bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pooled Analysis of Aids-Malignancy Consortium (AMC) Trials Evaluating Rituximab Plus Either CHOP or Infusional EPOCH Chemotherapy In HIV-Associated Non-Hodgkin's Lymphoma
Authors: Barta Stefan K , Lee Jeannette Y , Sparano Joseph A , Kaplan Lawrence D , Noy Ariela 
Published: October 2019

Abstract
Abstract 1797

Background:
Two consecutively performed randomized studies by the AMC evaluating chemoimmunotherapy for the treatment of HIV-associated NHL include AMC010 (Kaplan LD et al, Blood 2005: concurrent Rituximab [R] + CHOP vs. CHOP, N=150) and AMC034 (Sparano JA et al, Blood 2010: concurrent R+EPOCH vs. Sequential EPOCH → R; N=106). In AMC010, the addition of Rituximab to CHOP was associated with an increased risk of infectious death (15% vs. 2%, p=0.04) without a significant improvement in complete response (CR) rate (58% vs.47%; p=0.15), event free survival (EFS), or overall survival (OS). In AMC034, the CR rate met its primary efficacy endpoint in the concurrent arm (73%; 95% confidence intervals [CI] 58%, 85%) but not the sequential arm (55%; 95% CI 41%, 68%).

Methods:
We performed a pooled analysis of these two consecutive trials including patients treated with R-CHOP and concurrent R-EPOCH in order to determine the influence of the age-adjusted International Prognostic Index (aaIPI), CD4 count (&lt; 100/uL vs. ≥ 100/uL), and treatment (CHOP vs. EPOCH) as variables on outcomes EFS, OS and CR.

Results:
The characteristics and outcomes of the study populations are shown in table 1. Patients treated with R-EPOCH tended to have better outcomes in both the low and high risk IPI groups. In a multivariate analysis that included pooled data from both consecutive studies, features that were significantly associated with improved EFS, OS, and CR rate included low aaIPI score and baseline CD4 count of at least 100/ul. Additionally patients treated with concurrent R-EPOCH exhibited improved EFS and OS even when adjusted for prognostic covariates including aaIPI score and CD4 count (table 2).

Conclusions:
These findings suggest that treatment outcomes may be superior with concurrent R-EPOCH compared with R-CHOP, and support the design of an ongoing phase III trial comparing concurrent R-EPOCH with R-CHOP in immunocompetent patients with diffuse, large B-cell lymphoma (NCT00118209). This analysis provides additional level 2 evidence supporting the use of concurrent R-EPOCH in patients with HIV-associated lymphoma. Acknowledgments: This study is presented on behalf of the AIDS Malignancy Consortium.

Disclosures:
No relevant conflicts of interest to declare.
Rituximab Maintenance Treatment for a Maximum of 5 Years In Follicular Lymphoma: Safety Analysis of the Randomized Phase III Trial SAKK 35/03
Authors: Taverna Christian J. , Bassi Simona , Hitz Felicitas , Mingrone Walter , Pabst Thomas , Cevreska Lidija , Giglio Auro del , Vorobiof Daniel A. , Simcock Mathew , Ghielmini Michele 
Published: October 2019

Abstract
Abstract 1802

Background:
Rituximab maintenance has been shown to be effective in patients with follicular lymphoma. The optimal duration of maintenance remains unknown.

Methods:
We prospectively registered 270 patients with untreated, chemotherapy resistant or relapsed follicular lymphoma. All patients received rituximab induction consisting of 4 weekly doses (375 mg/m2). Responding patients (PR and CR) were randomized to a short maintenance consisting of four doses of rituximab (375 mg/m2) every two months (arm A) or prolonged maintenance consisting of rituximab every two months for a maximum of five years or until disease progression or unacceptable toxicity (arm B). Primary endpoint is event-free survival. Here we present the safety analysis results after a median long-term maintenance period of 3.3 years.

Results:
From October 2004 to November 2007 165 patients were randomized, 82 in arm A and 83 in arm B. The median follow-up time is 3.2 years for arms A and B combined. While receiving maintenance therapy a total of 899 hematological and non-hematological adverse events were observed, 28 of grade 3 and 6 of grade 4. After randomization five patients experienced subsequent cancers. Seven grade 3 and 4 infections were reported. Two grade 3 infections occurred after 2 years of maintenance. Grade 3 and 4 neutropenia occurred in 6 (3.6 %) patients, decreased levels of IgG were observed in 24 (14.6 %) patients. In arm B, maintenance was stopped due to unacceptable toxicity in 2 patients after 16 and 42 months respectively and due to subsequent breast cancer in 1 patient after 20 months. One patient died 4 months after randomization because of ileus and consecutive peritonitis, considered to be unrelated to therapy. Sixty-three patients are on maintenance for two or more years of which 48 patients are on for three or more years. Two patients have completed the 5 years of maintenance.

Conclusions:
Rituximab maintenance beyond two years is feasible without evidence for increased toxicity. However, close follow up of patients under prolonged rituximab maintenance is still necessary. The trial has been closed for accrual but there are still patients on treatment.

Disclosures:
Taverna: Roche: Membership on an entity's Board of Directors or advisory committees. Ghielmini:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau.
Variations of Noxa Levels Caused by p38 MAPK Signaling Result In Heterogeneous Sensitivity to ABT-737 In CD40L-Stimulated CLL Cells
Authors: Tromp Jacqueline M , Geest Christian R , Elias Judith , van Laar Jacoline , Van Oers Marinus H.J. , Eldering Eric 
Published: October 2019

Abstract
Abstract 1825
Chronic lymphocytic leukemia (CLL) is characterized by relentless relapses. It is postulated that this might be due to microenvironment-induced resistance to cytotoxic agents. Previously we have shown that in vitro CD40 stimulation of peripheral blood derived from CLL patients can to a certain extent mimic the lymph node (LN) microenvironment and result in resistance to cytotoxic drugs. This is correlated with CD40-induced changes in apoptosis regulating Bcl-2 family members. The BH3 mimetic drug ABT-737 antagonizes the anti-apoptotic molecules Bcl-XL and Bcl-2, but not Mcl-1 or Bfl-1. At present it is unknown whether patient-specific variations in expression of apoptosis regulating proteins occur and to what extent they correlate with sensitivity or resistance to ABT-737.
In the present investigation we assessed the variability in response to ABT-737 in CD40 stimulated CLL cells. Although in all tested CD40-stimulated CLL patients Mcl-1 and Bfl-1 levels increased, there was a heterogeneous response in cell death to ABT-737 when used as a single agent. Notably, time course analyses showed variations in Noxa levels upon CD40 triggering, which differed between CLL patients. High Noxa/Mcl-1 ratios correlated with sensitivity to ABT-737. This was confirmed by Noxa knockdown as well as Mcl-1 and Bfl-1 overexpression, which resulted in resistance to ABT-737. To determine the signaling pathways involved in Noxa regulation, CLL cells were stimulated with CD40L in the presence of various kinase inhibitors. We observed that Noxa levels were specifically inhibited by the p38 MAP kinase inhibitor SB203580. Preliminary data indicate that after CD40 stimulation, phosphorylation of p38 decreased over time, correlating with a decrease in Noxa levels. Importantly however, a minority of CD40 stimulated CLL samples were sensitive to ABT-737 and showed high levels of phosphorylated p38 and increasing Noxa levels over time.
In conclusion, we demonstrate that following CD40 triggering of CLL cells the p38 MAPK signaling pathway regulates Noxa levels and that patient-specific variations in this pathway contribute to the responsiveness to ABT-737. These findings raise the question whether assessment of p38 MAPK activation status and Noxa levels in vivo could predict the response of CLL patients to ABT-737. Moreover our findings offer possible new targets for the treatment of CLL.

Disclosures:
No relevant conflicts of interest to declare.
Stem-Like Tumor Cells Confer Drug Resistant Properties to Mantle Cell Lymphoma
Authors: Jung Hyun Joo , McCarty Nami 
Published: October 2019

Abstract
Abstract 1840

Background:
We have recently identified clonogenic malignant stem cell populations in human mantle cell lymphoma (MCL), is a particularly deadly subtype of Non-Hodgkin's Lymphoma (NHL). We have discovered that CD45+CD19-MCL cells, which we termed MCL-initiating cells (MCL-ICs), are highly tumorigenic and display self-renewal capacities in vivo; in contrast, CD45+CD19+ MCL cells, which constitute the vast majority of cells within the tumors, show no self-renewal capacities and display greatly reduced tumorigenicity. Given the newly appreciated roles of cancer stem cells in the drug resistance of some cancers, it is critical to investigate whether MCL-ICs play roles in drug resistance of human MCL.

Methods:
CD45+CD19- and CD45+CD19+ cells isolated from MCL patients was tested for functional roles of MCL-ICs in drug-resistance of MCL using clinically-relevant chemotherapeutic regimens: R-CHOP, R-hyperCVAD, R-DHAP, R-HAD+B, and fludarabine-based regimen. We compared the cytotoxic effects and IC50 values of above regimens between two cell groups. To understand molecular mechanisms of drug resistance of MCL-ICs, we examined the cell cycle status of MCL-ICs using Rhodamine 123.

Results:
Cytotoxicity assay showed that MCL-ICs are more resistant to clinically relevant combined chemotherapeutic regimens in vitro as compared to bulk MCL tumor cells. Annexin V apoptosis assay supported this finding. IC50 values of chemotherapeutic agents that can induce the effective cytotoxicity of CD45+CD19-MCL-ICs were significantly higher than those of CD45+CD19+ MCL cells in most regimens. In contrast with CD45+CD19+ MCL cells, no significant growth inhibition was noted in CD45+CD19-MCL-ICs with combined drug treatments as well as a single agent. Rhodamine 123 efflux activity tests showed that MCL-ICs are maintained in a quiescent status.

Conclusions:
We have discovered MCL-ICs were more resistant to various clinically relevant chemotherapeutic agents in combination or in a single regimen compared to CD45+CD19+ MCL cells. The resistance of MCL-ICs to drugs was largely due to quiescent properties with enriched ABC drug transporters. In conclusion, designing novel therapies that can kill MCL-ICs may prevent relapse and increase patient survival.

Disclosures:
No relevant conflicts of interest to declare.
Clinical Experience with Azacitidine In Secondary Myelodysplastic Syndrome In Spain
Authors: García Regina , Sanz Guillermo F , Llorente Dunia de Miguel , Nomdedeu Benet , Romero M Mar , Bernal Teresa , Besalduch Juan , Amutio Elena , Brunet Salut , de Smd Grupo Andaluz 
Published: October 2019

Abstract
Abstract 1852

Introduction:
Secondary myelodysplastic syndromes (MDS) and acute leukemias are some of the most serious adverse side effects in the treatment with chemotherapy or radiotherapy, as those therapies affect the DNA methylation profile of different tissues. New data suggest that abnormalities in the DNA methylation profile would contribute to secondary leukemogenesis. In general, secondary MDS has a worse prognosis than de novo MDS. Azacitidine (AZA) is an hypomethylating agent approved in Europe for the treatment of MDS, based on the AZA-00 clinical trial. No secondary MDS was included in this trial. Until its approval in May 2009, AZA was used in Spain under compasionate use in clinical trials.

Materials and Methods:
Retrospective, longitudinal, multicenter Spanish study of data, promoted by the Hematology and Hematotherapy Andalusian Asociation and the Andalusian Group of MDS, on the course and management of patients treated with AZA under compasionate use. We present the analysis of clinical data of the 30 patients with Secondary MDS included in the registry.

Results:
Median age at diagnosed was 76 years. Male/female ratio: 13/17. ECOG performance status score 0–1 was 60%. The most frequently used initial dose of AZA was 75 mg/m2 in cycles of 28 days, administered subcutaneously (80%). The mean received cycles was 6. Overall response to treatment was 46.6% (International Working Group 2006 criteria): 16% complete response, 3.3% complete medullary response, 6.6% partial response and 20% hematological response. In addition, 23.3% had stable disease. AZA was generally tolerated well. The 3–4 grade adverse events documented in these patients were: Neutropenia (26%), thrombocytopenia (33%), anemia (20%), febrile neutropenia (3%), rash (6%), lumbar pain like colic type (3%) and subcutaneous reaction at the injection area (6%). Similar response ranges were found in patients with primary and secondary MDS, both within the registry as well as in the published literature.

Conclusion:
Our results show that patients with secondary MDS respond to AZA in the same manner as the primary patients do, although their prognosis is traditionally worse. These favorable results in secondary MDS suggest that these patients respond to the hypomethylating treatment, probably by the DNA methylation alterations involved in the leukemogenesis. More data from this registry and from different clinical trials are needed to confirm these data, and complete answers with survival analyses.

Disclosures:
García: Celgene : Research Funding.
Risk of Second Primary Malignancies in Patients with AL Amyloidosis Treated with Lenalidomide
Authors: Sanchorawala Vaishali , Shelton Anthony C , Doros Gheorghe , Seldin David C 
Published: October 2019

Abstract
Abstract 1873
An increase in second primary malignancies (SPM) has been reported in patients with myeloma treated with lenalidomide, particularly in association with melphalan. To determine the rate of second primary malignancies in AL amyloidosis patients treated with lenalidomide, we reviewed data on 82 patients treated on clinical trials at Boston Medical Center from 2004–2011. Data from lenalidomide and dexamethasone treatment in AL amyloidosis (ClinicalTrials.gov: NCT00091260) were analyzed in a post-hoc fashion for the incidence rate for SPM. The median age of these 82 patients was 62 years (range, 40–82); and 52 (63%) were male. There were 62 patients (76%) with lambda clonal plasma cell dyscrasia, and 43 (52%) had cardiac involvement by the consensus criteria from the Xth International Amyloidosis Symposium. Median duration for lenalidomide treatment was 9 cycles (range, 1–69); and 16 (20%) received lenalidomide for > 24 months. Of the 82 patients, 78 (95%) patients had prior therapies and 77 (94%) had prior alkylating agents based treatment. The median follow-up of the 82 patients was 28 months (range, 3–92). One patient, a smoker, treated with lenalidomide for 24 months, developed metastatic lung cancer. Additionally, there were 5 non-melanoma skin cancers. There was no case of hematologic malignancy or B-cell lymphoproliferative disorder in this group. This corresponds to an incidence rate of 0.44 per 100 patient-years for invasive cancer. The annual incidence of invasive cancers is 2.1 per 100 patient-years for the general population in the US. In conclusion, lenalidomide based treatment in AL amyloidosis did not appear to increase the incidence rate of SPM compared to incidence rate for the invasive cancers in general population. Longer prospective follow-up may be needed in a larger patient population to better define the risk.

Disclosures:
Sanchorawala: Celgene Corporation: Research Funding. Off Label Use: Use of lenalidomide in the treatment of AL amyloidosis. Seldin:Celgene Corporation: Research Funding.
DOCK2 Is Critical for FC to Induce Regulatory T Cells
Authors: Wen Yujie , Elliott Mary J , Huang Yiming , Corbin Deborah R , Miller Thomas O , Ildstad Suzanne T 
Published: October 2019

Abstract
Abstract 1885
CD8+/TCR− graft facilitating cells (FC) significantly enhance engraftment of hematopoietic stem cells (HSC) in both allogeneic and syngeneic recipients. We have shown that DOCK2−/− FC are compromised in cell migration in vitro and facilitating HSC engraftment in vivo. DOCK2 activates the small GTPase Rac and is indispensable for migration of neutrophils, lymphocytes and plasmacytoid dendritic cells (DC). A recent study demonstrated that DOCK2−/− DC were defective in antigen uptake and presentation. FC are a heterogeneous cell population, with a predominant subpopulation resembling plasmacytoid precursor DC. We previously found that FC induced antigen-specific regulatory T cells (Treg) in vitro and in vivo. In the present study, we evaluated whether DOCK2−/− FC could induce Treg. 5×105 wild-type (WT) sorted CD4+CD25− splenocyte T cells were incubated with 1×105 WT FC or DOCK2−/− FC at a 5:1 ratio in U bottom 96-well plates with long-term culture medium (IMEM with 20% horse serum, 10−6M hydrocortisone and 50μM β-mercaptoethanol) for up to 6 days. The co-cultures were harvested and CD4+CD25+ T cells were analyzed for FoxP3 by flow cytometry intracellular staining. WT CD4+CD25− splenocytes were cultured as negative control. Phagocytosis of APC-labeled polystyrene beads by WT and DOCK2−/− FC was assessed after incubating FC with the beads for 3 hours. We found that FC induced the generation of CD4+CD25+FoxP3+ Tregin vitro as expected, while DOCK2 deficiency completely abrogated the ability of FC to induce Treg generation. Moreover, the uptake of beads by DOCK2−/− FC was significantly impaired compared to their uptake by WT FC. In summary, DOCK2−/− FC were unable to induce the generation of CD4+CD25+FoxP3+ Tregin vitro and were compromised in phagocytosis.

Disclosures:
Ildstad: Regenerex, a biotech start-up company: Equity Ownership.
Abstract Title Submitted by Hollie Pegram to the 2012 ASH Annual Meeting: Expansion and Modification of Umbilical Cord Blood T Cells with a Chimeric Antigen Receptor and IL-12
Authors: Pegram Hollie J. , Barker Juliet , Giralt Sergio , Brentjens Renier J 
Published: October 2019

Abstract
Abstract 1907
Transplantation of unrelated umbilical cord blood (CB) derived stem cells is often used to treat adult patients with B-cell acute lymphoblastic leukemia (B-ALL). However, patients can relapse post transplant and prognosis of those with advanced or refractory disease is poor. We hypothesize that additional therapy involving adoptive transfer of CB derived T cells modified to express a CD19-specific chimeric antigen receptor (CAR) could improve patient outcome following CB transplantation in this population. We have previously demonstrated that human T cells which express the anti-CD19 1928z CAR, containing the signaling domains of the co-stimulatory CD28 receptor and CD3z chain, effectively eradicate CD19+ tumors in SCID-Beige mice, and have shown promise in early clinical trials.
In this study, we demonstrate the ability to effectively isolate and expand T cells from CB, necessary for application of adoptive CB T cell therapy. We compared T cell expansion in in vitro cultures with the addition of exogenous stimulatory cytokines, including IL-2, IL-7, IL-12, IL-15 or combinations thereof. We demonstrate that in vitro culture in the context of exogenous IL-12 combined with IL-15 resulted in optimal expansion of CB T cells (over 150-fold). In addition, expansion of T cells in the context of exogenous IL-12 and IL-15 resulted in a favorable phenotype, with maximal expression of memory T cell markers, CD62L and CCR7. Furthermore, these cells were shown to produce high levels of IFNγ and express high levels of CD107a following stimulation with PHA. CB T cells expanded in IL-12 and IL-15 were therefore shown to have a unique memory cell phenotype combined with effector T cell function.
Previous studies in our laboratory have demonstrated that expression of IL-12 in tumor targeted T cells resulted in increased anti-tumor function. Given these studies and the favorable effect of IL-12 on CB T cell expansion we used retroviral modification to express both 1928z CAR and IL-12 in CB T cells. CB T cells modified with both IL-12 and 1928z were shown to have increased cytokine secretion when cultured with CD19+ tumor cells, compared to UCB T cells modified with a CAR alone. Additionally, these cells were demonstrated to have increased lytic function, resulting in increased specific lysis of CD19+ tumor cells in a 51Cr release assay.
Our data suggest that CB T cells modified to express both CAR and IL-12 will have improved anti-tumor function, and could therefore decrease relapse and improve overall survival following CB transplant for the treatment of B-ALL.

Disclosures:
Giralt: Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding.
Efficacy and Safety of Micafungin for the Prophylaxis of Invasive Fungal Disease During Neutropenia in Children and Adolescents Undergoing Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Park Hyeon Jin , Park Meerim , Han Mira , Nam Byung Ho , Koh Kyung Nam , Im Ho Joon , Lee Jae Wook , Chung Nak Gyun , Cho Bin , Kim Hack Ki , Yoo Keon Hee , Koo Hong Hoe , Kang Hyoung Jin , Shin Hee Young , Ahn Hyo Seop , Lim Young Tak , Kook Hoon , Lyu Chuhl Joo , Hah Jeong Ok , Park Jun Eun , Seo Jong Jin 
Published: October 2019

Abstract
Abstract 1932

Introduction:
The use of micafungin, a member of the novel class of antifungal agents, the echinocandins, in adults has proven to be effective and safe for antifungal prophylaxis in allogeneic hematopoietic stem cell transplantation (HSCT) recipients. However, there are few reports describing its prophylactic use in pediatric patients. The objectives of this study were to evaluate the efficacy and safety of micafungin for the prevention of invasive fungal disease (IFD) in patients undergoing allogeneic HSCT exclusively focusing on children and adolescents.

Patients and Methods:
This was prospective, multi-center, open-label, single arm study. The study drug, micafungin, was administered intravenously at a dose of 1 mg/kg/day for patients < 50 kg and 50 mg/day for patients ≥50 kg from the beginning of conditioning until neutrophil engraftment. Treatment success was defined as the absence of suspected, probable, or proven IFD through the end of 4 weeks after therapy. Clinical and laboratory toxicities were graded according to the Common Terminology Criteria for Adverse Events version 4.0.

Results:
From April 2010 to December 2011, 152 patients were enrolled from 10 institutions in Korea, and a total of 144 patients were analyzed. The median age of the patients was 9.5 years (range, 0.4 – 19.8 years). Approximately 94% of patients received myeloablative conditioning regimen. Graft source included bone marrow (11.9%), peripheral blood (82.5%) and cord blood (5.6%). Most commonly, patients received HSCT for treatment of acute myeloid leukemia (27.8%), acute lymphocytic leukemia (27.1%), or severe aplastic anemia (19.4%). The median duration of prophylactic micafungin treatment was 23 days (range, 4 –169 days). Of the 144 patients, 117 patients completed micafungin prophylactic administration until neutrophil engraftment. Eleven patients developed suspected (n=5), possible (n=3), or probable (n=3) IFD. No patients died of IFD at any time during the study. Thirty-eight patients experienced adverse events (AEs) possibly related to micafungin. Only two patients discontinued micafungin prophylaxis due to AEs. Common AEs included hepatotoxicity, gastrointestinal discomfort, electrolyte imbalance and myelosuppression.

Conclusions:
This study shows the efficacy and safety of micafungin for the prevention of IFD after allogeneic HSCT in children and adolescents.

Disclosures:
No relevant conflicts of interest to declare.