bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Retrospective Multi-Center Analysis of Prognostic Factors Determining Outcomes In Patients with Secondary AML
Authors: Mohan Sanjay R. , Maciejewski Jaroslaw P , Tejura Bindu , Erba Harry P , Stone Richard M , Sekeres Mikkael A. 
Published: October 2019

Abstract
Abstract 2139

Introduction:
Secondary AML (sAML), a well recognized poor prognostic factor in AML, is a heterogeneous group of diseases, including both AML evolving from myelodysplastic syndromes (MDS, MDS→AML) and AML following chemotherapy for another malignancy, i.e. treatment-related AML (tAML). These two subtypes of poor risk AML have similar outcomes when treated with the same cytarabine-based chemotherapy regimen, supporting their inclusion into the same clinical category. A combined data set of patients from a single centre and a phase II study was analyzed to determine which patient and disease factors were of prognostic significance in predicting response to treatment. This is a large data set of sAML patients including patients treated with a variety of cytarabine-based induction regimens.

Materials and Methods:
Data from 77 newly diagnosed sAML patients treated with cytarabine-based induction chemotherapy at the Cleveland Clinic between 1997 and 2007 and 88 newly diagnosed sAML patients treated with amonafide + cytarabine in a phase II study were combined. The focus of the analysis was to ascertain the prognostic factors affecting overall survival (OS) from time of diagnosis. Initially, univariate Cox proportional hazard models for each prognostic factor were fitted. Hazard ratios and their associated 95% confidence intervals and Wald test p-values were produced. Prognostic factors were: age at diagnosis (<60 years, ≥60 years), gender (male, female), WBC (<20 x109/L, ≥20 x109/L), peripheral blasts (<20%, ≥20%), bone marrow blasts (<40%, ≥40%), cytogenetics CALGB class (unfavorable, intermediate, favorable, unknown), secondary disorder class (MDS, tAML), prior chemotherapy (yes, no), prior radiotherapy (yes, no). Subsequently a multivariate model was produced using the stepwise selection method and a significance level of 5%, having imputed missing data with mean/median values as appropriate.

Results:
In the combined data set of 165 patients with newly diagnosed sAML, the results for each significant prognostic factor are outlined in the table below.
The final multivariate model (displayed in the table below) determined unfavorable cytogenetics, male gender and advanced age as prognostic factors predictive of worse OS.

Conclusions:
In a combined data set of 178 patients with sAML from 22 US centers, cytogenetics, age and gender were identified as prognostic factors of significance in determining the outcome when treating sAML patients with induction chemotherapy. For patients with these risk factors, additional therapeutic strategies, including early stem cell transplantation, should be considered.

Disclosures:
Tejura: Antisoma: Employment. Sekeres: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees.
RANKL Expressed by Acute Myeloid Leukemia Cells Impairs NK Cell-Mediated Immune Surveillance
Authors: Schmiedel Benjamin J , Wende Constantin M , Baessler Tina , Scheible Carolin , Wirths Stefan , Azuma Miyuki , Schneider Pascal , Grosse-Hovest Ludger , Kanz Lothar , Salih Helmut R 
Published: October 2019

Abstract
Abstract 2164
NK cells play an important role in tumor immunosurveillance, especially of leukemia. Their reactivity is governed by various activating and inhibitory molecules expressed by their targets including multiple members of the TNF family. The TNF family member Receptor Activator of NF-κB ligand (RANKL) and its receptors RANK and osteoprotegerin (OPG) are key regulators of bone remodelling, but recently have also been shown to influence progression of hematopoetic malignancies. Here we studied the yet unkown role of the RANK/RANKL molecule system in NK cells and their reactivity against acute myeloid leukemia (AML). Primary leukemia cells from AML patients were found to substantially express RANKL mRNA and surface protein in 75% of the investigated cases (n=40). Reverse signaling via surface-expressed RANKL into AML blasts induced the release of soluble factors including the immunoregulatory cytokines TNF and IL-10, which impaired NK cell anti-tumor reactivity. Moreover, we observed upregulation of RANK on NK cells among PBMC of healthy donors upon exposure to IL-10. This was not caused by direct effects on NK cells, but was rather due to yet unidentified factors released by monocytes among the PBMC upon IL-10 exposure and could be prevented by the activating cytokine IL-2. Furthermore, functional experiments with NK cells and RANKL transfectants or RANKL-negative controls revealed that forward signaling into RANK-expressing NK cells by tumor-expressed RANKL also directly impaired NK cytotoxicity and IFN-γ production. In line, blocking RANK-RANKL interaction using anti-RANKL antibodies or RANK-Fc fusion protein increased cytotoxicity and cytokine production of allogenic NK cells in cultures with RANKL-positive primary AML cells. Our data indicate that RANKL expression enables immune evasion of leukemia cells both by directly inhibiting reactivity of RANK-expressing NK cells and by orchestrating a reciprocal interplay between AML cells, monocytes and NK cells resulting in an immunosuppressive cytokine milieu. Thus, therapeutic modulation of the RANK/RANKL system, e.g. with Denosumab/AMG162, which is presently being evaluated for treatment of both non-malignant and malignant osteolysis, holds promise to reinforce NK reactivity against hematopoietic malignancies.

Disclosures:
No relevant conflicts of interest to declare.
Ara-C Treatment of Acute Myeloid Leukemia Does Not Lead to Prolonged Enrichment of Stem Cells or a Cell Cycle Arrest
Authors: Perry Robin L. , Sarry Jean-Emmanuel , Danet-Desnoyers Gwenn-ael , Carroll Martin 
Published: October 2019

Abstract
Abstract 2178
The major therapeutic barrier in acute myeloid leukemia is chemotherapy resistance. Although most patients will respond to treatment with chemotherapy over 50% of responders will relapse and eventually die of disease. Many hypotheses have been proposed to explain chemotherapy resistance but none of these have lead to new therapies or a complete understanding of the molecular mechanisms of AML chemotherapy resistance. In order to develop an improved understanding of chemotherapy resistance in AML, we have developed a chemotherapy model of human AML in NSG mice. Mice are engrafted with primary AML samples from patients seen at diagnosis or relapse of disease or who demonstrated primary chemotherapy resistance. After demonstrating AML engraftment, mice are treated with cytosine arabinoside (Ara-C) given IP daily for 5 days as a single agent at 10mg/kg daily, 30mg/kg daily, and 60 mg/kg daily which correlates with human dosing. In >75% of mice treated with 10 mg/kg of Ara-C there is a cytoreductive effect at 2 weeks post-treatment with relapse at 4 weeks post-treatment. In all mice treated with 30 mg/kg of Ara-C there was a cytoreductive effect at 2 weeks post-treatment with relapse at 4 weeks post-treatment. In all mice treated with 60 mg/kg of Ara-C there was a cytoreductive effect at 2 weeks post-treatment with relapse 4–13 weeks post-treatment when relapse occurred, demonstrating that there is a dose response relationship in the model in terms of nadir leukemic burden and time to peripheral blood relapse. Two weeks after treatment, there was up to a 50-fold decrease in total AML cell burden in the peripheral blood of mice treated with 30 mg/kg and and up to a 70-fold decrease in the peripheral blood of mice treated with 60 mg/kg of Ara-C. We found no enhancement in quiescent or G0 cells after chemotherapy treatment. We did however, in 1/5 samples tested see a change in phenotype after chemotherapy treatment with an increase in the total number of CD34+38+ cells with a concomitant decrease in CD34-38+ cells. In all other samples tested, there was no change in phenotype after chemotherapy treatment. These results are in contrast to recent studies using a 1 gm/kg dose of Ara-C and analysis at Day 3 following a single treatment. These results have implications for understanding the physiologic response to Ara-C at different doses. We are currently analyzing mRNA expression arrays of AML without or with Ara-C treatment to identify novel mechanisms of chemotherapy resistance. Taken together, this model provides a novel approach for development of new therapies in AML.

Disclosures:
Carroll: Sanofi Aventis Corporation: Research Funding; Kyowa Hakko Kirin Pharmaceuticals: Research Funding; Agios Pharmaceuticals: Research Funding.
Methotrexate-Asparaginase-Dexamethasone Regimen for Blastic Plasmocytoid Dendritic Cell Neoplasm treatment
Authors: Vaida Ioana , Royer Bruno , Gruson Berengere , Damaj Gandhi , Harrivel Veronique , Marolleau Jean Pierre 
Published: October 2019

Abstract
Abstract 2194
Blastic plasmacytoid dendritic cell neoplasm (BPDCN), previously named CD4 CD56 haematodermic neoplasia is a rare malignancy, associated with poor prognosis; it affects older patients and has a typical clinical pattern, with initially skin involvement and evolution toward leukaemia. To date, best responses for patients younger than 60 yrs are obtained after induction chemotherapy acute lymphoblastic leukaemia-like and allogeneic bone marrow transplantation (Dalle, BJD 2010); for older patients there is no standardized treatment in first line; the CHOP or CHOP-like regimens don't improve the outcome of these patients. We report our experience in 6 patients with BPDCN treated with Methotrexate-Asparaginase (MTX ASP) steroid regimen, active in lymphoid malignancies.
From august 2006 to December 2009, 6 patients (pts) were newly diagnosed BPDCN according to main immunophenotyping features of this entity: CD4+, CD56+, HLA-DR+, CD123+, absence of B-, T- and myeloid associated markers (Tsagarakis, Leukemia Research, 2010); the mean age was 62 yrs (range, 55–74); 83% were males; 100% of patients presented at diagnosis with cutaneous disease and bone marrow involvement; all patients received the MTX-ASP steroid regimen; 4 pts were treated in 1st line and 2 pts in relapse, after CHOP-like regimen. The treatment schema was: Methotrexate 3g/m2 day 1, L-asparaginase 6000UI/m2, on day 2, 4, 6, 8 and Dexamethasone 40 mg day 1 to 4; the treatment was administered monthly till progression.

Results:
Overall complete remission (CR) rate was 83, 3% after 3 cycles: 5 pts were in CR and one patient had a progressive disease (PD). The 5 responders followed the same regimen until progression (total number of cycles for 6 to 11). The mean CR duration was 7, 8 months. One patient underwent allo HSCT after 7 courses and is still alive. The MTX-ASP regimen was well tolerated without severe haematological and non-haematological toxicity; there was no episode of infection and despite high doses of L-Asparaginase, no deep venous thrombosis was seen.

Conclusions:
The BPCDN treatment is not standardised, mainly due to the rarity of this entity; for younger patients best responses are obtained after allogeneic bone marrow transplantation and induction chemotherapy LAL-like; for older patients the CHOP or CHOP-like regimens don't improve the outcome of these patients. In our experience, methotrexate-asparaginase steroid regimen induces a high rate of CR and seems an interesting treatment option especially for older patients. The treatment toxicity is acceptable. We need to standardize our therapeutic approach in this rare malignancy.

Disclosures:
No relevant conflicts of interest to declare.
Jak2 Plays a Critical and Non-Redundant Role In Hematopoiesis throughout Pre- and Post-Natal Life
Authors: Park Sung , Gnanasambandan Kavitha , Sayeski Peter P. 
Published: October 2019

Abstract
Abstract 2238
In early Jak2 murine models, conventional germline knockout of Jak2 tyrosine kinase resulted in embryonic lethality at E12.5 due to severe defects in hematopoiesis. However, what role, if any, that Jak2 plays in late gestational development and post natal life is currently unknown. To achieve some understanding of this, we utilized a conditional knockout approach that allowed for the temporal deletion of Jak2 at various stages of embryonic and postnatal growth. Specifically, Jak2 conditional knockout mice were produced by crossing estrogen receptor inducible Cre mice (RosaCreER) with loxP inserted Jak2 conditional knockout mice (FL/FL). Injection of the bigenic mice with tamoxifen (TM), a synthetic estrogen receptor modulator, accordingly results in a Jak2 null allele. TM was injected into pregnant dams at E12.5 and into postnatal mice at day 4 and day 60. The animals were then euthanized at E16.5 (late gestation), postnatal at day 18 (an active stage of postnatal development) and day 90 (adult stage), respectively. We found that deletion of Jak2 throughout all stages of murine development resulted in marked hypocellular bone marrow, significantly reduced spleen size, an absence of extramedullary hematopoiesis, and profound anemia. Analysis of peripheral blood samples indicated that the Jak2 null mice have significantly decreased hematocrits characterized by increased numbers of abnormal red blood cells that were either immature or lacking hemoglobin. Furthermore, the number of platelets was also significantly reduced in the null mice when compared to aged matched littermate controls. Overall, these results indicate that Jak2 plays a critical and non-redundant role in hematopoiesis throughout all stages of prenatal and postnatal life.

Disclosures:
No relevant conflicts of interest to declare.
The Optimal Timing for Stem Cell Collection After Induction Therapy for Patients with Multiple Myeloma
Authors: Nazha Aziz , Vogl Dan T. , O'Doherty Una , Mangan Patricia , Cunningham Kathleen , Luger Selina , Porter David L. , Schuster Stephen J. , Gardler Marie , Sell Mary , Siegel Don L. , Stadtmauer Edward A 
Published: October 2019

Abstract
Abstract 2252

Introduction:
High dose chemotherapy and stem cell transplant remains an integral part of the therapy for Multiple Myeloma patients under age of 70. The collection of sufficient number of stem cells for one or more transplant is however sometimes a challenge. Moreover, the optimal timing for stem cell collection after induction chemotherapies is controversial. The standard recommendation is for stem cell collection after 4–6 cycles of non-alkylator regimen, however studies to support this practice are limited.

Material and Method:
We conducted a retrospective analysis of 366 patients who were diagnosed with multiple myeloma and mobilized at the Hospital of University of Pennsylvania between January 2002 and December 2008. Patients who did not meet the initial inclusion criteria were those who had induction regimens containing an alkalytor agent or whose regimens were not well documented and were excluded from futher analysis (85). Every 4 cycles of any non-alkalytor agent was considered to be one treatment session for the purpose of this analysis. 245 patients received 1 or 2 treatment sessions and 36 received &gt; 2. All patients were mobilized with either Cyclophosphamide/G-CSF (CY/G-CSF), Plerixafor/G-CSF (AMD/G-CSF), or G-CSF alone.

Result:
The mean number of collected CD 34+ cells (CD 34+) was 9.22 × 106 CD34+/Kg in the patients who received 1 or 2 sessions and 6.87 × 1106 CD34+/Kg in the patients who received &gt; 2 sessions (P= 0.005). The number of the patients who collected &gt; 6 × 106 CD34+/Kg was 63%(153/246), 53%(19/36) respectively, (p= 0.005). The patients who mobilized with either CY/G-CSF or AMD/G-CSF collected higher number of CD34+ than the patients mobilized with G-CSF alone in both groups. (Table 1, 2.)
The mean number of collected stem cells was 7.14 × 106 CD34+/Kg in the patients who received more than 2 sessions of different regimens and 6.26 × 106 CD34+/Kg in the patients who received &gt; 2 sessions of the same regimen.

Conclusion:
The patients who mobilized after fewer than 8 cycles of non-alkylator agents (2 sessions) collected a higher number of CD 34+ than those with greater than 8 cycles. CY/G-CSF or AMD/G-CSF are similar and superior to G-CSF alone in the more heavily treated patients. The patients who received multiple sessions of the same regimen have similar outcome compared to those who received multiple different regimens suggesting that the duration of the treatment may impact stem cell collection more than the content of the regimen. Prospective studies in this regards are warranted.

Disclosures:
No relevant conflicts of interest to declare.
Adoptive Transfer of EBNA1-Specific T-Cells as a Treatment of Epstein-Barr-Virus Reactivation Following Allogeneic Stem Cell Transplantation
Authors: Icheva Vanya , Opherk Kathrin , Bethge Wolfgang A. , Kayser Simone , Greil Johann , Handgretinger Rupert , Lang Peter , Feuchtinger Tobias F. 
Published: October 2019

Abstract
Abstract 2342
Reactivation of Epstein-Barr-Virus (EBV) after allogeneic stem cell transplantation (SCT) is responsible for significant morbidity and mortality. EBV is also assotiated with the development of some malingancies, such as Burkitt-Lymphoma or nasopharyngeal carcinoma (NPC). In particular, the EBV-induced lymphoproliferative disorder (PTLD) is a rare but severe condition after SCT. PTLD is often associated with insufficient immune responses against EBV in transplant recipients. There is no effective antiviral drug treatment against EBV by now. Given that T-cell immunity is crucial for protection against infection or reactivation of EBV, cellular immunotherapy is a promising therapeutic option. The Epstein-Barr-Virus Nuclear Antigen 1 (EBNA-1) has been shown to contain immunodominant T-cell epitopes with T-cell responses in the majority of the healthy population. Here we report adoptive EBNA-1-specific T-cell transfer in seven pediatric and adult patients with chemorefractory EBV-reactivation after allogenic SCT. Four patients had PTLD and one had metastatic relapse of a NPC. EBNA-1-specific T-cells were isolated from the SCT-donor by using an IFNγ-capture technique. These small T-cell populations were immediately infused to the patient without in vitro expansion steps. The adoptive T-cell transfer contained both, CD4+ T-helper cells and CD8+ cytotoxic T-cells. The patients with a mean age of 20 years were treated with antigen specific T-cells from haploidentical, matched unrelated or matched sibling donor SCT between day 72 and 410 post SCT. The T-cell dose varied from 150–7750 T-cells/ kg. No acute toxicity was observed. In vivo T-cell responses before adoptive T-cell transfer were absent and were detectable in all of the patients within the first weeks after adoptive transfer, associated with a partial clinical and/or virological response to the adoptive T-cell transfer. In three of the patients a second specific T-cell administration was needed to achieve an improvement of the EBV-related condition. PTLD or EBV-infection was not a cause of death in any of the other six patients. In conclusion we could show that adoptive T-cell-immunotherapy is safe, feasible and a promising therapeutic option in patients with EBV- infection and/or PTLD, having the advantage of not being immunosuppressive compared to chemotherapy against PTLD. Infusion of small IFNγ producing EBNA-1-specific T-cell populations resulted in an in vivo expansion of specific T-cells. Emergence of in vivo T-cell responses was closely associated with a clearance or reduction of the viral load.

Disclosures:
No relevant conflicts of interest to declare.
Older Patients with AML Undergoing Matched Related Allogeneic Transplantation Have Significantly Older Donors but Equivalent Survival as Patients Receiving Unrelated Donor Transplants
Authors: Hill Brian T. , Rybicki Lisa , Bolwell Brian J. , Dean Robert , Pohlman Brad , Tench Shawnda , Sobecks Ronald , Andresen Steven , Copelan Edward A. , Kalaycio Matt 
Published: October 2019

Abstract
Abstract 2356

Introduction:
Allogeneic stem cell transplantation (SCT) is commonly offered to patients with acute myeloid leukemia (AML) over the age of 55 with good performance status. For this patient population, potential sibling donors are necessarily older and have more comorbidities than siblings of younger patients. It is not known whether the advanced donor age of older patients outweighs the beneficial effect of having a sibling donor. To address this question, we retrospectively analyzed data from 62 consecutive patients who received allogeneic SCT at the Cleveland Clinic from 1990–2009.

Methods:
Inclusion criteria were: age ≥ 55 years, diagnosis of AML, and history of myeloablative or nonmyeloablative allogeneic SCT from related or unrelated adult donors. 31 patients underwent transplantation from matched related donors (30 siblings, 1 cousin). 31 patients received unrelated donor transplants. The median age was 59 for patients with related and unrelated donors (P=0.89). There was an equal percentage of males (64.5%) in both groups (P=1.0). There was an equivalent distribution hematopoietic cell transplant comorbidity index scores of low, intermediate and high for patients with related and unrelated donors (38.7%, 37.1% and 24.2% vs. 38.7%, 32.3%, and 29.0% P = 0.65). 45.2% of patients with related donors underwent myeloablative conditioning vs. 54.8% for patients with unrelated donors (P =0.61).

Results:
Sibling donors were significantly older than unrelated donors [median 59 years (range 41–75) vs. 36 (range 24–58), P < 0.001]. The incidence of acute and chronic graft-versus-host disease (GVHD) was similar in both groups. At five years, the cumulative incidence of relapse (43.2% vs. 38.7%, P = 0.88), non-relapse mortality (48.1% vs. 48.8%, P =0.91) and overall survival (17.2% vs. 24.1%, P =0.88) were similar for recipients of matched related and unrelated donor transplants. Older donor age was not predictive of death in univariate or multivariate analysis. Kaplan-Meier estimates of overall survival for recipients of related and unrelated donor transplants are shown.

Conclusion:
Patients with AML 55 years or older who underwent related donor transplantation had significantly older donors but equivalent survival when compared to patient who underwent unrelated donor transplantation. Advanced donor age should not be a contraindication to allogeneic SCT for older patients with AML.

Disclosures:
No relevant conflicts of interest to declare.