; 13:852-60). When bone marrow from TNF receptor-deficient mice was transplanted into irradiated wild type mice, neurons in the brain were more vulnerable to epileptic seizures, suggesting that TNF suppresses neuronal excitability (Guo et al., Neuromolecular Med. 2004; 5:219-34). In other studies we found that a mutation in presenilin-1 (PS1) that causes early-onset inherited Alzheimer's disease (AD) perturbs lymphocyte signaling (Morgan et al., Neuromolecular Med. 2007; 9:35-45). Splenic T cells isolated from PS1 mutant knockin mice respond poorly to proliferative signals and have downregulated cluster designation 3 and interleukin (IL)- 2-receptor expression necessary for a normal T-cell immune response. The adverse effect of mutant PS1 involves perturbed calcium regulation and cytokine signaling in lymphocytes, and associated sensitivity of lymphocytes to mitochondria-mediated apoptosis. These findings suggest that abnormalities in immune function might play roles in the pathogenesis of AD. Finally, I describe very recent findings that suggest roles for toll-like receptor signaling in learning and memory processes, and in neuronal responses to energy deprivation (Tang et al., Proc Natl Acad Sci U S A. 2007; 104:13798-803). Emerging findings therefore suggest that both innate and humoral signaling from BMDC to neurons play interesting roles in regulating neuronal plasticity and energy metabolism in health and disease.

Disclosures

No relevant conflicts of interest to declare.
Defining the Mechanism of Transcription Factor-Induced Epigenetic Reprogramming.
Authors: Plath Kathrin , Sridharan Rupa , Tchieu Jason , Mason Mike J. , Chin Mark , Yachechko Robin , Kuoy Edward , Zhou Qing , Lowry Bill
Published: October 2019

Abstract SCI-41

The great excitement surrounding induced pluripotent stem (iPS) cells is tempered by the fact that little is known about how they are generated and why this process is so inefficient. We have set out to ask how the four transcription factors Oct4, Sox2, cMyc and Klf4 can induce pluripotency. By analyzing the role of the reprogramming factors Oct4, Sox2, Klf4 and cMyc during the initial step of reprogramming and comparing their binding and global expression in fully and partially reprogrammed cells, we previously uncovered that cMyc has a central role in the repression of the somatic cell expression program. With respect to the upregulation of the embryonic cell transcription, the four factors cooperate to activate the metabolic program, followed by binding of Oct4, Klf4 and Sox2 to genes encoding pluripotency regulators leading to the self-sustained, pluripotent state. Thus, we suggested that the factors have separable and temporal contributions to the reprogramming process. We are particularly interested in further deciphering the mechanism of reprogramming, understanding barriers of the reprogramming process, and comparing the embryonic stem cell state with the iPS cell state.

Disclosures

No relevant conflicts of interest to declare.
Genetic Risk Factors of Thrombosis.
Authors: Reitsma Pieter H.
Published: October 2019

Abstract SCI-43

Venous thrombosis is a common episodic disease with a steep age gradient. Interactions between various risk factors determine the development of the disease, and the proportion of variance attributable to genetic factors may be as high as 50-60%. There are six (moderately) strong genetic risk factors. First there are heterozygous deficiencies of the natural anticoagulants protein C, protein S, and antithrombin. These deficiency states are quite rare in the general population (in all races) and their genetic architecture is complex with hundreds of documented mutations. The risk for the development of venous thrombosis may be increased 10-20-fold in these deficiency states. There is no consistent evidence that deficiencies of other members of the anticoagulant systems - such as thrombomodulin, EPCR, and heparin co-factor II - are also strong risk factors for venous thrombosis, possibly because these natural anticoagulants are associated with other episodic or chronic diseases. Secondly there are three genetic factors associated with an increase, directly or indirectly, in the procoagulant potential of the coagulation system: blood group non-O, factor V Leiden and prothrombin G20201A. The genetic architecture of these risk factors is extremely simple. The prevalence in the general Caucasian population is modest for prothrombin G20210A and factor V Leiden; in other races these two risk factors are extremely rare. The increase in thrombotic risk is about 3-fold or 7-fold for prothrombin G20210 and Factor V Leiden respectively. Blood group non-O is the most common of the prothrombotic genetic risk factors and approximately doubles the risk of venous thrombosis, and may do so in all races. In addition to these six ‘classical’ risk factors, a growing list of weak genetic risk factors has been discovered. Almost without exception, these weak risk factors are common single nucleotide polymorphisms in coagulation factor genes - e.g. those encoding for fibrinogen, factor XIII, factor IX, et cetera - that have a small effect on gene function, and consequently a small effect on thrombotic risk. This list of weak but common risk factors is expected to grow considerably in the near future as the large-scale genome wide association studies that are currently under way deliver their results. Moreover, deep resequencing studies are expected to start soon, whether based on a candidate gene approach or genome-wide, which will yield unprecedented insight in the extend to which rare genetic variation determines individual thrombotic risk.

Disclosures

No relevant conflicts of interest to declare.
Immunologic Responder Groups.
Authors: Sloan Steven R.
Published: October 2019

Abstract SCI-47

Transfusion medicine has long recognized that there is significant variation in the human immune response to red blood cell (RBC) transfusions.1 All allogeneic RBC transfusions expose the recipient to multiple foreign antigens, but very few RBC transfusions induce a detectable humoral immune response. Using statistical analyses of antibody responses among transfused patient populations, we found that the response closely approximates a geometric distribution that would be predicted by a random memory-less (stochastic) process. These statistical analyses demonstrate that most patients fail to mount immune responses to RBC transfusions but a distinct group of patients, termed potential responders, is capable of mounting an immune response to blood transfusions. Potential responders comprise approximately 13% of the transfused population and this proportion does not depend on pathologic diagnoses, age, gender or racial group. The only group that has a higher rate of potential responders are pregnant women, but those patients have a second route of antibody exposure. Although the ability to immunologically respond to blood transfusions appears to be limited to the relatively small population of potential responders, even potential responders do not mount an immune response to most RBC transfusions. Additionally, the specific antibodies that patients make are not completely independent of each other. Indeed, patients who have made some specific antibodies are more likely to subsequently make one set of anti-erythrocyte antibodies and less likely to make another set of anti-erythrocyte antibodies. This suggests that the potential immune repertoire differs between patients and the difference in potential repertoire is not solely explained by the antigens expressed on the patients' erythrocytes. Moreover, the potential repertoire is influenced by the age of the patient. Younger patients have a more diverse immune response producing antibodies against a broad spectrum of RBC antigens. As patients get older, the immune response becomes more limited and usually only responds against the most immunogenic RBC antigens. In summary, these results suggest that potential responders to intravenous administration of RBCs comprise a genetically distinct group and that additional factors determine which transfusion will induce an immune response in potential responders. The factors that cause a person to be a potential responder and the factors that cause a potential responder actually respond to a specific transfusion are subjects of ongoing research. In the meantime, transfusion services may consider minimizing immunologic stimuli to patients who are clearly responders. 1. Higgins JM, Sloan SR. Stochastic modeling of human RBC alloimmunization: evidence for a distinct population of immunologic responders. Blood. 2008;112:2546-2553.

Disclosures

No relevant conflicts of interest to declare.
Codanin-1, the Product of the Gene Mutated In Congenital Dyserythropoietic Anemia Type I (CDA I), Binds to Histone Chaperone Asf1a and Inhibits Its Nucleosome Assembly Activity
Authors: Tamary Hannah , Marcoux Nathaly , Noy-Lotan Sharon , Yaniv Isaac , Dgany Orly
Published: October 2019

Abstract 1004

Congenital dyserythropoietic anemia type I (CDA1) is an inherited recessive macrocytic anemia associated with ineffective erythropoiesis. The disorder is characterized by the accumulation of erythroid precursors containing spongy heterochromatin and internuclear chromatin bridges. The mutated gene (CDAN1) encodes an ubiquitously expressed protein (codanin-1) of unknown function. We have previously shown that codanin-1 is a direct transcriptional target of the E2F1 transcription factor and that the levels of codanin-1 increase during S-phase and decrease during mitosis. In an attempt to further define the role of codanin-1, we conducted a yeast two-hybrid screen using a human bone marrow library and found that codanin-1 binds to Asf1a. Asf1 (anti silencing function) is a H3/H4 histone chaperone involved in the chromatin structure dynamics by its role in nucleosome assembly and disassembly. Using coimmunoprecipitation experiments we confirmed that histone chaperone Asf1a is a direct binding partner of codanin-1. Minimal 100 amino acids domain of codanin-1, involved in binding Asf1, was identified and defined as the Asf1-binding domain. We found that codanin-1 binds to the conserved N-terminal core of Asf1a, where histones and other histone chaperones also bind. FLAG-tagged codanin-1 or its Asf1-binding domain immunoprecipitated from transfected Hela cells and subsequently coimmunoprecipitated histone H3 and Asf1a simultaneously. A pull-down assay of purified Asf1-binding domain in the presence of core histones showed, however, no direct binding of this domain of codanin-1 to H3/H4 histones. By using the replication-independent nucleosome formation assay we noticed that the nucleosome assembly activity of GST-Asf1a was severely decreased by the addition of the purified Asf1-binding domain of codanin-1, a phenotype similar to the one observed in Asf1 depletion. One possible explanation is that binding of codanin-1 inhibits dissociation of histones from Asf1a, which therefore cannot be deposited onto DNA. It will be of interest to determine if codanin-1 is involved in modulating Asf1a activity in vivo and also in response to DNA replication or damage and to determine its role in erythroid heterochromatin formation.

Disclosures:

No relevant conflicts of interest to declare.
Mutant BCL2 Co-Operates with CBFβ/PEBP2β-MYH11 to Promote Expansion of Leukemia Initiating Cells with a Predominantly Pro-Apoptotic Mechanism Via Recruitment of Ras-GTP In a Mouse Model of Progressive Acute Myeloid Leukemia.
Authors: Omidvar Nader , Pogam Carole Le , Beurlet Stephanie , Noguera Maria-Elena , Janin Ann , Kogan Scott C. , Weissman Irving L. , Pla Marika , Chomienne Christine , Padua Rose Ann
Published: October 2019

Abstract 1050

Mutations and translocation of the core binding factor complexes frequently co-operate with other lesions in Acute Myeloid Leukemia (AML). In order to study the molecular mechanisms and develop therapeutic platforms we have developed highly penetrant and tractable mouse models.

We crossed single transgenic mice that express the human (h)BCL2 or NRASD12 under the control of the myeloid promoter MRP8 with single transgenic mice that express the protein fusion CBFβ/PEBP2β-MYH11 (Inv16) under the same promoter. Whereas single transgenic mice have a normal lifespan, the double transgenic mice develop rapid and fatal hematologic disease. The NRASD12/Inv16 mice are already known to develop strong features of dysmyelopoiesis, developing severe thrombopenia and anemia associated with leucocytosis (Kogan SC, et al. PNAS USA 95:11863-11868). Here within marrow and spleen cells we find abnormal eosinophils with Charcot-Leydan crystals associated with an increase of myeloid blasts, features that are found in human AML4 with eosinophilia. The hBCL2/Inv16 mice develop anemia and leucopenia, with greater than 30% bone marrow blast cells associated with enlarged infiltrated liver and spleens. Consequently hBCL2/Inv16 animals demonstrated significantly reduced survival as compared to litter mate controls (median 65 days; p<0.001). Immunophenotyping of circulating myeloid cells revealed lack of differentiation; namely a raised Mac-1hi/Gr-1lo profile. We further demonstrate that there is an expansion of the primitive Lin-/Sca-1+/c-Kit+ compartment for both NRASD12/Inv16 and hBCL2/Inv16 models in comparison with the singles. The colony assays performed show an increase of all myeloid progenitors for the hBCL2/Inv16 mice whereas NRASD12/Inv16 assays revealed a strong increase of CFU-M. The diseases are transplantable into irradiated syngenic recipients, supporting the expansion of the leukemic initiating cell compartment.

To further elucidate signaling mechanisms we employed phospho-interrogation of spleen samples using the capillary isoelectric focusing methodology via NanoPro CB1000 (Cell Biosciences). Novel data reveals the balanced role of ERK/BCL2 phosphorylation states illustrating pro versus anti-apoptotic signaling. Surprisingly during disease progression, hBCL2/Inv16 recruits endogenous Ras, with a pro-apoptotic phenotype, providing tangible targets for the treatment of progressive AML.

Disclosures:

Weissman: Amgen, Systemix, Stem cells Inc, Cellerant: Consultancy, Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.
Identification of Recurring Tumor-Specific Somatic Mutations In Acute Myeloid Leukemia by Transcriptome Sequencing.
Authors: Greif Philipp A , Eck Sebastian H , Konstandin Nikola , Benet-Pages Anna , Dufour Annika , Vetter Anna , Popp Henning , Lorenz-Depiereux Bettina , Meitinger Thomas , Bohlander Stefan K , Strom Tim M
Published: October 2019

Abstract 1059

Aims:

Genetic lesions are crucial for cancer initiation. Recently, whole genome sequencing using next generation technology was used as a systematic approach to identify mutations in genomes of various types of tumors including melanoma, lung and breast cancer as well as cytognetically normal acute myeloid leukaemia (CN-AML). Despite its technical feasibility, whole genome sequencing is still time consuming and cost intensive. As an alternative approach, here we identify tumor-specific somatic mutations by sequencing transcriptionally active genes.

Methods:

Mutations were detected by comparing the transcriptome sequence of a CN-AML with the corresponding remission sample. In a single Genome Analyzer II run, we generated 4.35 Gbp of CN-AML and 5.54 of remission transcriptome sequence from the same patient. 63% of AML reads and 74% of remission reads mapped to exon regions. 10,152 genes had an average read depth of at least 7-fold and 6,989 genes an average read depth of 20 or greater in both samples. By comparing the 8,978 coding Single Nucleotide Variants (SNVs) discovered in the CN-AML sample with the remission sample, we identified 5 non-synonymous mutations specific to the tumor sample.

Results:

We found 5 tumor-specific somatic mutations. Among them is a nonsense mutation affecting the RUNX1 gene, which is a frequent mutational target in AML, and a missense mutation in the putative tumor suppressor gene TLE4, which encodes a RUNX1 interacting protein. A second missense mutation was identified in SHKBP1, which acts downstream of FLT3, a receptor tyrosine kinase mutated in about 30% of AML cases. The frequency of mutations in TLE4 and SHKBP1 in a cohort of 95 CN-AML patients was 2%.

Conclusion:

Our study demonstrates that whole transcriptome sequencing leads to the rapid detection of recurring point mutations in the coding regions of genes relevant to malignant transformation.

Disclosures:

No relevant conflicts of interest to declare.
Pediatric Experience with Low Dose Decitabine In Very High Risk Relapsed AML.
Authors: Phillips Christine L , Davies Stella M. , McMasters Richard , O'Brien Maureen , Absalon Michael J. , Moscow Jeffrey A. , Smolarek Teresa , Perentesis John P.
Published: October 2019

Abstract 1070

Background:

Children with relapsed AML and organ dysfunction or fungal infections rarely tolerate intensive retrieval therapies and have a very poor prognosis. Low-dose decitabine has encouraging clinical activity for adults with AML and a favorable toxicity profile. Experience regarding the use of decitabine in children and young adults with relapsed/refractory AML is lacking.

Methods:

We report the use of decitabine in a cohort of children and young adults with refractory/relapsed AML, who had either failed multiple standard retrieval regimens and/or were not candidates due to prior toxicities (e.g. severe cardiomyopathy, invasive fungal infections). Patients received decitabine at 20 mg/m2 IV for days 1–10 at four week intervals. Patients who responded to therapy but had prolonged myelosuppression received 5 days of therapy in subsequent course.

Results:

Eight patients were treated with median age of 4 years [range 2–26]. One patient was refractory to primary induction therapy. The remaining patients were in first through fifth relapse. Five patients had at least one previous bone marrow transplant. One patient had normal karyotype, 2 patients had complex karyotype (≥3 abnormalities). Three others had unfavorable cytogenetics including monosomy 7; 5 q deletion, t(11;17) with MLL rearrangement. None of the patients had low risk cytogenetics (t(8;21), inv 16). A total of 24 cycles to were administered to 8 patients (mean number of cycles = 3). Six of 8 total patients (75%) achieved at least partial response with 3 patients (38%) achieving CR, CRp or CRi. One responder who did not meet CRi criteria had no evidence of leukemic blasts on a hypocellular marrow following the second cycle of decitabine and remained in peripheral blood remission with 100% donor chimerism for two additional months. Of the 2 non-responding patients, 1 had stable disease, and 1 had progressive disease. In responders, best response was seen after a median of 3 cycles [range 1–4 cycles]. Of the 5 patients with prior transplantation, donor chimerism improved in the three responders by a mean of 57% with treatment. Therapy was well tolerated with neutropenia being the most common toxicity. There were only two documented bacterial infections in 24 cycles, with no fungal infections or treatment related deaths.

Conclusions:

Decitabine administered at low doses has activity in this cohort of heavily pre-treated children and young adults with relapsed/refractory AML. The toxicity profile is very favorable compared with conventional chemotherapy. These encouraging results warrant further investigation of decitabine in prospective pediatric studies of high risk relapsed/refractory AML.

Disclosures:

Off Label Use: Decitabine is not FDA approved for the treatment of pediatric acute myeloid leukemia.
High Body Mass Index (BMI) as a Predictor of Differentiation Syndrome (DS) In Acute Promyelocytic Leukemia (APL).
Authors: Jeddi Ramzi , Achour Béchir , Guerci-Bresler Agnès , Ghédira Héla , Dombret Hervé , Huguet Françoise , Chevallier Patrice , Vey Norbert , de Botton Stephane , Bordessoule Dominique , Muller Beatrice U. , Eclache Virginie , Gardin Claude , Meddeb Balkis , Adès Lionel , Fenaux Pierre
Published: October 2019

Abstract 1078

Background:

High BMI was recently identified as a new predictor of differentiation syndrome (DS) in a relatively small Tunisian series of 39 APL patients (pts) treated with ATRA and anthracycline based chemotherapy (Leuk Res 2010; 34: 545–547). We analyzed this parameter in a larger pt cohort included in European APL 93 and APL 2000 trials.

Methods:

Between 1993 and 2006, 1196 APL patients (pts) were included in APL93 and 2000 trials, of whom 1016 APL had BMI determination (524/576 in APL 93 and 492/620 in APL 2000). In both trials, induction treatment consisted of ATRA and DNR + AraC except in one arm of APL 2000 trial where standard risk pts (ie low and int risk using Sanz score) received no AraC. Chemotherapy (CT) was started on day 1 of ATRA treatment in high risk (Sanz score) pts and on day 3 of ATRA treatment in standard risk pts except in one arm of APL 93 where standard risk pts received CT after ATRA. In APL 2000 (but not APL 93) trial, high risk patients received prophylactic dexamethasone from day 1 of ATRA.

Results:

Median age was 45 years (range: 1–80). 260 (25.6%) pts were high risk, 420 (41.3%) int risk and 336 (33%) low risk. Median BMI was 25.8 kg/m2 (range: 10–38). CR was achieved in 92.9% pts. Overall incidence of DS (according to Frankel's criteria) was 23.3%. Prognostic factors associated with an increased risk of DS were baseline WBC > 3×109/l (p=0.03) (best cut-off for WBC count), inclusion in APL2000 trial (p<0.0001) and randomization arm without AraC (p=0.028). When focusing on the low risk group, univariate analysis and multivariate analysis showed BMI > 25.5 (p=0.031) and inclusion in APL 2000 (p=0.002) to be significantly associated with occurrence of DS whereas age, sex, baseline WBC and absence of AraC had no prognostic impact. In low risk pts, occurrence of DS was associated with a trend for shorter survival (p=0.051). BMI however lost its prognostic value for DS in intermediate and high risk pts.

Conclusion:

High BMI may be associated to a higher risk of DS, at least in low risk APL, suggesting that those patients may have to be monitored closely during induction treatment of APL.

Disclosures:

Fenaux: CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.
Arsenic Containing Triple-Agent Therapy for Acute Promyelocytic Leukemia-Comparison of Tetra-Arsenic Tetra-Sulfide vs. Arsenic Trioxide in the Long-Term Follow-up at a Single Hospital.
Authors: Wu Shu-Lan , Lu Dao-Pei , Zhao Yan-Li , Liang Lan-Qing , He Jun-Bao , Zou Wei , Fei Xin-Hong , Jiang Bin , Shan Fu-Xiang , Yang Ping-Di , Zhao Jie , Tong Chun-Rong
Published: October 2019

Abstract 1081

Our previous study has demonstrated that oral tetra-arsenic tetra-sulfide (As4S4) alone is highly effective and safe in both induction and maintenance therapy in acute promyelocytic leukemia (APL) (Dao-Pei Lu et al., Blood 2002; 99: 3136). Triple-agent treatment with As4S4, all-trans retinoid acid (ATRA) and low-dose chemotherapy has achieved expeditiously consecutive complete remission (CR) without death during induction, and it has also improved leukemia-free survival (LFS) (Tong Wu et al., ASH abstract 591 2007). To learn the efficacy and safety of As4S4 and arsenic trioxide (ATO), a total of 88 consecutive cases of newly diagnosed APL patients who have been treated with triple-agent regimen with arsenic, either As4S4 (n=42) or ATO (n=46), ATRA and low-dose chemotherapy at Beijing Dao-Pei Hospital were analyzed retrospectively. Major clinical characteristics in two groups were similar. Purified natural oral As4S4 (Dao-Pei Lu's Lab) or commercially available intravenous ATO were used. The regimens for induction, consolidation and maintenance therapy have been reported previously. All 88 patients attained hematological CR (HCR) after induction therapy without early death. A total of 84 cases were monitored for PML/RARA fusion transcript by RQ-PCR. Molecular CR (MCR) reached in all evaluable cases (100%) in As4S4 group and 93.5% of cases in ATO group. In As4S4 group, 3-year and 5-year LFS rates were all 100% with a median follow-up of 57 months (range, 12–103 months). In ATO group, however, 5 cases relapsed and 2 patients died with a median follow-up of 36 months (range, 12–96 months). The 3-year and 5-year LFS rates were both 86.6%. The difference of LFS between As4S4 and ATO groups were remarkable (p=0.028). Three-year and 5-year overall survival (OS) rates were all 100% in As4S4 group, 96.7% and 88.6% in ATO group respectively. Statistically there was no significant difference (p=0.1015). The side effects in As4S4 group were mild and all patients could continue the therapy. However, a total of 15 side events in ATO group including hepatic, cardiac or lung complications led to discontinuation of therapy. Our encouraging clinical results indicate that arsenic, either As4S4 or ATO in combination with ATRA and low-dose chemotherapy is highly effective in the induction of both HCR and MCR in newly diagnosed APL patients. As4S4 containing triple-agent protocol has better results in the prevention of relapse and improvement of LFS, and has less toxicity. Our clinical study has shown for the first time that all consecutive newly diagnosed cases of APL have achieved long-term LFS with As4S4 containing triple-agent regimen, which are significantly better than that of ATO containing one.

Disclosures:

No relevant conflicts of interest to declare.
Incidence of Secondary Neoplasms In Patients with Acute Promyelocytic Leukemia Treated with All-Trans-Retinoic Acid (ATRA) with Chemotherapy or with Arsenic Trioxide (ATO).
Authors: Eghtedar Alireza , Faderl Stefan , Kantarjian Hagop , O'Brien Susan , Garcia-Manero Guillermo , Ferrajoli Alessandra , Kadia Tapan , Pierce Sherry A. , Shan Jenny , Cortes Jorge E. , Ravandi Farhad
Published: October 2019

Abstract 1085

Background:

Progress in the treatment of patients (pts) with acute promyelocytic leukemia (APL) with the use of modern all-trans retinoic acid (ATRA)-containing regimens has resulted in the majority of pts achieving long-term disease-free survival. There is little data on the incidence and patterns of secondary neoplasms in pts treated with these regimens.

Objective:

To compare the incidence of secondary neoplasms in pts with APL treated with two different ATRA-containing regimens.

Methods:

We retrospectively examined the charts of 160 pts with APL treated with ATRA plus chemotherapy (n=54) or ATRA plus arsenic trioxide (ATO)(n=106) as their initial induction regimen at the University of Texas – M. D. Anderson Cancer Center from 1991 to 2009. Twenty seven (17%) pts had a remote history of a prior unrelated cancer. Pt characteristics and the incidence of secondary cancers per unit time of follow-up were compared.

Results:

The median age at diagnosis of the entire population was 44 years (range, 13 – 81) and the median age for the chemotherapy plus ATRA group was 38 years (range, 13–67) vs. 46 years (range, 14 – 81) for the pts treated with ATO plus ATRA (p= 0.001). Thirty (55%) and 54 (50.9%) in each cohort were women (p=0.52) and 2 (3.7%) and 26 (24.5%) were older than 60 years of age, respectively (p= 0.001). Twenty (37%) and 30 (28.3%) had high risk disease (WBC > 10 × 109/l)(p= 0.3), and 34 (62.9%) and 76 (71.6%) had low risk disease (WBC ≤ 10 × 109/l), respectively. Fifty one (94.4%) and 105 (99%) pts treated using the two regimens achieved a CR. The median follow-up time for the two cohorts was 136 and 29 months [ranges, (5 to 193) and (1 to 93), respectively]. Nine and 2 pts in the two groups developed secondary cancers including 2 breast cancers, 3 MDS/AML, 1 vulvar cancer, 1 prostate cancer, 1 colon cancer and 1 soft tissue sarcoma in the chemotherapy group vs. 1 melanoma and 1 pancreatic cancer in ATO group. The cumulative incidence of secondary cancers in the two cohorts is shown in figure 1.

Conclusion:

Treatment of pts with APL using the non-chemotherapy regimen of ATRA plus ATO is not associated with a higher incidence of secondary cancers (p=0.29) adjusted for unit time exposure.

Disclosures:

Off Label Use: Use of arsenic trioxide in frontline therapy of APL. Ravandi:Cephalon: Honoraria, Research Funding, Speakers Bureau.
Thromboprophylaxis In Multiple Myeloma Patients Undergoing Immunomodulatory Therapy with Thalidomide and Lenalidomide: A Systematic Review and Meta-Analysis.
Authors: Carrier Marc , Gal Gregoire Le , Tay Jason , Wu Cynthia M. , Lee Agnes Y.
Published: October 2019

Abstract 1090

Background:

The incidence of venous thromboembolism (VTE) in patients with multiple myeloma (MM) is high in patients treated with thalidomide (T)- and lenalidomide (L)-based regimens containing dexamethasone (D) and/or cytotoxic chemotherapy (C). Consensus guidelines recommend routine thromboprophylaxis but reliable data from randomized controlled trials are lacking. Recent observational studies have suggested that thromboprophylaxis might be efficacious in decreasing the risk of VTE in this population.

Purpose:

To determine the absolute rates of VTE with and without different thromboprophylactic agents (ASA, warfarin, low-molecular-weight-heparin [LMWH]) in patients with newly diagnosed or previously treated MM receiving T- or L-based regimens.

Data Source:

A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews of published studies up to Jan 2010.

Results:

A total of 66 studies were included in the analyses. Of these, 61 (4264 patients) and 5 (1119 patients) assessed T- and L-based regimens, respectively.

Thalidomide-based regimens

The rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with T-based regimens:

The rates of VTE (per 100 patient-months) in patients with previously treated MM managed with T-based regimens:

Lenalidomide-based regimens

The rates of VTE (per 100 patient-cycles) in patients with newly diagnosed MM treated with L-based regimens:

The rate VTE (per 100 patient-months) in patients with previously treated MM managed with L-based regimens:

None of the studies reported major bleeding events.

Limitations:

The definition for VTE varied across studies. Most studies did not outline the diagnostic criteria for VTE. Data are not available (NA) for all prophylaxis regimens.

Conclusion:

Patients with newly diagnosed or previously treated MM receiving T- or L-based regimens are at high risk of VTE. It is uncertain whether thromboprophylaxis provides a clear benefit, especially in those receiving L-based therapy or have previously treated disease. Randomized controlled trials are needed to address this important clinical need.

Disclosures:

Lee: Eisai: Research Funding; Sanofi Aventis: Consultancy, Honoraria; Leo Pharma: Consultancy; Pfizer: Consultancy, Honoraria; Bayer: Honoraria; Boehringer Ingelheim: Consultancy, Honoraria, Speakers Bureau.
Thrombin Generation Is a Sensitive Measure of Low Molecular Weight Heparin Anticoagulant Activity.
Authors: Gatt Alexander , Riddell Anne , Lanning Lesley , Aghighi Saman , Kanagasapathy Pamala , Chowdary Pratima
Published: October 2019

Abstract 1099

Current guidelines recommend monitoring of low molecular weight heparins (LMWHs) using the anti-Xa assay in high risk patients like those with renal impairment, pregnancy or overweight and in children. However, it is well accepted that this test does not accurately predict the anticoagulant effect of these drugs1. This is understandable since the various LMWHs available affect the coagulation cascade in different ways relative to their different molecular structure. Notoriously, the larger LMWHs like Tinzaparin have a higher anti-IIa to anti-Xa ratio that is not detected by the anti-Xa assay.

We hypothesized that thrombin generation (TG) is a better, more sensitive way how to monitor LMWH anticoagulant activity since it is a measure of the interplay of all coagulation proteins.

Blood samples from patients with acute thrombosis, pregnancy and other conditions and having LMWH monitoring were analysed using a chromogenic anti-Xa assay and a TG assay as per Hemker et al2 together with a chromogenic anti-IIa and FVIII clotting assay (FVIII:C). A tissue factor trigger of 10pM Innovin was used for the TG experiments. Patient samples were divided into 2 groups: those on Tinzaparin (n=45) or Enoxaparin (n=39).

There was no difference between the FVIII:C levels of the Tinzaparin and Enoxaparin groups (mean 250 vs 327IU/ml P>0.05). A higher lower mean anti-Xa and a higher mean anti-IIa level was achieved with Tinzaparin (0.48 vs 0.63 U/ml P= >0.05 for anti-Xa and 0.3 vs 0.15U/ml P=0.005 for anti-IIa respectively). The endogenous thrombin potential (ETP) was significantly lower with Tinzaparin than Enoxaparin despite a higher anti-Xa (705 vs 1216nM.min P=0.006). Linear regression analysing TG with anti-Xa of the two LMWHs shows that 1.0U/ml antiXa activity for Enoxaparin is as potent as 0.7U/ml Tinzaparin in suppressing TG to similar levels. Significant inter-individual variation in TG suppression was noted with both LMWHs.

This study demonstrates that anti-Xa results achieved for different LMWHs do not have the same anticoagulant significance. Using TG, we achieved similar therapeutic anti-Xa levels as achieved from the individual LMWH clinical trials3. It is clear that TG is a better test to predict LMWH anticoagulant activity. This needs to be proven in clinical studies.

1. Baglin T et al British Journal of Haematol. 2006; 133(1): 19–34.

2. Hemker HC et al Pathophysiol Haemost Thromb, 33, 4-15.

Boneu B and de Moorloose P. Semin Thromb Hemost 2001; 27(5): 519–522.

Disclosures:

No relevant conflicts of interest to declare.
Nematode Antocoagulant Protein c2 (NAPc2) Interferes with Factor Xa Dimerization: Structural Alteration of Factor Xa Upon Dimerization.
Authors: Chattopadhyay Rima , Koklic Tilen , Majumder Rinku , Lentz Barry R.
Published: October 2019

Abstract 1128

Nematode Anticoagulant protein c2 (NAPc2) from the hematophagous hookworm, Ancyclostoma canimum, is a potent inhibitor of factor × activation to Xa by the Xase complex composed of VIIa and tissue factor. Factor Xa (FXa) plays a crucial role in blood coagulation; including formation of a prothrombin activating complex with its co-factor Va. NAPc2 also inhibits activation of prothrombin by this complex. FXa forms a functionally inactive dimer upon binding to either membrane bound or solution phosphatidylserine (PS) in the presence of calcium, and that the structure of FXa in the dimer is altered (Chattopadhyay et al, 2009; Koklic et al., 2009). The dimer interface predicted from mass spectroscopy involves a residue in the hirudin-binding site. NAPc2 interacts with two regions in FXa, one overlapping with the hirudin site and another in the substrate binding exosite (Murakami et al., 2007; Yegneswaran et al., 2003; Wilkens et al., 2002). We show that NAPc2 at low concentration does not interfere with dimerization, but at high concentration it destabilizes the dimer as documented with homoFRET studies with FEGRXa (Fluorescein-GLU-GLY-ARG-chloromethylketone-Xa). Proteolytic activity (prothrombin as substrate) suggested that the species Xa · NAPc2 (NAPc2 binding to FXa monomer) and FXa2 · NAPc2 (NAPc2 binding to FXa dimer) have activity comparable to FXa dimer. A model is suggested in which initial NAPc2 binding to the substrate-binding region in FXa alters interactions in the hirudin-binding region and thus alters dimer formation. Supported by USPHS grant HL072827 to BRL.

Disclosures:

No relevant conflicts of interest to declare.