bluuebunny/crossref_metadata_2025_split 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
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
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
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
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
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
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
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
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
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.