bluuebunny/crossref_metadata_2025_split huggingface dataset:
First Use of Temozolomide in Primary Intra-Ocular Lymphoma (PIOL): a Very Well Tolerated and Potentially Effective Treatment.
Authors: Mesmoudi Mohamed , Cassoux Nathalie , Leblond Veronique , Merle-Beral Helene , Baudet Sylvie , Choquet Sylvain 
Published: October 2019

Abstract
Abstract 4760

Background
PIOL is a rare subset of primary central nervous system lymphoma (PCNL), representing 5 to 20% of PCNL. It is usually an aggressive diffuse large B-cell lymphoma. There is no consensus on treatment procedures, classical attitudes are systemic chemotherapy (SC), radiotherapy or intraocular injection of methotrexate (IM). Relapse rate is high, with more than 10% of cases relapsing in brain. New treatments are necessary, especially with a good tolerance profile. Temozolomide (Te) has some efficiency on PCNL and seems to be a potential candidate.

Methods
we retrospectively analyzed PIOL treated by Te in our unit. Inclusion criteria were a diagnosis established on cytological and molecular analysis after vitrectomy or anterior chamber puncture, and the absence of brain or meningeal localization. Interleukin 10 (IL10) and 6 (IL6) dosages were made by enzyme-linked immunosorbent assay on ocular material. IL10/6 ratio >1 is a specific and sensitive test for PIOL diagnosis and IL10 kinetic a good marker of response in parallel with clinical examination. Treatment consisted in Te at 150mg/m2 orally 5 days per month, in monotherapy, without corticosteroid use.

Results
four patients were analyzed, 3 males and one female. All received systemic chemotherapy with at least high dose methotrexate in first line, two with addition of high dose cytarabin. First patient, aged 84 at diagnosis, relapsed 15 month after CR and received Te for three months until here death, probably by CNS lymphoma. Second patient, aged 65, progressed under SC and subsequently received IM without any success; Te was used in third line but no effect was seen. Third patient, aged 48, had a partial response after first line treatment and received SC with high dose cytarabin and stem cell transplantation; after CR he relapsed 33 months later and then received Te, partial response was clinically confirmed at 3 months and is stable at 6 months. Last patient, age 71, had a localized PIOL 3 years after the treatment of a follicular lymphoma; PIOL relapsed 6 month after the first line and Te began; clinical response was spectacular, with a vision normalization in less than one month, a clinical CR confirmed at two months, IL10 dosages were at more than 1500 pg/ml in both eyes before Te, at 22 pg/ml (left eye) after one month and 202 pg/ml (right eye) after two months, response is stable at 5 months. No toxicity appeared during treatment except for hematological grade I or II.

Conclusion
Temodal is a safe and effective treatment of PIOL after classical chemotherapy. Longer follow-up and larger studies are necessary to confirm these data

Disclosures:
No relevant conflicts of interest to declare.
Gemcitabine Is An Active Agent in the Treatment of T Cell Non Hodgkin Lymphomas.
Authors: Jajeh Ahmad 
Published: October 2019

Abstract
Abstract 4771
Approximately 12- 15% of non- Hodgkin lynphoma NHL are caused by malignant Tcell lymphocytes. The success of the treatment in the aggressive form has lagged behind that of B -Cell in term of poor resonse and durability. Peripheral T-Cell lymphoma PTCL and cutaneous T-Cell lymphoma CTCL are two major charachterized classifiction in the World Health Organization based on their morphology, growth patern and genetics. Stem cell transplant and high dose chemotherapy have been associated with long term response rate of 45%. However this treatment is not well tolerated and not feasible for many patients. Other theraputic options include cytotoxic drugs CHOP,CVP regimen, purine analogues, Denileukin diftitox, Histone deacetylation inhibitors and novel antifolates drugs. In this abstract we will show our experience with gemcitabin an active antimetabolite as a single agent or in combination with other active drugs. Eight patients with PTCL, five with visceral stage of mycosis fundoides( one patient with HIV infection), two with refractory anaplastic Ki positive NHL and one with angioimmunoblastic type. All patients failed a minimum two lines of therapy. Mean age 58 years( range 28-75). Eight blacks, two whites, four hispanics and one asian. Meduim cycles given are four. The dose range 800-1000 mg/M2, given weekly x3 every 28 days cycle. Overall response rate is 85%. Complete response rate CR in eight patients ( three PTCL, three mycosis fungoides and two anaplastic large cell NHL). Partial response PR in four and stable disease in one. Median duration of response is nine months, range six to two years. Median time for response is six weeks. In conclusion:Gemcitabine is an active drug in T-Cell lymphomas particularly when used in combination with other active agents. Maintenance dosing or retreatment with this drug should be investigated.

Disclosures:
No relevant conflicts of interest to declare.
Identification of a Predictive Factor for Reversible Neurological Adverse Events in a Subset of Non-Hodgkin Lymphoma Patients Treated with CD19-Specific BiTE ® Antibody Blinatumomab.
Authors: Zugmaier Gerhard , Nagorsen Dirk , Klinger Matthias , Bargou Ralf C , Goebeler Mariele , Viardot Andreas , Baeuerle Patrick A , Kufer Peter 
Published: October 2019

Abstract
Abstract 4793
Blinatumomab is a CD19/CD3-bispecific antibody construct of the bispecific T cell engager (BiTE®) class showing as single agent a high rate and duration of responses in patients with relapsed non-Hodgkin lymphoma (NHL) and B-precursor acute lymphocytic leukemia (ALL). Blinatumomab has a favorable safety profile with exception of a subset of patients developing neurological adverse events (AEs) during the first days of treatment, such as confusion, speech impairment or cerebellar symptoms. Thus far, all relevant neurological AEs (11 out of 48 patients) were transient, fully reversible and resolved without sequelae within 3 to 72 hours after stop of infusion. In no case, pathological findings were seen upon cranial magnetic resonance imaging. Despite treatment discontinuation, 4 patients with neurological AEs have achieved an objective lymphoma remission. Analysis of cerebrospinal fluid (CSF) taken within hours after stop of infusion showed detectable levels of blinatumomab in the majority of affected patients, while in one patient without neurological symptoms no blinatumomab was detectable in CSF during infusion. Moreover, increased levels of albumin and T lymphocytes in CSF support a disturbance of the blood brain barrier (BBB) as a possible underlying event. Analyses of patient serum samples for angiopoetin-2 and S100b are ongoing to investigate whether levels of the endothelial stress and BBB integrity marker, respectively, correlate with neurological AEs. In a retrospective analysis of 39 NHL patients, a baseline B cell to T cell (B:T) ratio in peripheral blood at or below 1:10 was identified as the only predictive factor for the subsequent occurrence of neurological AEs. The predictive value was then prospectively confirmed in 8 additional patients. Of note, ALL patients –despite very low B:T ratios– rarely showed neurological AEs, which may relate to previous intrathecal chemotherapy depleting target cells in the brain. Potential mechanisms for the neuroprotective effect of peripheral B cells are being investigated. In conclusion, we identified a simple measure to prospectively identify patients at risk of developing neurological AEs after onset of blinatumomab treatment. Mitigating measures are currently tested in these high-risk patients in order to avoid discontinuation of treatment.

Disclosures:
Zugmaier: Micromet: Employment, Equity Ownership. Nagorsen:Micromet: Employment, Equity Ownership. Klinger:Micromet: Employment, Equity Ownership. Bargou:Micromet: Consultancy, Patents & Royalties. Baeuerle:Micromet: Employment, Equity Ownership. Kufer:Micromet: Employment, Equity Ownership, Patents & Royalties.
Effect of Protein Kinase C β Specific Inhibition On Acute Lymphoblastic Leukemia Cell Lines.
Authors: Saba Nakhle S , Safah Hana F , Levy Laura S 
Published: October 2019

Abstract
Abstract 4817
Acute lymphoblastic leukemia (ALL) is the most common leukemia in children and accounts for 20% of acute leukemia in adults. The intensive induction–consolidation–maintenance therapeutic regimens used currently have improved the 5-year disease free survival to around 80% in children and to 25%-40% in adults. The poorer response in adults is basically due to the inability to tolerate the intensive chemotherapy, and to the biology of adult disease which is associated with poor-risk prognostic factors. In the present era of target-specific therapy, PKCβ targeting arose as a new, promising, and well tolerated treatment strategy in a variety of neoplasms, especially in B-cell malignancies. It showed encouraging results in preclinical and clinical studies involving chronic lymphocytic leukemia, diffuse large B-cell lymphoma and multiple myeloma. PKCβ plays a major role in B-cell receptor signaling, but studies describing the role of PKCβ in B-cell ALL are lacking. In the present study, we measured the sensitivity of a variety of B-cell ALL cell lines to PKCβ specific inhibition. Three cell lines were studied: RS4;11 (characterized by the t(4;11) chromosomal abnormality), TOM-1 (characterized by the t(9;22) chromosomal abnormality), and REH (characterized by the t(12;21) chromosomal abnormality). Cells were tested for PKCβ1 and PKCβ2 expression by immunoblot. Cell viability was measured when PKCβ-specific inhibitor at concentrations of 1, 2.5, 5, 10, 20 and 30 μM was added for 48 hours in the presence of 10% fetal bovine serum (FBS). MTS assay was performed to quantify cell viability. Results showed that all three cell lines express PKCβ1 and PKCβ2. Treatment with PKCβ-specific inhibitor resulted in a dose-dependent inhibition of cell proliferation; Sensitivity was evident at 1 μM for RS4;11 cell line, and at 2.5 μM for TOM-1 and REH cell lines, with 10% cell growth inhibition; Growth inhibition increased to 90% for all cell lines at an inhibitor concentration of 30 μM. These results indicate that PKCβ plays an important role in the malignant process in B-cell ALL, and suggest that PKCβ targeting should be considered as a potential treatment, whether in combination with the current regimens used or as a single agent monotherapy. Ongoing studies in our lab will detail the mechanism of PKCβ and adverse cytogenetics like t(4;11) and t(9;22).

Disclosures:
No relevant conflicts of interest to declare.
AICAR Induces Apoptosis in Chronic Lymphocytic Leukemia Cells through the Mitochondrial Pathway and Independently of p53 Pathway and AMPK Activation.
Authors: Gil Joan , Santidrián Antonio F , González-Gironès Diana M , Iglesias-Serret Daniel , Coll-Mulet Llorenç , Cosialls Ana M , de Frias Mercè , Campàs Clara , González-Barca Eva , Alonso Esther , de Sevilla Alberto Fernandez , Viollet Benoit , Pons Gabriel 
Published: October 2019

Abstract
Abstract 4819
AICAR (5-aminoimidazole-4-carboxamide riboside or acadesine) induces apoptosis in different cell types including chronic lymphocytic leukemia (CLL) cells. Here, we have analyzed the mechanisms involved in AICAR-induced apoptosis in CLL cells. AICAR induced apoptosis through the mitochondrial pathway, since inhibition of caspase-8 did not protect CLL cells from AICAR-induced apoptosis and caspase inhibition did not alter cytochrome c release induced by AICAR. AICAR induced a significant increase in the mRNA levels of the proapoptotic BH3-only genes BIM, BNIP3, BNIP3L, HRK, MOAP1, and NOXA. These changes were AICA ribotide (ZMP) accumulation-dependent and adenosine monophosphate-activated protein kinase (AMPK) activation-independent in CLL cells. Furthermore, AICAR induced the accumulation of NOXA protein in all CLL samples and BIM protein in about half of these samples, without modifying the levels of other BCL-2 family proteins analyzed. Importantly, AICAR induced apoptosis irrespective of the tumor suppressor TP53 and ataxia telangiectasia mutated status in CLL cells. AMPK activation with phenformin or A-769662 did not induce apoptosis in CLL cells. Finally, AICAR induced apoptosis in B lymphocytes from AMPKa1−/− mice. Taken together, our results demonstrate that AICAR induces apoptosis in B lymphocytes through the mitochondrial pathway by an AMPK- and p53-independent mechanism.

Disclosures:
Gil: Advancell-In Vitro Cell Technologies S.L.: Patents & Royalties, Research Funding. Campàs:Advancell-In Vitro Cell Technologies : Employment, Patents & Royalties.
The Study of Bortezomib Alone or in Combination with Arsenic Trioxide on Multidrug Resistance of HL60/ADR cells.
Authors: Meng Fanyi , Huang Ming 
Published: October 2019

Abstract
Abstract 4823

INTRODUCTION
Proteĉ¢msome inhibitor bortezomib has used in treatment of hematology malignancies widely. We found it may reduce cell survival rate of HL60/ADR cell line and induce cell apoptosis in previous study. Now we are to investigate the effect of bortezomib alone or combined with arsenic trioxide (As2O3) on reversing multidrug resistance of HL60/ADR cell line and the possible machines.

METHODS
HL60/ADR cells were incubated with bortezomib at different doses alone and in combination with As2O3. The proliferation ratio was observed by MTT assay. Cell apoptosis was studied by fluorescence microscopy and flow cytometry. Intracellular concentration of daunorubicin (DNR) and multidrug resistance related protein-1 (MRP1) was determined by flow cytometry. P65Ap-p65Abcl-2AbaxAcaspase-3Acaspase-9APARP proteins were determined by western blot.

RESULTS
In bortezomib-treated tumor cells, inhibition rate increased in time- and dose-dependently, as well as apoptotic cells. Compared to bortezomib alone, combination with As2O3 inhibited the proliferation and induced the apoptosis of HL60/ADR cells more evident. Bortezomib can enhance the intraceflular accumulation of DNR and decrease MRP1 in HL60/ADM cells. The dual combination of As2O3 with bortezomib presents a superior anticancer and MRP1-decreased efficiency to either one of the drugs alone. Bortezomib can also elevate the expression of bax, caspase-3, caspase-9, PARP, and decelerate the expression of bcl-2, NF-κB p65, p-p65.

CONCLUSIONS
Bortezomib can reverse multidrug resistance of HL60/ADR cells and decrease the expression of MRP1 in cells. When combined with As2O3, it appears to synergistic effects. Its mechanisms might be associated with the inhibition of NF-κB activation, also with inhibiting anti-apoptosis proteins, boosting pro-apoptosis proteins, with followed activating caspase pathway.

Disclosures:
No relevant conflicts of interest to declare.
Re-Exposure of Cord Blood (CB) to Non-Inherited Maternal HLA Antigens (NIMA) Improves Transplant Outcome in Patients (pts) with Hematologic Malignancies and May Reduce Relapse.
Authors: van Rood Jon J , Stevens Cladd E , Smits Jacqueline , Carrier Carmelita , Carpenter Carol , Scaradavou Andromachi 
Published: October 2019

Abstract
Abstract 661
CB hematopoietic stem cell transplantation (CBT) can be successful even if donor and recipient are not fully matched for human leukocyte antigens (HLA). This may result, at least in part, from tolerance-inducing events during pregnancy, but this concept has not been tested to date. Hence we analyzed the impact of fetal exposure to NIMA of the HLA-A, -B antigens or -DRB1 alleles on the outcome of 1121 pts with hematologic malignancies. All pts received single CB units provided by the NYBC, for treatment of ALL (N=451), AML (N=376), CML (N=116), MDS (N=79), other (N=99); 22% were transplanted in advanced stage. Median age was 9.7 years (range: 0.1-67); 29% of recipients were >16 years. Most pts (96%) received myeloablative cytoreduction. Sixty-two pts received fully matched grafts while 1059 received units mismatched (MM) for one or two HLA antigens. Of these, 79 (7%) had a MM antigen which was identical to a donor NIMA (Example: Pt: A1, A3; CBU: A1, A2; mother-CBU: A1, A3; A3 is NIMA). NIMA match was found in 25 recipients with one HLA MM and 54 of those with two MM. The NIMA match was identified after the transplant and was not used in unit selection. In multivariate analyses, NIMA matched transplants (NMTs), showed faster neutrophil recovery (RR=1.3, p=0.043), even for grafts with cell dose <3×107 (RR=1.6, p=0.053). There was no difference in the incidence of acute (grade II-IV) or chronic GvHD. 3-year relapse risk (cumulative incidence 22%) was reduced compared to 1 or 2 HLA MM no NIMA matched transplants, especially in pts with myelogenous malignancies given units with 1 HLA MM (RR=0.2, p=0.074). Further, 3-year transplant-related mortality was reduced (RR=0.7, p=0.034), particularly in pts ≥5 years old (RR=0.5, p=0.006), as was the 3-year overall mortality (RR= 0.7, p=0.029 and RR=0.6, p=0.015, respectively). As a result, in the NMTs, treatment failure (relapse or death) was significantly lower, particularly in pts ≥5 years (RR=0.7, p=0.019) and DFS was significantly improved (figure) and was similar to that of the 0 HLA MM group. These findings are the first indication that donor exposure to NIMA can improve post-transplant survival in unrelated CBT and might reduce relapse. We propose to include the NIMA of CB units in search algorithms. Thus, for pts lacking fully HLA matched grafts, HLA MM but NIMA matched CB units could be selected preferentially, since no adverse effects were seen. This strategy of selecting HLA MM grafts with optimal outcome effectively “expands” the current CB Inventory several-fold.Patient GroupNRR(95% Cl)p value0 MM360.5(0.3–0.8)0.0051 MM / NIMA Match180.4(0.2–0.9)0.0262 MM / NIMA Match400.8(0.5–1.2)0.3091 MM / No NIMA Match229reference group2 MM / No NIMA Match4871.1(0.9–1.3)0.365

Disclosures:
No relevant conflicts of interest to declare.
Identification of New Recurrent Multiple Small Interstitial Deletions Affecting Genes Coding for Kinases in Chronic Lymphocytic Leukemia (CLL): a New Pathogenic Mechanism?.
Authors: Rinaldi Andrea , Mian Michael , Rossi Davide , Forconi Francesco , Deambrogi Clara , Spina Valeria , Cencini Emanuele , Sozzi Elisa , Drandi Daniela , Ladetto Marco , Santachiara Rita , Marasca Roberto , Chigrinova Ekaterina , Cavalli Franco , Gattei Valter , Zucca Emanuele , Gaidano Gianluca , Kwee Ivo , Bertoni Francesco 
Published: October 2019

Abstract
Abstract 672

BACKGROUND:
CLL is the most common adult-onset leukemia in the Western world. The most common known genetic lesion is the 13q14.3 deletion targeting MIR15/MIR16. We applied a very high resolution array to identify new genetic lesions in CLL.

METHODS:
266 CLL samples were analyzed with Affymetrix Human Mapping 6.0 arrays, comprising over 1,8 million probes with a median distance of less than 1 Kb. Copy number was inferred using the circulary binary segmentation (CBS) algorithm. Minimal common regions (MCR) were defined using a modified version of the algorithm by Lenz et al. (PNAS 2008), specifically altered to identify very small genomic losses covered by only 2-9 probes and occurring in at least 5% of the cases (mMCRs). mMCRs having 100% overlap with known copy number variations were discarded.

RESULTS:
mMCRs occurred in 75 known genes. The most commonly affected genes were CDC73 (cell division 73; 63% of the cases, 3 probes), RREB1 (ras responsive element binding protein 1; 60%, 5 probes), JAK2 (47%, 8 probes), CCDC88A (AKT-phosphorylation enhancer,; 47%, 3 probes), AKT3 (43%, 4 probes). Other affected genes at a lower frequency were PIK3CA (26%), EGFR (25%), XRCC4 (18%), JAK1 (18%), PTPRK (15%), RB1 (14%), ERBB2 (10%), PDGFRA (8%), FHIT (7%). A functional analysis performed with DAVID 2008 (http://david.abcc.ncifcrf.gov/) identified the terms “anti-oncogene” and “tyrosine-protein kinase” and five KEGG (http://www.genome.jp/kegg/) pathways (“prostate cancer”, “non-small cell lung cancer”, “pancreatic cancer”, “endometrial” cancer”) as enriched among the 75 genes with a statistically significant p-value <0.05 after Benjamini multiple test correction. Besides tumor suppressor genes such as RB1 and FHIT, very interestingly, many of the genes appeared to code for kinases and for oncogenes. The mMCRs occurred in intronic regions, and apparently targeted highly conserved regions. These regions might represent regulatory loci and their loss may cause gene activation. Validation of selected genes is on-going.

CONCLUSIONS:
The application of high resolution arrays on a large series of CLL samples has shown frequent small interstitial deletions targeting a discrete number of genes, highly enriched for transcripts coding for kinases. A potential mechanism of action might be the loss of regulatory regions determining gene activation. Once validated, the current data would provide the basis to explore the rationale for the use of kinase inhibitors in the treatment of CLL.

Disclosures:
No relevant conflicts of interest to declare.
Ikzf1 Haploinsufficiency Contributes to the Pathogenesis of BCR-ABL1 Positive Acute Lymphoblastic Leukemia.
Authors: Collins-Underwood Racquel , Miller Christopher B , Downing James R. , Mullighan Charles G. 
Published: October 2019

Abstract
Abstract 678
Expression of the constitutively active tyrosine kinase BCR-ABL1 is the hallmark of two diseases with distinct pathologic and clinical features: chronic myeloid leukemia (CML), an expansion of relatively mature granulocytes that typically responds well to kinase inhibition, and pre-B cell acute lymphoblastic leukemia (ALL), an aggressive malignancy of lymphoid progenitors that has a dismal prognosis. The basis for this dichotomy has been poorly understood. Recent studies profiling genome-wide DNA copy number alterations in CML and ALL have identified a near-obligate deletion of IKZF1 (encoding the lymphoid transcription factor IKAROS) in de novo BCR-ABL1 positive ALL, and at the progression of CML to lymphoid blast crisis, suggesting that perturbation of IKAROS activity is a key event in the pathogenesis of BCR-ABL1 lymphoid leukemia. To test this hypothesis, we have examined the effect of Ikaros haploinsufficiency in a retroviral bone marrow transplant model of murine BCR-ABL1 B-progenitor ALL. Unmanipulated marrow from either Ikzf1 wild type mice or mice heterozygous for an Ikzf1 null allele was transduced with MSCV bicistronic retrovirus expressing GFP and p185 BCR-ABL1 and transplanted into lethally irradiated C57BL/6 recipients. Recipients of MSCV-GFP-p185 BCR-ABL1-transduced Ikzf1+/− marrow developed leukemia with markedly increased penetrance and reduced latency in comparison to recipients of wild-type marrow (46 vs. 122 d, P<0.0001). The resulting leukemias resulted in bone marrow replacement by lymphoblasts, pancytopenia, extramedullary infiltration, and frequent clinical and histologic central nervous system involvement. The leukemias were of pre-B immunophenotype and uniformly transplantable into sublethally irradiated secondary recipients. Importantly, detailed enumeration of lymphoid subsets in Ikzf+/+ and +/− marrow did not demonstrate an expansion of lymphoid progenitors in Ikzf1+/− marrow, suggesting that the observed increased penetrance of B-ALL in Ikzf1+/− animals was not simply due to the expansion of targets of BCR-ABL1 transformation. Thus, Ikaros haploinsufficiency cooperates with BCR-ABL1 to induce an aggressive pre-B leukemia with clinical and pathologic features recapitulating human BCR-ABL1 ALL. These results support genomic analyses of human leukemia suggesting that IKAROS loss is important in the pathogenesis of this disease. Experiments evaluating the interaction of Ikzf1 loss with other targets of genomic alteration in BCR-ABL1 ALL (e.g. CDKN2A/B, PAX5), and the role of dominant negative isoforms of Ikaros in leukemogenesis will be of interest.

Disclosures:
No relevant conflicts of interest to declare.