bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I/II Study of Myeloablative Anti-CD20+ Radioimmunotherapy with I-131-Rituximab in High-Risk CD20-Positive Non Hodgkin Lymphoma
Authors: Schwarz Kathleen , Julia Wagner , Schreiber Susanne , Schmidt Burkhard , Hoellein Alexander , Verbeek Mareike , Schwaiger Markus , Peschel Christian , Scheidhauer Klemens , von Schilling Christoph , Keller Ulrich
Published: October 2019

Abstract 3700

Background:

Radioimmunotherapy (RIT) has been successfully used to treat primary and relapsed/refractory CD20+ Non-Hodgkin-Lymphoma (NHL). Myeloablative anti-CD20 RIT allows delivering high radiation doses to lymphoma sites when followed by autologous stem cell infusion (autoSCT). However, RIT is infrequently used at present and long-term data is lacking.

Patients, Design and Methods:

23 patients with relapsed/refractory CD20+ NHL who did not achieve a complete response to salvage chemotherapy were enrolled in this Phase I/II trial to evaluate RIT with 131I-labelled Rituximab (131I-R) in a myeloablative setting between January 2000 and October 2004. Biodistribution and dosimetry studies were performed in all patients to determine 131I activity required to induce a total body dose of 21 to 27 Gy to the critical organs lung and kidney. In 6/23 patients RIT was combined with high dose chemotherapy (HD-CTx) followed by autoSCT. 8/23 patients received a sequential HD-CTx with a second autoSCT. The median follow-up is 9.5 years.

Results:

188–525 mCi 131I were delivered to achieve the limiting organ dose. No grade 3/4 non-hematologic toxicity was seen with RIT alone. Significant grade 3/4 toxicity (mucositis, neutropenic fever, pneumonia, sepsis) including one therapy related death was observed in all patients treated with RIT combined with HD-CTx/autoSCT. The overall response rate was 87% (64% complete response rate). The median progression free (PFS) and overall survival are 47.5 and 101.5 months. After long-term follow up, 9 patients are progression free and 10 patients are alive. An elevated (>1) international prognostic index (IPI) was most predictive for overall survival.

Conclusion:

Myeloablative 131I-Rituximab RIT followed by autoSCT is feasible, well tolerated and effective in high risk CD20+ NHL and prolongs PFS compared to last standard chemotherapy. Patients additionally treated with high dose chemotherapy experienced significantly increased toxicity. Long-term results for progression free survival and overall survival in this trial are encouraging.

Disclosures:

No relevant conflicts of interest to declare.
Long-Term Follow-up of Chronic Phase Chronic Myeloid Leukemia Patients Who Failed Interferon Alpha and Switched to Imatinib
Authors: Breccia Massimo , Loglisci Giuseppina , Salaroli Adriano , Serrao Alessandra , Zacheo Irene , Latagliata Roberto , Alimena Giuliana
Published: October 2019

Abstract 3742

Few data were reported about the long-term outcome of patients treated with imatinib after interferon-alpha (IFN) failure. Recently, MDACC group reported a 10-year survival rate of 68%. We report here the outcome of 134 adult Ph+ CML patients who switched to imatinib after IFN failure. Response criteria used are in accordance to ELN guidelines; survival was calculated from start of imatinib until death for any cause, progression-free survival (PFS) was calculated from start of imatinib to advent of accelerated/blastic phase or death for any cause and event-free survival (EFS) was calculated from start of therapy to development of any event leading patient to discontinue the drug. There were 74 males and 60 females, median age was 47 years. Median follow-up was 96 months. Sokal score identified 66 patients as low risk, 49 patients as intermediate and 17 as high risk, whereas Eutos score identified 107 patients as low risk and 10 patients as high risk. Overall, 103 patients (76.8%) achieved a CCyR as their best cytogenetic response and 68 (51%) achieved a MMR, after a median time of 52 months. Complete molecular remission (CMR, undetectable transcript according to ELN recommendations) was achieved as the best response in 60 patients after a median follow-up of 76 months. The estimated 9-year overall survival rate was 74%, the PFS rate was 71% and the EFS was 54%. Progression to accelerated/blastic phase was detected in 19 patients. Due to resistance or intolerance to imatinib, 22 patients switched to dasatinib (12 patients for cytogenetic resistance, 5 patients for intolerance, 2 for molecular resistance and 3 for BC) and 17 patients switched to nilotinib (11 patients for cytogenetic resistance and 6 for molecular resistance): 18 patients (64%) achieved or maintained CCyR and 11 patients (35%) achieved MMR. Achieving at 12 months a CCyR or an MMR was associated with a significant better OS in the long-term (82%) as compared to less than PCyR (70%) or only CHR (12%). Baseline factors that correlated with a poor OS were clonal cytogenetic evolution, higher percentage of basophils and blast cells in peripheral blood, high Sokal and Eutos score, whereas age did not correlate with a worse OS. The results of our study support the validity of rescuing with imatinib patients failing IFN, with an estimated 9-year survival rate of 74% that is similar to that reported in other recent studies.

Disclosures:

No relevant conflicts of interest to declare.
Incidence of Late Chronic Anemia in Newly Diagnosed Patients with Chronic Myelogenous Leukemia Responsive to Imatinib
Authors: Volpicelli Paola , Latagliata Roberto , Breccia Massimo , Vozella Federico , Finsinger Paola , Carmosino Ida , Loglisci Giuseppina , Santopietro Michelina , Salaroli Adriano , Diverio Daniela , Mancini Marco , Tafuri Agostino , Alimena Giuliana
Published: October 2019

Abstract 3769

Anemia has been reported in about 5–8% of newly diagnosed patients with Chronic Myelogenous Leukemia (CML) treated with imatinib in the first 6 months of therapy, and has been generally regarded as transient like neutropenia and thrombocytopenia: in patients responsive to imatinib, however, it is still unclear if the prolonged treatment could induce the appearance of a late chronic anemia. To highlight this issue, we revised 104 CML patients (M/F 54/50, median age at diagnosis 58.0 years, interquartile range 43.3 – 70.2) treated at our Institution with 1st line imatinib therapy for at least 36 months and in stable complete cytogenetic response (CCyR). At the 36th month of imatinib treatment, a late chronic anemia (defined as Hb levels < 11 g/dl for > 6 months) was present in 16/104 patients (15.4%): the anemia was severe (Hb < 10 g/dl) in 10 patients (9.6%) and moderate/mild (Hb ≥ 10 < 11 g/dl) in 6 patients (5.8%). Clinical features at diagnosis of patients who had late chronic anemia at the 36th month compared to the remaining 88 patients without late anemia are shown in the Table:

Hb < 11 g/dl at the 36th month Hb ≥ 11 g/dl at the 36th month p M/F 6/10 48/40 0.209 Median age (yrs) (IR) 68.0 (58.9 – 75.4) 56.6 (43.1 – 69.1) 0.016 Sokal Score: Low 3 44 0.002 Int 8 39 High 5 5 Median Hb (g/dl) (IR) 11.6 (10.4 – 13.3) 12.7 (11.2 – 13.8) 0.098 Median WBC (× 109/l) (IR) 79.0 (33.2 – 136.6) 60.5 (31.8 – 112.4) 0.423 Median PLTS (× 109/l) (IR) 624 (299 – 835) 412 (296 – 557) 0.122

All patients with late chronic anemia had a low reticulocyte count and 7/16 a condition of iron deficiency with reduced serum ferritin but no clinical and instrumental sign of chronic blood loss: in this latter group, oral iron supplementation was always ineffective. Four out 16 patients (25%) needed 1 or more red cell transfusions during the follow-up. At landmark analysis from the 36th month of imatinib treatment, there was no significant difference in the cumulative 4-year overall survival for patients with and for those without late chronic anemia (80%, 95% CI 44.8 – 100%, vs 94%, 95%CI 85.8 – 100%, respectively; p=0.068). In conclusion, the occurrence of a late chronic anemia during long-lasting treatment with imatinib has been observed in > 15% of our responsive patients and was severe in about 10% of cases: its occurrence seems more common in elderly patients with higher Sokal score at diagnosis. Late chronic anemia does not seem to affect OS, but the real impact should be evaluated on a large cohort of patients.

Disclosures:

Tafuri: Sigma Tau Pharmaceuticals: Research Funding.
Identification of AADACL1 As a Novel Regulator of Human Platelets Via Chemoproteomics
Authors: Holly Stephen P. , Chang Jae Won , Niessen Sherry , Boulaftali Yacine , Smith Matthew C. , Phillips Ryan M. , Black Justin L. , Piatt Raymond , Li Weiwei , Weyrich Andrew S. , Bergmeier Wolfgang , Cravatt Benjamin F. , Parise Leslie V.
Published: October 2019

Abstract 381

A comprehensive knowledge of the platelet proteome is necessary for understanding important vascular pathologies such as myocardial infarction and stroke. To discover new signaling pathways in human platelets that may represent potential therapeutic targets, we took a combinatorial approach utilizing small library screening coupled with an innovative proteomics technique known as competitive activity based protein profiling (ABPP), a highly sensitive mass spectrometry (MS) technique that queries active enzymes from endogenous biological sources. Human platelets were pretreated with a novel carbamate library designed to interrogate enzymatically active proteins belonging to the serine hydrolase superfamily, which is estimated to represent 1% of the human proteome. Carbamate screening resulted in the identification of several novel inhibitors that reduced fibrinogen binding and P-selectin exposure on agonist-stimulated platelets. An endogenous protein target of the most selective inhibitor was identified by competitive ABPP as arylacetamide deacetylase-like 1 (AADACL1, also known as NCEH1), a lipid deacetylase implicated in cancer growth and atherosclerosis. Using highly selective second generation inhibitors of AADACL1 and MS-based metabolomics, we show that AADACL1 regulates platelet aggregation, Rap1 and PKC activation, lipid metabolism and fibrinogen binding. Elimination of AADACL1 protein levels via RNA interference in a megakaryocytic cell line that responds to platelet agonists also reduces inside-out signaling to αllbβ3. Furthermore, inhibition of AADACL1 reduces collagen-dependent thrombus growth under arterial shear conditions, suggesting that AADACL1 may be a relevant therapeutic target. Collectively, these data identify AADACL1 as a novel regulator of important signaling pathways in platelets and megakaryocytes and validate activity-based proteomics as a means to identify new classes of anti-platelet targets for thrombotic diseases.

Disclosures:

Parise: BD: Consultancy; Biogen-Idec: Consultancy; NIH: Research Funding; AHA: Research Funding; SCDAC-NIH: Membership on an entity's Board of Directors or advisory committees; BRI Milwaukee: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Eptifibatide, a glycoprotein IIb/IIIa inhibitor, was evaluated as treatment for acute pain episodes in patients with sickle cell disease.
A 15 Mg/M2/d Dose of Decitabine Confers Comparable Responses and Better Tolerance Than the Standard Regimen in MDS patients—results of a Multicenter Prospective Cohort Study
Authors: Li Xiao , Song Qiang , Chen Yu , Chang Chunkang , Wu Dong , Wu Lingyun , Su Jiying , Song Luxi , Zhang Zheng , Xu Feng , Hou Ming
Published: October 2019

Abstract 3832

To further optimize the decitabine schedule for the treatment of myelodysplastic syndrome (MDS), a multicenter, prospective cohort study was performed. Out of 80 MDS patients, 46 were treated with a reduced dose of 15 mg/M2/d of decitabine by daily intravenous infusion for 5 consecutive days every 4 weeks. The remaining 34 patients were treated with the standard dose of 20 mg/M2/d of decitabine for 5 days every 4 weeks. All of the clinical and experimental baselines, as well as the course number used, were statistically comparable for the two groups. The results showed that the patients receiving the reduced dose of decitabine achieved statistically comparable overall response rate (ORR) (63% vs 71%), complete remission (CR) (30% vs 26%), cytogenetic CR (50% vs 46%) and overall survival (OS) (20.5 vs 19.6 months) compared with the standard dosage group. The decitabine concentration in the blood at a fixed time point after drug intake was decreased in the reduced-dose group but showed a similar degree of p15ink4b grading for the responders in the two groups. A reduced dose caused less severe cytopenia, fewer cases of proven infection and a shorter median course interval (28 days vs 35 days in the standard-dose group). We concluded that a 15 mg/M2×5 day decitabine schedule yielded the same clinical benefit as the standard schedule and improved the bone marrow tolerance in this intermediate-sized cohort study. This trial was registered at www.clinicaltrials.gov as #ChiCTR-ONRC-12002004.

Disclosures:

No relevant conflicts of interest to declare.
Identification of Gene Expression Based Prognostic Markers in the Hematopoietic Stem Cells of Patients with Myelodysplastic Syndromes
Authors: Pellagatti Andrea , Benner Axel , Mills Ken I , Cazzola Mario , Giagounidis Aristoteles , Perry Janet , Malcovati Luca , Della Porta Matteo G , Jadersten Martin , Verma Amit , McDonald Emma-Jane , Killick Sally , Hellstrom-Lindberg Eva , Bullinger Lars , Wainscoat James S , Boultwood Jacqueline
Published: October 2019

Abstract 3857

The diagnosis of patients with myelodysplastic syndromes (MDS) is largely dependent on morphologic examination of bone marrow aspirates. Several criteria that form the basis of the classifications and scoring systems most commonly used in clinical practice are affected by operator-dependent variation. In order to identify more standardized molecular markers that would allow a more reliable prediction of prognosis, we have used gene expression profiling (GEP) data on CD34+ cells from MDS patients to determine the relationship between gene expression levels and prognosis in this disorder. GEP data on CD34+ cells from 125 MDS patients with a minimum 12-month follow-up since date of bone marrow sample collection were included in this study. Prediction for overall survival was performed using supervised principal components (“SuperPC”) and lasso penalized Cox proportional hazards regression applying the “Coxnet” algorithm. Supervised principal components analysis was performed on patients randomly split in a training set (n=84) and a test set (n=41), and 139 genes were identified the expression of which was significantly associated with MDS patient survival, including LEF1, CDH1, WT1 and MN1. In order to identify a smaller set of genes associated with patient survival, a second approach aiming at building sparse prediction models was used. A model was generated using the Coxnet algorithm and a predictor consisting of 20 genes was identified. Eight genes identified by the supervised principal components method were in common with the genes identified by the Coxnet model: ADHFE1, BTBD6, CPT1B, LEF1, FRMD6, GPR114, C7orf58 and LOC100286844. The Coxnet predictor outperformed other predictors including one which additionally used clinical information. To validate our findings, we evaluated the performance of our prognostic Coxnet gene signature in an independent gene expression profiling dataset on MDS bone marrow mononuclear cells (Mills et al, Gene Expression Omnibus series GSE15061). Our Coxnet gene signature based on CD34+ cells significantly identified a low-risk patient group in this independent GEP dataset based on unsorted bone marrow mononuclear cells, demonstrating that our signature is robust and may be applicable to bone marrow cells without the need to isolate CD34+ cells. These GEP-based signatures correlating with clinical outcome may significantly contribute to a refined risk classification of MDS.

Disclosures:

No relevant conflicts of interest to declare.
Tissue-Specific Transgene Expression in Induced Pluripotent Stem (iPS) Cell-Derived Megakaryocytes: Correction of Glanzmann Thrombasthenia (GT)
Authors: Sullivan Spencer K. , Mills Jason A. , Zhai Li , Paluru Prasuna , Vo Karen , Lambert Michele , Koukouritaki Sevasti B. , Fang Juan , Wilcox David A. , French Deborah L. , Poncz Mortimer , Gadue Paul
Published: October 2019

Abstract 387

Megakaryocyte-specific transgene expression in patient-derived iPS cells offers a new approach to study and potentially treat disorders that affect megakaryocytes and platelets. The feasibility of this method was demonstrated in GT, a disorder resulting from an absence of functional platelet integrin alphaIIb/beta3, leading to impaired platelet aggregation and clinically presenting with severe bleeding. While rare, GT can serve as a model of an inherited platelet disorder that would benefit from corrective cell therapy. For this study, iPS cells were generated from the peripheral blood of healthy controls and two patients with GT. Patient 1 is homozygous for a novel alphaIIb exon/intron 4 splice site mutation, leading to an alternatively spliced transcript and premature stop codon. Patient 2 is homozygous for a previously reported alphaIIb missense mutation in exon 8 (p.G273D), leading to impaired intracellular transport and surface expression of the heterodimer. Both patients express <5% alphaIIb/beta3 on the surface of their platelets, which was confirmed in IPS cell-derived megakaryocytes. To achieve megakaryocyte-specific expression, transgene constructs were created using the murine proximal GPIbalpha promoter driving either an eGFP reporter or wild type alphaIIb cDNA. These constructs were inserted into the AAVS1 safe harbor locus using zinc finger nuclease-mediated homologous recombination. When targeted to a single allele of the AAVS1 locus in human ES cells, the GPIbalpha promoter driving eGFP showed a high-level of expression in ES cell-derived megakaryocytes. Inserting the GPIbalpha promoter driving alphaIIb into a single allele of the AAVS1 locus in GT iPS cells restored ∼60% surface expression of integrin alphaIIb/beta3 when compared to control iPS cell-derived megakaryocytes. Transgenic alphaIIb mRNA levels were similar to endogenous alphaIIb mRNA levels in differentiated megakaryocytes. When stimulated with thrombin, corrected GT iPS cell-derived megakaryocytes demonstrated both PAC-1 antibody binding and fibrinogen binding. This study shows the GPIbalpha promoter construct targeted to the AAVS1 locus drives a high-level of expression in iPS cell-derived megakaryocytes, which offers a novel tool to study megakaryocyte and platelet biology in samples obtained from affected individuals. For GT, this study demonstrates a higher level of correction than seen with a lentiviral approach. To our knowledge, this is the first report of the generation and correction of iPS cell lines from patients with a disease affecting platelet function.

Disclosures:

No relevant conflicts of interest to declare.
IL4 and CD40L Prevent Apoptosis of Chronic Lymphocytic Leukemia Cells Via Intracellular pSTAT6 and NFkB Signaling and Not Via Receptor Kinetics
Authors: Mertens Daniel , Bhattacharya Nupur , Häbe Sarah , Döhner Hartmut , Stilgenbauer Stephan
Published: October 2019

Abstract 3893

Chronic lymphocytic leukemia (CLL) cells are highly dependent on microenvironmental input for their extended survival in vivo, but the underlying molecular mechanism is still unclear. Compared to non-malignant B-cells, CLL cells are more responsive to contact dependent complex stimuli like coculture on bone marrow derived stromal cell lines of both human (p<0.0001) and murine origin (p<0.01), but also to soluble factors (human conditioned medium p<0.0001, murine conditioned medium p<0.001, all student′s t-test). In order to understand the intrinsic difference of the anti-apoptotic phenotype of CLL cells, the signalling circuitry of the malignant cells was modelled. Compared to candidate ligands like SDF-1 (at concentrations between 10–1000ng/ml), BAFF (250–1000ng/ml), APRIL (250–1000ng/ml) and soluble anti-IgM (1–25μg/ml), the factors CD40L (10–2000ng/ml) and IL4 (0.1–10ng/ml) were the most efficient ligands in rescuing CLL cells from spontaneous death in vitro. The dose response of IL4 and CD40L displayed different saturation and cooperativity between CLL cells and non-malignant B-cells. Using IL4, saturation was reached both for CLL cells and B-cells at 0.2pM, but at 52% survival (+/− 8%) for CLL cells and 28% (+/−7%) for B-cells, and the estimated dissociation constant Kd was 0.01pM for both ligands. For CD40L, CLL cell survival reached saturation at 40nM, while no saturation was reached for B-cells. Intriguingly, B-cells showed cooperativity in their response to CD40L, with a cooperativity coefficient of 2.0 and a Kd of 70pM, while cooperativity for CD40L was lost in CLL cells (Kd of only 2.6pM). This pointed towards distinct differences in ligand-receptor interactions or in downstream signaling between CLL cells and non-malignant B-cells. However, high-throughput spatial analysis with a microscope-coupled cytometer did not show differences of receptor quantity or receptor distribution between malignant and non-malignant cells. In contrast, quantity and phosphorylation levels of downstream signalling nodes like STAT6 (measured by flow cytometry and validated by Western-blot) and the activity of NF-kB (p65 binding to DNA measured by oligonucleotide-coupled ELISA) were higher in CLL cells compared to B-cells from healthy donors. Therefore, the defect in IL4 and CD40L signalling that leads to an enhanced survival in CLL cells is likely caused by changes in the intracellular circuitry.

Disclosures:

No relevant conflicts of interest to declare.
The Expression Pattern of Small Nucleolar and Small Cajal Body-Specific RNAs Characterizes Distinct Molecular Subtypes of Multiple Myeloma
Authors: Ronchetti Domenica , Todoerti Katia , Tuana Giacomo , Agnelli Luca , Mosca Laura , Lionetti Marta , Fabris Sonia , Colapietro Patrizia , Miozzo Monica , Ferrarini Manlio , Tassone Pierfrancesco , Neri Antonino
Published: October 2019

Abstract 3955

Small nucleolar RNAs (snoRNAs) and small Cajal body-specific RNAs (scaRNAs) are non-coding RNAs involved in the maturation of other RNA molecules and generally located in the introns of host genes. It is an emerging evidence that altered sno/scaRNAs expression may play a pathological role in cancer. Impaired sno/scaRNAs expression has recently been reported both in acute leukemia and smoldering myeloma that rapidly progressed to symptomatic disease. In addition, as regards multiple myeloma (MM), very recent data suggested an oncogenic role for SCARNA22 in those MM patients over-expressing SCARNA22/MMSET as a result of t(4;14) translocation. However, comprehensive information concerning the expression behavior of sno/scaRNAs in MM is still lacking.

This study elucidates the patterns of sno/scaRNAs expression in MM by profiling purified malignant plasma cells from 55 MMs, 8 secondary plasma cell leukemias (sPCL) and 4 normal controls using Human Gene 1.0 ST arrays.

Overall, a global sno/scaRNAs down-regulation was found in MMs and at more extent in sPCLs compared to normal plasma cells. Whereas SCARNA22 resulted the only sno/scaRNA characterizing the TC4 MM, TC2 group displayed a distinct sno/scaRNA signature overexpressing members of SNORD115 and SNORD116 families located in a region finely regulated by an imprinting center at 15q11 which, however, resulted overall hypomethylated in MMs independently of the SNORD115 and SNORD116 expression levels. In addition, impaired expression of sno/scaRNAs raised from the comparison between MM and sPCL, suggested a role in tumor progression. Furthermore, to uncover possible mechanisms at the basis of sno/scaRNAs deregulation, we investigated the correlation between sno/scaRNAs and the corresponding host-genes expression levels, outlining the coordinated expression of up to 50% of sno/scaRNAs/host-genes pairs. Finally, we investigated whether the sno/scaRNAs transcriptional pattern may be influenced by allelic imbalances involving their genomic location, as already demonstrated concerning mRNA expression, and revealed a dosage effect involving several chromosomal regions.

Our data extend the current view of sno/scaRNAs deregulation in cancer and add novel information into the bio-molecular complexity of plasma cell dyscrasias. Furthermore, our findings may contribute to develop functional approaches to examine the activity of deregulated sno/scaRNAs in MM, as well as to further enlighten their possible role as targets of novel therapeutic agents.

Disclosures:

No relevant conflicts of interest to declare.
Lenalidomide and Dexamethasone in the Treatment of AL Amyloidosis: Final Results of A Phase II Trial
Authors: Nair Divya , Sanchorawala Vaishali , Shelton Anthony C , Fennessey Salli A , Finn Kathleen T , Skinner Martha , Zeldis Jerome B. , Seldin David C
Published: October 2019

Abstract 4084

AL amyloidosis is a plasma cell dyscrasia in which clonal immunoglobulin light chains misfold, forming fibrils that are deposited in tissues and vital organs. Immunomodulatory drugs including thalidomide, lenalidomide (LEN), and pomalidomide have activity in AL amyloidosis. We conducted a prospective phase II trial of LEN with dexamethasone (DEX) in the treatment of AL amyloidosis (ClinicalTrials.gov: NCT00091260), enrolling 82 patients from 2004–2011. We now report the final results of this trial. The majority of the patients were treated with LEN at a starting dose of 15 mg/d for 21 days out of a 28 day cycle, and received DEX at 20 or 40 mg weekly, depending upon age, congestive heart failure, and/or peripheral edema, and aspirin prophylaxis for venous thromboembolism (VTE) was used for most. Of the 82 patients, the median age was 62 (range, 40–84) and 63% were men. 95% of the patients had prior therapy for AL, often including high dose melphalan and autologous stem cell transplantation. The median number of cycles delivered was 11 (range, 1–69). Of the 68 evaluable patients, 16% achieved a complete hematologic response, 44% achieved a partial hematologic response, 9% achieved a minor hematologic response, and 29% had no response to treatment. The median time to best hematologic response was 6 months. Sixty-three patients had quantifiable organ involvement prior to treatment with LEN/DEX, and 44% of those patients had measurable organ response. Reasons for discontinuation of study drug were side effects (29%), non-response (39%) and complete response or completion of trial (15%). The most common side effects during treatment were fatigue (88%), anemia (67%), muscle cramps (66%), dizziness/lightheadedness (60%), respiratory tract infections (55%), increased creatinine (56%) and skin rash (48%). In conclusion, LEN administration achieved a 60% hematologic response rate (CR+PR) even in heavily pre-treated AL patients, when used at a starting dose of 15 mg/d with weekly dose-modified DEX, VTE prophylaxis, and appropriate management of side effects.

Disclosures:

Off Label Use: Lenalidomide for AL amyloidosis. Sanchorawala:Millennium: Research Funding. Zeldis:Celgene: Employment. Seldin:Celgene: Research Funding.
Mycophenolate Mofetil Vs. Methotrexate for the Prophylaxis of Graft-Versus-Host-Disease - Systematic Review and Meta-Analysis of All Comparative Trials
Authors: Ram Ron , Yeshurun Moshe , Vidal Liat , Shpilberg Ofer , Gafter-Gvili Anat
Published: October 2019

Abstract 4169

Background:

Mycophenolate mofetil (MMF) has emerged as a potential substitute to methotrexate in patients given calcineurin inhibitors for the prophylaxis of GVHD prior to allogeneic hematopoietic cell transplantation. However, a comprehensive literature evaluation of MMF vs. methotrexate is lacking.

Objectives:

This study aims to compare the efficacy and safety of MMF vs. methotrexate as part of the GVHD prophylaxis regimen in patients given allografts.

Methods:

Systematic review and meta-analysis of all comparative trials of patients given allografts and administered GVHD prophylaxis with a regimen containing MMF or methotrexate. Electronic search was conducted until June 2012. Primary outcome was acute GVHD. Secondary outcomes were all-cause mortality, relapse rate, non-relapse mortality, chronic GVHD, rate of mucositis, and the time to neutrophil and platelet engraftment. For dichotomous data, relative risks (RR) with 95% confidence intervals (CIs) were estimated and pooled. For continuous variables we calculated weighted mean difference (WMD).

Results:

Our search yielded 11 trials, 3 were randomized control trials (RCTs) and 8 were either one arm intervention trials compared to historical controls or retrospective studies. There was no difference in the overall incidence of acute GVHD (RR 1.06; 95% CI 0.93–1.21, 11 trials) with similar results in a sensitivity analysis including only RCTs. Conversely, incidence of grade 3–4 acute GVHD was higher in patients given MMF (RR 1.61; 95% CI 1.18–2.20, 6 trials, Figure). However, this association was no longer statistically significant when only patients given allografts from matched siblings or those given myloablative conditioning were analyzed (RR 1.56; 95% CI 0.95–2.55, 5 trials and RR 1.40; 95% CI 0.82–2.39, 4 trials). All cause mortality, non relapse mortality, relapse rate and the incidence of chronic GVHD were comparable between the two groups. Incidence of mucositis was significantly lower in patients given MMF (RR 0.35; 95% CI 0.25–0.49, 8 trials) and the time to neutrophil and platelet engraftment was shorter in the MMF arm (WMD (−4.05); 95% CI (−6.17) – (−1.3), 6 trials and WMD (−3.74); 95% CI (−6.3) – (−1.18), 4 trials, respectively).

Conclusions:

MMF, compared to methotrexate, given as GVHD prophylaxis is associated with reduced transplantation associated toxicities, however with increased severity of acute GVHD. Further RCTs to identify the subgroups of patients who will benefit the most from MMF are warranted.

Disclosures:

No relevant conflicts of interest to declare.
Minor Histocompatibility Antigen Mismatch and Incidence of Graft Versus Host Disease, Event-Free, and Overall Survival in Patients Undergoing Unrelated Donor Allogeneic Hematopoietic Cell Transplantation
Authors: Shaffer Brian C , Tremblay Christine , Peaceman Daniel , Hsu Jennifer , Steinberg Seth M. , Uribe Marcela , Adams Sharon , Flegel Willy A. , Pavletic Steven Z.
Published: October 2019

Abstract 4201

Graft versus Host Disease (GvHD) is a potentially devastating complication of allogeneic hematopoietic cell transplantation (HCT) initiated in part due to donor-recipient disparities in immunoreactive proteins, or minor histocompatibility antigens (mHAgs). There are no established prognostic tools to predict which patients will get acute or chronic GvHD. Analysis of mHAg mismatch is a potential predictive tool for GvHD; however, previous studies attempting to establish a relationship between mHAg mismatch and GvHD have been largely equivocal. Here we tested the hypothesis that analysis of an expanded set of mHAgs for mismatch in the GvH direction can be predictive of acute or chronic GvHD by NIH criteria. We additionally analyzed event-free (EFS) and overall survival (OS) in the mHAg matched and mismatched subgroups. Recipient/donor pairs from 45 HLA-A, -B, -C, and DRB1 matched unrelated donor transplants from 2007–2011 were retrospectively typed for 19 mHAgs using an SSP-PCR typing kit (Minor Histocompatibility Antigen Typing Kit; Life Technologies, Carlsbad, CA). Genomic DNA was obtained from peripheral blood mononuclear cells. EFS and OS were estimated using the Kaplan-Meier method. The relationship between mismatch and acute or chronic GvHD was described using Fischer's Exact Test. Cumulative incidence of treatment related mortality (TRM) was calculated using the Gooley Method. Two patients expired of early TRM and were excluded from the GvHD analyses. The rate of acute GvHD grades II-IV was 6 of 14 in those without a mHAg mismatch and 21 of 29 in those with a mismatch (43% versus 72%, P = 0.062). The rate of chronic GvHD was 8 of 14 in those without a mismatch and 10 of 29 in those with a mismatch (53% versus 34%, P = 0.140). The presence of a mismatch did not significantly impact EFS (P = 0.42) or OS (P = 0.26). The cumulative incidence of TRM at 24 months post transplantation was greater in patients with a mismatch (36% versus 13%). Two year OS was superior in patients who were conditioned with alemtuzumab (N = 24) and had a lower degree of mismatch (0–1 mismatch = 72% versus 2+ mismatches = 38%, P = 0.038). This study suggests the possibility of a relationship between mHAg mismatch and acute GvHD and TRM. Further study using this expanded mHAg analysis on a larger cohort of individuals would more adequately define the potential benefit of mHAg mismatch analysis in the context of unrelated donor HCT.

Disclosures:

No relevant conflicts of interest to declare.
Incidence and Geographic Distribution of Adult Acute Lymphoblastic Leukemia in the State of Georgia
Authors: El Rassi Fuad , Arellano Martha , Heffner Leonard T , Waller Edmund K. , Winton Elliott F. , Ward Kevin , Khoury H. Jean
Published: October 2019

Abstract 4309

We investigated an apparent increase in acute lymphoblastic leukemia (ALL) referral from north Georgia to Emory University Hospital, a tertiary care center located in Atlanta, Georgia. Cases reported between 1999 and 2008 to the Georgia Comprehensive Cancer Registry (GCCR) and the national Surveillance Epidemiology and End Results (SEER) cancer registry were analyzed. Age-adjusted incidence rates were calculated for all counties and public health regions within the state of Georgia and compared to national rates calculated using SEER 17 data for those ages 20 and above. Cases of adult acute myeloid leukemia (AML) served as control for health referral patterns, completeness of data collection and healthcare availability. The associations between geographic residence and acute leukemia were analyzed using Poisson regression analysis, and additional models were created to control for the effects of race and ethnicity. The age-adjusted incidence rate of adult ALL (0.8/100,000) and AML (4.6/100,000) for the state of Georgia were comparable to the national rates (0.9/100,000 and 5.2/100,000 respectively). Overall, the rate of ALL observed in parts of the North Georgia region (1.1 (95% CI 0.8, 1.5) were similar when compared to the rest of the state; and not affected after adjusting for race. We conclude that the higher number of cases of ALL cases referred from North Georgia is likely related to a physician-related referral pattern rather than an increased incidence.

Age-adjusted incidence rate of ALL by state and public health region and rate ratios comparing the rate of ALL within each region to the pooled rates demonstrated in all other Georgia public health regions.

Region of Georgia (GA) Rate SE Lower CI Upper CI Count Pop GA: Clayton (Jonesboro) 1.1 0.3 0.6 1.8 17 1,715,865 GA: DeKalb 0.8 0.1 0.5 1.1 37 5,111,685 GA: Fulton 0.6 0.1 0.4 0.8 37 6,565,834 GA: Northwest (Rome) 0.9 0.1 0.6 1.2 35 3,962,399 GA: North Georgia (Dalton) 0.9 0.2 0.6 1.4 23 2,632,276 GA: North (Gainesville) 1.1 0.2 0.8 1.5 41 3,723,276 GA: Cobb-Douglas 0.8 0.1 0.5 1.1 38 5,357,377 GA: Gwinnett 0.7 0.1 0.5 1 38 5,712,772 GA: LaGrange 0.8 0.1 0.5 1.1 37 4,818,090 GA: South Central (Dublin) 0.3 0.2 0.1 0.9 4 1,009,356 GA: North Central (Macon) 0.7 0.1 0.4 1 24 3,476,472 GA: East Central (Augusta) 0.7 0.2 0.4 1.1 20 3,017,677 GA: West Central (Columbus) 0.6 0.2 0.3 1 14 2,492,172 GA: South (Valdosta) 0.3 0.1 0.1 0.8 5 1,638,741 GA: Southwest (Albany) 0.9 0.2 0.5 1.3 22 2,500,405 GA: Coastal (Savannah) 0.8 0.2 0.6 1.2 29 3,568,163 GA: Northeast (Athens) 0.9 0.2 0.6 1.3 26 2,903,745 GA: All Georgia 0.8 0 0.7 0.8 463 62,540,286

Rates are per 100,000 and age-adjusted to the 2000 US Std Population (19 age groups - Census P25–1130) standard; Confidence intervals (Tiwari mod) are 95% for rates.

Disclosures:

Waller: Outsuka: Research Funding.
The Mechanisms of Synergistically Cytotoxicity Induced by Homoharringtonine and Aclarubicin in Acute Myeloid Leukemia Cells
Authors: Wang Lei , Jin Jie
Published: October 2019

Abstract 4313

Previous studies showed HAA regime [HHT (homoharringtonine), cytarabine and ACR (aclarubicin)] resulted in a high complete remission (CR) rate and a better overall survival (OS) rate in patients with primary acute myeloid leukemia. To confirm if a synergistically cytotoxicity was found in AML cells, we investigated the antitumor effect relationship of HHT and ACR against AML cells. Using in vitro system, we demonstrated that simultaneous exposure to HHT and ACR resulted in strong synergistic anti-proliferative effect and apoptosis inducing in AML cells. In vivo, combination of HHT and ACR may be result in a favorable survival in AML xenograft mice. The assay of microarray gene expressing profiling highlighted apparent difference in expression of PI3K gene and WNT3a gene between cells treated by HHT and cells exposure to ACR. Furthermore, decreased expression of PI3K110 and P-AKT protein were observed in AML cells treated with HHT for 3h while no significant change in the expression of two proteins was observed in 90nM of ACR-treated cells. Western Blot analysis also showed ACR could obviously inhibit WNT3a and β-catenin protein levels in AML cells after 3 hours exposure. Although HHT could not inhibit WNT3a protein, it also could apparently down-regulate expression of β-catenin in AML cells. Simultaneous decrease of PI3K signal and WNT3a signal was induced by the combination of HHT and ACR in AML cell lines and primary AML cells. To explore possible targets of synergistically cytotoxity induced by combined HHT/ACR, we silenced wnt3a expression by RNA interference. Then we found suppression of wnt3a expression could enhance the cytotoxity of HHT and AKT inhibitor. Moreover, combining ACR with AKT inhibitor resulted in a synergistically cytotoxic effect too. β-catenin is a shared molecular in both AKT pathway and WNT pathway. Up-regulating of β-catenin expression failed to reduce cell apoptosis induced by HHT plus ACR while partially decrease the growth inhibition rate caused by combining treatment. β-catenin is required for the self-renewal of AML-LSC. Our study also suggests that combining HHT and ACR may synergistically induce apoptosis in LSC-enriched cells. These results indicate that simultaneously inhibiting activity of PI3K/AKT pathway and WNT/β-catenin pathway is a possible mechanism of synergistically cytotoxity induced combinated HHT/ACR in AML cells.

Disclosures:

No relevant conflicts of interest to declare.
The Efficacy of Time-Sequential Administration of GO After Conventional Chemotherapy for AML
Authors: Takada Satoru , Sato Naru , Kobayashi Nobuhiko , Takumi Hoshino , Hatsumi Nahoko , Sakura Toru
Published: October 2019

Abstract 4338

Background and aim:

Gemtuzumab ozogamicinamicyn (GO) is an anti-cancer drug for acute myelogenous leukemia (AML), which targets CD33 positive leukemic cells. It has been approved by basis of effectiveness for refractory and relapse AML as single agent. However, the optimal method of administration is also currently under investigation. We evaluated the efficacy of time-sequential administration of GO after conventional chemotherapy as consolidation therapy for AML.

Subjects and methods:

AML patients in second complete remission (CR), who received time-sequentially GO after conventional chemotherapy as consolidation, were included. The duration of second CR (+CRi), overall survival, and toxicity were examined retrospectively. To evaluate the efficacy, the duration of first CR and second CR (+CRi) was compared.

Result:

Ten patients received time-sequentially GO followed by conventional chemotherapy. Six patients were male, and four were female. Median age was 69 (62–79) years old. At the onset of AML, 7 patients had normal karyotype, 2 patients inv (16), and one patient trisomy 8, respectively. All patients were treated in lamina airflow room at the beginning of chemotherapy. All but one patient received GO 3mg/‡uat day 10 after short MEC therapy (MIT 7mg/‡u day1–3, VP16 80mg/‡u day1–5, AraC 100mg/‡u day1–5). One patient received 6 mg/‡uat day 7 after short MEC therapy. Hydrocortisone was administered before and after GO administration to prevent infusion reaction. Prevention for veno-occulusive disease was not performed. Six patients received 3 courses of treatment, one patient 2 courses, and 3 patients one course, respectively. The median duration of second CR (+CRi) and overall survival from second CR was 376 (56–2100) days and 576 (123–2099) days, respectively. In eight of ten patients, the duration of second CR was longer than first CR. All patients experienced Grade 4 toxicities of neutropenia and thrombopenia. Median period when neutrophils were less than 500/μl was 16 (9–35) days. Non-hematologic toxicities of grade 3 or more were sepsis for7 patients, febrile neutorpenia for2 patients, loss of appetite for one patient, liver dysfunction for one patients, and cardiac dysfunction for one patient. Veno-occulusive disease and infusion reaction was not experienced. Treatment-related death was not observed.

Conclusion:

Although our experience has been limited, time-sequential administration of GO after conventional chemotherapy as consolidation therapy in second CR was very effective. Non-hematological toxicities except infections were limited. As bone marrow suppression caused by this treatment is very strong, it is very necessary to pay enough attention to infectious disease.

Disclosures:

No relevant conflicts of interest to declare.
Standard Administration and Fractionated Administration of Gemtuzumab Ozogamicin for Patients with Relapsed and Refractory Acute Myeloid Leukemia
Authors: Yahagi Yuichi , Usui Noriko , Yamaguchi Yuko , Dobashi Nobuaki , Yano Shingo , Takei Yutaka , Sugiyama Katsuki , Takahara Shinobu , Ogasawara Yoji , Saito Takeshi , Kasama Kinuyo , Yokoyama Hiroki , Kamiyama Yutaro , Katsube Atsushi , Aiba Keisuke
Published: October 2019

Abstract 4342

(Purpose) We retrospectively analyzed the data regarding patients who received fractionated administration (FR) of gemtuzumab ozogamicin (GO) and standard administration (ST) of GO for the treatment of their refractory and relapsed acute myeloid leukemia in order to review the efficacy and safety of GO in each type of administration. (Method) The patients with relapsed and refractory acute myeloid leukemia (excluding patients with acute promyelocytic leukemia) who were treated with the ST of GO received 2 doses of monotherapy with 9 mg/m2 GO as a 2-hour intravenous (iv) infusion with a 14–28-day interval. The fractionated GO group received 2 doses of GO monotherapy administered as a 2-hour iv infusion of 3 mg/(m2·day) on days 1, 3, and 5 with a 14–28-day interval. (Result) Eleven patients received ST and 9 received FR. The median age of all patients was 66.1 (55–77) years. Overall response rates (CR+CRp) in the ST and FR groups were 27% and 33%, respectively. The adverse events (grade 3–4) in the ST and FR groups were neutropenia (100% vs. 100%), thrombocytopenia (90.9% vs. 88.9%), and hypertransaminasis (18.2% vs. 0%). Grade 3–4 hypertransaminasis was seen only in the ST group. Infusion reactions occurred in 5 patients: 3 in the ST group and 2 in the FR group. The median CD33 positivity of blast cells of patients who received CR or CRp was 90.9% (78.2–99.5%). (Discussion) The response rates of the ST and FR groups were similar. However, the incidence of grade 3–4 hypertransaminasis tended to be higher in the ST group. These data suggest that FR of GO is less toxic than ST. Thus, FR of GO is safer than ST even for Japanese patients with acute myeloid leukemia.

Disclosures:

No relevant conflicts of interest to declare.
Role of CD74 in Mesenchymal Stem Cell Dysfunction in Patients with Acute Myeloid Leukemia
Authors: Patel Shyam Ajay , Rameshwar Pranela
Published: October 2019

Abstract 4344

Mesenchymal stem cell (MSC) dysfunction has been implicated in the biology of the acute myeloid leukemia (AML). Preliminary studies from our laboratory have demonstrated that MSCs derived from AML patients have diminished T cell immunosuppressive capacity, and these MSCs demonstrate signs of transformation. In the current study, we seek to explore the mechanisms of MSC dysfunction in patients with AML. Recent reports have implicated migration inhibitory factor (MIF) and its receptor CD74 in cancer progression. CD74 is a cell surface glycoprotein that also serves as the invariant chain for the class II major histocompatibility complex (MHC-II). The significance of these studies is two-fold: (1) CD74 participates in intracellular signal transduction via NF-kappaB, ERK, and PI(3)K pathways, thereby promoting cell proliferation, and (2) MHC-II invariant chain expression in MSCs may prevent tumor antigen loading and presentation to T cells, allowing for immune subversion. Our results show increased expression of CD74 on MSCs derived from AML patients. The readily targetable phenotype and the availability of anti-CD74 antibody milatuzumab merits further investigation into the role of CD74 in AML biology.

Disclosures:

No relevant conflicts of interest to declare.
A Software for the Prescription of Prophylactic Treatment of Venous Thromboembolism (VTE) in Hospitalized Patients. Evaluation of the Prescriptive Mode
Authors: Santi Roberto , Contino Laura , Davio Piero , Levis Alessandro
Published: October 2019

Abstract 4371

Background/Aim:

Using of a software for venous thromboprophylaxis prescription in hospitalized patients. Evaluation of the prescriptive mode in relation to the risk profile of the patient.

Materials and Methods:

Has been developed a software, which guides the physician to the choice of prophylaxis of VTE on the basis of a thromboembolic risk score (The Padua Prediction Score), renal function and the type of admission. We analyzed data derived from prescriptions over a period of 14 consecutive months.

Results:

3125 patients were included. 68% of the patients were “high-risk (HR)” and 32% at “low risk (LR)”. Were treated with drug therapy, 89% of HR patients and 40% of LR. 11% of HR patients were not treated for severe renal failure or high risk of bleeding.

Conclusion:

All HR patients were considered for thromboprophilaxis. 89 % of HR patients and 40% of LR were treated. In our initial experience the software is an effective tool to identify patients at high risk and more effective prophylactic strategy. Furthermore, the evaluation of creatinine clearance allows to assess the bleeding risk associated with prophylactic treatment.

Disclosures:

No relevant conflicts of interest to declare.