bluuebunny/crossref_metadata_2025 huggingface dataset:
High-Dose Cytarabine-Based Consolidation Shows Superior Results for Elderly AML Patients with Intermediate Risk Cytogenetics in First Complete Remission
Authors: Hassanein Mona Fawzy Ramadan , Atenafu Eshetu G , Gupta Vikas , Schuh Andre C. , Yee Karen , Minden Mark D. , Schimmer Aaron D , Brandwein Joseph M.
Published: October 2019

Abstract 3574

Introduction:

In elderly patients with acute myeloid leukemia (AML) treated intensively, the optimal post-remission strategy is unclear. High dose cytarabine (HiDAC) 3 g/m2 is the standard consolidation dose for younger adults with AML with favorable and intermediate risk disease, but is associated with high rates of severe toxicity and early death in older adults that counteract any improvement in efficacy when compared to standard dose cytarabine. We have used a modified high-dose cytarabine consolidation regimen, and compared this to a similar cohort receiving a conventional-dose regimen.

Methods:

164 patients with AML age 60 years and over, who achieved complete remission after standard induction therapy consisting of cytarabine 100 mg/m2/day continuous IV infusion × 7 days and dauorubicin 60 mg/m2 IV daily × 3 (7+3) from 1998 – 2008, received two different types of post-remission therapy in sequential cohorts. Group 1 (n=55), treated from 1998–2002, received 2 consolidation cycles, each consisting of cytarabine 1.5 g/m2 q12h × 6 doses + daunorubicin 45 mg/m2/day × 2, while group 2 (n=109), treated from 2003–2008, received a first consolidation using 7+3 followed by a second cycle consisting of mitoxantrone 10 mg/m2 IV daily × 5 plus etoposide 100 mg/m2 IV daily × 5 (NOVE).

Results:

The two groups did not differ with respect to median age (68 vs. 69 years), mean baseline WBC, gender, prior malignancy/AHD and proportion of patients undergoing allogeneic HSCT in CR-1 (9.1 vs.8.3%). 40 patients (72.7%) in the first group, and 86 patients (78.9%) in the second group received the intended consolidation regimen (p=0.38). Among the entire cohort (n=164), and in the subgroup with adverse risk cytogenetics, there was no significant difference in OS or DFS between the two groups. For patients with intermediate risk cytogenetics, on an intention-to-treat basis, the disease-free survival (DFS) was significantly higher for group 1 vs. group 2 (Table 1).

Conclusion:

Older patients with intermediate-risk cytogenetics, who received a modified high-dose cytarabine-based consolidation regimen combined with anthracycline, had a superior DFS and a trend toward superior OS, as compared to those who received conventional-dose consolidation therapy. These findings require further evaluation in a prospective randomized study but, if confirmed, suggest that older fit patients with intermediate risk cytogenetics should receive more intensified post-remission therapy with modified high-dose cytarabine.

Disclosures:

No relevant conflicts of interest to declare.
Pomalidomide Cyclophosphamide and Prednisone (PCP) Treatment for Relapsed/Refractory Multiple Myeloma
Authors: Palumbo Antonio , Larocca Alessandra , Montefusco Vittorio , Rossi Davide , Carella Angelo Michele , Mina Roberto , Crippa Claudia , Sciacca Mariella , Galli Monica , Scalabrini Delia Rota , Marcatti Magda , Guglielmelli Tommasina , Giuliani Nicola , La Verde Giacinto , Baldi Ileana , Muccio Vittorio Emanuele , Boccadoro Mario , Corradini Paolo
Published: October 2019

Abstract 446

Background:

The outcome of myeloma (MM) patients who are no longer responding to thalidomide, lenalidomide or bortezomib is poor, with a median event-free survival of 5 months and median overall survival (OS) of 9 months (Kumar SK et al, Leukemia 2012). The newer immunomodulatory drug pomalidomide, has shown significant activity in these clinical conditions.

Aims:

We assessed dosing, efficacy and safety of pomalidomide-cyclophosphamide-prednisone (PCP) in MM patients relapsed/refractory to lenalidomide.

Methods:

Pomalidomide was administered in doses ranging from 1 to 2.5 mg/day on days 1–28, cyclophosphamide at 50 mg every other day on days 1–28 and prednisone at 50 mg every other day on days 1–28 for 6 cycles, followed by maintenance therapy with pomalidomide-prednisone. Thromboprophylaxis with aspirin 100 mg/day or low-molecular weight heparin was recommended at physician's discretion.

Results:

The maximum tolerated dose (MTD) of pomalidomide was defined as 2.5 mg/day. Fifty-two patients were enrolled at the MTD and evaluated after completing at least 1 PCP cycle. Median age was 69 years (range 41–83). The median time from diagnosis to enrolment was 55 months (range 15–203). Best responses to PCP included 6% of complete response (CR), 19% of at least very good partial response (VGPR), 54% of at least partial response (PR) and 75% of at least minimal response (MR). Time to PR was rapid (median 1.8 months). After a median follow-up of 11 months (range 1–18), 1-year progression-free survival (PFS) and OS rates were 52% and 78%, respectively. PFS was not significantly different in patients with high-risk cytogenetic compared with patients with standard-risk disease and in patients younger or older than 75 years.

Toxicities were primarily hematologic and included grade 4 neutropenia (13%) and thrombocytopenia (4%). At least grade 3 non-hematologic toxicities included infections (8%), rash (6%) and neurologic (6%). Thromboembolism occurred in 1 patient. Four patients discontinued treatment for toxicity (2 infections, 1 neurologic and 1 hepatic toxicity).

Conclusions:

PCP induced high response rates and prolonged PFS after prior exposure to lenalidomide and bortezomib (Table), without adding significant toxicity. PCP could be considered a valuable salvage option for pre-treated MM patients.

Disclosures:

Palumbo: Celgene: Consultancy, Honoraria. Larocca:Celgene: Honoraria. Sciacca:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Guglielmelli:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Boccadoro:Celgene: Consultancy, Honoraria.
Functional Hyposplenism in Pediatric Chronic Graft-Versus-Host Disease
Authors: Rozmus Jacob , Ke Janny , Schultz Kirk R.
Published: October 2019

Abstract 4493

Introduction:

Functional hyposplenism is a well-recognized complication of chronic graft versus host disease (cGVHD). Whether the hyposplenism in cGVHD is transient and if there is any association between the severity of cGVHD and degree of hyposplenism are not well understood. The pitted red cell count has been shown to be a simple and reliable biomarker of splenic function that correlates well to other tests such as quantitative Howell-Jolly bodies and 99mTc sulfur-colloid liver-spleen scans. It measures the ability of the splenic red pulp to pinch off intracellular vesicles, or pits, from red blood cells as they pass through narrow adjustable slits in an endothelial lining.

Methods:

We hypothesized that functional hyposplenism correlates with the severity of cGVHD in pediatric BMT patients. We performed a single-center, retrospective review of pediatric allogeneic bone marrow transplant (BMT) patients who had more then one pit count performed post-BMT and clinical diagnosis of cGVHD based on NIH consensus criteria.

Results:

We identified 9 pediatric BMT recipients (3 males, 6 females; average age at BMT = 9.6 years) that met our criteria. Indications for BMT were AML (2), ALL (1), biphenotypic acute leukemia (1), CML (2) and thalassemia (3). All 9 had functional hyposplenism with active cGVHD as determined by a pit count > 2%. We identified two distinct groups. In 7 of the 9 BMT recipients, there was a return to normal splenic function that lagged between 12 and 18 months after clinical improvement/resolution of cGVHD symptoms and successful weaning of immunosuppressive therapy. In the other 2 patients there was no correlation between abnormal pit count and cGVHD symptoms.

Conclusions:

Our single-centre retrospective cohort study provides evidence that the functional hyposplenism associated with cGVHD is not permanent but improvement in cGVHD symptoms and successful weaning of immunosuppressive therapy should not be used as indicators of return to normal splenic function and reasons to stop Penicillin prophylaxis. We propose that all patients post-BMT should have serial pit counts performed, as resolution of cGVHD clinical symptoms does not ensure normal splenic function.

Disclosures:

No relevant conflicts of interest to declare.
Molecular Screening for Hepatitis B and Hepatitis C Viruses in Allogeneic Hematopoietic Stem Cell Transplantation– a Pilot Study
Authors: Sobczyk-Kruszelnicka Malgorzata , Markiewicz Miroslaw , Wieczorkiewicz-Kabut Agata , Wieclawek Agnieszka , Soja Anna , Dzierzak-Mietla Monika , Koclega Anna , Bialas Krzysztof , Kyrcz-Krzemien Slawomira
Published: October 2019

Abstract 4494

Introduction:

Viral hepatitis is, despite graft versus host disease (GVHD) and veno-occlusive disease (VOD), the third cause of hepatic complications after allogeneic hematopoietic stem cell transplantation (alloHSCT). The aim of this study was to analyze the effectiveness of molecular screening for hepatotropic viruses: hepatitis B virus (HBV) and hepatitis C virus (HCV), basing on a single centre experience.

Materials and methods:

We have evaluated 30 pts (15 women, 15 men), median age 33.5 years (18–61), who underwent alloHSCT from HLA-identical sibling (7) or unrelated donors (23) in years 2011–2012. The stem cell source was peripheral blood in all pts. Indication for allo-HSCT was: AML(11pts), ALL (10pts), OMF (4pts), SAA(2pts), PNH (2pt) and CML(1pt). Preparative regimen was myeloablative in 20pts (BuCy:10pts, Cy+TBI:10pts) and reduced in 10pts (Flu+Bu:5pts, Treo+Flu:3pts, Treo+Cy:1pt, Flu+Cy:1pt). Standard GVHD prophylaxis consisted of cyclosporine, methotrexate and pre-transplant anti-thymocyte globulin (in 28pts). Molecular quantitative polymerase chain reaction (QPCR) HBV-DNA and HCV-RNA tests and screening for serological markers of HBV (HBc-Ab, HBs-Ab, HBs-Ag, HBe-Ab, HBe-Ag) and HCV (HCV-Ab) infection were performed at four time-points (before the start of conditioning treatment and on days +28, +100 and +180 post-transplant).

Results:

HBc-Ab was initially positive in 2 pts, who presented negative results of other serological markers and molecular tests. In remaining 28 pts all serological and molecular markers were negative. No pt developed hepatitis infection and/or reactivated virus replication. Both pts who were initially HBc-positive did not develop any markers of HBV reactivation after one year observation, despite the intensive immunosuppression.

Outcomes of our pilot study do not justify the routine molecular screening of hepatotropic viruses in patients undergoing alloHSCT, despite the profound immunosuppression. The routine molecular screening should be reserved only for patients with positive serological markers or/and those with symptoms of hepatitis.

Disclosures:

No relevant conflicts of interest to declare.
Clofarabine As the Element of Conditioning Regimen in Matched Related Allogeneic Transplantation – Single Center Experience
Authors: Mensah-Glanowska Patrycja , Piatkowska-Jakubas Beata , Skotnicki Aleksander
Published: October 2019

Abstract 4516

Since June 2010 to July 2012 since in Department of Hematology of the University Hospital in Krakow five patients with advanced hematological malignancies have been subjected to allogeneic transplantation from matched related donors with clofarabine as a part of conditioning regimen.

Indications for transplantation were relapsed/refractory acute myeloid leukemia in four patients and CML lymphoblastic crisis in relapse after RIC alloPBSCT in one patient. In a case of three patients conditioning regimen consisted of two phases. First phase: cytoreduction with clofarabine 20mg/m2/day + ARA-C 2000 mg/day for 4 days in 2 patients with refractory AML and Clofarabine 20mg/m2/day + Cyclophosphamide 400mg/day for 4 days in one (CML lymphoblastic crisis). Second phase: Busilvex + Fludarabine (Bu4Flu). Two later patients were treated without cytoreduction. One patient with extramedullary AML in second CR was treated with Clofarabine 30mg/m2 for 4 days + TBI. Last patient with early AML relapse was conditioned with Clofarabine30mg/m2 for 5 days+ Busilvex (BuClo). G-CSF mobilized peripheral blood was used as a source of stem cells in all the patients.

Results:

One patient died during conditioning regimen after cytoreduction (Clofarabine + Cyclophosphamide). It was the patient with CML lymphoblastic crisis relapse after RIC allogeneic transplantation. The other patients treatment toxicity was moderate (mucositis garde I-III). Aplastic period was complicated in one patient with septic infection. One patient relapsed 5 months after transplantation. He was diagnosed with AML secondary to MDN/MPD with very high cytogenetics (t(3;3) with 7 monosomy) Three of patient series remain in complete remission. All of them were diagnosed with relapse/refractory AML with CR duration 6 months to 26 months.

Conclusions:

Use of clofarabine as a part of conditioning regimen is valuable therapeutic option especially in the group of patients with relapsed/refractory AML.

Disclosures:

No relevant conflicts of interest to declare.
Fractionated Stem Cell Infusions for Patients with Multiple Myeloma Undergoing Autologous Stem Cell Transplant
Authors: Wood Kevin , Giralt Sergio A , Koehne Guenther , Chung David , Lendvai Nikoletta , Hassoun Hani , Lesokhin Alex , Hoover Elizabeth , Devlin Sean , Landau Heather
Published: October 2019

Abstract 4550

Background:

High dose therapy with autologous stem cell transplant (SCT) is an established therapeutic modality for multiple myeloma (MM). Although effective, it is associated with significant symptom burden due to the obligate period of neutropenia in addition to an increased risk of infectious complications. In animal models, infusing stem cells over a period of days enhances immune reconstitution (Felfly H, et al. Br J Haematol. 2009; 148: 646–658). We hypothesized that multiple stem cell infusions could reduce the period of neutropenia and enhance immune recovery resulting in a better tolerated procedure.

Methods:

We are conducting a phase II trial of multiple fractionated autologous stem cell infusions after high-dose Melphalan. We compared initial engraftment kinetics of the first 14 patients to receive multiple infusions (Days 0, +2, +4, +6) after high-dose Melphalan (study group) to 23 patients receiving high-dose Melphalan followed by the standard single stem cell infusion (Day 0) (standard group). Pegfilgrastim was given to all patients on Day +1. All patients underwent SCT between October 2011 and July 2012.

Results:

Results are shown in Table 1. Similar numbers of stem cells were collected in the study and standard groups. The total number of stem cells infused was 9.7 × 10∧6 CD34+ cells/kg in the study patients compared to 5.0 × 10∧6 CD34+ cells/kg in the standard patients. To date, the median duration of neutropenia (days of ANC < 500) and lymphopenia (days of ALC < 500) as well as the days to neutrophil, lymphocyte and platelet engraftment are similar. There are no significant differences in the number of red cell or platelet transfusions, days of fever, diarrhea, empiric antibiotics or documented infections. Despite receiving multiple infusions, none of the patients in the study group experienced an infusion reaction. Engraftment syndrome occurred in 3/14 (21%) of the study patients. The median duration of hospitalization was 15 days in the study cohort versus 17 days in the concurrent control group (P = 0.01).

Conclusion:

Multiple stem cell infusions following high dose Melphalan in patients with MM were not associated with a higher incidence of adverse side effects from DMSO nor unexpected frequency of engraftment syndrome. Fractionating stem cells over a period of days may result in less antibiotic use, reduced frequency of infection and was associated with shorter hospitalizations. We continue to collect patient reported symptom scores in order to determine if we can improve patient experience during SCT.

Disclosures:

No relevant conflicts of interest to declare.
Clinical Study of Allogenetic Hematopoietic Stem Cell Transplantation for Three Cases of Leukodystrophy
Authors: Feng Xiaoqin , Li Chunfu , Li Na , Wu Xuedong
Published: October 2019

Abstract 4559

Objective:

Allogenetic hematopoietic stem cell transplantation (Allo-HSCT) can be used to cure some genetic leukodystrophy patients in current. This clinical study is to investigate efficacy and practicability of Allo-HSCT in treatment of genetic leukodystrophy in China.

Methods:

Three boy diagnosed genetic leukodystrophy (2 cases of metachromatic leukodystrophy, 1 case of X□|linked adrenoleukodystrophy) had undergone allogeneic Stem cell Transplantation. A 32 month old boy accepted HLA 8/10 high-resolution matched unrelated umbilical cord blood as graft, which contained nucleated cells 13.5×107/kg. A 2 year-old boy accepted HLA high-resolution 10/10 matched unrelated peripheral blood stem cells (PBSC) as graft which contained mononuclear cells 8 ×108/kg. The conditioning regimen consisted of cyclophosphamide (60–100 mg/kg), fludarabine (150–200mg/kg), TT (5mg/kg) and busulfan (12–13.2 mg/kg). A 12 year-old boy accepted sibling HLA low resolution 6/6 (A, B, DRB1) matched bone marrow as graft which contained mononuclear cells 1.23 ×108/kg. The conditioning regimen consisted of busulfan (16mg/kg) and cyclophosphamide (200mg/kg). Cyclosporine A and mycophenolate mofetil were used to prevent graft versus host disease (GVHD). ATG-Fresenius (15 mg/kg) and low dose of methotrexate were added for prophylaxis of GVHD in unrelated PBSC transplantation. XY chromosome by the FISH method or quantitative PCR for short tandem repeat (STR) were used to identify the chimerism. ASA level in peripheral blood leukocytes and C26:0 plasma level were monitored after transplantation respectively.

Results:

Conclusion:

Allogenetic hematopoetic stem cell transplantation is effective and feasible in the treatment of some childhood genetic leukodystrophy patients. These patients should accept allo-HSCT in the early stage of disease in order to get good survival.

Disclosures:

No relevant conflicts of interest to declare.
Genomic Analysis of Serial Chronic Lymphocytic Leukemia Samples Suggests That Epigenetic Changes, Rather Than Clonal Evolution, May Drive the Progression of This Leukemia
Authors: Ghia Emanuela M. , Smith Erin , DeBoever Christopher , Rassenti Laura Z. , Rozenzhak Sophie , Shepard Peter , Alakus Hakan , Harismendy Olivier , Barrett Christian L , Frazer Kelly A , Kipps Thomas J.
Published: October 2019

Abstract 4563

The clinical course of patients with chronic lymphocytic leukemia (CLL) is heterogeneous, with some patients requiring treatment relatively soon after diagnosis and others having indolent disease for many years. Some patients with indolent disease, however may develop more aggressive disease over time that requires therapy. To identify genetic and epigenetic changes that associate with the transition from indolent to aggressive disease, we used genomic methods to analyze sequential samples obtained from 19 CLL patients evaluated at the UC San Diego Moores Cancer Center who ultimately required treatment, as per iwCLL guidelines.

For all patients, the first time point sample collection (SC1) was obtained within 1 year post-diagnosis and the second time point sample collection (SC2) was obtained within 1 year before treatment. We performed whole-exome sequencing (Agilent 50Mb capture, 100×) and methylation (450K) array analyses on leukemia cells and germline DNA. Somatic allele frequencies ranged from < 10% to 50%, suggesting heterogeneity within the tumor. When comparing SC1 versus SC2, we observed changes in somatic allele frequency for 6 (32%) of 19 patients, however 13 (68%) of 19 patients did not have evidence for clonal evolution at the somatic level, suggesting that the acquisition of additional somatic mutations did not drive CLL progression and that the clonal population structure remains stable throughout disease progression with multiple clones per patient. Using 450K CpG methylation arrays, we identified 52,409 sites (FDR=0.05) that changed consistently between SC1 and SC2 across 19 patients, suggesting that epigenetic changes were widespread, even without detectable somatic mutations.

In summary, our results imply that CLL progression can occur in the absence of somatic mutations, but rather may reflect non-stochastic alterations in the epigenome altering RNA expression.

Disclosures:

No relevant conflicts of interest to declare.
Divergence in CD19-Mediated Signaling Unfolds Intra-Clonal Diversity in Chronic Lymphocytic Leukemia Which Correlates with Disease Progression
Authors: Herishanu Yair , Kay Sigi , Dezorella Nili , Perry Chava , Deutsch Varda , Polliack Aaron , Naparstek Elizabeth , Katz Benzion
Published: October 2019

Abstract 4570

Emerging data on intra-clonal diversity imply that this phenomenon may play a role in the clinical outcome of patients with chronic lymphocytic leukemia (CLL), where subsets of the CLL clone responding more robustly to external stimuli may gain a growth and survival advantage. Here we report intra-clonal diversity resolved by responses to CD19 engagement in CLL cells, which can be classified into responding (CD19-R) and non-responding (CD19-N) sub-populations. Engagement of CD19 by anti-CD19 antibody rapidly induced cellular aggregation in the CD19-R CLL cells. The CD19-R CLL cells expressed higher surface levels of CD19 and c-myc mRNA and exhibited distinct morphological features. Both sub-populations reacted to IgM stimulation in a similar manner and exhibited similar levels of Akt phosphorylation, pointing to functional signaling divergence within the B-cell receptor. CD19 unresponsiveness was partially reversible, where CD19-N cells spontaneously recover their signaling capacity following incubation in vitro, pointing to possible in vivo CD19-signaling attenuating mechanisms. This concept was supported by the lower CD19-R occurrence in bone marrow-derived samples compared with cells derived from the peripheral blood of the same patients. CLL patients with more than 18.5% of CD19-R cell fraction had a shorter median time to treatment compared to patients with less than 18.5% of CD19-R cell fraction.

Conclusions:

Divergence in CD19-mediated signaling unfolds both inter-patient and intra-clonal diversity in CLL. This signaling diversity is associated with physiological implications including the location of the cells and disease progression.

Disclosures:

No relevant conflicts of interest to declare.
Array Comparative Genomic Hybridization: A Better Alternative for Genomic Profiling and Prognosis of Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Leon Annette , Sevilla Deborah , Marino Joseph M , Moreno Kenneth D , Obrera Rev , Lee PoShing , Ye Donjiu , Talwar Jotica , Persad Rajendra , Villamil Cesar , Maya Melissa , Mehta Nirav , Kemel Yelena , Weisberger James
Published: October 2019

Abstract 4572

Traditional cytogenetic techniques such as chromosome analysis and fluorescence in situ hybridization (FISH) have provided valuable genetic information in the evaluation of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). However, many genomic abnormalities remain undetected due to the limitations intrinsic to these techniques. We designed, validated, and clinically applied a combined targeted-whole genome custom oligonucleotide microarray for the evaluation of hematological malignancies. Incorporation of array comparative genomic hybridization (aCGH) analysis has enabled us to identify previously undetected copy number changes with an increased resolution and sensitivity and more precisely determine genomic breakpoints and gene content with diagnostic and prognostic relevance in CLL/SLL. A cohort of 300 patients diagnosed with CLL/SLL was studied using concurrent cytogenetics, FISH and aCGH analyses on either peripheral blood or bone marrow aspirate samples. Array CGH identified clinically significant genomic alterations in 75% of the cases compared to 57% and 47% by cytogenetics and FISH analyses, respectively. There were no statistically significant differences detected between peripheral blood and bone marrow samples. Recurrent alterations such as deletions in chromosomes 11q (ATM, adverse prognosis), 13q (RB1, DLEU1, 2, and 7, MIR15A and 16–1, favorable prognosis in general), 17p (TP53, adverse prognosis) and gain of one copy of the entire chromosome 12 (ETV6, KLRK1, CD27, KRAS, MDM2, HIP1R, KITLG, intermediate prognosis) were identified in 55% of cases by aCGH. Of these cases, chromosome and/or FISH analyses did not detect these abnormalities in 42% and 27% of cases respectively. In addition, aCGH study more fully characterized the interstitial deletion in chromosome 13q recently suggested to have different outcomes based on size and gene content. Important findings exclusively by aCGH analysis in 7% of cases include loss of genetic material in chromosomes 3p (KAT2B, FHIT, clonal evolution), 6q (MAP3K7, PRDM1, AIM1, TNFAIP3, intermediate prognosis), 8p (TNFRSF10D, disease progression), 9q (JAK2, MLLT3, CDKN2A and B, DAPK1) and gain of genetic material in chromosome 2p (ACP1, MYCN, ALK, REL, BCL11A) associated with unmutated IGHV status, advanced disease stage and adverse prognosis. The results obtained in this study demonstrate the superior resolution and detection rate of aCGH technology as well as the importance of incorporating this methodology into current algorithms for the diagnosis and prognosis of CLL/SLL.

Disclosures:

No relevant conflicts of interest to declare.
Forest Plot to Compare Therapies in a Network Meta-Analysis in First Line Chronic Lymphocytic Leukemia
Authors: Piciocchi Alfonso , Bontempi Katia , Fazi Paola , Vignetti Marco , Mandelli Franco
Published: October 2019

Abstract 4596

Several therapies, composed by single agent or combinations, are available for untreated patients in chronic lymphocytic leukemia and it is difficult to rank treatments according to their effect size when not all treatments have been compared directly. Direct randomized comparison is the most reliable way of comparing treatments but when the number of available treatments increases the number of possible pairwise comparisons increases quadratically, so it is common for only a small fraction of the possible comparisons to be performed. Network meta-analysis permits to add indirect estimates for assessing the relative effectiveness of two treatments when they have not been compared directly in a randomized trial but have each been compared to other treatments. Network meta-analysis of randomized controlled trials was used to combine direct and indirect estimates of the effect of four drugs and their combinations from five randomized controlled trials (Fig. IA) in CLL patients based on a systematic review conducted by M.M. Cheng et al. (Cancer Treatment Review 2012) on 2625 patients where Chorambucil, Fludarabine, Rituximab, Alemtuzumab, Bendamustine, Cladribine and Pentostatin have been considered as primary first-line agents for CLL. Patients were younger (59–65 years), had good performance status (ECOG: 0–1) and early stage disease (Rai 0-II, Binet A or B). We carried out an analysis based on the endpoint of PFS, described as the duration of the time from randomization until disease progression or death from any cause and to consider the heterogeneity among the studies a random effects model was performed. The differences in PFS of all therapies considered in the analysis were compared with combination of Fludarabine and Chorambucil (FC). The results were summarized by forest plot (Fig IB) in terms of reduction or increase of Hazard Ratio. As the forest plot shows, FCR has relatively higher potential of preventing disease progression in younger patients affected by chronic lymphocytic leukemia.

Respect to a traditional meta-analysis, which usually compares only two treatments, network meta-analysis is a useful method to combine direct and indirect comparisons of treatments from RCTs and to analyze the hierarchy in treatment effects and tests for consistency of the relations of the network.

Disclosures:

No relevant conflicts of interest to declare.
A Neonate with Type 3 Von Willebrands Disease and Life Threatening Bleeding Treated Successfully with a FVIII/VWF Concentrate (wilate®)
Authors: Hegener Oliver , Efford Jemma , Bartram Jack L , Henderson Lesley , Khair Kate
Published: October 2019

Abstract 4633

Case presentation

A 1 day old male presented to local hospital in collapsed state following normal vaginal delivery at 41 weeks gestation. The baby had sudden onset of limpness at home. On arrival at hospital he was making no spontaneous movement had slowly reactive pupils, oxygen saturation was 76% in air. He was intubated and blood was noted on his vocal cords. His haemoglobin was 2.3g/dl and coagulation grossly abnormal with APTT of >100seconds. There was no family history of bleeding diathesis. The baby was transferred to neonatal intensive care unit at this hospital.

Management

On arrival at this hospital the baby was ventilated, had received both FFP and blood transfusion and an additional dose of Vitamin K whilst clotting factor assays were awaited. Abdominal distention was noted and an ultra sound of the abdomen revealed a large collection of blood in the abdominal cavity. Severe vWD (FVIII 8iu/dl and VWF Rapid 5iu/dl post FFP) was diagnosed. Treatment with Wilate 60iu/kg/dose was initiated and continued for 7 days during which time there was no further bleeding.

Outcomes

The baby was ventilated for 72 hours, a central line was inserted for venous access and administration of Wilate. Subsequent factor assays (with out FFP) reveal FVIII <1 iu/dl and vWF <1 iu/dl. The baby was discharged from hospital aged 2 weeks and has had no further major bleeds but has been treated with Wilate for minor bleeding following trauma. He is now 7 months old and is thriving and well. Genetic analysis confirms severe vWD inherited in an autosomal recessive manner.

Conclusion

The FVIII/VWF concentrat, Wilate, proved effective in achieving lasting haemostatsis in the management of this acutely unwell neonate with significant spontaneous intra-abdominal bleeding.

Disclosures:

Hegener: Octapharma: Employment.
Regulatory Role of Host IL-17 Via Control of Host Macrophage Activation Contributes to Less Acute Gvhd
Authors: Kuroda Rie , Sato Katsuaki , Maeba Hideaki , Fujiki Toshihiro , Mase Shintaro , Araki Raita , Naka Kazuhito , Naito Makoto , Iwakura Yoichiro , Yachie Akihiro , Koizumi Shoichi , Nishimura Ryosei
Published: October 2019

Abstract 4669

IL-17 has emerged as a key pro-inflammatory cytokine, however, recent studies demonstrated that IL-17 has also anti-inflammatory effects. In addition, a wide variety of IL-17 producing cells are identified not only in T-cells but also in subpopulation of monocytes and macrophages, mast cells, Paneth cell in the gut so on. Therefore, IL-17 mediated immune responses are becoming much more complicated. In hematopoietic stem cell transplantation, we have reported that host-derived IL-17 has a protective effect against acute graft-versus-host disease (GVHD) using rodent models, in contrast, donor-BM-derived IL-17 exacerbates chronic GVHD. In acute GVHD model, lethally irradiated IL-17 knockout (KO) recipient mice receiving allogeneic BM with low dose splenocytes developed more severe acute gut GVHD compared to wild type (WT) host mice and finally half of them died (p<0.05). Much higher number of infiltrated monocyte/macrophage cluster was observed in spleen and gut in IL-17 KO host mice. Furthermore, residual host-typed peritoneal macrophages in IL-17 KO host mice were highly activated with the expression of TNF-α, while activation of donor-typed macrophages was much less with the production of anti-inflammatory cytokine IL-10. It suggested that these activated and increased macrophages might deeply involve in the pathogenesis of lethal GVHD. To test this, IL-17 KO recipient mice were given lipoCL2MDP intraperitoneally on day -7 before BMT to deplete host macrophages. As shown in the figure below, the macrophages depleted IL-17 KO host mice given splenocytes to induce lethal GVHD showed a significant survival benefit compared with IL-17 KO mice without depletion of macrophages. In conclusion, host IL-17 has a protective effect against acute GVHD with suppression of the activated macrophages. This is the first report that IL-17 has the immuno-regulatory role via control of activated host macrophages in acute GVHD.

Disclosures:

No relevant conflicts of interest to declare.
Surveillance of Healthcare Associated Infection in the Adult Hematology Unit
Authors: Lamchahab Mouna , Cherkaoui Siham , Ouhaddouss Mohamed , Qachouh Meryem , Benchekroun Said , Quessar Asmaa
Published: October 2019

Abstract 4712

Background:

Patients with hematological malignancies are at risk for Healthcare Associated Infection (HAIs) due to malignancy types, antineoplastic chemotherapies, immunosuppressant treatment, and prolonged hospital day. HAIs cause delay in cancer treatment, increase morbidity or mortality and increase costs of treatment affecting successful outcomes of cancer care. We describe the outcome of the surveillance in adult hematology patients in our hospital and identified groups most at risk for HAIs. We describe the outcome of the surveillance study in adult hematology patients in Morocco. Methods: A prospective surveillance study included all patients admitted to the adult hematology unit from March 2011 to August 2011. They excluded patients from the transplant unit and day hospital. The Center for Disease Control and Prevention standard definitions were used to determine if an infection was hospital acquired. We collected data in demographics, risk factors, the presence or absence of HAIs and its type. Results: A total of 180 patients that represented 377 admissions, with 4438 hospitalization-days, were included in the study. They have a mean age of 35 years (18–78 years). The sex-ratio H/F was 1.7. The distribution of the patient's diagnosis is related in Table1. 63 patients had 110 episodes of HAIs. The incidence rate of HAIs was 24.74/1000 hospitalization-days. The most frequent of infectious episodes were bacteremia (38.18%) and pneumonia (24.54%). The fever of unknown origin represented 35.45%.The distribution of the intrinsic risk factors with regard to episodes of HAIs was the following: 83.48% presented with neutropenia, 59.79% presented with severe neutropenia. With regard to extrinsic risk factors for HAIs, 61.03% of the infectious episodes had central venous catheterization. The mortality rate due to HAIs was 8%. Conclusion: Although the overall HAI rate is in line with published reports in hematology units, our mortality rate is higher. This finding suggests that we must be more aggressive to prevent infections in the patients in these units. Table I: Distribution of patient's diagnosis and incidence rate of HAIs Infection Incidence rate (/1000 hospital day) N n % Age (years) 18–40 41–60 > 60 Hematologic neoplasia 245 97 35 70 31 9 28,57 31,96 25,71 Acute myeloid leukemia 147 98 89,00 35,27 Acute lymphoblastic leukemia 83 5 4,54 Non Hodgkin's lymphoma 102 5 4,54 Hodgkin's disease 36 0 Aplastic anemia 3 2 Others 6 0 Total 377 110 100

Disclosures:

No relevant conflicts of interest to declare.
Peripheral Blood Lymphocyte and Platelet STEM CELL Expansion in Autologous Platelet-Derived Growth Factor-RICH Plasma
Authors: Salas Rodolfo J , De Salvo Dalila , De Salvo Cardullo Luigi , Hassanhi Manzur , Paz Luis S , Salas Dalida , Fuenmayor Alba , Acurero Zulay , Carrizo Ricardo , Herrera Humberto , Nunez Iris
Published: October 2019

Abstract 4717

Research on stimulatory and inhibitory factors present in the hematopoietic microenvironment promoted development of ex-vivo cell culture methods. Recent investigations strive to select natural and novel mitogenic substances within defined conditions to culture and harvest specific progenitor cells and cell lines. Optimal large scale cell expansion of HSCs remains to be developed. The present study documents ex-vivo human lymphocytes and platelet culture in autologous human blood plasma (BP) complemented with a novel ionic metal polysulphide. Resulting plasma is growth-factor rich (FRP) with a high platelet count (HPC) containing > 4.5×10E6 plts/ul. Co-culture expansion for 3-days of normal peripheral blood cells from n=20 healthy individuals in FRP promotes lymphoid and platelet series stem cell lineage growth and differentiation. Cultured cells characterized using conventional hematology and flow cytometry methods on CD3, CD4, CD8, CD34, CD38, CD41, CD61 antigen bearing cells; and average values reported. Result analysis of CD3 and CD4 bearing cells before-after a 3-day culture indicates a 4 % and 18 % respective increase, while CD8 cell population decrease 7%. A stimulation response obtained on CD34 and CD38 cells with a 67.30% and 53.89 % respective increase. Cell growth of CD41 and CD61 antigen bearing cells increased 50.89 % and 69.22 %, respectively. Functional platelet counts (before-after culture) correspond with a 3–5 fold increase of original concentration, and presence of recently reported proto-platelets. Minimum and maximum values varied among studied population. Discrete elevation in Neutrophils and Granulocytes counts observed. Potential applications thought for immunosuppression, cancer and organ transplant.

Disclosures:

No relevant conflicts of interest to declare.
Eltrombopag, but Not Romiplostim or Thrombopoietin, Inhibits Growth of Thrombopoietin Receptor Positive and Negative Human Leukemia Cell Lines
Authors: Rusnak David W. , Rudolph Sharon K. , Safavi Afshin , Erickson-Miller Connie L.
Published: October 2019

Abstract 4726

The thrombopoietin receptor agonists (TPO-RA), romiplostim and eltrombopag, are presently indicated for the treatment of certain patient groups with immune thrombocytopenia purpura. In a clinical study with romiplostim in patients with low-/intermediate-1 risk myelodysplastic syndromes (MDS), cases of transient increases in blast cell counts were observed and cases of MDS disease progression to acute myeloid leukemia (AML) were reported.

In the present study, we evaluated the impact of romiplostim, eltrombopag, and recombinant human thrombopoietin (TPO) on the proliferation of 5 human AML and 1 TPO-dependent megakaryoblastic cell line. The cell lines evaluated include the TPO-dependent cell line, N2C TPO; the TPO-R positive AML lines, HEL92.1.7 and OCI-AML-3; and the TPO-R negative AML cell lines, HL60, THP-1, and NOMO-1. All cells were exposed to 11-point dose response curves of the 3 agents at concentrations sufficient to generate a full stimulatory response in the N2C TPO cell line. Cells were exposed to concentrations of romiplostim and eltrombopag that met or exceeded the reported Cmax achieved for each agent in high-dose clinical trials and were 3- (eltrombopag) to 30-fold (romiplostim) above trough levels from the same clinical trials.

Neither romiplostim nor TPO treatment resulted in detectable stimulation or inhibition of leukemia cell growth at concentrations up to 10 μg/mL. Treatment with eltrombopag up to 40 μg/mL caused inhibition of all AML cell lines with mean IC50 values ranging from 6.4 to 13.5 μg/mL. These IC50 values reflect concentrations that are 3- to 6-fold below the Cmax of a 300 qd dose of eltrombopag (40.5 μg/mL) and at concentrations as low as 2-fold below Ctau levels (12.4 μg/mL). Cmax exceeded the IC90 for these AML cell lines, which ranged from 18.5 to 27.9 μg/mL. No stimulation of AML growth was evident through the range of the eltrombopag dose response curve on any of the cell lines evaluated. The results of this study confirm earlier in vitro studies (Will 2009, Erickson-Miller 2010) showing inhibitory effects of eltrombopag on leukemic cell lines and support clinical studies to evaluate a potential anti-leukemic effect of higher doses of eltrombopag in patients with AML.

Disclosures:

Rusnak: GlaxoSmithKline: Consultancy, Equity Ownership, Patents & Royalties. Off Label Use: Eltrombopag is an oral TPO agonist indicated for chronic ITP being studied in MDS/AML. Rudolph:GlaxoSmithKline: Consultancy, Equity Ownership. Erickson-Miller:GlaxoSmithKline: Employment, Equity Ownership, Patents & Royalties, Research Funding.
New Method for in Vivo Hematopoiesis Microenvironment Research: Tissue-Engineering-Bone Femur Repairing Model and Semi-Solid Decalcification
Authors: Jiang Shan , Jiang Qianli , Zhu Liqiong , Chen Feili , Yuan Lezhong , Zhao Peiran , Yang Mo , Sun Jing , Meng Fanyi
Published: October 2019

Abstract 4732

Background:

Bone defection repairing is a good model to study the hematopoiesis and its environment, during which there are reformations of niches and marrow cavity, different cells' migrations and evolutions, etc. Tissue-engineering-bone (TEB) is a kind of scaffold that degrades gradually during bone reformation. In order to observe different cells growing within the rigid, opaque, friable and porous TEB, we established a novel technique named semi-solid decalcification (SSD).

Aim:

With the TEB repairing model, we hope to address 3 questions: Firstly, could a functional bone with marrow cavity be reformed with the TEB? Secondly, what are the contributions of cells within and outside the TEB? Thirdly, how do the hematopoietic cells cross-talking with the microenvironment during bone reformation?

Method:

Results:

Conclusion:

This eGFP-to-mRFP transgenic mice femur repairing model was proved, at least in principle, to be efficient to mimic the reforming of bone marrow and stem cell niche. With the help of SSD, we can easily study the relationship and cross-talking of cell-cell and cell-matrix in a 3-D pattern, which is of the most important to understand the mechanism of hematopoiesis microenvironment. However, further researches are carrying on, to exclude the possible mixture of eGFP+ hematopoietic cells into mesenchymal cells before TEB-MC-GFP implantation and to better identify the subtypes of existing cells within the TEB.

PS: Thanks to the support of NSFC (No.30901367, 31070866).

Disclosures:

No relevant conflicts of interest to declare.
A Case Series: Chiari Malformation and Sickle Cell Disease
Authors: Gowhari Michel , Molokie Robert , Testai Fernando , Gordeuk Victor R. , Ajayi Olaide I.
Published: October 2019

Abstract 4772

Introduction:

Chiari type I malformation is defined as tonsillar herniation of at least 3 to 5 mm below the foramen magnum. The prevalence of Chiari type I malformation in the general population is estimated to be 0.1 to 0.5%. In the SIT (Silent Infarct Transfusion) Trial in children with sickle cell disease, Chiari type I malformation was found as an incidental finding in 22 of 953 (2.3%) of the individuals imaged. Thus, the incidence of Chiari type I malformation in the SIT Trial appeared to be about five times greater than in the general population (Jordan et al Pediatrics 2010). Recently, four hemoglobin SS patients aged 6–17 years with and Chiari type I malformation were reported from one institution (Chonat el al J Pediatr Hematol Oncol 2011). Here we describe six sickle cell disease patients aged 17–24 years with Chiari type I malformation from two institutions.

Discussion:

All of the cases had severe sickling phenotype, either hemoglobin SS or sickle/B°thalassemia. The majority of the patients were experiencing neurologic symptoms that were subsequently attributed to Chiari type I malformation. Five of the six cases were eventually evaluated by neurosurgery. Neurosurgical intervention with posterior fossa decompression was recommended in four of these individuals. To date one patient has undergone surgery with relief of symptoms. Although Chiari type I malformation is thought to be primarily a congenital disorder, it has also been associated with disorders that are non-congenital. Individuals with sickle cell disease may have a thick calvarium as a result of erythroid hyperplasia and expansion of the diploe of the skull bones. Other conditions with severe anemia and thalassemia have been associated with increased thickness of the calvarium caused by diploic erythroid hyperplasia. One can question whether the increased thickness of the calvarium in some sickle cell patients results in craniocephalic disproportion with a subsequent acquired cerebellar ectopia, hence the increased Chiari type I malformation in patients with sickle cell disease. Central nervous system involvement in sickle cell disease is common. Any patient with sickle cell disease presenting with symptoms indicative of an ongoing or impending neurological event requires an in depth investigation and entails a broad differential. Chiari malformations may need to be part of this differential diagnosis.

Disclosures:

No relevant conflicts of interest to declare.
Outcome of Acute Myeloid Leukemia AML &High Risk MDS Treated According to the Standard of Care in Community Hospital, Data From Single Center ( 2001–2010)
Authors: Al-Ameri Ali , Abdelfatah Mohamed , Kanaan Zeyad , Haller Nairmeen
Published: October 2019

Abstract 4796

Background:

Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults causing the highest number of annual deaths secondary to leukemias in the United States. Age, cytogenetics, molecular features are the most important factors in the prognosis, whereby increased age and monosomal karyotypes carry the worst prognosis. The most favorable cytogenetics are patients with normal karyotypes, who can receive standard therapy.

Aim:

Study the overall survival (OS) of AML/High risk MDS treated according to standard of care at a community teaching hospital.

Methods:

A retrospective study of AML & High risk MDS patients treated at AGMC, Akron, Ohio USA, during 2002–2010. After IRB approval, we reviewed patient demographics, diagnosis types/subtypes, treatment, and cytogenetics. Patients were classified as low-intermediate risk or high risk according to cytogenetics background using WHO criteria. We also classified patients according to presence of bone marrow fibrosis and health insurance coverage at the time of diagnosis. Overall survival (OS) rates were determined by Kaplan-Meier Survival Analysis. Prognostic factors were evaluated by Log Rank analysis.

Results:

We were able to classify 98 (75%) pts, with 52 (53%) pts as high risk and 46 (47%) pts as low-intermediate risk. Median age was 55 years (range: 19–90), 43 (45%) pts were older than 75 years. AML pts made up 71%, 45 patients (35%) had complex cytogenetics, and 15% had AML arise from MDS. Median survival overall was 22.4 weeks; 14.4 weeks for high risk and 53.8 weeks for low risk (p<0.01). Median survival for pts greater than 75 years was 11.5 weeks compared to 35.8 weeks for those younger than 75 years (p<0.05). We classified 103 pts according to insurance; 29 pts had private insurance and 74 pts had medicare/Medicaid. Cox regression analysis was performed to examine for the net effect of each of age, insurance, and fibrosis status after controlling for the effect of other variables in the model. Data showed that survival is inversely related to age at diagnosis (p value=.01) while the variables fibrosis status, medicaid/uninsured, and private insurance did not contribute significantly to the model (p value=.97 and.14.34, respectively).

Conclusions:

No significant differences in OS regarding insurance status or presence of bone marrow fibrosis. This was likely because the majority of pts received standard of care therapy and overall survival, in general, was low in the study population. OS was lowest in high risk patients and those greater than 75 years, and was better in low risk pts and those younger than 75 years respectively. Early referral to a specialized center, or possible clinical trial enrollment may be an alternative way to approach those pts.

Disclosures:

No relevant conflicts of interest to declare.