bluuebunny/crossref_metadata_2025_split huggingface dataset:
Upfront Imatinib in Pediatric Chronic Myeloid Leukemia Yields Results Comparable to Stem Cell Transplant,
Authors: Ganesan Prasanth , Sagar Tenali Gnana , Kannan Krishnarathnam , Rajendranath Rejiv 
Published: October 2019

Abstract
Abstract 3763

Background:
Imatinib mesylate (IM) is the standard therapy in adult patients with chronic myeloid leukemia (CML). In children, the superiority of Imatinib over allogenic transplantation is not well established. Concerns exist about the long term effects of Imatinib in this population.

Methods:
Outcomes of children (≤18 years) diagnosed with chronic phase CML from 2002 to 2008 were retrospectively analysed. All received Imatinib at a dose of 260–300mg/m2/day. Progression free survival (PFS- time from starting treatment till loss of complete hematologic response (CHR), or disease acceleration), ad Overall survival (OS) were estimated by the Kaplan Meier method. Those who progressed received higher doses of Imatinb or were changed to hydroxyurea. No patient had access to second line tyrosine kinase inhibitors or to allogenic stem cell transplant.

Results:
31 patients, median age 13 (6–18)years, Males-17 (48.6%), were treated. The presenting complaints over a median symptom duration of 1 month (10 days to 12 months) were abdominal distension and/or pain (68%), fever (38%), weight loss (13%), bone pains (10%), anemic symptoms (16%). Examination revealed splenomegaly (100%), heptomegaly (47%) and lymphadenopathy (6%). Laboratory: Hemoglobin (9.3g/dL;4.2–10.9), White cell count (228,000/mm3;10,000–800,000), Platelet count (412,000/mm3, 120,000–12,80,000), peripheral eosinophilia (2%;0–10), basophilia (2%; 0–7). CHR was seen in 30/31 (97%) at a median of 2 months (1.5–8). Sokal risk category was low in 13 (41%), intermediate in 15 (48.4%) and high in 3 (9.7%). The cumulative incidence of Major and Complete cytogenetic response (MCR and CCR) among those who had not progressed by 2 years (n=23) was 82% and 70% respectively. Molecular assessment done in 11 patients who had achieved CCR by 2 years showed MMR in 6/11 (55%). After a median follow up of 49.2 months (4.4 – 86.4) disease progression occurred in 8 patients (5-year PFS 68%-median not reached) which led to death in 6 patients (5-year OS 75.8%). Among those with cytogenetic data, the PFS for those with CCR vs those without was 93.8% and 53.6 % respectively at 5 years (p=0.048). The drug was well tolerated with no discontinuation because of toxicity.

Conclusions:
Imatinib is a reasonable option in the first line therapy of pediatric CML and gives 5 year PFS and OS rates comparable to the results of upfront allogenic transplant. It is to be considered as an alternative especially in resource constrained settings where options for transplant are limited.

Disclosures:
No relevant conflicts of interest to declare.
Final Phase I/II Results of Rigosertib (ON 01910.Na) Hematological Effects in Patients with Myelodysplastic Syndrome and Correlation with Overall Survival,
Authors: Raza Azra , Greenberg Peter L. , Olnes Matthew J. , Silverman Lewis R. , Wilhelm Francois 
Published: October 2019

Abstract
Abstract 3822
Rigosertib is a multi-kinase inhibitor that selectively induces mitotic arrest leading to apoptosis in cancer cells and blasts, while being non-toxic to normal cells. We analyzed bone marrow (BM) response and overall survival (OS) in 60 patients (pts) with myelodysplastic syndrome (MDS), including 51 patients with refractory anemia and excess blasts (RAEB) and 9 patients with refractory cytopenia and multilineage dysplasia (RCMD) enrolled in 4 independent phase 1/2 clinical trials. These pts were treated with rigosertib administered as a continuous intravenous infusion (CIV) from 2 to 6 days weekly or every other week with BM response initially assessed per protocol by week 4 or 8 and every 8 weeks thereafter. Overall survival (OS) analyses were performed by the method of Kaplan-Meier. OS was related (p=0.04) to FAB/WHO classification (see Table 1) in all MDS pts. Eight pts had hematological improvements. OS was also related to IPSS scoring (p=0.02; Table 2) and to BM blastic response (Table 3; p=0.008) in the 51 RAEB-1,-2,-t pts and in a subset of 38 RAEB-1,-2,-t pts refractory or relapsing after treatment with hypomethylating agents (azacitidine/decitabine) (Table 4; p=0.001). A 49-week OS was found in 15 patients in this last group treated with 3-day rigosertib infusions (1800 mg/day) every other week. Rigosertib infusions were well tolerated without evidence of bone marrow myelotoxicity. These results and the predictive value of BM response to rigosertib for estimating OS survival have led to the initiation of a randomized Phase III survival trial of rigosertib 3-day CIV infusions vs best supportive care in RAEB -1, -2 and-t pts who failed or progressed after receiving hypomethylating agents.Table 1.Overall Survival by FAB/WHO Classification in 60 MDS ptsFAB/WHO ClassificationRCMDRAEB-1RAEB-2RAEB-tP valueN pts9172113Median OS (weeks)988235210.04Table 2.Overall Survival by IPSS Scoring in 51 RAEB-1, -2, -t ptsIPSS ScoringIntermediate-1Intermediate-2High RiskP valueN pts101427Median OS (weeks)Not Reached37280.02Table 3.Overall Survival by BM Blast Response in 51 RAEB-1, -2, -t ptsBM Blast Response≥ 50% Blast DecreaseStable BM ResponseProgressive DiseaseNot AssessedP valueN pts1620510Median OS (weeks)513715110.008Table 4.Overall Survival by BM Blast Response in 38 RAEB-1, -2, -t pts Refractory or Relapsing After Azacitidine/Decitabine TreatmentBM Blast Response≥ 50% Blast DecreaseStable BM ResponseProgressive DiseaseNot AssessedP valueN pts1312310Median OS (weeks)444915100.001

Disclosures:
Raza: Onconova Therapeutics Inc: Research Funding. Greenberg:Onconova Therapeutics Inc: Research Funding. Olnes:Onconova Therapeutics Inc: Onconova Therapeutics Inc provided study drug. Silverman:Onconova Therapeutics Inc: Research Funding. Wilhelm:Onconova Therapeutics Inc: Employment, Equity Ownership.
Increased CD39 Expression on CD4+ T-Lymphocytes Has Clinical and Prognostic Significance in Chronic Lymphocytic Leukemia,
Authors: Herishanu Yair , Hazan-Hallevi Inbal , Kay Sigi , Deutsch Varda , Polliack Aaron , Naparstek Elizabeth , Perry Chava 
Published: October 2019

Abstract
Abstract 3895
Chronic lymphocytic leukemia (CLL) cells depend on their microenvironment for proliferation and survival. Ectonucleotidase CD39 has anti-inflammatory properties as it hydrolyzes pro-inflammatory extra-cellular ATP, generates anti-inflammatory adenosine and also protects regulatory T cells from ATP-induced cell death. In this study we investigated the clinical significance of CD39 expression on CD4+T-cells in 45 patients with CLL as well as its compartmental regulation and explored the possible mechanisms for its induction. Compared to healthy individuals, CD4+CD39+ lymphocytes were increased in the peripheral blood of patients with CLL (4.6%±2.28 vs. 17.3%±12.49, respectively, p=0.004), and correlated with advanced stage of disease (9.72%±5.76, 18.15%±12.03 and 25.90%±16.34, of CD4+ lymphocytes, in patients with Rai stages 0, 1+2 and 3+4, respectively, p=0.019). CD4+CD39+ cells were also higher in patients with CLL who needed therapeutic intervention (untreated; 12.99%±10.63 vs treated; 22.21%±12.88, p=0.01) and in those who were ZAP70+ or had b2-microglobulin levels>3g/L. There were more CD4+CD39+ lymphocytes in the bone marrow compartment (22.25%±16.16) than in the peripheral blood (16.60%±15.84, p=0.009). In-vitro studies showed that CD39 can be induced on CD4+cells by exposure to ATP or indirectly, following B-cell receptor (BCR) engagement (CD4+CD39+ lymphocytes increased by 1.56 fold, in the BCR engaged samples compared to their paired controls; 20.27%±11.3 vs. 13%±9.42, respectively, p=0.0006). Conclusions: Increased CD39 expression on CD4+ T-lymphocytes in CLL associates with an aggressive disease. This may reflect the ability of the leukemic cells to suppress the surrounding immune environment, and contribute to a poorer prognosis. CD39+ may also serve as a future target for the development of novel therapies with immune modulating anti–tumor agents in CLL.

Disclosures:
No relevant conflicts of interest to declare.
Non-Lineage/Stage Restricted Effects of a Gain-of-Function Mutation in Tyrosine Phosphatase Ptpn11 (Shp2) on Malignant Transformation of Hematopoietic Cells
Authors: Xu Dan , Liu Xia , Yu Wen-Mei , Meyerson Howard J. , Gerson Stanton L. , Qu Cheng-Kui 
Published: October 2019

Abstract
Abstract 392
SHP2, a protein tyrosine phosphatase implicated in multiple cell signaling processes, plays an essential role in hematopoietic cell development. Our previous studies have demonstrated that this phosphatase is required for erythroid, myeloid, and lymphoid development and that it functions in cytokine signaling in both catalytically-dependent and –independent manners. Notably, germline and somatic mutations (heterozygous) in PTPN11 (encoding SHP2) have been identified in 35% of the patients with juvenile myelomonocytic leukemia (JMML), a childhood myeloproliferative disorder (MPD). Furthermore, PTPN11 mutations are also found in pediatric myelodysplastic syndromes (10%), B cell lymphoblastic leukemia (B-ALL) (7%), acute myeloid leukemia (AML) (4%), and sporadic solid tumors. These mutations result in hyperactivation of SHP2 catalytic activity. In addition, PTPN11 disease mutations, especially leukemia mutations, enhance the binding of mutant SHP2 to signaling partners. Although previous studies have shown that Ptpn11 mutations induce cytokine hypersensitivity in myeloid progenitors and MPD in mice, it is unclear whether Ptpn11 mutations also play a causal role in the pathogenesis of acute leukemias. If so, the underlying mechanisms and the cell origin of leukemia initiating/stem cells (LSCs) remain to be determined. PTPN11E76K mutation is the most common and most active PTPN11 mutation found in JMML and acute leukemias. However, the pathogenic effects of this mutation have not been well characterized. We created Ptpn11E76K conditional knock-in mice. Global Ptpn11E76K/+ mutation resulted in early embryonic lethality associated with enhanced ERK signaling. Induced knock-in of this mutation in pan hematopoietic cells led to MPD as a result of aberrant activation of hematopoietic stem cells (HSCs) and myeloid progenitors. These animals subsequently progressed to acute leukemias. Intriguingly, in addition to AML, T-ALL and B-ALL were evolved. PTPN11E76K/+ mutation induced LSC development not only in stem cells but also in lineage committed progenitors as tissue-specific knock-in of Ptpn11E76K/+ mutation in myeloid, T lymphoid, and B lymphoid progenitors also resulted in AML, T-ALL, and B-ALL, respectively. Further analyses revealed that Shp2 was distributed to centrosomes and that Ptpn11E76K/+ mutation promoted LSC development partly by causing centrosome amplification and genomic instability. Thus, Ptpn11E76K mutation has non-lineage specific effects on malignant transformation of hematopoietic cells and initiates acute leukemias at various stages of hematopoiesis. This mutation may play an initiating role in the pathogenesis of pediatric acute leukemias.

Disclosures:
No relevant conflicts of interest to declare.
Endogenous Oncogenic Nras Signaling Promotes Proliferative Exhaustion of Hematopoietic Stem Cells Through a Dose-Dependent Hyperactivation of ERK,
Authors: Wang Jinyong , Liu Yangang , Du Juan , Ryu Myung-Jeom , Ranheim Erik A. , Zhang Jing 
Published: October 2019

Abstract
Abstract 3997
Both monoallelic and biallelic oncogenic NRAS mutations are identified in human leukemias, suggesting a dose-dependent role of oncogenic NRAS in leukemogenesis. We recently characterized conditional mouse models that express one or two copies of constitutively active Nras G12D in the hematopoietic compartment (Nras G12D/+ and Nras G12D/G12D). Nras G12D/G12D results in stronger downstream signaling than Nras G12D/+ and consequently distinct hematopoietic phenotypes. In particular, we found that somatic expression of Nras G12D/G12D but not Nras G12D/+ leads to an acute myeloproliferative neoplasm (MPN). The development of acute MPN is associated with cytokine-evoked hyperactivation of ERK but not Stat5 and Akt in hematopoietic stem/progenitor cells (HSPCs). Interestingly, genetically altered HSCs appear to be required for initiation and maintenance of chronic and acute MPD phenotypes mediated by Nras G12D/+ and Nras G12D/G12D, respectively. Furthermore, Nras G12D/G12D-mediated signaling promotes excessive HSC proliferation and leading to HSC exhaustion. Exhaustion of HSCs is tightly associated with diminished MPN phenotypes in non-engineered recipient mice into which Nras G12D/G12D HSCs are transferred by bone marrow transplantation. To investigate the molecular mechanisms underlying the exhaustion of Nras G12D/G12D HSCs, we performed a microarray analysis using highly purified control, Nras G12D/+, and Nras G12D/G12D HSCs. To our surprise, neither p16INK4a and p15INK4b, critical cell senescence genes, or other genes or pathways known to involve in HSC self-renewal were differentially expressed in Nras G12D/G12D HSCs. In contrast, gene ontology analysis revealed significant differential expression of genes in the MEK/ERK pathway in Nras G12D/G12D HSCs. This result is consistent with our phospho-flow study showing that Nras G12D/G12D selectively hyperactivates ERK in HSPCs. It has been documented that prolonged ERK signaling is a potent inducer of differentiation in cultured PC12 cells and inhibition of normal ERK signaling by a chemical inhibitor increases self-renewal in mouse embryonic stem cells. Thus, we are currently testing whether hyperactivation of ERK promotes depletion of Nras G12D/G12D HSCs through promoting HSC differentiation and whether blocking hyperactivation of ERK restores the normal HSC function and prevents MPN development.

Disclosures:
No relevant conflicts of interest to declare.
Adoptive Immunotherapy with CMV Specific Cytotoxic T Lymphocytesfor Stem Cell Transplant Patients with Refractory CMV Infections,
Authors: Bao Lei , Cowan Morton Jerome , Dunham Kimberly , Horn Biljana N. , McGuirk Joseph , Gilman Andrew , Lucas Kenneth 
Published: October 2019

Abstract
Abstract 4033
Adoptive immunotherapy with cytomegalovirus (CMV) specific cytotoxic T lymphocytes (CTL) is an effective strategy for preventing and treating viral reactivation following allogeneic stem cell transplantation (SCT). We have previously shown that CMV CTL can be generated in 1–2 weeks by stimulating donor lymphocytes with peptide mixes derived from full length pp65 and IE1. We conducted a multi-institutional study of CMV specific CTL for patients with persistent or anti-viral resistant CMV infections following allogeneic SCT, to determine the safety, feasibility, and immunologic effects of this approach. We were successful in stimulating CTL from 10/10 donors with pooled CMV overlapping peptide mixes. Five of the 7 subjects who met infusion criteria had new onset CMV specific CTL activity detected within 4–6 weeks post infusion. Of the two subjects who did not have immunologic responses post-infusion, one received CTL with a low viability post-thawing, and the other patient was receiving cyclosporine A and systemic corticosteroids at the time of the infusion, achieving only a low, transient increase (10%) in pp65 specific activity. There was no GVHD attributable to these infusions. These findings indicate that the infusion of CTL stimulated over 1–2 weeks with overlapping CMV peptides can result in virus specific immune reconstitution in SCT recipients, without exacerbations of GVHD.

Disclosures:
No relevant conflicts of interest to declare.
Microenvironment Shields Myeloma From Adoptive Immunotherapy by Cell Adhesion Mediated Immune Resistance (CAM-IR),
Authors: de Haart Sanne J , Minnema Monique C. , Aarts-Riemens Tineke , Bovenschen Niels , Lokhorst Henk M. , Mutis Tuna 
Published: October 2019

Abstract
Abstract 4039
Cellular immunotherapy can induce long term remissions in multiple myeloma (MM) patients. Despite reported successes in a limited number of patients, the immune system fails to completely eradicate MM in the majority, proving the ability of MM cells to evade cellular immunity. The nature and mechanism of this immune escape remains not fully understood. Most studies have focused on mechanisms by which tumor cells down-regulate their antigenicity or suppress immune effector cells. Here we show a critical role for the tumor microenvironment in inducing a cell-adhesion mediated ability in MM cells to resist T cell mediated killing; a mechanism similar to cell-adhesion mediated drug resistance (CAM-DR).
We used a compartment-specific bioluminescence-based viability assay, in which luciferase transduced MM cell lines were co-cultured with MM-reactive CD4+ and CD8+cytotoxic T cells (CTLs) in presence and absence of accessory cells. In these co-culture assays, we demonstrated the effective CTL-mediated lysis of MM cells. However, this lysis was significantly decreased in the presence of accessory cells, such as bone marrow stromal cells, including patient derived stromal cells, activated endothelial cells and fibroblasts.
We identified that the reduction of CTL-mediated lysis was predominantly due to the induction of a cell-cell contact mediated resistance in MM cells against CTL killing, proving for the first time the existence of a cell-adhesion mediated immune resistance (CAM-IR). In support to this, blocking the adhesion of MM cells to accessory cells with an ICAM-1 antibody or with RGD peptide, which is a ligand for cell surface integrins, abrogated the resistance of MM cells against CTL-mediated lysis. Intracellular mechanisms of this immune resistance were evaluated by western blot. Adherence of MM cells to accessory cells significantly increase the expression levels of survivin in MM cells, a well known inhibitor of apoptosis protein (IAP), which blocks the CTL mediated apoptotic events via inhibiting the phosphorylation of caspase-3. Our current focus is the restoration of MM cell sensitivity to T cell mediated killing via downregulation of survivin expression.
In conclusion, we report for the first time the potentially important role of microenvironment in compromising immunotherapy by the induction of CAM-IR. Our results suggest that immunotherapy may be improved by modulating the interaction of MM with its microenvironment

Disclosures:
No relevant conflicts of interest to declare.
The Immature Reticulocyte Fraction Predicts Marrow Recovery and Can Obviate the Need for Bone Marrow Examination in Persistently Neutropenic Cancer Patients
Authors: Haider Sajjad , Katragadda Lakshmikanth , Muzaffar Jameel , Grazziutti Monica , Akbar Muhammad R , Cottler-Fox Michele H. , Barlogie Bart , Anaissie Elias J. 
Published: October 2019

Abstract
Abstract 4526

Introduction:
Prolonged and persistent neutropenia (white blood cell (WBC) ≤1000/μL) after chemotherapy is associated with increased risk for infection in cancer patients and is often an indication for a diagnostic bone marrow aspirate and biopsy. A test that predicts WBC recovery ≥ 1000/μL and that obviates the need for marrow sampling would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid production and hence a recovering marrow.

Materials and Methods:
We identified 17 myeloma patients with prolonged pancytopenia after either myeloablative or non-myeloablative chemotherapy between March 2010 and February 2011, and compared the time of occurrence of IRF doubling (IRF-D) to the findings on bone marrow examination.

Results:
The time to IRF doubling preceded increase of WBC ≥ 1000/μL in 15 of 17 patients by a mean of 4.5 days (range 0–18 days). In two patients, the IRF-D coincided with WBC ≥ 1000/μL. The IRF doubled 2–4 days before the bone marrow examination in four patients and at a mean of 3.7 days (range 1–13 days) after the marrow examination in the remaining 13.

Conclusion:
We conclude that the IRF-D is a simple, inexpensive and widely available test that can precede marrow recovery by several days and may therefore obviate the need for a diagnostic bone marrow aspirate and biopsy in patients with prolonged and persistent neutropenia.

Disclosures:
No relevant conflicts of interest to declare.
Comparison of Sirolimus and Mycophenolate Mofetil As Salvage Treatment for Acute Graft-Versus-Host Disease
Authors: Nishihori Taiga , Pidala Joseph , Kim Jongphil , Tomblyn Marcie , Anasetti Claudio 
Published: October 2019

Abstract
Abstract 4548
Acute graft vs. host disease (aGVHD) refractory or dependent on glucocorticoid therapy is a major source of mortality following allogeneic hematopoietic cell transplantation (HCT). Comparative studies to evaluate the efficacy of available salvage immune suppressive agents are lacking. We retrospectively compared the efficacy of sirolimus (SIR) and mycophenolate mofetil (MMF) as salvage aGVHD therapy for glucocorticoid refractory, dependent or intolerant patients. Of 281 consecutive patients who received HCT at Moffitt Cancer Center from 07/2004 to 09/2009, we identified 84 patients who received tacrolimus/methotrexate (Tac/MTX) as GVHD prophylaxis, were treated with systemic glucocorticoids as first line therapy for acute GVHD grades 2–4, were refractory (n=72) or dependent (n=12) to glucocorticoids, and received second line GVHD treatment with MMF (n=56) or SIR (n=28). Patient demographics and treatment variables were similar between the two groups except for year of transplant, which was earlier for MMF. Median age of the entire group was 50 (range 17 – 68). Disease diagnoses included AML (n=27), NHL (n=14), MDS (n=12), ALL (n=9), CML (n=7), CLL (n=4), SAA (n=2), MPD (n=5), MM/PCL (n=3), and HL (n=1). Conditioning regimens were busulfan/fludarabine for 71, and other regimens for 13. Except for 1 bone marrow graft in each group, all received peripheral blood stem cells. Graft sources were from HLA-matched siblings (35), or 8/8 HLA-matched unrelated donors (49). Overall grade distribution of aGVHD at time of salvage for MMF vs. SIR was the following: grade 1 (13 vs. 2), grade 2 (31 vs. 16), grade 3 (9 vs. 5) and grade 4 (3 vs. 5). Median steroid dose at the time of salvage was 1 (range 0.17 – 2.28) mg/kg for MMF group and 1 (range 0.12 – 2.0) mg/kg for SIR group. Median time from steroid to salvage was 20 (range 1 – 208) days for MMF and 19 (range 1 – 275) days for SIR (p=0.84). Complete response (CR) rates following initiation of MMF or SIR did not significantly differ at the following time points: 1 week (MMF 30%, SIR 21%), 4 weeks (MMF 44%, SIR 46%), and 6 weeks (MMF 60%, SIR 58%). Overall response rates (ORR) also did not differ significantly: 1 week (MMF 57%, SIR 42%), 4 weeks (MMF 57%, SIR 77%), and 6 weeks (MMF 72%, SIR 75%). Flare or progression of aGVHD while on salvage regimen was noted in 50% (MMF) and 36% (SIR) of patients (p=0.64). Median overall survival from the time of salvage therapy for MMF vs. SIR did not significantly differ, 11.6 (95% CI 7.0 – 28.1) vs. 9.7 (95% CI 5.4 – 15.9) months, log-rank p = 0.88. These retrospective data suggest that MMF and SIR have comparable activity in the treatment of steroid refractory or dependent acute GVHD.

Disclosures:
No relevant conflicts of interest to declare.