bluuebunny/crossref_metadata_2025 huggingface dataset:
Enhanced Antitumor Efficacy of MUC-16 Targeted T Cells Further Modified to Constitutively Express the IL-12 Cytokine in a Syngeneic Model of Ovarian Cancer,
Authors: Chekmasova Alena A , Sandadi Samith , Spriggs David R , Brentjens Renier J
Published: October 2019

Abstract 4176

T cells may be genetically modified to recognize tumor associated antigens (TAAs) through the introduction of genes encoding artificial T cell receptors termed chimeric antigen receptors (CARs). We have constructed SFG retroviral vectors encoding first (4H11mz) and second (4H11m28mz) generation CARs as well as IL-12 modified CAR (4H11m28mzIRESmIL12) targeted to the retained extra-cellular domain of MUC16, termed MUC-CD. This antigen is over-expressed on most ovarian carcinoma tumor cells. IL-12 is a potent inducer of a Th1 CD4+ T cell response and serves as a “signal 3” in concert with TCR activation (signal 1) and CD28 co-stimulation (signal 2) to CD8+ T cells, resulting in optimized clonal expansion and effector function. In order to mimic the clinical setting, we generated a syngeneic tumor model using the C57BL6 (B6) mice intraperitoneally (i.p.) injected with ID8(MUC-CD) cells. In our studies treatment of mice bearing established ID8(MUC-CD) ovarian tumor with MUC-CD specific T cells expressing IL-12 gene, in contrast to T cells targeted to MUC-CD alone, fully eradicate advanced intraperitoneal ovarian tumors. The mechanism of IL-12 expressing MUC-CD targeted T cell antitumor efficacy was mediated through enhanced persistence and engraftment of modified T cells, as well as the ability of IL-12 secreting T cells to recruit endogenous T cells to the tumor site. Furthermore, we observed elevated secretion of the pro-inflammatory cytokines (IFN-g and TNF-a) in the serum of IL-12 treated mice, compared to 4H11m28mz and control CD19 targeted T cell treated groups. Treatment of B6 mice with MUC-CD targeted T cells expressing IL-12 gene was dependent upon recruitment of the NK and NKT cells to the tumor site. Finally, we demonstrated the ability of IL-12 secreting T cells to overcome the immunosuppressive tumor microenvironment by switching the phenotype of the tumor-associated macrophages (TAMs) from a predominately immunosuppressive M2 to an immunostimulatory M1 phenotype. These data, obtained in the context of a clinically relevant syngeneic tumor model supports the application of this approach in the treatment of the patients with relapsed ovarian carcinomas.

Disclosures:

No relevant conflicts of interest to declare.
Refractory / Relapsed Myeloid Leukemia of Down Syndrome Is Resistant to Second-Line Chemotherapy and Hardly Salvaged by Hematopoietic Stem Cell Transplantation: A Retrospective Study by the Japanese Pediatric Leukemia / Lymphoma Study Group (JPLSG)
Authors: Taga Takashi , Saito Akiko , Kudo Kazuko , Tomizawa Daisuke , Terui Kiminori , Moritake Hiroshi , Kinoshita Akitoshi , Iwamoto Shotaro , Nakayama Hideki , Takahashi Hiroyuki , Tawa Akio , Shimada Akira , Taki Tomohiko , Kigasawa Hisato , Koh Katsuyoshi , Adachi Souichi
Published: October 2019

Abstract 4276

Introduction:

Myeloid leukemia in Down syndrome patients (ML-DS) is known to have good sensitivity against cytotoxic agents, especially to cytarabine, and outcomes in recent clinical trials are favorable with more than 80 % probability of long-term event-free survival (EFS). However, little have been focused on refractory / relapsed cases, since most of the treatment failures consist of toxicities rather than resistant or recurrent leukemia. We present here a retrospective analysis of the patients with refractory / relapsed ML-DS.

Patients and Method:

Among the ML-DS patients diagnosed between 2000 and 2011 at the 120 hospitals in Japan, twenty-nine refractory / relapsed patients were enrolled in this retrospective study.

Result:

Median follow-up period for all 29 patients was 10.9 months (range, 2.8 –76.7 months). Male/Female ratio was 18/11. The age at initial diagnosis for ML-DS was between 7 months and 16 years old (median, 2 years old). All the patients were initially treated with one of the protocols specifically designed for ML-DS; twenty patients with AML99 Down protocol, eight with JPLSG AML-D05 protocol, and one with JCCLSG AML9805 Down protocol. There were 3 induction failures and 26 relapsed cases. Among the 26 relapsed cases, duration from initial diagnosis to relapse was 2.4 month to 71.8 months (median 8.6 months); Twenty-eight relapsed at bone marrow and one patient relapsed at skin site. Twenty-six out of the 29 patients received various re-induction chemotherapies and 13 of them achieved complete remission (CR). Eight of the 13 patients with CR subsequently received allogeneic stem cell transplantation (SCT) and 4 survived. On the other hand, five of the 13 cases with CR were treated with chemotherapy alone, and 4 were alive with no evidence of leukemia. All the 12 patients who failed to achieve CR and the 2 patients who only received palliative therapy eventually died. The 3-year overall survival rate was 22.6 ± 8.8 %. Achievement of CR with second-line chemotherapy and longer duration from initial diagnosis to relapse were significant favorable prognostic factors. SCT did not influence the prognosis even if performed after achieving further remission.

Conclusion:

The Japanese strategy treating ML-DS have been successful with very low-intensive chemotherapy regimen, however, rescue of refractory / relapsed patients with ML-DS seems difficult even with SCT.

No relevant conflicts of interest to declare.

Disclosures:

No relevant conflicts of interest to declare.
Treatment Related Mortality of AML Pediatric Patients in a Single Center in Saudi Arabia
Authors: Jastaniah Wasil , Abrar Mohammed Burhan , Khattab Taha
Published: October 2019

Abstract 4291

Despite minimal changes in therapeutic approach, the outcome of acute myeloid leukemia (AML) in pediatric patients has improved significantly in the past two decades. Supportive care measures may have contributed to this success by reducing treatment related mortality (TRM) and thereby improving the overall survival (OS) of patients. Yet their impact on outcome remained unknown and masked under protocol effect. To assess the impact of supportive care measures on outcome, we undertook a retrospective review of all pediatric patients diagnosed with AML between 1986 and 2011and treated in our institution, the Princess Norah Oncology Center, King Abdulaziz Medical City, Jeddah. A total of 87 patients were reviewed. Of these, two patients whose parents refused treatment and one lost to follow-up were excluded. A total of 84 patients were qualified for the study. These patients were treated with two different protocols based on treatment eras. Patients diagnosed between 1986 and 1995 (era 1) were treated following AML-BFM-78 protocol while patients diagnosed between 1996 and 2011 (era 2) were treated following the MRC AML10. The cumulative TRM incidence was 76% in era1 compared to 11.5% in era 2 (P = 0.0001). This resulted in an improved 5-year OS from 10.5% in era 1 to 56% in era 2 (P = 0.007). The protocols used in both eras were different and may have improved OS. Significant difference in TRM however, suggests that other factors contributed to the improved OS. To gain further insight of the contributing factors, patients who received only MRC AML10 protocol (in era2) were partitioned into two sub-eras based on supportive care measures introduced sequentially in our institution as follows: 1996 to 2002 (era 2a) and 2003 to 2011 (era 2b).The cumulative TRM incidence was 48.6% in era 2a and 4.7% in era 2b (P = 0.001). This also resulted in an improved OS from 33.3% in era 2a to 56.2% in era 2b despite using the same protocol (P = 0.007). Our findings highlight the importance of supportive care as a significant factor in outcome of children. Comparing protocols per se masks the importance of supportive care measures in impacting outcome. We suggest devising a standardized scoring system to evaluate center-specific supportive care measures to quantify the impact of supportive care on TRM and survival outcomes while simultaneously allowing us to distinguish the effect of supportive care from that of protocol and other factors such as ethnicity.

Disclosures:

No relevant conflicts of interest to declare.
Prevalence of Heparin Induced Thrombocytopenia Antibodies During the Period 2004–2011. Relevance to Heparin Contaminants
Authors: Fareed Jawed , Adiguzel Cafer , Hoppensteadt Debra , Jeske Walter , Walenga Jeanine M. , Lewis Bruce E , Messmore Harry L. , Bansal Vinod
Published: October 2019

Abstract 4326

In conjunction with an ongoing program to investigate the prevalence of HIT antibody (HIT Ab) in ESRD, blood samples were collected from patients (n=53–89) on maintenance hemodialysis and retrospectively analyzed for the presence of these antibodies during the period February-April 2004–2011. Specified cut off levels were used to determine the positive and negative results. Two ELISA methods (GTI. Brookfield, WI) and (Aniara, Mason, Ohio) were used to quantitate the HIT antibodies. The prevalence of the HIT Ab during the period 2004–2011 was < 15% with the exception of 2007 where it was 35% and in 2008 it was 30%. While the assay based differences were noted, overall there was a decreased prevalence during the period 2009–2011 (13–15%). The antibody titers as quantified by optical density measurement were relatively higher during the year 2007 and 2008. Moreover, the subtyping of these antibodies in 2007 and 2008 showed a higher proportion of IgG subtype. Interestingly the platelet counts did not differ in the different groups. Similar trends were noted in the prevalence of HIT antibodies when other methods to detect HIT antibodies were used. None of the patients recruited in this study exhibited any clinical signs of HIT syndrome. Moreover, the serotonin release assays were also negative on all these patients. Some of the batches of heparin and low molecular weight heparins used during the period 2007–2008 were found to contain varying amounts of dermatan sulfate (up to 30%) and OSCS (up to 30%). Thus the presence of these carry over products and intentionally added OSCS are most likely to contribute to this increased prevalence and seroconversion of HIT antibodies. In conclusion, these observations suggest that heparin contaminants may have contributed to the higher prevalence of HIT antibodies during the period 2007–2008.

Disclosures:

No relevant conflicts of interest to declare.
Functional Characterization of BAX 855, a PEGylated Recombinant FVIII
Authors: Schrenk Gerald , Varadi Katalin , Gritsch Herbert , Rottensteiner Hanspeter , Ehrlich Hartmut J. , Scheiflinger Friedrich , Turecek Peter L
Published: October 2019

Abstract 4359

Baxter and Nektar have developed BAX 855, a longer-acting PEGylated form of Baxter’s recombinant FVIII (ADVATE process) using stable PEG technology from Nektar. BAX 855 was functionally characterized in vitro and its features were compared with those of the unmodified parent rFVIII. The overall hemostatic potency of BAX 855 was assessed using a thrombin generation assay. Human FVIII-deficient plasma containing less than 1% of FVIII was supplemented with different concentrations of BAX 855 and unmodified rFVIII and coagulation was triggered by adding a small amount of recombinant human tissue factor complexed with phospholipid (PL) micelles to the plasma. Similar to unmodified rFVIII, BAX 855 corrected the impaired thrombin generation of the FVIII deficient plasma in a concentration-dependent manner. The role of FVIII within the tenase complex was determined by measuring the kinetics of FXa generation with a FIXa-cofactor activity assay, using either untreated or thrombin activated BAX 855. Comparison of the kinetic parameters and the maximum FXa generated revealed similar characteristics between BAX 855 and unmodified rFVIII. A similar approach revealed that BAX 855 fully retained its ability to be activated and inactivated by thrombin. The susceptibility of BAX 855 to activated protein C (APC) inactivation was also similar for BAX 855 and unmodified rFVIII. The binding affinities for VWF were similar for unmodified rFVIII (KD 0.6 nM) and BAX 855 (KD 0.8 nM) and the binding capacity of BAX 855 was also only slightly reduced. In contrast, the binding capacity of BAX 855 to the low-density lipoprotein-receptor-related protein (LRP) clearance receptor was 55% less than that of the unmodified rFVIII. In summary, the functional properties of BAX 855 were fully retained, indicating that PEGylation did not have an impact on the functional properties of rFVIII.

Disclosures:

Schrenk: Baxter Innovations GmbH: Employment. Varadi:Baxter Innovations GmbH: Employment. Gritsch:Baxter Innovations GmbH: Employment. Rottensteiner:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment. Turecek:Baxter Innovations GmbH: Employment.
Impact of the Approval of Eculizumab by the Food and Drug Administration on the Frequency of Patients Screened for Paroxysmal Nocturnal Hemoglobinuria
Authors: Munoz Javier , Younes Mohamad A. , Olarte-Merida Karen , Kuriakose Philip
Published: October 2019

Abstract 4377

Background:

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired complement-mediated hemolytic disorder. Eculizumab, a monoclonal antibody designed to inhibit terminal complement activation, reduces intravascular hemolysis while leading to improvements in anemia, fatigue, and quality of life as well as reductions in blood transfusions and thrombosis. This medication was approved by the Food and Drug Administration (FDA) in March 16, 2007. The intent of our study was to assess if the number of patients screened for PNH has increased after the approval of eculizumab by the FDA.

Methods:

Retrospective single institution chart review over a period of 6 years from January 2004 to June 2010. Our study population comprised 174 patients screened for PNH by flow cytometry.

Results:

Between January 2004 and March 16, 2007 (39 months), a total of 68 cases were screened for PNH. On the other hand, between March 17, 2007 (date of FDA approval) and June 2010 (39 months), a total of 106 cases were screened for PNH with an increase in the frequency of testing by 55.8% (Figure 1). 1 out of 68 cases (1.5%) screened before March 16, 2007 were positive for PNH. 6 out of 106 cases (5.6%) screened after March 16, 2007 were positive for PNH (Table 1). 74 patients were male (42.5%) and 100 were female (57.5%). Average age at screening for PNH was 53.3 years. Screening was most commonly requested by Hematology (151 cases; 86.7%) followed by Internal medicine (5 cases), Hepatology (3 cases), Neurology (1 case) and Pulmonary (1 case). We found no information available in 13 cases regarding the location of the patient or the service that requested PNH screening. The clinical indications to screen for PNH were cytopenias (110 cases; 63.2%), thrombotic events (39 cases; 22.4%), or a combination of cytopenia plus a thrombotic event (9 cases; 5.2%). No indication for PNH screening was documented in 16 cases.

Conclusion:

Our hypothesis is that an approval of a new medication can increase both, the awareness of a disease among physicians, and the frequency of ordering its diagnostic tests. The number of patients screened for PNH sharply increased after the approval of eculizumab by the FDA, confirming our hypothesis.

Disclosures:

No relevant conflicts of interest to declare.
Heme Oxygenase 1-Induced Resistance to Imatinib In Chronic Myelogenous Leukemia Cells
Authors: Tibullo Daniele , Barbagallo Ignazio , Branca Antonio , Giallongo Cesarina , La Cava Piera , Li Volti Giovanni , Palumbo Giuseppe A , Motterlini Roberto , Vanella Angelo , Di Raimondo Francesco
Published: October 2019

Abstract 4410

Heme oxygenase 1 (HO-1) is the rate-limiting enzyme in heme degradation leading to the generation of free iron, biliverdin and carbon monoxide (CO). In this study, K562 cells were incubated for 24 h with imatinib (1 μM) alone or in combination with: 1) cobalt protoporphyrin (CoPP, 10 μM), a potent inducer of HO-1; or 2) tin mesoporphyrin (SnMP, 10 μM), an inhibitor of HO activity. CoPP was able to overcome the inhibitory effect of imatinib while SnMPP restored the cytotoxicity. Interestingly, neither bilirubin nor CO (using the CO-releasing agent CORM-3) were able to protect K562 cells from imatinib-induced toxicity. The protective effect of CoPP was mitigated by addition of a protease inhibitor (Ed64), which was able to stop HO-1 nuclear translocation. We also analyzed 96 kinase genes and found that addition of CoPP in combination with imatinib leads to at least seven kinases being significantly increased while the expression of these genes was reduced in cells treated with imatinib alone or in the presence of SnMP. All of them are able to activate mitogenic signals. We also found that 1 μM imatinib was able to increase the formation of cellular reactive oxygen species and this effect was inhibited by CoPP and restored in presence of SnMP. In conclusion, the protective effect of HO-1 on imatinib-induced cytotoxicity does not involve the action of its catabolites, but rather a translocation of HO-1 to the nucleus after proteolytic cleavage. Migration to the nucleus activates several kinases able to induce mitogenic signals thus enabling HO-1 to reduce oxidative stress induced by imatinib.

Disclosures:

Di Raimondo: celgene: Honoraria.
GeneXpert Essay for BCR-ABL Compared to RT-PCR for Clinical Management of CML
Authors: Pica G. , Catania G. , Castelli F. , Repetto C , Carella A. M. , Mussap M.
Published: October 2019

Abstract 4416

Reverse transcriptase-polymerase chain reaction (RT-PCR) is considered the most sensitive method available for detecting low copy numbers of the BCR-ABL gene fusion. The difference between the BCR-ABL Ct (threshold cycle) and ABL Ct is expected to represent the ratio of the two populations of mRNAs and ultimately the percentage of neoplastic cells present.

An international scale (IS) has been proposed for BCR-ABL RQ-PCR measurements. To enable testing centers to gain access to the IS, the Adelaide laboratory initiated a process to develop and validate laboratory-specific conversion factors (CFs) that can be used to convert local values to IS values. Recently, Cepheid introduced its GeneXpert-based assay for the identification of the BCR-ABL gene fusion in cells from blood samples. This system comprises a walkaway self-contained instrument that combines cartridge- based microfluidic sample preparation with reverse transcriptase-polymerase chain reaction-based fluorescent signal detection and BCR-ABL and ABL Ct determination. The CF provided by Cepheid for this procedure is 0.47. We tested this BCR-ABL fusion detection system, compared with a classical RT-PCR analysis as a clinical diagnostic tool for CML patients.

We tested 19 patient peripheral blood samples by both methods. The negative control group included 3 blood samples, obtained from 3 patients with hematological disorders unrelated to BCR-ABL gene fusion: one with essential thrombocythemia, one with chronic myelomonocytic leukemia, one with T-cell-prolymphocytic leukemia. The remaining 16 clinical samples belonged to 12 patients with an established diagnosis of CML in chronic phase and to one patient with Philadelphia chromosome-positive acute lymphoblastic leukemia (p210).

GeneXpert software reported as negative 2 samples with a numerical threshold limit calculated on Ct (i.e. BCR-ABL was not detected at a detection limit of 0.00046%); the 3rd negative control was indicated as BCR-ABL invalid: this result was probably due to the high proportion of ABL detected as consequence of hyperleukocytosis (WBC 559,6 × 109/L) in T-Cell prolymphocytic leukemia patients. Therefore, the performance of GeneXpert test in this series was: Sensitivity 100%, Specificity 0,66%, Positive Predictive Value 100%, Negative Predictive Value 100%.

Among the series of 16 true positive samples GeneXpert revealed mean 8,67; mean standard deviation 27,55; median 1,48. Whereas in the same series RT-PCR results were: mean 37,09; mean standard deviation 59,33; median 3,37.

In conclusion GeneXpert essay for BCR-ABL could be an important tool for diagnose and monitor CML but require complete clinical data for the correct interpretation of results.

Disclosures:

No relevant conflicts of interest to declare.
Role of ABL Gene Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib and Results of Treatment Shift to Second-Generation Tyrosine Kinase Inhibitors
Authors: Marce Silvia , Zamora Lurdes , Cabezon Marta , Xicoy Blanca , Boqué Concha , Dominguez Diana , Ribera Jordi , Fernandez Cristalina , Rodriguez Lluis , Portal Imma , Plensa Esther , Velez Patricia , Medina Jorge , Grau Javier , Xandri Marisol , Navarro Jose-Tomas , Fernandez de Sevilla Alberto , Ribera Josep-Maria , Feliu Evarist , Millá Fuensanta
Published: October 2019

Abstract 4442

Introduction:

Chronic myeloid leukemia (CML) is a model of disease in the development of targeted therapies. Tyrosine kinase inhibitors (TKIs) have transformed the approach to management of CML and have dramatically improved patients' outcome. Clinical response is obtained in the majority of patients. However, a significant proportion of patients do not achieve the optimal desirable outcome or are completely resistant to this treatment. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKIs has produced high rates of hematologic and cytogenetic response in mutated ABL patients.

The aim of this study was analyzed the presence of ABL mutations in imatinib resistant patients and determine the importance of changing to second-generation TKIs treatment as soon as failure or suboptimal response is recognized.

Patients and methods:

From 420 CML patients diagnosed in 6 centers between 2004 and 2010, we have amplified and sequenced the ABL1 domain from BCR-ABL1 amplicon of 45 imatinib resistant patients (23 patients with suboptimal response, 14 with treatment failure, 4 who lost the molecular response and 4 patients who progressed to blast phase). The obtained sequences were compared with the published ABL1 sequence, GenBank U07563, using BLAST 2 software.

Results:

We have detected mutations in 15 of 45 patients (33%), some of them with more than one mutation (Table 1). Seven of these patients were treated with second-generation TKIs as a single treatment. Three of them achieve a major molecular response (MMR), one patient is in complete cytogenetic response (CCyR) and the other two patients are in major (MCyR) and partial (PCyR) cytogenetic response. Another patient received nilotinib followed by hematological stem cell transplantation (HSCT) and is in MMR. Two patients were submitted to a HSCT and achieve MMR. Only one patient treated with nilotinib as second option has not reach a cytogenetic response one year after detection of the mutation.

Two of the patients with the T315I mutation were treated with IFN and nilotinib achieving PCyR and MCyR, respectively, and are still alive. The other T315I patient, and two patients in blast-crisis (BC) disease with the F317L mutation who received dasatinib prior to the study of ABL mutations, died before a change of treatment could have been performed.

Conclusions:

Disclosures:

No relevant conflicts of interest to declare.
Rearrangements of 12p in Acute Myeloid Leukemia (AML) Remain a Significant Adverse Prognostic Marker When Patients Are Treated with Stem Cell Transplantation
Authors: Walter Claudia Ulrike , Almhareb Fahed , Chaudhri Naeem A. , Zahrani Hazzaa Al , Chebbo Wahiba , Ibrahim Khalid , Bakr Mohammad , Mohamed Said , Rasheed Walid , Alsharif Fahad , Aljurf Mahmoud , Albitar Maher
Published: October 2019

Abstract 4464

Background:

Alterations of the short arm of chromosome 12, most often resulting in loss of chromosomal material, are a recurrent feature in myeloid malignancies and occur in about 5 % of cytogenetically abnormal AML. Chromosomal abnormalities of 12p in AML have been reported to be associated with a non-favorable outcome. However, it is unclear how dismal the outcome is, as AML with 12p abnormalities is variably included in the intermediate or poor prognosis groups. Moreover, the role of allogeneic hematopoietic stem cell transplantation (HSCT) on outcome of patients with 12p abnormalities is not known. We investigated whether HSCT can improve the poor survival of patients with 12p abnormalities.

Method:

Bone marrow conventional cytogenetic and FISH data from 110 adult AML patients was reviewed and patients were divided into three cytogenetic risk groups according to the European LeukemiaNet reporting system while separating the patients with 12p aberrations into one independent fourth group. We also compared outcome of the 12p group with to the intermediate group alone or after combining intermediate with favorable, since there was no significant difference between the favorable and the intermediate groups. The AML cohort included 62 (56%) patients treated in their first remission (CR1) while most non-CR1 AML patients were treated with HSCT in CR2. The median age of all patients was 25 years (range: 14–58).

Result:

Patients with 12p abnormalities were 4 (4%). Patients with 12p abnormalities had a significantly shorter overall survival (OS) (P=0.03) and event-free survival (EFS) (P=0.04). Their outcome was similar to the adverse-risk cytogenetic group, and survival was significantly shorter than in the intermediate group (P=0.02). The poor outcome was significant even when only patients treated with HSCT in first remission were considered. All four patients with 12p abnormalities were treated with HSCT in CR1.

Conclusion:

Although the number is small, this data suggests that 12p chromosomal changes in AML are significant adverse abnormalities, not different from complex cytogenetics, and treatment with HSCT does not change this dismal outcome. This also suggests that for patients with 12p abnormalities, alternative therapeutic approaches should be considered.

Disclosures:

No relevant conflicts of interest to declare.
A Clinical Study on Double-Unit Umbilical Cord Blood Transplantation in Adults with Hematologic Disease
Authors: Ma Xiao , Depei Wu , Sun Aining
Published: October 2019

Abstract 4486

Objective:

In this study, we explored the efficiency and toxicity of 46 cases of double-unit CBT in adults with hematologic disease.

Methods:

The tolerance; transplant related complications; survival rate and disease free survival rate were observed and analyzed. A nonmyeloablative conditioning regimen included cyclophosphamide, fludarabine and 2Gy TBI. Cyclosporine combined mycophenolate mofetil and ATG were used to prevent graft versus host disease (GVHD).

Results:

All these 46 patients tolerated the therapy well while four patients had graft failure. Severe acute GVHD was presented in 6 patients. Chronic GVHD was occurred in 18 patients. Fatal infection complications were occurred in 7 patients (including CMV idiopathic pneumonia in 2 patients) and 5 patients relapsed after transplantation. Neutrophil engraftment obtained on day +17 and platelet reconstitution occurred on day +42 on median. In the follow-up duration of 29 months on median, the expected 3-year relapse mortality was 16.7%; non-relapse mortality was 26.1%; overall survival was 57.7%, and disease free survival was 48.2%.

Conclusion:

The use of double-unit CBT after reduced intensive conditioning therapy in adults with hematologic disease is an effective and safe treatment. Fatal infection and relapse are the main reasons of failure.

Disclosures:

No relevant conflicts of interest to declare.
Total Body Irradiation (TBI) or Busulfan (Bu) Plus High Dose Melphalan After Bortezomib (Bz) Containing Regimen As Front Line Treatment of High Risk Multiple Myeloma (MM) Patients with 17p Deletion and/or t(4;14) Translocation
Authors: Arnulf Bertrand , Szalat Raphael , Karlin Lionel , Harel Stephanie , Asli Bouchra , Malphettes Marion , Soulier Jean , Fermand Jean Paul
Published: October 2019

Abstract 4501

Despite recent improvement of overall survival of MM due to the use of novel agents, the high risk sub group of patients, especially with 17p deletion and/or t(4;14) still have a poor prognosis. New therapeutic strategies are needed to improve this outcome. We report preliminary results of a study using TBI or intravenous Bu to reinforce the high dose Melphalan after a Bz containing regimen as induction therapy in patients with 17p- and/or t(4;14) MM.

Between 01/2009 and 08/2010, twenty three patients (7F and 16M, median age 55 years) were treated. At diagnosis, anemia and hypercalcemia and renal failure were noted in 14, 8 and 4 patients, respectively. The median percentage of bone marrow plasma cell was 30% and 10 (43%) had an IgA isotype. One patient had a light chain MM (65g/dl), a plasma cell leukemia was diagnosed in one patient and one patient presented with specific fever and biological inflammatory features. A 17p deletion and t(4;14) translocation were detected, using RQ-PCR and FISH analysis, in 7 and 17 patients, respectively with one patient harboring the two abnormalities. Patients were treated with a median of 3 cycles of the VTD (Bz/Thalidomide/dexamethasone) combination, 12 received a PAD regimen (Bz/doxorubicine/dexamethasone) and 1 had 4 cycles of VD (Bz/ dexamethasone). High dose therapy consisted in Melphalan 140 mg/m2 associated with Bu in 16 patients and TBI in 7 patients. Thirteen patients (4 with 17p- and 9 with t(4;14) had a consolidation with 4 cycles of VTD (n=11) or TD (n=2).

Grade >2 mucositis and gastrointestinal toxicity was noted in all patients treated with TBI but Bu was well tolerated. No patient died early from toxicity. One patient had a reactivation of a virus B hepatitis and one patient had a peripheral thrombocytopenia 3 months after HDT. No venous occlusion disease was observed. Overall response rate after high dose therapy (HDT) was 91% (21/23) including 9 VGPR, 6 CR+nCR and 6 PR. Consolidation treatment led to an improvement of response in 4 patients. Nine patients relapsed, including 6 within 6 months after HDT and 3 at 8,9, and 10 months, respectively. At analysis, five patients had died, all because of progressive disease, and 14 patients (10 CR and 4 VGPR) patients were still in first remission.

Although a larger number of patients and additional follow up are needed, these data suggest that intensifying high dose therapy regimen is feasible and correctly tolerated in pts with high risk MM, especially using intravenous Busulfan, and may be an interesting approach to improve the current poor prognosis of patients with 17p deletion and/or t(4;14).

Disclosures:

No relevant conflicts of interest to declare.
Promising Efficacy with the 308 Nm Excimer Laser Phototherapy in Early Stage Mycosis Fungoides
Authors: Deaver Darcie , Cauthen Ashley , Cohen George , Sokol Lubomir , Glass L. Frank
Published: October 2019

Abstract 4990

Background:

Mycosis fungoides is the most common type of cutaneous T-cell lymphoma. Early stage disease is effectively managed with skin directed therapies such as UV light and topical steroids. Excimer laser (EL) delivers monochromatic, UVB light at a wavelength of 308 nm via hand held device that covers an area of 2 × 2 cm. It generates a short-pulse radiation that is concentrated on an affected area of skin, thereby allowing a delivery of higher dose on precisely targeted tissue. In contrast to other phototherapy techniques such as narrow band UV light, the EL is ideally suited for patients with small number of patch lesions. Although EL was successfully utilized in the management of psoriasis and vitiligo, there is not extensive experience with this modality in patients with CTCL.

Objectives:

To assess safety and efficacy of EL therapy in patients with early stage MF who failed ≥1 skin directed therapy.

Design and Methods:

This is a retrospective analysis of seven consecutive patients with stage 1 MF treated with EL phototherapy between January 2011 and August 2011 in a single institution. Seven patients with histologically confirmed common type MF, and one patient with folliculotropic MF received 308 nm EL therapy after failure of at least one prior skin directed therapy. The median age was 48 years (range 24–77 yrs). Four (57%) were male, 3 (43%) were female, six (86%) were Caucasian, and 1(14%) were African American. Biopsies and photos were obtained at diagnosis and after the completion of 24 treatments.

Results:

Treatment was initiated at a dose of 200 millijoules (mJ) and was increased by 10–15% each subsequent treatment. The max dose of treatment ranged from 240 mJ to 850 mJ. The total number of administered treatments was 24 delivered over period of 3 months. The median number of treated lesions was 2 (range 1–5). The surface area of treated lesions was <10%. Six patients achieved clinical improvement in appearance of lesions and intensity of pruritis; 2 (29%) achieved clinical remission as confirmed with photos and post-treatment biopsies. One (14%) patient developed first degree burn and 1 (14%) patient developed pruritis. These resolved by the second treatment with EL. There were no treatment-related serious adverse events observed.

Conclusion:

Our results suggest that EL is effective and well tolerated skin-directed treatment modality for selected patients with early stage MF. However, longer follow-up will be required to assess durability of responses. Advantages of this approach include shorter treatment duration and lower risk of carcinogenesis in the non-affected areas of skin. Prospective study with a larger cohort of patients is necessary to further assess efficacy and safety of this approach.

Disclosures:

No relevant conflicts of interest to declare.
Prognostic Significance of Cytogenetic Abnormalities, Serum P53 Protein Concentration, Staging, Patient Factors in Chinese Patients with Non–Hodgkin Lymphomaprognostic Significance of Cytogenetic Abnormalities, Serum P53 Protein Concentration, Staging, Patient Factors in Chinese Patients with Non–Hodgkin Lymphoma
Authors: Zhou Min , Cen Ling , Yang Jianhe , Li Jianyong
Published: October 2019

Abstract 4993

Objective:

To investigate prognostic significance of cytogenetics abnormalities, staging, patient factors, serum p53 protein concentration with Non–Hodgkin lymphoma (NHL). Methods: 43 patients with NHL were identified form August 2003 to December 2010. The clinical characteristics of these cases were performed by morphological, immunohistochemical, cytogenetic analyses and quantitative detection of human serum p53 protein were performed. Results: After conventional chemotherapy, a higher proportion of complete/ partial remission (CR/PR) rates and a prolonged overall survival (OS) in patients with early-stage(I–II) lymphoma, normal karyotype and lower level of Serum p53 protein compared with patients with advanced-stage (III–IV) lymphoma, cytogenetic abnormalities and higher p53 protein level (≥0.35U/ml) in serum, respectively. Bone marrow infiltration is also a predictor of poor response and OS. No statistical difference was noted with respect to the rate of disease remission between male versus female(<70 years versus ≥70 years), B-cell lymphoma versus T-cell lymphoma subgroups. Conclusions: Staging is an effective way of assessing disease extent; Cytogenetic examination provided useful information on diagnosis, staging and prognostic estimation; Serum p53 protein level may be a potential prognostic marker in patients with NHL.

Disclosures:

No relevant conflicts of interest to declare.
Obesity Is Poor Prognostic Factor in Lower Risk Myelodysplastic Syndrome
Authors: Mishra Asmita , Rollison Dana E , Al Ali Najla H , Corrales-Yepez Maria , Epling-Burnette Pearlie K , Lancet Jeffrey E. , List Alan F. , Komrokji Rami S.
Published: October 2019

Abstract 5018

Background:

Obesity was associated with a more than 2-fold greater risk of myelodysplastic syndrome (MDS) in a recent epidemiological study (Ma et al, Am J Epidemiol. 2009 June 15; 169(12): 1492–1499). The impact of obesity on outcome of disease in patients with an established diagnosis of MDS has not been studied. We examined the prognostic value of obesity in a large cohort of lower risk MDS patients treated at the Moffitt Cancer Center (MCC).

Methods:

Data were collected retrospectively from the Moffitt Cancer Center (MCC) MDS database and individual charts reviewed. The primary objective was to evaluate the impact of obesity on overall survival (OS) in lower risk patients with MDS. Patients with low or intermediate-1 (int-1) risk disease by International Prognostic Scoring System (IPSS) were included. Obesity was defined as a body mass index (BMI) ≥ 30 (Standard definition) measured at time of referral to MDS program at MCC. Patients were divided into two groups according to BMI ≥ 30 or BMI < 30. All analyses were conducted using SPSS version 19.0. Chi square and independent t-test were used to compare baseline characteristics between the 2 groups for categorical and continuous variables, respectively. The Kaplan–Meier method was used to estimate median overall survival. Log rank test was used to compare Kaplan–Meier survival estimates between two groups. Cox regression was used for multivariable analysis.

Results:

Between January 2001 and December 2009, 479 low/int-1 IPSS risk MDS patients were included. Among those, 132 (27.6%) had BMI ≥ 30 and 325 (67.8%) had BMI <30; BMI was missing in 22 patients (4.6%). The baseline characteristics between the two groups were comparable. No difference was noted in mean age, WHO subtype, karyotype, MD Anderson risk model group, red blood cell transfusion dependency (RBC-TD), or serum ferritin (Table-1).

The median OS was 59 mo (95%CI 48–70) in patients with BMI <30 compared to 44 (95%CI 38–50) in patients with BMI ≥ 30. (p=0.03). There was no difference in rate of AML transformation according to BMI, 12.9% and 15.7% respectively for BMI ≥ 30 and BMI <30. (P=0.3). In Cox regression analysis obesity predicted inferior OS (Hazard ratio (HR) 1.7 (95%CI 1.15–2.4) (P=0.007) after adjustment for age, MD Anderson risk group, serum ferritin, RBC-TD, use of hypomethylating agents and tobacco use.

Conclusion:

Our data suggest that obesity is an independent adverse prognostic factor for OS in patients with lower risk MDS. Obesity may be associated with other comorbidities and metabolic dearrangements that contribute to the pathogenesis of the underlying disease.

Disclosures:

No relevant conflicts of interest to declare.
Overall Survival by Prognosis Score in High-Risk Myelodysplastic Syndromes (MDS) Patients Receiving Decitabine Treatment: Results From Clinical Experience
Authors: Iastrebner Marcelo , Jang Jun Ho , Kim Kihyun , Jung Chul W. , Nucifora Elsa , Sackmann Federico , Orlando Sergio , Klein Graciela , Garcia Juan , Belli Carolina , Quiroga Luis , Santini Fernando , Bernard Haydee i , Salvatierra Lino , Taborda Gustavo , Bengió Raquel
Published: October 2019

Abstract 5024

Background The DNA-targeted hypomethylating agent, decitabine, has made a real impact on response rate in Myelodysplastic Syndromes (MDS) patients, and may improve overall survival in high-risk patients. Aim: To describe overall survival by prognosis score in decitabine-treated MDS patients. Methods: From May 2007 to January 2011, MDS patients who received decitabine were followed at centers in Argentina and South Korea. Patients ≥18 years of age with de novo MDS (all WHO Subtypes and CMML type-1 and type-2) were included, provided they had received ≥4 cycles of decitabine (recommended dose, 20 mg/m2 IV over 1 hour × 5 days every 4 weeks) and had stable disease or better by IWG 2006 criteria. Median life expectancy was determined according different categories of the MD Anderson and International Prognostic Scoring Systems (MDAPSS and IPSS). Decitabine treatment was effective when the patient outlived the median life expectancy. Results: Sixty-one patients received ≥4 cycles of decitabine and had stable disease or better. Median age was 61 years and 69% were male. All patients had de novo MDS with ECOG ≤2. Median time from MDS diagnosis was 24 months. Baseline WHO classification was: RA (0%); RARS (2%); RCMD (18%); RCMDRS (3%); RAEB-1 (13%); RAEB-2 (30%); MDS/MPD (2%); AML/MDS (5%); CMML type-1 (21%); and CMML type-2 (6%). Forty one percent had comorbidities. Patients received a median of 8 cycles of decitabine (range, 4–18). Forty four percent died during the study and 31% progressed to AML. Median overall survival was higher than life expectancy among patients with high-risk MDS by MDAPSS (Kantarjian H. et al. Cancer 2008; 113: 1351) and by IPSS (Greenberg P. et al. Blood 1997; 89: 2079). Survival exceeded life expectancy for 90%, 100%, and 86% of patients with MDAPSS 7–8, MDAPSS ≥9, and IPSS Int-2 + High, respectively. Conclusion: High-risk MDS patients who received ≥4 cycles of decitabine and had stable disease or better showed improvement in survival compared with predicted life expectancy published in literature.Median OS, MonthsPredictedActual*p-ValueMDAPSS (N=61)0–454395–625697–81431> 96230.014IPSS (N=58)Int-14237Int-2 + High14 to 5290.001*Kaplan-Meier and log-rank Test (Mantel-Cox).

Disclosures:

No relevant conflicts of interest to declare.
TET2 mRNA Expression in Bone Marrow Mononuclear Cells of the Patients with Myelodysplastic Syndromes and it's Clinical Significances
Authors: Shao Zonghong , Wang Wei , Fu Rong , Wang Jun , Li Lijuan , Ruan Erbao , Qu Wen , Liang Yong , Wang Guojin , Wang Xiaoming , Liu Hong , Song Jia , Wu Yuhong , Xing Limin , Guan Jing , Wang Huaquan
Published: October 2019

Abstract 5036

Objective

This study was aimed to investigate the expression of TET2 mRNA in the bone marrow mononuclear cells(BMMNC)of patients with myelodysplastic syndrome(MDS)and its clinical significance.

Methods

The mRNA expression of TET2 in bone marrow mononuclear cells(BMMNC) of 25 patients with MDS and 16 controls were detected by RT-PCR. Results The expression of TET2 mRNA in BMMNC was down-regulated in MDS (0.9509±0.3841)compared with that in controls(1.2515±0.3749)(P<0.05), but was no significant difference of BMMNC expression of TET2 among RA, RCMD and RAEB. Patients with higher expression of TET2(≥0.9) presented significantly lower proportion of bone marrow blasts[(1.04±1.68)%] than that [(6.13±8.17)%] of those with lower expression (<0.9) of TET2 (P<0.05). The expression of TET2 mRNA in BMMNC of MDS patients was inversely correlated with malignant clone burden (r=-0.398,P<0.05) and IPSS (r=-0.480,P<0.05).

Conclusions

The mRNA expression of TET2 in BMMNC of MDS patients decreased, which might useful as an important indicator for the evaluation of MDS clone burden.

Disclosures:

No relevant conflicts of interest to declare.
Pulmonary Hypertension May Be a Relevant Comorbidity in Patients with Myelodysplastic Syndromes
Authors: Kqiku Xhylsime , Kovacs Gabor , Reitter Sonja , Sill Heinz , Olschewski Horst
Published: October 2019

Abstract 5039

Background:

Pulmonary hypertension (PH) is characterized by elevated pulmonary arterial pressure and increased pulmonary vascular resistance, leading to right-sided heart failure and death. PH is defined as an increase in mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest. PAP values can be non-invasively estimated by Doppler echocardiography while right heart catheterization is needed for definite diagnosis. Hematologic disorders are associated with PH but it is unknown if myelodysplastic syndromes (MDS) bear an increased risk for PH. The objective of this study was to investigate the prevalence of PH in patients with MDS.

Patients and Methods:

From March 2009 to July 2011 consecutive MDS patients were recruited from the Hematology Division of the Medical University of Graz and enrolled in this PH screening program. All patients underwent Doppler echocardiography. PH was suspected if resting systolic pulmonary arterial pressure (SPAP) exceeded 40 mmHg.

Additionally six minute walk distance (6MWD), pulmonary function test (PFT), laboratory tests including N-terminal pro brain natriuretic peptide (NT-proBNP), IPSS Score and WHO functional class were determined.

Results:

Fourty four MDS patients (female:male=18:26, age 70±12 years, disease onset 5±8 years, NYHA functional class I:II:III:IV=21:16:7:0, IPSS low/intermediate-I/intermediate- II/high/unknown=16:14:8:3:3; hemoglobin: 11±2 g/dl, white blood cell count 4±3 g/l; platelet count 159±125 g/l; regular transfusions n=19; WHO Classification: RCUD/RARS/RCMD/MDS del(5q)/RAEBI/RAEB II/MDSU=2:3:21:2:6:6:4 ) were included.

Six patients had elevated SPAP (PH group, SPAP: 56±9mmHg) vs. 38 patients with normal values (SPAP 29±5mmHg). PH group were slightly older (79±9 vs. 69±11 years, p=0.53), had a decreased right ventricular function (TAPSE: 18±5mm vs. 22±4mm, p=0.05), a larger left atrium (46±5mm vs. 36±9mm measured in the parasternal long axis, p=0.005), a slightly decreased left ventricular systolic function (fractional shortening: 30±11% vs. 38±9 %, p=0.1) a significantly lower 6MWD (275±117m vs. 438±105m, p=0.01) and higher NT proBNP (4515±4732 pg/ml vs. 313±252 pg/ml, p=0.001) than patients with normal SPAP. In 4/6 PH group patients a relevant diastolic dysfunction of the left ventricle was suggested by echocardiography.

Conclusion:

According to our data, PH is present in about 15% of MDS patients and is associated with decreased physical capacity and heart failure. This suggests that PH may be considered as a relevant comorbidity in this cohort of patients. The reason of PAP increase may be multifactorial, postcapillary factors probably playing a relevant role.

Disclosures:

No relevant conflicts of interest to declare.
Azacitidine Is Feasible and Safe in Patients with MDS and Co-Existing Plasma Cell Dysplasias (PCD) - Report on 9 Patients From the Austrian Azacitidine Registry (AAR)
Authors: Auberger Jutta , Pleyer Lisa , Weiss Lukas , Egle Alexander , Greil Richard
Published: October 2019

Abstract 5056

Azacitidine (AZA) has been approved for the treatment of higher-risk MDS and therefore marks a cornerstone in the development of hypomethylating agents. Recent clinical trials raise questions regarding optimal sequencing and also about combining hypomethylating agents with other classes of drugs targeting epigenetic processes. It has been postulated that unspecific demethylation of promotors may lead to the activation of oncogenes, and therefore result in an elevated rate of secondary malignancies.

We report on 9 patients from the Austrian Azacitidine Registry (AAR) with co-excisting plasma cell dyscrasias (PCD) receiving treatment with AZA for MDS. Six male and 3 female patients had a median age of 73 years at time of diagnosis of MDS and 73 years at time of diagnosis of PCD. They were diagnosed with Waldenstrom macroglobulinemia (WMG) (n=3), multiple myeloma (n=2) and MGUS (IgG (n=2), IgM (n=1), IgA (n=1)). All PCD were diagnosed either before or at least at the same time as MDS. None occurred after diagnosis of MDS or after treatment initiation with AZA. However, one patient with multiple myeloma likely had treatment–related MDS due to prior treatment with MPT (melphalan, prednisone, thalidomide).

At the time of writing, the mean number of AZA cycles given was 9 (range 1–27). Two patients were concomitantly treated with Rituximab (R) whilst on AZA treatment. Importantly, no additional toxicities occurred and there seemed to be no negative interaction between Rituximab and AZA. In all patients treated with AZA for MDS, M-gradient remained stable, and in some cases significant improvement was noted. One patient even achieved complete remission of WMG following AZA/R treatment (data will be shown; Weiss L et al, J Clin Oncol. 2011 Jul 25 [Epub ahead of print]). Importantly, no progression of PCD was seen in any of the 9 patients treated with AZA, and PCD did not contribute to death in any of these patients.

In conclusion, AZA treatment of MDS in patients with co-existing PCD seems safe, combination with Rituximab seems feasible, no aggravation of PCD was seen and remarkably, one patient with WMG achieved CR following AZA/R.

Disclosures:

Pleyer: Celgene: Research Funding. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.