bluuebunny/crossref_metadata_2025 huggingface dataset:
First-Line Radio-Immunotherapy of Newly Diagnosed, Advanced Follicular Non-Hodgkin Lymphoma with 131I-Rituximab: The INITIAL Study,
Authors: McQuillan Andrew D , Macdonald William BG , Leahy Michael F , Turner J Harvey
Published: October 2019

Abstract 3719

Introduction:

Radio-immunotherapy (RIT) with 131I-rituximab has demonstrated efficacy in relapsed and refractory non-Hodgkin lymphoma (NHL). 131I-tositumomab has been shown to be an effective first-line agent in follicular NHL with durable response. We aimed to evaluate the efficacy and safety of first-line 131I-rituximab RIT and the duration of response in previously untreated patients with follicular NHL, given that this radiolabeled chimeric antibody treatment can be repeated upon relapse.

Methods:

Fifty consecutive patients with newly diagnosed, symptomatic, advanced follicular NHL received a prescribed therapy activity of 131I-rituximab predicated upon a fixed, whole-body radiation dose of 0.75 Gy. All patients were treated as outpatients. All patients received a standard four-week course of rituximab at a dose of 375 mg/m2 in conjunction with the radionuclide therapy, and subsequent rituximab maintenance at 3-monthly intervals for one year. Response was determined by 18F-FDG PET/CT scans at baseline, and at 3 and 12 months post-treatment.

Results:

Overall response rate (ORR) at 3 months was 98%, with complete response (CR) seen in 38 patients (76%) and partial response (PR) in 11 patients (22%). Four patients (36%) assessed as having PR at 3 months converted to CR in the year following treatment, so that 84% of patients were in CR at one year. During median follow-up of 33 months (range 12–61 months) only one patient (2.6%) among those who had achieved CR has relapsed, while progressive disease has been seen in seven patients (64%) of those with PR at first post-treatment assessment. Only three of the seven patients with PD have so far required further treatment; one with local radiotherapy and two who have received combination chemotherapy. Median progression-free survival (PFS) has not yet been reached. Toxicity was limited to hematological Grade 4 neutropenia in 5 patients (10%) and thrombocytopenia in 5 patients (10%). One patient received a single platelet transfusion. There were no episodes of bleeding or infection. Three patients have died; one from transformed, aggressive NHL (the only non-responder) and the other two from non-hematological malignancies not apparent at study entry.

Conclusion:

First-line 131I-rituximab RIT of advanced follicular NHL is effective and safe. Early response rates are similar to those observed with combination chemotherapy and rituximab regimens. Durable CR is present in 82% of patients over a median follow-up of 33 months and median PFS has not yet been reached. Of those with documented PR at 3 months, approximately one-third subsequently converted to CR, while the remaining two-thirds developed PD.

Disclosures:

Off Label Use: radiolabelled rituximab.
Pretreatment with Anti-CD3 Monoclonal Antibody Depletes Recipient CCR7+ Dendritic Cells and Prevents Graft-Versus-Host Disease While Preserving GVL Effects,
Authors: Liu Can , He Wei , Li Xiaofan , Johnston Heather F , Wang Miao , Racine Jeremy , Martin Paul J , Forman Stephen , Zeng Defu
Published: October 2019

Abstract 4024

Administration of anti-CD3 after allogeneic hematopoietic cell transplantation (HCT) has been applied in humans to directly prevent alloreactive donor T cell activation/expansion and prevent as well as treat graft versus host disease (GVHD), but the results are discouraging. We recently reported that anti-CD3 treatment of recipients before allogeneic HCT prevented GVHD and preserved strong GVL effects in mice, but the mechanisms remained unclear. Moreover, the applicability of this approach in humans is limited by cytokine storm syndrome induced by FcR-binding anti-CD3 mAb. In the current studies, we observed that treatment with anti-CD3 seven days before HCT did not reduce donor T cell activation/expansion but markedly reduced donor T expression of tissue-specific homing and chemokine receptors (i.e. gut homing α4β7 and CCR9 or skin homing E-ligand, P-ligand,CCR4, and CCR10) and prevented donor T migration into GVHD target tissues. Furthermore, recipient CCR7+ dendritic cells in the mesenteric and peripheral lymph nodes were required to induce donor T expression of tissue-specific homing and chemokine receptors. Anti-CD3 treatment before HCT depleted the host CCR7+ DCs in lymph nodes via induction of apoptosis. Thus, activated donor T cells were confined to lympho-hematopoietic tissues in the recipient where they could mediate GVL effects, but they could not migrate into recipient epithelial tissues where they would otherwise cause GVHD. Reinfusion of DCs from PBS-treated recipients into anti-CD3-treated recipients restored the presence of CCR7+ DCs in the lymph nodes, induced donor T expression of homing and chemokine receptors, and induced GVHD. These results demonstrate that depletion of host CCR7+ DCs in lymph nodes after anti-CD3 treatment plays an important role in preventing GVHD while preserving GVL effects. Additionally, injection of FcR-non-binding anti-CD3 IgG3 before treatment with FcR-binding anti-CD3 prevented cytokine storm syndrome without reducing the effectiveness of GVHD prevention. We propose that similar treatment of recipients with anti-CD3 mAb could be used to prevent GVHD in humans.

Disclosures:

No relevant conflicts of interest to declare.
Dual Production of IL-2 and IFN-Gamma by CMV-Specific CD8+ T-Cells Is a Hallmark of Their Ability to Control CMV Reactivation in Patients After Hematopoietic Stem Cell Transplantation,
Authors: Kalina Tomas , Krol Ladislav , Stuchly Jan , Keslova Petra , Hubacek Petr , Pelak Ondrej , Sedlacek Petr , Stary Jan , Hrusak Ondrej
Published: October 2019

Abstract 4081

Introduction:

Depletion of cellular immunity as a consequence of conditioning before allogeneic hematopoietic stem cell transplantation (HSCT) frequently results in CMV reactivation, which may in turn lead to life-threatening infections and require timely antiviral treatment.

Methods:

We have investigated the ex vivo response of CMV-specific CD4+ and CD8+ T-cells to CMV antigen (combined CMV total lysate, pp65 and IE-1 peptide mix) in 191 samples from 118 individuals. We included patients with either high or undetectable viral loads, and those who controlled or did not control their CMV reactivations. All patient subsets were compared to healthy donors. Polychromatic flow cytometric measurements of CD154 (CD40L), intracellular cytokines (IFNγ, IL2), and a degranulation marker (CD107a) revealed the functional status of various T-cells simultaneously.

Results:

We found that dual IFNγ/IL2 producing CD8+ T-cells were significantly increased in patients controlling their CMV reactivations (average 0.33%, SD=0.4%) compared to non-controllers (average=0.02%, SD=0.07%). In contrast, CD8+ T-cells that produced IFNγ only were the most abundant subtype but they were present in a substantial number of both, controllers (average 4.36%, SD=4.8%) and non-controllers (average 1.64%, SD=3.7%). Hierarchical clustering of distinct functional signatures revealed that polyfunctional CD8+ T-cells were acting in concert with other subsets, whereas the isolated production of IFNγ by CD8+ T cells heralds insufficient collaboration with others. On a subset of patients with reactivation of CMV post HSCT, we have evaluated the sensitivity and specificity of functional signature test (n=64 samples) to predict reactivation control. When dual IFNγ/IL2 producing cells above 0.1% cut-off were considered protective, sensitivity of 75% and specificity 93% was achieved, while IFNγ-only production by more 0.3% cells had sensitivity of 88% but specificity of 73% only.

Conclusions:

Our study revealed functional signatures that are useful readout of immune monitoring. Furthermore, our data may modify the interpretation of previous studies that assessed only IFNγ.

Supported by the Czech Ministry of Health grant NS/9996-4, MZØFNM2005 and Czech Ministry of Education MSMT21620813

Disclosures:

No relevant conflicts of interest to declare.
Gonadal Function In Patients with Beta-Thalassemia Major Following Bone Marrow Transplantation,
Authors: Farsi Khalil Al , Al-Khabori Murtadha K. , Zia Fehmida , Abdul-Rahim Moez , Al-Habsi Yusra , Al-Manthari Eman , Dennison J. David , Daar Shahina
Published: October 2019

Abstract 4105

Introduction:

Conditioning chemotherapy prior to allogeneic bone marrow transplantation (BMT) can induce impairment in gonadal function. Patients with beta-thalassemia major generally undergo BMT at a young age and long-term data on its effects on gonadal function in this patient population are limited.

Aims and objectives:

To address the effect of BMT on gonadal function in long term survivors with beta-thalassemia major following successful BMT.

Materials and methods:

The hormonal profiles of gonadotrophins (LH and FSH), sex hormones (total and free testosterone in males, and 17 beta-estradiol in females) and inhibin B were assayed yearly after BMT. We analyzed data on patients who underwent BMT between January 1996 and June 2009 in whom the pubertal process should have started.

Results:

A total of 84 patients received BMT for thalassemia major; 51 (20 females and 31 males) have reached the age of puberty at the time of this analysis. Median age at transplant was 10 years (range: 3 – 17). With a median follow-up of 8 years (range: 2–15), the median age at last follow-up was 18 years (range: 13 – 26). All transplants were from matched sibling donors. Conditioning was myeloablative and consisted of: Busulfan, total dose of 600mg/m2 and Cyclophosphamide, total dose 200mg/kg (BuCy) before January 2005 and Busulfan, total dose 520mg/m2, Fludarabine, total dose 180mg/m2 and ATG, total dose 40mg/kg (BuFluATG) from January 2005 onwards. The impact of BMT appears to be different in the two sexes. 18 of 20 (80%) female patients had evidence of primary ovarian failure. Leydig cell failure was seen in only two male patients. However, injury to the germinal epithelium (as shown by low inhibin B levels which is predictive of oligo- or azoospermia) was seen in 22 of 31 (70%) male patients. A correlation was not found between the low inhibin B levels and age at BMT or type of conditioning regimen.

Conclusion:

Our data confirm that gonads in male and female thalassemic patients are affected by the cytotoxic effects of the preparative regimens of BMT, albeit at different levels. These findings emphasize the need for vigilant long term follow up of thalassemic patients post-BMT so that those requiring hormone replacement therapy can be identified and treated early. These findings are also important for pre- and post-BMT counseling.

Disclosures:

No relevant conflicts of interest to declare.
Assessing Potential Genotoxicity of Sleeping Beauty Transposition Events in T-Cell Immunotherapy by Supercomputer-Based High Throughput Profiling,
Authors: Ang Sonny O. , Maiti Sourindra , Moriarity Branden , Ossowski Martin , Andrews Kim , Tzeng Kathy , Talbot Richard , Kellar Denise , Huls Helen , Kebriaei Partow , Largaespada David A. , Champlin Richard , Hackett Perry , Cooper Laurence J N
Published: October 2019

Abstract 4174

The first-in-human clinical trial using Sleeping Beauty (SB) transposition for T-cell immunotherapy is under way at the University of Texas MD Anderson Cancer Center. To understand potential genotoxic risks involved in our non-viral SB transposition-based immunotherapy, we employed high throughput sequencing (Illumina) and profiling (BlueBioU supercomputer) of the SB insertion sites in T cells. Our SB clinical vector inserted 99.999% of the time at expected TA dinucleotide sites, with 44% of the insertions localizing to intragenic loci and the remainder 56% intergenic. The vast majority (96.5%) of intragenic insertions are intronic while the majority (>60%) of intergenic transpositions fall within non-coding repeat regions. By linking microarray gene expression profile to the vector insertion profile, we find that the number of transcriptional start sites (TSS) hit is proportional to the expected ‘open' conformational loci for the starting population of quiescent T cells. Compared to immunotherapy infusing T cells genetically modified with retrovirus, the integration profiles for SB-modified T cells are favored as: 1) there are more insertions within intergenic regions (56% SB vs. 44% in retroviral), 2) insertions concentrated at TA sites which have a different genomic distribution profile than retroviral insertion sites, 3) TSS associated with quiescent T cells were favored reflecting the electro-transfer of SB DNA plasmids into non-proliferating T cells vs. retroviral protocols that require transduction of activated T cells. Scanning for potential danger loci (e.g. oncogene, tumor suppressor, miRNA etc.), SB integration profiles compare favorably with retroviral insertions. In addition, we identified potential “safe harbor” genetic loci for future targeted modifications. Opportunities in immunotherapy and other personalized medicine modalities will be fully realized when the actual and perceived risks are understood and perhaps mitigated. In the absence of targeted insertions by clinical vectors, the next best option is random integration with an evenly distributed insertion profile across the whole genome to minimize hot spot and clonal expansion of therapeutic T cells. We now seek to proactively profile the T-cell products prior to infusion and follow up sampling to help clinicians in data-driven decision making in a time-sensitive manner. Our methods and findings are consistent with the human application of SB system and the harnessing high throughput supercomputing resources to help clinicians mitigate potential risks.

Disclosures:

No relevant conflicts of interest to declare.
ACUTE LYMPHOBLASTIC LEUKEMIA In Qatar: Clinico-Pathological PROFILE and OUTCOME
Authors: Yassin Mohamed A. , Ibrahim Firyal , Al-Badri Mina M. , El-Ayoubi Hanadi Rafii , Kamzoul Rami T
Published: October 2019

Abstract 4233

Background:

advances in immunophenotyping, cytogenic, and molecular genetics have not only considerably improved our knowledge of the pathophysiology of acute leukemia’s, but have also contributed to a refined classification of acute lymphoblastic leukemia(ALL)subtypes and outcome. With the different treatment modalities complete remission (CR) rates of 80–85%and leukemia –free survival (LFS) rates of 30–40%can be achieved in adult acute lymphoblastic leukemia (ALL).

Aim:

to study the clinico-pathological features and outcomes of adult patients patients with acute lymphoblastic leukemia in Qatar

Patients & METHODS:

thirty adult patients (age>14 years) diagnosed as all at AL-AMAL Hospital, the oncology hematology center in Qatar, the periode betweenJan06 and Jan 2011 were Retrospectively studied with respect to their clinical. morphological, immunopathologica features at presentation and their treatment outcomes, diagnosis was based on combined morphologic, immunophenotyping and cytogenetic studies.treatment protocols used were BFM mainly for adolescent patients,GMALL and UKALL 12 for adults.

RESULTS:

ALL constituting 25% of all acute leukemia cases diagnosed during the period the study. the median age was 28.5 years with a male to female ratio 21.six were Qatari and 24 non-Qatari. the most common presentation was with symptomatic anemia and fever (63.3%).laboratory features at presentation revealed.WBC.>30*109/L in13((43.3%).Immunophenotyping showed that 25(83.3%)were B-ALL, only one case9450was of the matureB-phenotype(Burkitt is),twenty two (80%) were CD10positive (common/pre Bsubtypes),two were CD10 negative PreB.non were subtype as proBALL.diagnosis of T-ALL was established in 5 (16.7%)patients.aberrantexpression was noted in14 cases (46.6%)combined expression of both CD13&CD33 being the most common seen in seven cases (50%).OUT OF THE 22 CASES 954.550.Five(22.7) had t (9.22)and one (4.5%)t (4.11).normal in

10(45.5%).thirteen patient travelled before having treatment. two pretreatment death (septic shock. two elderly patients with co morbidities were considered for palliative treatment.13patients were treated in doha, 11 out of 13 (84%)went into complete remission

(CR) and two (16%) underwent successful allogeneic bone marrow transplant abroad.

CONCLUSION:

Although.the series is small to have a final conclusion, however, this study showed that almost all of our ALL cases are of the favorable immunological subtypes (common/ pre ALL) with high CR rate.

Disclosures:

No relevant conflicts of interest to declare.
Effectiveness of Intrathecal Liposomal Cytarabine in Treatment of Childhood Hematopoietic Malignancies – Experience of Polish Pediatric Leukemia/Lymphoma Study Group
Authors: Szczepanski Tomasz , Kajdas Lidia , Pobudejska-Pieniazek Aneta , Irga Ninela , Niedzwiecki Maciej , Derwich Katarzyna , Wachowiak Jacek , Sobol Grazyna , Krupa Malgorzata , Stefaniak Jolanta , Mlynarski Wojciech , Niedzielska Ewa , Kazanowska Bernarda , Palgan Izabela , Kurylak Andrzej , Wieczorek Maria , Urasinski Tomasz , Kowalczyk Jerzy R
Published: October 2019

Abstract 4240

Introduction:

Liposomal Cytarabine for intrathecal administration is characterized by prolonged activity and better penetration to central nervous system (CNS). This makes it promising medicine for treating children with hematopoietic malignancies relapsing in CNS or refractory CNS disease.

The purpose of the Study:

The study aimed at retrospective evaluation of the effectiveness of liposomal Cytarabine (Depocyte®) administrated intrathecally as a part of the treatment of hematopoietic malignancies in Polish children.

Patients and methods:

The study group consisted of 23 patients, 11 boys and 12 girls, treated in the centers of Polish Pediatric Leukemia/Lymphoma Study Group, including 18 patients with acute lymphoblastic leukemia (ALL), 3 patients with acute myeloid leukemia (AML) and two children with high grade Non-Hodgkin’s Lymphomas (NHL). The median age of the children was 10.8 years (range: 1.3 to 18 years). Liposomal cytarabine treatment was administered on compassionate basis to 20 children with relapsed acute leukemia / NHL, a single child with secondary leukemia, one patient with severe neurotoxicity after intrathecal Methotrexate during front-line treatment and in one child with large granulocytic sarcoma, penetrating into CNS. Thirteen patients received liposomal cytarabine dosage of 50 mg, while the remaining 10 children were exposed to the doses of 25–35 mg, all in association with prophylactic dexamethasone administration. The number of liposomal Cytarabine injections ranged from 1 to 11, mean 5 doses per patient.

Results:

The clearance of CNS disease was achieved in 15 of 23 patients (65%). Eight children were alive during the follow-up procedure, including 3 patients in complete remission after treatment completion. Grade IV neurotoxicity was observed in five children, which might be also partly related to CNS malignancy. Another side effects occurred in 4 patients, including headache, vertigo, paresthesias and seizures.

Conclusion:

Liposomal cytarabine administered intrathecally is effective treatment for CNS disease in children with relapsed acute leukemia/NHL with acceptable toxicity profile.

Disclosures:

No relevant conflicts of interest to declare.
Preliminary Results of a Consolidation Therapy Consisting Single Anthracycline Agent and Alternative All-Trans Retinoic Acid in Acute Promyelocytic Leukemia
Authors: Jie Zhang , Meng Xiaojian , Cai Zhen , Ye Xiujin , Huang He
Published: October 2019

Abstract 4284

Background:

Acute promyelocytic leukemia (APL) is a subtype of acute myeloid leukemia (AML) with distinctive biologic and clinical features that is now highly curable. However, there are complicated issues in treatment strategies for induction, consolidation and maintenance that remain to be studied. The optimal regimen and the duration of consolidation is one of the above controversies.

Patients and methods:

Six patients (4 males, 2 females) were enrolled in this observation with a median age of 28 years (18–36). All were diagnosed de novo APL with demonstration of the abnormal increased promyelocytes of 53–90% accompanied with detection of t(15;17) or PML/RARα rearrangements. At diagnosis, WBC counts were 0.9–4.6×109/L and platelet counts were 13–84×109/L.

Induction therapy was composed of all-trans retinoic acid (ATRA) with or without anthracycline or homoharritonine. After achieving complete remission (CR) following the above regimens, consolidation therapy was given monthly consisting single anthracycline agent of idarubincin (8–10 mg/m2/d, day 1–3) or aclarubicin (8–12 mg/m2/d, day 1–7) and alternative ATRA (25 mg/m2/d, day 1–15). After 12–18 months of consolidation, patients received maintenance therapy including methotrexate (12 mg/m2/d, per week) plus 6 mercaptopurine (30 mg/m2/d, qod ×12 days) and alternative ATRA (25 mg/m2/d, day 1–15) for one year.

Results and conclusions:

At present, all of the six patients are in continuous CR status, four of whom ceased treatment and are undergoing regular monitoring. Preliminary results from our experience demonstrates that single anthracycline and alternative ATRA can act as a valid option with limited toxicity for APL and might be used as a consolidation strategy, particularly for low and intermediate-risk patients.

Disclosures:

No relevant conflicts of interest to declare.
Therapy of Refractory AML with Del(5q) with Low-Dose Lenalidomide
Authors: Motorin Dmitry , Goryunova Elena , Romanova Ekaterina , Girshova Larisa , Alexeeva Yulia , Nikulina Tatiana , Zaritskey Andrey
Published: October 2019

Abstract 4286

AML M-4 with >30% bone marrow myeloblasts was detected in 63 y old woman 2 mo after a diagnosis of chronic myelomonocytic leukemia (CMMLgrade 2).Â Cytogenetics showed 46, XX, del(5)(q12 q14) (N=4)/46, XX (N=18). Immune-phenotyping showed CD34+ CD117+ CD13+ CD33+ CD38+ HLADR+ CD2+. Leukemia cells were negative for inv (16), BCR/ABL, NPM, TEL/AML1, MLL/AF4, PML/RARA and AML1/ETO.Â She was RBC-transfusion-dependent. Therapy with cytarabine and daunorubicin and later with FLAG was ineffective and bone marrow myeloblasts increased to >70% with severe granulocytopenia and infection including pulmonary aspergillosis. She then received lenalidomide, 10 mg/d for 21 d every 4 w Bone marrow myeloblasts decreased to about 20% and granulocytopenia resolved. RBC-transfusionÂ–dependence decreased. Cytogenetic and FISH-testing showed no detectable cells with del(5). This has persisted for 5 mo.

Disclosures:

Off Label Use: Lenalidomide for the treatment of AML with 5q- deletion.
CAG (cytarabine, aclarubicin, G-CSF) Regimen Is Effective and Well Tolerated in 367 Elderly Patients with AML in China and Japan: A Meta-Analysis
Authors: Wei Guoqing , Liu Delong
Published: October 2019

Abstract 4290

Background:

Current therapy is still unsatisfactory in elderly patients (pts) with acute myeloid leukemia (AML). CAG regimen (cytarabine, aclarubicin, G-CSF) has been commonly used in China and Japan for the treatment of elderly AML pts. The aim of this study is to summarize the data and to analyze the efficacy as well as the toxic effects of CAG regimen in elderly AML pts.

Methods:

The databases of PubMed, Wanfang Data, as well as American Society of Hematology (ASH) annual meeting abstracts were searched for articles published in English, Chinese and Japanese languages from January 1995 to December 2010. Eligible studies were relevant clinical trials of elderly AML pts treated with CAG regimen. Complete remission (CR) rate, odds ratio (OR) and 95% confidence intervals (CIs) of chemotherapy were compared through a meta-analysis using a random-effects or fixed-effects model.

Results:

19 trials with a total of 367 elderly AML pts were identified and included for analysis. Among the 367 AML pts treated with CAG, 266 pts were newly diagnosed AML, 54 pts were relapsed/refractory (R/R) AML. The AML status was not specified in the rest 47 pts. The CR rate for the 367 elderly AML pts was 52.0% (95% CI 46.8%-57.2%). Interestingly, no significant difference in CR rates was noted between the newly diagnosed (54.7%, 95% CI 48.6%-60.7%) and R/R AML pts (45.7%, 95% CI 32.4%-59.6%) (Q=1.332, p=0.248). Three studies compared the CR rates of elderly AML pts according to the karyotype. The CR rate was significantly higher in pts with intermediate (72.4%, 95% CI 58.0%-83.3%) cytogenetics than those with unfavorable one (35.7%, 95% CI 18.7%-57.2%) (Q=7.803, p=0.005). These elderly AML pts tolerated CAG well with low cardiotoxicity (0.73%, 2/273) and ED (8.48%, 29/342).

Conclusions:

CAG regimen induced high CR rates in elderly pts with new and relapsed/ refractory AML. This regimen was well tolerated with low cardiotoxicity and early death rate.

Disclosures:

No relevant conflicts of interest to declare.
Experimental Study of As2O3 Nanoparticles in the Therapy of Acute Promyelocytic Leukemia
Authors: Liu Ziling , Dong Xiaoyan , Li Wei , Ma Ning , Liu Mengmeng , Shan Jiying , Jin Fenglan , Fan Xiuli
Published: October 2019

Abstract 4302

This paper explores the preparation of As2O3 nanoparticles and examines their antitumor effects on NB4 cells. As2O3 nanoparticles were prepared using the sol-gel method and characterized by transmission election microscopy (TEM) and energy dispersive spectrometer (EDS). The results indicated that As2O3 nanoparticles prepared in our study were round or elliptical, well dispersed, and about 40 nm or less than 10 nm in diameter. The antitumor effects of As2O3 nanoparticles at various concentrations were analyzed by the methyl thiazolyl tetrazolium (MTT) assay and flow cytometry (FCM) and were compared with those of traditional As2O3 solution. At the same concentration and incubation time (48 h), the survival rate of cells treated with As2O3 nanoparticles was significantly lower than that of cells treated with As2O3 solution. The inhibition rate under both treatments was time- and dose-dependent. In addition, at the some concentration and incubation time, the apoptosis ratio of cells treated with As2O3 nanoparticles was significantly higher than that of cells treated with As2O3 solution. Furthermore, As2O3 nanoparticles resulted in a greater reduction in the expression of the anti-apoptotic protein Bcl-2 compared with As2O3 solution. In conclusion, AS2O3 nanoparticles, prepared by sol-gel method, produce a stronger cytotoxic effect on tumor cells than As2O3 solution, possibly through inhibiting Bcl-2 expression.

Disclosures:

No relevant conflicts of interest to declare.
Antifungal Prophilaxis with Low Dose Amphotericin B Lipid Complex In Patients with Acute Myeloid Leukaemia: A Single Centre Experience
Authors: Veggia Barbara , Saltarelli Francesca , Montefusco Enrico , Conte Esmeralda , Antolino Giusy , Porrini Raffaele , Monarca Bruno , Ferrari Antonella
Published: October 2019

Abstract 4303

INTRODUCTION

Invasive fungal infections (IFI) represent an important cause of mortality and morbidity in patients with Acute Myeloid Leukemia (AML) undergoing intensive chemotherapy. A prophylactic antifungal therapy is often administered during intensive chemotherapy, however the optimal antifungal prophylaxis protocol is still unknown. Amphotericin B lipid complex (Abelcet®) has been commonly used as a standard treatment for IFIs caused by Aspergillus and Candida, but its effectiveness in prophilaxis has not been clearly estabilished.

METHODS

From September 2010 to April 2011 we treated six patients with newly diagnosed AML using low dose amphotericin B lipid complex as antifungal prophilaxis. Patients observed were three females and 3 males, median age was 54 years (range 21–74 years) and they were all fit to receive intensive chemotherapy. Three patients older than 60 years received Fludarabine based chemotherapy regimen during both induction and consolidation. Three patients aged less than 60 years old were treated using a chemotherapy protocol based on Citarabine, Daunorubicin and Ethoposide association. One patient in this group also underwent BuCy conditioned autologous stem cell transplant. Amphotericin B lipid complex was administered intravenously at 100 mg once a day. Antifungal prophilaxis was started when the absolute neutrophil count was ≤ 500 cells/μ l and was continued until neutrophils recovery was ≥ 500 cells/μ l, without any evidence of IFI.

RESULTS

Five patients did not experience any proven fungal infection during all treatment. Anyway one patient died during induction due to a severe bacterial lung infection. One patients discontinued antifungal prophylaxis due to extensive skin rash during the second infusion of the drug. Amphotericin B lipid complex was otherwise well tolerated by patients. One patient was diagnosed with lung aspergillosis infection by evidence of galattomannan positivity on BAL and a lung CT scan showing a single nodular escavated lesion on left upper lobe; subsequentely he was successfully treated with voriconazole.

CONCLUSIONS

In our experience, Amphotericin B lipid complex showed to be an effective and safe antifungal prophylaxis for newly diagnosed AML patients. Further clinical studies are certainly required to obtain definitive data.

Disclosures:

No relevant conflicts of interest to declare.
Generation and Optimization of a Chimeric Antigen Receptor Against CD22: A New Immunotherapeutic Agent for Treating B Lineage Leukemia and Lymphoma
Authors: Orentas Rimas J , Haso Waleed , Morgan Richard A. , Pastan Ira , Mackall Crystal L
Published: October 2019

Abstract 4313

CD22 is expressed on a number of hematologic malignancies. A recombinant immunotoxin composed of an anti-CD22 Fv fused to a 38 kDa fragment of Pseudomonas exotoxin A (Moxetumomab pasudodtox, HA22) is currently being evaluated in the treatment of B cell malignancies. We used the Fv sequence to construct a series of chimeric antigen receptors (CARs) to determine the optimal affinity, domain structure, and signaling required for optimal anti-leukemic activity. The original anti-CD22 binding domain, BL22, or a newer generation high-affinity domain, HA22, were fused to transmembrane and signaling sequences derived from the TCR zeta-chain, CD28, and CD137. In some constructs we extended the binding domain away from the membrane using constant domains from IgG (CH2CH3). Retroviral gene vectors were used to transduce activated primary T cells with CAR constructs. We found: HA22 Fv, 2 as opposed to 3 signaling motifs, and non-CH2CH3 containing CARs were superior in short-term in vitro tumor cell cytolysis assays, indicating that Fv affinity, signaling, and 3-D structure of the CAR all impact the anti-leukemic effectiveness of CARs. Finally, direct comparison to CD19-specific CAR showed an equivalent or superior killing activity in 2 out of 3 ALL lines tested. Using Scatchard analysis to define the number of CD22 moleules on the surface, the ALL line with the lowest number of CD22 molecules is also the least able to be killed by CAR-transduced T cells. The supeior lytic activity of CD19-CAR for this single cell line was due to preservation of high levels of CD19 at the cell surface. We are currently testing the in vivo activity of anti-CD22 CAR in an immunodeficient mouse model bearing human cell lines and primary patient-derived ALL. Our results indicate that CD22-CAR should be developed for the immunotherapy of CD22+ hematologic malignancies.

Disclosures:

No relevant conflicts of interest to declare.
The Analysis of Patients with Refractoriness to Platelet Transfusion Due to Anti-HLA Antibodies During the Treatment of Acute Leukemia
Authors: Takada Satoru , Koya Hiroko , Yuzuriha Akinori , Shimizu Hiroaki , Hatsumi Nahoko , Sakura Toru
Published: October 2019

Abstract 4339

Background and aim:

Refractoriness to platelet transfusion is one of complications during the treatment of acute leukemia. The major reason is destruction of transfused platelets by anti-human leukocyte antigen (HLA) antibodies to HLA on donor’s platelets. We investigated retrospectively the incidence and characteristics of patients with refractoriness to platelet transfusion due to anti-HLA antibodies during the treatment of acute leukemia.

Method:

From 2000 to 2010, 348 acute leukemia patients underwent chemotherapy at our hospital. Among them, we surveyed 325 patients who received platelet transfusions more than five times. Examination of anti-HLA antibodies was performed when clinically an attending physician suspected that platelet transfusion was not effective. The existence of anti-HLA antibodies were tested both lymphocyte cytotoxicity test (LCT) and anti human immunoglobulin-LCT (AHG-LCT).

Result:

Of the 325 patients, males were 186, and female were 139. Two hundred sixty-three patients and 62 patients suffered from acute myeloid leukemia (AML) and acute lymphocytic leukemia (ALL), respectively. The median age of all patients was 57 (15–86) years. All patients had received red blood cell and platelet products from which leukocytes were removed by filtration. Of all patients, 23 (7.1%) were positive for anti-HLA antibodies. The median age of patients with anti-HLA antibodies was 57(24–76) years. The number of male and female were 2(8.7%) and 21 (91.3 %), respectively. All female patients with anti-HLA antibody had a history of delivery. 8.3 % of AML patients and 1.6% of ALL patients were positive for anti-HAL antibodies.The median number of platelet transfusions until the presence of anti-HLA antibodies was 11 (4–48). The median date of anti-HLA antibodies detection was 27(8–263) days after first platelet transfusion. After detection of anti-HLA antibodies, all patients with anti-HLA antibodies received HLA-matched platelets, and fatal bleeding was not seen. History of delivery (p<0.001), AML (p=0.0147) and age over 50 years (p=0.0490) were risk factors for the presence of anti-HLA antibodies. The presence of anti-HLA antibodies had no impact for the survival (p=0.6033).

Conclusion:

During chemotherapy for the treatment of acute leukemia, 7% of patients suffered from refractoriness to platelet transfusion due to ant-HLA antibodies. The frequency was low compared with other blood disorders. Elderly AML patients with a history of delivery tended to produce anti-HLA antibodies. Patients with anti-HLA antibodies could obtain similar outcomes by using HLA-matched platelets, comparing with patients without anti-HLA antibodies.

Disclosures:

No relevant conflicts of interest to declare.
ADAMTS13 Cleavage of Von Willebrand Factor (VWF) in Commercial Concentrates and Effect on VWF Function
Authors: Fuchs Birte , Solecka Barbera , Kröning Mario , Kannicht Christoph , Schwartz Bruce A.
Published: October 2019

Abstract 4354

Objective:

The characteristic multimeric pattern of plasmatic VWF results from asymmetric cleavage by ADAMTS13. Regulation of VWF multimer distribution is critical for its physiological function. In human plasma, VWF multimer gels reveal species of various multimeric sizes with flanking satellite bands (triplets). The faster and slower migrating bands encompassing a VWF multimer lack one N-terminal fragment or possess an additional N-terminal fragment, respectively. Defects in VWF secretion, impaired assembly of multimers, or increased proteolysis can cause von Willebrand Disease (VWD). Distribution of VWF triplet bands is significantly altered in some plasma-derived VWF concentrates. The impact of triplet structure on VWF function has not been investigated so far.

Methods:

Four commercially available VWF concentrates were analyzed for ADAMTS13 content as well as VWF multimer- and triplet structure using agarose gel electrophoresis. ADAMTS13 activity was quantified by fluorescence resonance energy transfer (FRET) assay. Samples composed of different VWF triplet distribution but comparable multimers were obtained by heparin affinity chromatography. Platelet adhesion under flow was determined using a flow-chamber model.

Results:

VWF concentrates markedly differed with respect to their content of ADAMTS13 antigen and activity. A higher content of ADAMTS13 correlated with an altered triplet structure reflected by an increased presence of the faster migrating triplet band, indicating VWF proteolysis. VWF-mediated platelet adhesion under flow over time was increased using a VWF fraction predominantly containing the slower migrating triplet band.

Conclusion:

These findings suggest that an intact triplet structure has an impact on platelet adhesion at physiological high arterial shear rate conditions. The relevance of VWF N-terminal domains for platelet binding and potential clinical consequences of enhanced proteolysis in commercial concentrates has to be further evaluated.

Disclosures:

Fuchs: octapharma: Employment. Solecka:Octapharma: Employment. Kröning:Octapharma: Employment. Kannicht:Octapharma: Employment. Schwartz:Octapharma: Employment.
Successful Delivery of Patients with FXIII Deficiency on Prophylaxis in Iran
Authors: Naderi Majid , Eshghi Peyman , Cohan Nader , Yaghmaei Minoo , Miri Moghaddam Ebrahim , Sadeghi-Bojd Simin , Karimi Mehran , Hoorfar Hamid , Lak Manijeh , Narouie Behzad
Published: October 2019

Abstract 4363

Introduction

Coagulation factor XIII (FXIII) deficiency is a rare bleeding disorder with a general frequency of 1 in 2 million populations. Life-long bleeding tendencies, umbilical bleeding, defective wound healing and habitual abortions are the most important clinical problems in this patients.For prevention of abortion and pregnancy loss in severe FXIII-deficient women, replacement and prophylaxis with a source of FXIII throughout pregnancy is essential.The acceptance level of plasma FXIII level for successful delivery is above 10% as a result the administration of FXIII concentrate 250 IU weekly until 22 weeks gestation and 500 IU from 23 weeks is recommended to maintain this plasma level. The aim of this study was to evaluate the bleeding score and rate of successful delivery in Iranian FXIII deficient pregnant women on regular prophylaxis.

Material and methods

A total of 17 FXIII deficient Iranian women with age range 18–35 years old (mean 24 years old) were enrolled in this study. The first record bleeding episodes were cord bleeding in 10 patients, echymosis in 4 patients, hemarthrosis in 1 patient, hematoma in 1 patient and CNS bleeding in 1 patient. All patients had history of abortion (one abortion in 12 patients, 2 abortions in 2 patients and 3 abortions in 2 patients) except one patient. All of patients were on regular prophylaxis (10 IU every 2 weeks) for 24–62 months, every 4 weeks before pregnancy and every 2 weeks during pregnancy. The patients were followed for any bleeding episodes and also evaluated for bleeding score before and after prophylaxis according on standard form.

Results

The monochloroacetic acid test was normal in all patients during prophylaxis.

The bleeding score was significantly decreased from 11–16 (mean 12) to 1–2 (mean1.5) starting prophylaxis. Two bleeding episodes were recorded in 2 patients, one subject in 11 patients and 3 patients didn’t experience any bleeding episodes. All of patients had successful delivery at 36 weeks gestation without any significant coagulation complications.

Discussion

Pregnancy loss is a main complication in women with FXIII deficiency and prophylaxis is critical for pregnancy maintenance in these patients. In this study we experienced a successful pregnancy maintenance and delivery in Iranian women with FXIII deficiency. It is recommended to precise detection and diagnosis of FXIII in women with coagulation disorders for appropriate prophylaxis and prevention of pregnancy loss.

Disclosures:

No relevant conflicts of interest to declare.
Serial D-Dimer in Pregnancy Women with a History of Fetal Loss Syndrome and Invitro Fertilization
Authors: Atmakusuma Tubagus Djumhana , Muharam Raden
Published: October 2019

Abstract 4366

Background

We have reported in abstract P-Th-374 in a 2011 Kyoto ISTH Congress that an increased level of D-dimer in combination with umbilical artery systolic diastolic (UASD) ratio can be used as a timing to start with prophylactic anticoagulants In women with pregnancy failure, regardles of the antibody antiphospholipids (APAs) level, history of fetal loss syndrome or invitro fertilization (IVF).

The question is: Are there any differences of a serial D-dimer level if is compared to the APAs level, history of fetal loss syndrome and IVF?.

Methods.

A retrospective Cohort study was conducted on a total sampling subjects of pregnancy women who visited two hospitals in Jakarta, Indonesia, at a periode of January 2009 – December 2010. Serial D-dimer using chromogenic assay method (cut off normal level < 500 ng/ml) was tested during antenatal and post partum period. The data were analysed to compare a mean D-dimer with the level of APAs (ACA IgG/IgM, AntiB2GP1 IgG/IgM) tested using ELISA method, a history of fetal loss syndrome and IVF conception

Results

Of 83 pregnant women,19 women with high level of APAs (subgroup 1) showed a mean D-dimer level as follows: Trimester I: 892.15 ± 785.15 ng/ml, trimester II: 782.59 ± 440.53 ng/ml, trimester III:1282.62 ± 601.22 ng/ml, post partum 1367.45 ± 581.19 ng/ml; 31 women with normal APAs (subgroup 2) showed: Trimester I: 666.23 ± 396.24 ng/ml, trimester II: 896.66 ± 396.24 ng/ml, trimester II: 896.66 ± 496.32 ng/ml, trimester III: 1313.45 ± 850.20 ng/ml, post partum: 1991.75 ± 1388.70 ng/ml; 33 women with no data of APAs (subgroup 3) showed: Trimester I: 568.47 ± 482.70 ng/ml, trimester 2: 797.95 ± 934.59 ng/ml, trimester III: 966.89 ± 862.10 ng/ml, post partum: 1078.50 ± 836.29 ng/ml

Of 83 pregnant women, 47 women who have experienced 1 or ≥ 1 abortion or IUFD (subgroup 4) showed D-dimer level as follows: Trimester I:493.09 ± 385.89 ng/ml, trimester II: 740.23 ± 564.99 ng/ml, trimester III: 859.05 ± 549.88 ng/ml, post partum 1342.59 ± 1264.09 ng/ml. Meanwhile, 36 women who have no history of fetal loss (subgroup 5) showed: Trimester I: 892.17± 593.47 ng/ml, trimester II: 930.57± 807.02 ng/ml, trimester III: 1439.71 ± 932.12 ng/ml, post partum 1695.16 ± 1131.56 ng/ml.

Of 83 pregnant women, 10 women who became pregnant after embryo transfer of IVF (subgroup 6) showed: Trimester I: 493.09± 385.895 ng/ml, trimester II: 740.23± 564.99 ng/ml, trimester III:859.05 ± 549.88 ng/ml, post partum 1342.59 ± 1264.09 ng/ml.

Conclusion

Either in subgroup 1, 2, 3,4,5 and 6 mean D-dimer tend to increase from trimester I to trimester II and from trimester II to trimester III, except in subgroup 1 from trimester I to trimester II of pregnancy. Meanwhile, all groups showed a higher mean D-dimer post partum compared to antenatal period.

Disclosures:

No relevant conflicts of interest to declare.
Chemotherapy Plus Hematopoietic Growth Factor for Refractory Paroxysmal Nocturnal Hemoglobinuria: Diminishing PNH Clone and Stimulating Hematopoisis
Authors: Shao Zonghong , Dong Xifeng , Fu Rong , Qu Wen , Liang Yong , Wu Yuhong , Wang Guojin , Liu Hong , Song Jia , Wang Xiaoming , Xing Limin , Ruan Erbao , Guan Jing , Wang Jun , Wang Huaquan
Published: October 2019

Abstract 4376

BACKGROUND

Even complement inhibitor against C5 Eculizumab has been used in the treatment of paroxysmal nocturnal hemoglobinuria (PNH) acting as a “dam” protecting PNH clone and storing higher risk of hemolysis. So we carried out a study to investigate the efficacy and safety of chemotherapy plus growth factors, a traditional treatment for malignant hematological diseases, aiming at diminishing PNH clone and stimulating hematopoisis, in patients with refractory and relapsed PNH.

METHODS

10 patients were enrolled in this study. These patients were admitted into General Hospital affiliated to Tianjin Medical University(TMU) between 2006 to 2010, receiving either DAG (DNR 40mg/d, d1–2; 20mg/d, d3; Ara-C 100mg/d, d1-5; G-CSF until WBC return normal) or HAG (HHT 2–3mg/d, d1-5; Ara-C 100mg/d, d1-5; G-CSF until WBC return normal) regimen chemotherapy intravenously every 4 weeks for several cycles. The primary end points were the improvement of hemoglobin levels, decreased proportion of PNH clone and dosage of corticosteroid. Biochemical indicators of intravascular haemolysis and adverse events were also assessed.

RESULTS

All patients responded well. Overall improvement for anemia was achieved, transfusion independence(HB can keep more than 6g/L without transfusion) was achieved in 4 patients, hemoglobin levels reached normal gradually in 1 of them, 2 patients got prolonged transfusion interval, another 4 patients did not need transfusion all the time. Elevation of hemoglobin from (58.1±12.12) g/L to (90.20±21.55) g/L (P=0.000) was achieved for the 10 patients. The dosage of corticosteroid decreased significantly from (45.84±19.05)mg to (13.00±6.75)mg (P=0.000). The results of flow cytometry demonstrated that CD59− and CD55− erythrocytes and granulocytes in peripheral blood decreased significantly in 8 patients [(20.87±11.68)% vs (7.97±10.02)%, P=0.004 for CD59− erythrocytes; (63.76±25.36)% vs (28.44±23.50)%, P=0.002 for CD55− erythrocytes; (68.25±26.05)% vs (59.53±24.60)%, P=0.007 for CD59− granulocytes; (81.47±26.13)% vs (68.14±26.53)%, P=0.003 for CD55− granulocytes]. Indicators for haemolysis also improved. In 10 patients, apart from 1 patient with normal IBIL and TBIL all the time, IBIL decreased significantly from (36.8±29.2) U/L at baseline to (18.1±12.4) U/L (P= 0.015). Free hemoglobin level, Rous test, Ham ‘s test were carried out only in some of the patients and results of which were also encouraging. No patients died during chemotherapy; most common adverse events were infection, nausea, vomiting and fatigue. The duration of bone marrow depression ranged from 10 to 33 days.

CONCLUSIONS

DAG/HAG regimens Chemotherapy was an effective, safe and promising therapy for PNH.

Disclosures:

No relevant conflicts of interest to declare.