Sequential Therapy with Fitcy Preparative Regimen for Patients with Primary Refractory AML - a Single Center Retrospective Analysis

Abstract Introduction - primary refractory AML is associated with a dismal prognosis. Only 30% of patients will respond to salvage chemotherapy and continue to allogeneic hematopoietic cell transplantation (HCT) with a 10-20% long- term overall survival. Following from the FLAMSA protocol, we implemented a modified RIC regimen - FITCy (fludarabine, cytarabine +/- idarubicin and 4 Gy TBI) in all primary refractory patients with a donor available for transplant. Methods - all patients who were admitted with AML, were identified by the transplantation coordinator nurse and underwent donor evaluation within 2 days from diagnosis. Patients who received induction chemotherapy had a day 14 marrow examination and where leukaemia blasts were identified, donor search was prioritized. These patients went on to have a day 28 bone marrow examination to confirm refractory disease. Patients who were treated with azacitidine ±venetoclax had a 2-month BM evaluation and donor search was prioritized in case of refractory disease. All consecutive patients, diagnosed with primary refractory AML, underwent HCT with the FITCy regimen in the Tel Aviv Sourasky Medical Center. Patients who underwent sequential therapy for relapsed disease (either chemosensitive or refractory) or a second HCT were excluded from this analysis. The protocol was amended on January 2018 to include ATG for all patients after interim analysis showed a high rate of GVHD. Results - Between January 2014 and June 2021, 48 patients were identified with primary refractory disease and were eligible for the protocol. Median age was 63 (range, 22-75) years (Table). Median follow-up for surviving patients was 33 (range, 1-81) months. Prior to HCT, 12 (25%) patients had ongoing documented infections (either microbiology or clinically). Median days to engraftment of neutrophils (>500/dL) and to complete engraftment of platelets (>20000/dL) were 10 (range, 7-20) days, and 16 (9-35) days, respectively. 7 patients with early progression/non relapse mortality were not evaluated for this outcome. No patient had primary/secondary graft rejection. Severe mucositis was observed in only 7 patients (15%) and was mostly observed in the upper gut. 18 patients (38%) developed microbiology documented infections during the neutropenic period and in 7 (40%) this directly contributed to mortality. Only 2 patients (4%) developed sinusoidal obstruction syndrome. Complete remission was documented on day 30, in all but 1 patient with a median whole marrow donor chimerism of 98% (range, 73-100%).Cumulative incidences of grade 2-4 and 3-4 acute GVHD at day 100 were 55% and 15%, respectively. Cumulative incidences of overall chronic GVHD and moderate-severe chronic GVHD at 1 year after HCT were 64% and 24%, respectively. Cumulative incidences of relapse at 1 year and 2 years post HCT were 24% and 30%, respectively. Non-relapse mortality rates, at 30 days, 100 days and 1 year post HCT were 13%, 20%, and 32%, respectively. Cumulative incidences of 1, 2, and 3 years overall survival were 50%, 42%, and 42%, Figure. Cox regression analysis for overall survival identified increased time from diagnosis (HR-1.03, p=.046), mismatched donor (HR-1.4, p=.05) and the use of ATG (HR=.33, p=.006) to impact survival, while age, sex and comorbidity index were not predictive. Conclusions - Sequential therapy in patients with primary refractory AML provides a remarkable anti- leukemic effect. A timely donor search program is essential for the succession of this approach. Nevertheless, infection control and GVHD prophylaxis is still suboptimal and future protocols should focus on these domains while preserving graft vs. leukemia function. Figure 1 Figure 1. Disclosures Moshe: AbbVie: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Astellas: Membership on an entity's Board of Directors or advisory committees, Other: Lectures; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Lectures. Avivi: Novartis: Speakers Bureau; Kite, a Gilead Company: Speakers Bureau. Ram: Novartis: Honoraria; Gilead: Honoraria. OffLabel Disclosure: Off label Cellcepet for prophylaxis of GVHD

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Aberrant a-to-I RNA Editing and Prognostic Impact of Adar in Multiple Myeloma Patients with 1q Amplification

Blood ◽

10.1182/blood.v128.22.357.357 ◽

2016 ◽

Vol 128 (22) ◽

pp. 357-357

Author(s):

Alessandro Lagana ◽

Deepak Perumal ◽

Violetta V Leshchenko ◽

Pei-Yu Kuo ◽

Brian Kidd ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Rna Editing ◽

Copy Number ◽

Research Funding ◽

Cox Regression ◽

Advisory Committees ◽

Cox Regression Analysis ◽

Kaplan Meier ◽

Equity Ownership

Abstract Amplification of 1q is observed in 40% of Multiple Myeloma (MM) patients and is associated with a more aggressive clinical course of the disease. The frequency of 1q21 amplifications has been shown to increase significantly in the transition from monoclonal gammopathy of undetermined significance (MGUS) to overt myeloma and to relapse. Previous studies have reported genes on 1q such as ANP32E and CSK1B that have significant impact on survival. However, the biological mechanisms underlying disease aggressiveness associated to 1q amplification still remain unclear. ADAR (Adenosine Deaminase Acting on RNA) is an enzyme responsible for A-to-I editing, a post-transcriptional modification of double stranded RNA consisting in the conversion of specific Adenosines (A) into Inosines (I) by deamination. As Inosine is structurally similar to Guanosine (G), editing events can result in functional consequences in RNA and protein structure, including non-synonymous changes in protein coding sequences and creation/disruption of miRNA binding sites on UTRs. Dysregulation of A-to-I editing by ADAR has been recently linked to cancer. Since the ADAR gene is located in 1q21.3 (the critical minimally amplified region in MM), we asked whether 1q amplification affected ADAR expression, RNA editing and overall prognosis in MM patients. We identified 44 patients with 1q amplification from the IA6 release of the MMRF CoMMpass dataset. As a control group (wt), we selected an equal number of patients from CoMMpass without any 1q alteration. Gene expression analysis showed significantly higher expression of ADAR in 1q-amp patients compared to wt (q = 3.64e-7) (Fig. 1) and significant correlation between ADAR copy number and its expression (Spearman ρ=0.69, p = 4.52e-14). To evaluate the functional impact of ADAR up-regulation, we applied a computational pipeline based on the tool REDItools and our in-house scripts to detect A-to-I edited sites in RNA-Seq samples. The pipeline identified candidate A-to-G mutations in RNA sequences using corresponding Whole-Exome Sequencing data to filter out actual DNA mutations. We calculated sample-wise mean editing frequency across all edited sites and found significantly increased editing in 1q-amp patients compared to wt (p = 4.3e-5) (Fig. 2). Mean editing frequency was significantly correlated with ADAR expression (ρ = 0.62, p < 2e-16) and ADAR copy number (ρ= 0.5, p= 4.32e-7). Our analysis identified 3,286 sites residing in Alu sequences and 1,303 in non-Alu regions. A-to-I editing has been shown to occur predominantly in Alu elements, repetitive sequences abundantly interspersed throughout the human genome, mostly within introns and untranslated regions (UTRs). As expected, most sites were reported within 3' UTRs (66%) and introns (12%). Overall, at the site level, we observed increased editing in 1q-amp vs wt (p < 2e-16). We found that 2,173 sites (47%) had significant differential editing frequency between 1q-amp and wt patients (FDR < 20%). Next, we sought to assess the prognostic implications of ADAR activity. Cox regression analysis revealed a trend toward higher risk in terms of EFS (Event Free Survival) for 1q-amp vs wt (HR = 1.7, 95% CI = 0.83-3.59, p = 0.13), as well as for patients with higher expression of ADAR (HR = 2.4, 95% CI = 0.79-7.15, p = 0.11) and higher mean editing frequency (HR = 2, 95% CI = 0.72-5.59, p = 0.17). Since survival data in the CoMMpass dataset is not yet mature, we evaluated the effects of ADAR expression on survival on an independent dataset consisting of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658, Shaughnessy et al, Blood 2007; 109:2276-84). Cox regression analysis showed a significant difference in terms of overall survival between patients with low and high ADAR expression, the latter being correlated with higher risk (HR = 2, 95% CI = 1.18-3.66, p = 0.01) (Fig. 3). In conclusion, we found a significant increase in ADAR expression and aberrant A-to-I RNA editing in MM patients with amplification of 1q. These results demonstrate a novel mechanism by which 1q amplification can contribute to MM pathogenesis via induction of A-to-I RNA editing by ADAR. Figure 1 ADAR expression in 1q-amp vs wt patients. Figure 1. ADAR expression in 1q-amp vs wt patients. Figure 2 Difference in mean RNA editing frequency between 1q-amp and wt patients. Figure 2. Difference in mean RNA editing frequency between 1q-amp and wt patients. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by ADAR expression (GSE2658) Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by ADAR expression (GSE2658) Disclosures Chari: Janssen: Consultancy, Research Funding; Pharmacyclics: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Amgen Inc.: Honoraria, Research Funding; Array Biopharma: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Cho:Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Agenus, Inc.: Research Funding; Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Jagannath:Janssen: Consultancy; Celgene: Consultancy; Merck: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy. Dudley:NuMedii, Inc.: Patents & Royalties; AstraZeneca: Speakers Bureau; Ontomics, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; Ayasdi, Inc.: Equity Ownership; Janssen Pharmaceuticals, Inc.: Consultancy; GlaxoSmithKline: Consultancy; Personalis: Patents & Royalties.

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Vorinostat in Combination with Decitabine for the Treatment of Relapsed or Newly Diagnosed Acute Myelogenous Leukemia (AML) or Myelodysplastic Syndrome (MDS): A Phase I, Dose-Escalation Study.

Blood ◽

10.1182/blood.v114.22.2089.2089 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2089-2089 ◽

Cited By ~ 8

Author(s):

Mark Kirschbaum ◽

Ivana Gojo ◽

Stuart L. Goldberg ◽

Lisa Kujawski ◽

Ehab Atallah ◽

...

Keyword(s):

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Sequential Therapy ◽

Employment Equity ◽

Advisory Committees ◽

Concurrent Therapy ◽

Equity Ownership ◽

Experienced Treatment ◽

Refractory Aml

Abstract Abstract 2089 Poster Board II-66 Introduction: Although the introduction of epigenetic therapies, such as the DNA methyltransferase inhibitor (DNMT) decitabine, has improved options for the treatment of myeloid malignancies, use is limited by sub-optimal response rates. Therefore, there remains a need for more effective treatment strategies to improve outcomes in AML/MDS. Preclinical and clinical data suggest that broadening epigenetic targeting by adding histone deacetylase (HDAC) inhibitors to DNMTs may improve responses. In addition, it has been reported that outcomes may differ according to the sequence in which HDAC and DNMT inhibitors are combined. Aim: Here we present preliminary data from a Phase I, open-label, multicenter, dose-escalating study, designed to determine the maximum-tolerated dose (MTD) and recommended Phase II dose of the HDAC inhibitor vorinostat combined either concurrently or sequentially with decitabine in patients (pts) with AML/MDS. Other endpoints include tolerability and exploratory assessments of activity. Methods: Pts (≥18 years) with intermediate-high risk MDS, relapsed/refractory AML, or untreated AML (≥60 years; unsuitable for standard chemotherapy), with an ECOG performance status of ≤2, were enrolled into one of six dosing levels (Table) and received treatment for up to 24 months or until disease progression (PD). Results: As of August 3, 2009, 72 pts have entered the study: median age was 68 years (range 18-85) and 58% were male. To date, 69 pts have discontinued due to PD/lack of efficacy (n=37), withdrawal of consent (n=12), adverse events (AEs) (n=16), physician decision (n=3), and protocol deviation (n=1). Of 70 pts evaluable for safety, 69 experienced AEs, the majority of which were Grade 1/2 in severity and included nausea (n=48), diarrhea (n=41), fatigue (n=36), constipation (n=32), and vomiting (n=28). 62 (89%) pts experienced treatment-related AEs and 17 (24%) pts experienced treatment-related serious AEs. 14 deaths occurred during the study, although none were related to study treatment. One dose-limiting toxicity, prolonged QT interval, was documented in dose level 3a. Combinations of vorinostat and decitabine in the schedules in this protocol did not reach MTD. As per protocol, dose levels 3 and 3a were the maximum administered doses and have been expanded. Of the 61 pts evaluable for response, 11 had MDS, 25 had relapsed/refractory AML, and 25 had untreated AML. In pts with MDS receiving concurrent therapy (n=5), complete remission (CR) was achieved in 2 pts, stable disease (SD) in 1 pt, partial remission (PR) in 1 pt, hematologic improvement (HI) in 1 pt; all 6 of the pts who received sequential treatment experienced SD. In pts with relapsed/refractory AML receiving concurrent therapy (n=12), CR was achieved in 1 pt, CR without recovery of counts (CRi) in 1 pt, HI in 1 pt, SD in 6 pts, while 3 pts had PD; in those receiving sequential therapy (n=13), SD was achieved in 9 pts while 4 had PD. In pts with untreated AML receiving concurrent therapy (n=12), CR was achieved in 4 pts, CRi in 1 pt, PR in 1 pt, and SD in 6 pts, and in those receiving sequential therapy (n=13), CR was achieved in 2 pts, CRi in 2 pts, PR in 1 pt, HI in 2 pts, and SD in 5 pts. Overall, CR or CRi was achieved by 18% pts with MDS, 8% with relapsed/refractory AML, and 36% with untreated AML; and HI was reported in 9% pts with MDS, 4% with relapsed/refractory AML, and 8% with untreated AML. Conclusion: These preliminary data indicate that the combination of vorinostat with decitabine, either concurrently or sequentially, is possible without significant toxicity. In addition, the combination shows promising activity in MDS and untreated AML. Disclosures: Kirschbaum: Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celegene: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Off Label Use: Vorinostat is a histone deacetylase (HDAC) inhibitor that was approved in the FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma (CTCL) who have progressive, persistent, or recurrent disease on or following two systemic therapies. Goldberg:Merck: Research Funding. Marks:Merck: Research Funding. Di Gravio:Merck: Employment, Equity Ownership. Pyle:Merck: Employment, Equity Ownership. Rizvi:Merck: Employment, Equity Ownership. Issa:Eisai: Consultancy, Research Funding; Celegene: Research Funding; MGI Pharma: Research Funding.

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Allogenic Transplantation in Lymphomas: A Focused Analysis On Aggressive Lymphomas and Factors Predictive of Outcome in a Series of 179 Pts Treated At John Theurer Cancer Center.

Blood ◽

10.1182/blood.v120.21.3120.3120 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3120-3120

Author(s):

Anthony R Mato ◽

Kathryn Waksmundzki ◽

Tania Zielonka ◽

Ewelina A Protomastro ◽

Theresa Amatucci ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Board Of Directors ◽

Cox Regression ◽

Cancer Center ◽

Advisory Committees ◽

Stem Cell Source ◽

Cell Source ◽

Refractory Lymphoma ◽

Donor Source

Abstract Abstract 3120 Introduction: Chemo-immunotherapy (i.e. rituximab combinations) has clearly had a significant impact on the outcome of all B-cell NHL both in terms of PFS and OS. However in the relapse/refractory setting a large proportion of pts still do very poorly especially in aggressive subtypes including DLBCL and MCL. Salvage therapy followed by HDT-ASCT in relapsed DLBCL remains the standard, though pts with early failures (<1y) and/or prior exposure to rituximab still show dismal results (CORAL data). In MCL the use of HDT-ASCT in the relapse setting is debated given the frequency of chemo-resistance leading to poor results even in second CR. The use of allogeneic transplantation was developed based on observations c/w with a clear GVL effect in NHL as illustrated by pts going into remission after DLI injections. The development of non-myeloablative approaches has allowed expansion of use of allogeneic BMT in relapsed/refractory NHL. We report here one of the largest series (179 consecutive pts) with relapsed/refractory lymphoma focusing on overall survival and outcome predictors. Methods: Utilizing Kaplan-Meier survival and Cox regression methods, we report on the outcome of 179 consecutive pts with relapsed/refractory lymphoma who underwent allogeneic stem cell transplantation at the John Theurer Cancer Center between 1995–2012. The primary study endpoint was overall survival (OS) assessed by chart and SSDI database review. Secondary study endpoints included examination of the association between overall survival and allogeneic stem cell source, donor source, development of GVHD, pre-transplant chemo-sensitivity and prior failure to HDT-ASCT (second transplant). The proportional hazards assumption was met for this analysis. Results: Survival data on 179 pts (median age 48, range 20–71) were analyzed, representing 86 deaths and 5720 total months at risk (median follow up=12.3 months). Baseline characteristics included: ECOG PS (med 1, range 0–2), diagnosis (25% DLBCL, 21% HD, 20% MCL, 13% FCL, 13% PTCL, 8% other), donor source (50% matched SIB, 31% MUD, 19% mismatched MUD), stem cell source (73% PB, 23% BM, 6% Cord) and prior autologous SCT (38%). The median OS for the entire cohort was 31.2 months. OS KM curves by selected aggressive NHL subtypes are represented in Figure 1. We performed COX regression analyses to address outlined secondary endpoints. In univariate analyses statistically significant inferior outcomes were associated with the use of mismatched unrelated donor (HR 1.4, p=.01, Figure 2), bone marrow donor stem cells vs. PBSCT (HR=1.7 p=.04), pre-transplant stable/refractory disease (HR 1.8, p=.03), absence of cGVHD (HR=4.7, p<.001) and presence of acute GVHD (HR 2.8, p=.001). No difference in OS was detected whether pts had undergone allogeneic SCT as a second transplant (med time between auto/allo=20.9 months) following relapse after auto SCT (HR 1.14, CI .75–1.73, p=.5). Conclusions: This series represents a large cohort of poor risk, relapsed/refractory lymphoma pts treated consecutively with allogeneic stem cell transplantation over a > 10-year period at our institution with the following observations: Disclosures: Mato: Celgene: Speakers Bureau; Millennium: Speakers Bureau; Seattle Genetics: Speakers Bureau; Genentech: Speakers Bureau. Goldberg:Eisai: Speakers Bureau. Feldman:Allos: Speakers Bureau; celgene: Speakers Bureau; Seattle Genetics: Speakers Bureau; Merck: Speakers Bureau. Goy:Milennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; J & J: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

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The Impact of Rituximab and Radiotherapy On Treatment Outcome of Patients with DLBCL and Skeletal Involvement

Blood ◽

10.1182/blood.v120.21.690.690 ◽

2012 ◽

Vol 120 (21) ◽

pp. 690-690

Author(s):

Gerhard Held ◽

Samira Zeynalova ◽

Niels Murawski ◽

Marita Ziepert ◽

Barbara Kempf ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Cox Regression ◽

Multivariable Analysis ◽

Event Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Skeletal Involvement ◽

The Impact

Abstract Abstract 690 Background: There is limited information on the role of skeletal involvement in DLBCL patients treated with rituximab. Methods: In a retrospective subgroup analysis patients with aggressive B-cell lymphomas with and without skeletal involvement were compared with respect to clinical presentation, event-free and overall survival. Results: Of 3840 patients 292 (7.6%) had skeletal involvement. In a multivariable analysis of patients treated within the randomized MInT and RICOVER-60 trials, the two largest randomized trials addressing the role of rituximab in DLBCL to date, skeletal involvement was associated with a reduced hazard ratio (HR) of 0.8 (p=0.181) for event-free survival and 0.7 (p=0.083) for overall survival for patients treated without, but with an increased HR (1.5; p=0.048) for event-free and (1.1; p=0.828) for overall survival in patients treated with rituximab. This was due to the failure of rituximab to improve the outcome of patients with skeletal involvement. In the MInT trial, the 3-year EFS rates were 64% without and 63% with rituximab (p=0.680) and the 3-year OS rates were 83% without and 90% with rituximab (p=0.542). similarly, in the RICOVER-60 trial, the 3-year EFS rates were 45% without and 50% with rituximab (p=0.593) and the 3-year OS rates were 68% without and 68% with rituximab. In a Cox regression model for event-free survival adjusted for the IPI risk factors a relevant interaction (HR 1.5; p=0.056) term between rituximab and skeletal involvement was observed. In contrast to rituximab, additive radiotherapy to sites of skeletal involvement was associated with a better outcome: 3-year EFS rates were 40% without and 75% with radiotherapy (p<0.001), 3-year OS rates were 70% without and 86% with radiotherapy to sites of skeletal involvement (p=0.064). In a multivariable analysis radiotherapy reduced the risk for an event in EFS by 70% (HR=0.3; p=0.001) and by 50% in OS (HR=0.5; p=0.111). Conclusion: Addition of rituximab failed, but radiotherapy to sites of skeletal involvement did improve the outcome of DLBCL patients with skeletal involvement. Radiotherapy to sites of skeletal involvement, though abandoned by many cooperative groups world-wide, is recommended in the rituximab era, unless prospective trials demonstrate that it might be omitted in cases with a negative PET after immunochemotherapy. Disclosures: Dreyling: Roche: Membership on an entity's Board of Directors or advisory committees. Hallek:Roche: Membership on an entity's Board of Directors or advisory committees. Schmitz:Chugai: Membership on an entity's Board of Directors or advisory committees. Pfreundschuh:Roche: Membership on an entity's Board of Directors or advisory committees; Chugai: Consultancy.

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Higher Expression of Nuclear Cereblon in Bone Marrow Biopsies of Patients with Multiple Myeloma Treated with Imids in the HOVON-87/Nmsg-18 Trial Is Associated with Longer PFS and OS

Blood ◽

10.1182/blood-2019-128584 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3071-3071

Author(s):

Ruth Wester ◽

M Duin ◽

King Hong Lam ◽

Suzana Couto ◽

Yan Ren ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Cox Regression ◽

Employment Equity ◽

Advisory Committees ◽

Cytoplasmic Staining ◽

Cox Regression Analysis ◽

Cytogenetic Aberrations ◽

Equity Ownership ◽

Response Groups

Introduction Response to treatment in patients with multiple myeloma (MM) is variable. With increasing possibilities of treatment regimens, predictive factors for response are important. Immune modulating agents (IMiDs) require Cereblon (CRBN) for activity. Therefore, the aim of this study was to identify the genes involved in the CRBN pathway which predict the response to therapy with IMiDs. Methods Paraffin embedded bone marrow (BM) biopsies were used from newly diagnosed patients included in HOVON-87/NMSG-18 trial obtained at inclusion. In this trial, elderly patients with MM were randomized between treatment with Melphalan-Prednisone (MP)-Thalidomide (MPT) followed by thalidomide maintenance versus MP-Lenalidomide (MPR) followed by lenalidomide maintenance (Zweegman et al. Blood 2016;127:1109-1116). BM biopsies were stained with a fully automated dual color, bright-field immunohistochemical assay for CRBN, its neosubstrates Ikaros and Aiolos and the downstream targets IRF4 and c-MYC. CD138 was used to identify MM plasma cells in the BM samples. For CRBN, both nuclear and cytoplasmic staining was evaluated. The distribution and intensity of the immunostaining was assessed using the H-score. The H-scores were calculated using the following formula: [1 × (% cells 1+) + 2 × (% cells 2+) + 3 × (% cells 3+)] and range from 0-300 (0-600 for combined cytoplasmic-nuclear CRBN H-score). For the Cox regression analysis H-scores were corrected by dividing these by a factor 100: hazard rates were considered per 100 points increase of the H-score. Protein levels of the CRBN pathway were compared between patients with complete response (CR) or very good partial response (VGPR) vs partial response (PR) and no change/progressive disease (NC/PD). High-risk cytogenetic aberrations (FISH) were defined as having deletion of 17p, and/or translocation t(4;14) and/or t(14;16). Statistical analysis was done using univariate and multivariate Cox regression analysis for progression free survival (PFS) and overall survival (OS), and the Mann-Whitney test for comparing response groups. Kaplan-Meier survival curves were generated to illustrate survival. Results BM samples obtained at diagnosis from 149 patients were evaluated. Seventy-one patients were treated in the thalidomide arm vs 78 patients in the lenalidomide arm. Median age was 73 years [range 60-90]. Revised ISS stages I/II/III were 12%/80%/8% respectively. At the time of analysis, median follow up of the 45 patients still alive was 83 months [range 23 - 114 months]. Best response on protocol treatment was sCR/CR in 22%, VGPR in 30%, PR in 36% and NC/PD in 12%. Protein expression across the response groups showed higher nuclear CRBN in patients who responded better (sCR/CR/VGPR; median H-score: 178 (49-273)) compared to patients with a worse response (PR/NC/PD; median H-score: 157 (67-251)), albeit not statistically significant (Mann-Whitney p-value=0.06). Higher H-score of nuclear staining of CRBN was associated with a longer PFS and OS, with a hazard ratio (HR) of 0.52 for PFS (95% confidence interval (CI)=0.37-0.86, p<0.001) and a HR of 0.56 for OS (95% CI=0.36-0.78; p<0.01). Patients with the top quartile nuclear CRBN levels had a median PFS of 21 months longer compared to patients with the lowest quartile (38 months vs 17 months). In terms of OS, patients with the highest quartile nuclear CRBN expression demonstrated a median survival that was 2 times as high as found in patients with the lowest quartile (75 months vs 35 months; Figure 1). In addition, cytoplasmic staining of CRBN was associated with improved PFS (HR = 0.66 (95% CI=0.47-0.94; p=0.02), but not with OS (HR = 0.73 (CI=0.48-1.11); p=0.14). None of the other markers were associated with survival. In a multivariate analysis (which included study arm (MPT vs MPR), nuclear CRBN, high-risk cytogenetic aberrations and R-ISS), nuclear CRBN remained independently associated with OS as well as R-ISS and study arm. For PFS, only nuclear CRBN remained statistically significant after backward selection. Despite treatment arm being a statistically significant term in the multivariate Cox model for OS, no relation was found for treatment arm and nuclear CRBN, in terms of OS. Conclusions In this study we demonstrate that higher expression of nuclear CRBN in myeloma cells in BM of patients with MM was associated with a superior PFS and OS. Disclosures Couto: Celgene Corporation: Employment, Equity Ownership, Patents & Royalties. Ren:Celgene Corporation: Employment, Equity Ownership. Wang:Celgene Corporation: Employment, Equity Ownership. Thakurta:Celgene: Employment, Equity Ownership. Zweegman:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding.

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The Impact from Frontline CLL Chemo Immunotherapy Regimen Outcomes Based on Patient Tolerability

Blood ◽

10.1182/blood-2018-99-119462 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5551-5551

Author(s):

Jake Towriss ◽

Prosanta Mondal ◽

Waleed Sabry ◽

Mohamed Elemary ◽

Hadi Alphonse Goubran ◽

...

Keyword(s):

Patient Outcome ◽

Board Of Directors ◽

Real World ◽

Cox Regression ◽

Dose Intensity ◽

Front Line ◽

Advisory Committees ◽

Cox Regression Analysis ◽

Choice Of Treatment ◽

Number Of Cycles

Abstract Background: The addition of anti-CD20 monoclonal antibodies to chemotherapy regimens for Chronic Lymphocytic Leukemia (CLL) has led to significant improvements in response and survival (Burger, O'Brian, Nat Rev Clin Oncol 2018). However, toxicities with treatment exist and real world evidence suggests that tolerability of treatment protocols may differ than those established by clinical trials (Mato et. al. Am Soc Hematology 2017), making clinical treatment decisions challenging. This study retrospectively reviewed the tolerability of three front line chemo-immunotherapy options utilized at the Saskatchewan Cancer Agency (SCA): Fludarabine, Cyclophosphamide and Rituximab (FCR) for fit patients, Bendamustine plus Rituximab (BR) for older but fit patients or younger but frail and Obinutuzumab plus Chlorambucil (O-Chlor) for older and/or frail patients. SCA guidelines suggest the choice of treatment regimen should be based on patient age and fitness, a surrogate for ability to tolerate full dose treatment. However, neither these two criteria nor what constitutes tolerability is defined, resulting in a subjective assessment of fitness, a common problem in real world settings (Bouret et al, Hematologica 2013). We hypothesized that choice of treatment without these definitions would lead to poor choice of regimen selection and inferior patient outcome. Methods: We retrospectively reviewed the electronic medical records of CLL patients receiving front line chemo immunotherapy treatment at the SCA between 2015-2018. Patients' ability to tolerate treatment was assessed by the number of cycles completed, total dose intensity received, dose delays or change in therapy. Regimen tolerability was compared to physician calculated Cumulative Illness Rating Scale (CIRS) scores (an objective fitness measure) however, this was calculated after treatment regimen was determined. Kaplan-Meier analysis, univariable and multivariable Cox regression models were utilized to analyze the effect of tolerability and regimen received on patient outcome as defined by death due to CLL or progressive disease. Results: Ninety-six patient charts were reviewed. Regimen tolerability is shown in Table 1. A dose intensity of ≥ 75% was achieved by 91.3%, 69.9% and 48.7% of patients treated with FCR, BR and O-Chlor respectively. Dose intensity was statistically different among all 3 treatments (p=0.002) and specifically between FCR and BR (p=0.048). The number of cycles received for the 3 treatment groups were also statistically different most notably between FCR and O-Chlor (p=0.01) CIRS score of ≤ or > 6 was not different between the 3 groups. Median survival was statistically different between FCR (34.5 mo.), BR (36.1 mo.) and O-Chlor (25.4mo), (p=0.02) by Kaplan Meir Analysis. Univariate Cox regression analysis demonstrated the following statistically significant risk differences for death from CLL or disease progression; 1) Higher risk for O-Chlor versus BR [Hazard Ratio (HR)= 5.16, 95% confidence interval (CI): (1.65-16.13), P=0.004), 2) Lower risk for DI ≥ 75% for a 3 regimens [HR=0.19, 95% CI: (0.08-0.44), P=0.001], 3) each additional cycle of treatment received lowered the risk of death from CLL or disease progression by 33% [HR=0.67, 95% CI:(0.56-0.80), P<0.0001] and 4) if an additional cycle of treatment required dose reduction, the event rate decreased by 23% [HR=0.77, 95% CI: (0.59-0.99), P=0.047]. Multivariable Cox regression analysis demonstrated that only the regimen received and not specific tolerability remained statistically significant for patient outcomes. Conclusions: Dose intensity and the number of cycles received independently affected patient outcome indicating that certain aspects of regimen tolerability are important to consider when making treatment decisions. These results add to the growing body of real world evidence for front line CLL chemo immunotherapy. Disclosures Elemary: Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Lundbeck: Membership on an entity's Board of Directors or advisory committees.

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Utilizing Organ-Sparing Marrow Irradiation to Condition Patients Prior to Allogeneic Hematopoietic Cell Transplant with High-Risk Hematologic Malignancies: Results of a Pilot Study

Blood ◽

10.1182/blood-2021-150948 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2856-2856

Author(s):

Sumithira Vasu ◽

Meghan Kromer ◽

Qiuhong Zhao ◽

Hannah Choe ◽

Karilyn Larkin ◽

...

Keyword(s):

Overall Survival ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Transplant ◽

Advisory Committees ◽

High Incidence ◽

Grade Ii

Abstract Background: Total body irradiation (TBI) has long been incorporated as part of the conditioning regimen prior to hematopoietic stem cell transplant (HSCT). While the myeloablative TBI conditioning is associated with a lower relapse rate in high risk diseases such as Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS), and Acute Lymphoblastic Leukemia (ALL), it is also associated with substantial toxicities, and increased NRM so use of this regimen is limited to young patients with excellent performance status. In this study, we used a linac-based volumetric modulated arc therapy (VMAT) technique to deliver standard myeloablative radiation to high risk body sites while sparing radiation sensitive organs (Organ Sparing Marrow Targeted Irradiation, OSMI). We hypothesized that this technique would be feasible and safe in patients who are older or who have higher transplant specific comorbidity index (HCT-CI), typically ineligible for standard TBI conditioning. Methods: This is a single-arm prospective study. Patients from age 18-75 with high risk AML, MDS or ALL were eligible. There are 3 cohorts: (1) age 18-50 with HCT-CI of 3/4; (2) age 51-65 with HCT-CI of ≤ 3; and (3) age 66-75 with HCT-CI of ≤ 2. Patients receive OSMI to a total dose of 1200 cGy delivered twice daily for 6 fractions for a total of 7200 cGy. Clinical tumor volume includes total skeletal bone marrow and any sanctuary or high-risk areas. Graft-versus-host disease (GVHD) prophylaxis originally was tacrolimus and methotrexate. Given high incidence of bacterial infections related to mucositis, prophylaxis was changed to tacrolimus and sirolimus without methotrexate. All patients received Keratinocyte growth factor for prevention of mucositis. The primary objective was to assess feasibility and tolerability of OSMI based HSCT as defined by transplant-related mortality (TRM) at day 30 (D30) as well as rate of grade II/III organ toxicity (defined by Bearman Regimen-Related Toxicities Scale) attributable to conditioning occurring within 30 days. Results: Patient demographics for the 24 patients are shown in Table 1. Median age of recipients was 56.5 years. No graft failures were observed. The most common grade II or III Bearman toxicities include mucositis (grade 2: n=4), and diarrhea (grade 2: n=4). Clinical outcomes are shown in Figure 2. With a median follow-up of 3.3 years, overall survival (OS) and relapse-free survival (RFS) at 2 years was 78% and 74% respectively. Among the 5 patients who were not in complete remission at the time of transplant, 2-year OS and RFS rate was 40%. Incidence of Grades II-IV acute GVHD was 79% and Grades III-IV GVHD was 30%. Relapse incidence was 4% at 2 years. Incidence of Thrombotic microangiopathy by day 100 (TMA) as defined by Jodele's criteria was 17%. Incidence of chronic GVHD was 45% and severe chronic GVHD was 16%. One year non-relapse mortality was 22%, likely due to higher incidence of GVHD. Conclusions: Selected patients who are older or with higher HCT-CI, who are typically not candidates for standard TBI conditioning, were able to receive a radiation-based myeloablative conditioning regimen with 2 year overall survival rates of 78%. We observed a high incidence of TMA, possibly related to use of tacrolimus and sirolimus as GVHD prophylaxis, and a high incidence of Grade II-IV acute GVHD. Low incidence of relapse was observed. OSMI-based conditioning was feasible in this cohort with median age of 56 years and was associated with low rates of relapse and favorable 2 year overall survival. Figure 1 Figure 1. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: travel support; Kiadis, Inc.: Research Funding; Omeros, Inc.: Membership on an entity's Board of Directors or advisory committees. Jaglowski: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Juno: Consultancy; Kite, a Gilead Company: Consultancy, Research Funding; CRISPR Therapeutics: Consultancy. Brammer: Seattle Genetics: Speakers Bureau; Celgene: Research Funding; Kymera Therapeutics: Consultancy. de Lima: Incyte: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec: Research Funding.

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Reduced Severe aGVHD and Improved Survival Using Post Transplant Cyclophosphamide/Tacrolimus/Methotrexate Graft Versus Host Disease Prophylaxis in AML Patients Receiving Myeloablative Fractionated Busulfan Conditioning Regimen

Blood ◽

10.1182/blood-2019-125996 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3296-3296

Author(s):

Uday Popat ◽

Rima M. Saliba ◽

Rohtesh S. Mehta ◽

Amanda L. Olson ◽

Julianne Chen ◽

...

Keyword(s):

Overall Survival ◽

Board Of Directors ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Similar Proportion ◽

Myeloablative Conditioning ◽

Advisory Committees ◽

Post Transplant ◽

Gvhd Prophylaxis

Background: Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four day regimen. (Popat et al Lancet Haematology 2018). Subsequently, we added post-transplant cyclophosphamide (PTCy) GVHD prophylaxis to our fractionated regimen with a hypothesis that it will reduce GVHD and improve outcomes. Herein, we report the results of our retrospective analysis comparing outcomes of patients with AML who received fractionated busulfan myeloablative conditioning and PTCy versus standard tacrolimus (Tac) and methotrexate (Mtx) GVHD prophylaxis. Methods: Patients with AML between 18-70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor, who were treated on 4 consecutive protocols using fractionated busulfan were included in the analysis. All patients received two fixed doses of busulfan 80mg/m2 as outpatient either on days -13 and -12, or on days -20 and-13 followed by busulfan on day -6 to -3 dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. Fludarabine ± cladribine were given on day -6 to -3. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and Tac ± mycophenolate mofetil in PTCy cohort (n=53), or standard Tac+ Mtx (n=53). Patients in both the cohorts were matched 1:1 by propensity score. Results: Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 60 (range, 18-70) and 58 (range, 24-70) years, respectively, (P=0.3). Forty-nine percent were in CR, and 30% had comorbidity index >3 in each arm. Similar proportion of patients had ELN adverse risk in both arms (43% vs 40%, respectively P=0.7). The median follow up was 19 months (range, 3-36) in the PTCy and 46 months (range, 14-73) in Tac/Mtx cohort. Overall survival at 2-year was 78% vs 58% (P=0.03), non-relapse mortality was 6% vs 13% (P=0.2), incidence of grade 3-4 acute GVHD at 1-year was 6% vs 19% (P=0.07) and chronic GVHD at 2-year was 10% vs 29% (P=0.03) [Table 1 and figure 1]. The median time to neutrophil engraftment was prolonged by 3 days (15 vs 12 days; P<0.001) and platelet engraftment by 9 days (22 vs 13 days; P<0.001) in the PTCy cohort. Full donor chimerism at day 30 was noted in 79% vs 28% in the PTCy and Tac/Mtx cohorts respectively, (P<0.001). Conclusion: As compared to Tac/Mtx, PTCy-based GVHD prophylaxis not only reduced severe acute GVHD and chronic GVHD, but also improved overall survival in AML patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning. Prospective randomized trial is warranted to validate these findings. Disclosures Popat: Bayer: Research Funding; Incyte: Research Funding; Jazz: Consultancy. Bashir:Imbrium: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Kite: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; StemLine: Research Funding; Acrotech: Research Funding; Celgene: Research Funding. Ciurea:Kiadis Pharma: Membership on an entity's Board of Directors or advisory committees, Other: stock holder; MolMed: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Miltenyi: Research Funding. Kebriaei:Kite: Honoraria; Pfizer: Honoraria; Amgen: Research Funding; Jazz: Consultancy. Nieto:Astra-Zeneca: Research Funding; Affimed: Consultancy; Affimed: Research Funding; Novartis: Research Funding. Oran:Astex pharmaceuticals: Research Funding; AROG pharmaceuticals: Research Funding. Qazilbash:Genzyme: Other: Speaker; Amgen: Consultancy, Other: Advisory Board; Autolus: Consultancy; Bioclinical: Consultancy. Molldrem:M. D. Anderson & Astellas Pharma: Other: Royalties. Champlin:Johnson and Johnson: Consultancy; Actinium: Consultancy; Sanofi-Genzyme: Research Funding.

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Gemtuzumab in Children with Relapsed and Refractory Acute Myeloid Leukemia Treated on Compassionate-Use Basis: A Report of the AML-BFM Study Group

Blood ◽

10.1182/blood.v128.22.1637.1637 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1637-1637 ◽

Cited By ~ 2

Author(s):

Mareike Rasche ◽

Beate Lerius ◽

Ursula Creutzig ◽

Martin Zimmermann ◽

C. Michel Zwaan ◽

...

Keyword(s):

Bone Marrow ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Research Funding ◽

Treatment Options ◽

Refractory Disease ◽

Compassionate Use ◽

Advisory Committees ◽

Acute Myeloid ◽

Refractory Aml

Abstract BACKGROUND: Long-term survival in pediatric acute myeloid leukemia (AML) improved remarkably during the last decades. However, children with refractory disease or relapsed AML still suffer from exceedingly poor outcome, especially those who relapse within one year of diagnosis with very limited treatment options. Gemtuzumab ozogamicin (GO) is an anti-CD33 antibody linked to calicheamicin, a potent cytotoxic agent. Developed for targeted treatment of CD33-positive AML, studies in adults showed its efficacy in relapsed and refractory AML. We performed this retrospective analysis of patients with highly advanced pediatric AML, receiving GO as compassionate use. PATIENTS AND METHOD: In total, 96 children <18 years diagnosed from 1995 to 2014 with multiple relapsed or refractory AML received GO as compassionate use. Eighty-eight patients had sufficient data available for this retrospective analysis, evaluation of adverse effects during first cycle of GO was based on medical reports of 83 patients. Sixty-one patients were treated in refractory disease or early first relapse, but also including 7 patients with 2 relapses within the first year after diagnosis. Nine patients were in 2nd relapse (>1year from diagnosis) and one patient in 3rdrelapse, four children had AML as secondary malignancy. Fourteen children have been already transplanted once, one child twice before GO therapy. Fourty-seven children received monotherapy with GO, 35 children were treated combined with cytarabine and 3 children received other combinations with other agents (3 unknown). Fifty-three patients received one cycle, 34 received 2 cycles of GO, however one patient received 4 cycles of monotherapy. Of note, eight patients have been previously reported elsewhere (Zwaan et al., Br J Haematol. 2010). Time of database lock was 07/2016 with a median follow-up of 9.8 years for the surviving patients. RESULTS: Safety profile was comparable to other pediatric studies. Adverse effects during first cycle of treatment consisted mostly of fever in neutropenia (n=49), less frequently infections (n=9) or allergic reactions (n=18). A few patients reported about mild gastrointestinal symptoms, which was not clearly related to GO due to combination therapy. Two patients suffered from sepsis. Veno-occlusive disease (VOD) of the liver occurred in three patients, one of those had a previous VOD, but all of them have been treated successfully with defibrotide. No lethal event was observed during treatment with GO. One patient developed a VOD during subsequent transplantation despite of prophylactic use of defibrotide. Sixty patients were evaluable for response assessment of the bone marrow. Twenty-eight children showed a response with a blast reduction to 5% or less in the bone marrow samples after treatment (46%). Fourteen out of these patients, received GO combined with cytarabine, 12 patients had monotherapy, and two other combinations. Subsequently, 53 children proceeded to stem cell transplantation (SCT) (one patient unknown). Of note, 13 out of those, received further chemotherapy before HSCT was performed. In details, 47 patients proceeded to first SCT, whereas 5 patients received 2ndSCT (one unknown). Time to transplantation varied (<3 weeks, n=14; 3 to 6 weeks, n=28; >6 weeks, n=11 patients [median time to transplantation after GO: 30 days]). The probability of 4-year overall survival after treatment with GO of all patients (n=88) was 21±4%. In patients treated with monotherapy it was 18±6%. Eighteen patients of this cohort are still alive at time of database lock. CONCLUSION: To our knowledge, this analysis is the largest pediatric cohort of patients, treated with GO in a very advanced disease. The results of this retrospective trial indicate efficacy of GO, while having an acceptable toxicity profile, even in heavily pretreated patients. It can induce blast reduction and even survival in patients, who have no further conventional treatment options. Further randomized studies are necessary to learn more about efficacy and side effects in a relapse setting, especially for therapeutic implications in future. Disclosures Rasche: Jazz Pharma: Other: Travel accomodation. Zwaan:Pfizer: Research Funding; Pfizer: Consultancy. Reinhardt:Pfizer: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Jazz Pharma: Other: Travel Accomodation.

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Elacytarabine Is More Effective Preclinically Than Cytarabine In Combination With Daunorubicin In Primary Patient Xenografts Of AML

Blood ◽

10.1182/blood.v122.21.3958.3958 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3958-3958

Author(s):

Tereza Osdal ◽

Mihaela Lucia Popa ◽

Lene Mari Vikebø ◽

Andre Sulen ◽

Siv Lise Bendringaas ◽

...

Keyword(s):

Clinical Trial ◽

Bone Marrow ◽

Flow Cytometry ◽

Overall Survival ◽

Disease Progression ◽

Board Of Directors ◽

Near Infrared ◽

Advisory Committees ◽

Nsg Mice ◽

Refractory Aml

Abstract Acute myeloid leukemia (AML) is a heterogeneous disease with poor prognosis. The overall survival rate in AML patients has changed little in the last 20 years with overall survival rates for young patients (< 60 years) remaining at 35%. However, for elderly patients (> 60 years), survival is less than 10%. Despite the fact that AML represents one of the most molecularly characterized malignancies, the standard therapeutic option is unaltered in the last 15 years i.e. we still solely rely upon a combination of anthracycline and Cytarabine (Ara-C) as the cornerstone of induction therapy. Recently many potentially drugable targets have been discovered and while responses have been observed, these are generally amongst sub-sets of patients with good to intermediate prognostic factors and most often in combination with conventional therapy. Elacytarabine (ELA; CP-4055) is a fatty acid derivative (elaidic acid ester) of Ara- C, currently in undergoing phase II clinical trial as second-course remission-induction therapy in combination with anthracycline. In this study we determined the maximum tolerated dose for the combination of ELA with Daunorubicin (DAN) in immunodeficient NOD-scid-IL2Rγcnull (NSG) mice. Subsequently, we compared the preclinical efficacy of the combination of ELA (30 mg/kg; q.d.x5) or Ara-C (500 mg/kg; q.d.x2) with DAN (2.5 mg/kg; q.d.x3) in a primary patient xenograft model of refractory AML following relapse after Ara-C+DAN therapy (n = 24). Efficacy was evaluated employing a novel time-domain imaging strategy utilizing targeted monoclonal antibodies conjugated to near infrared dye that specifically recognize and bind to epitopes on AML cells enabling non-invasive monitoring of disease progression following therapy. Similarly, bone marrow aspirates were assayed for AML content by flow cytometry (CD45+/34+/33+) and IHC analysis. The combination of ELA and DAN was well tolerated in NSG mice xenografted with primary patient AML cells. While longitudinal near infrared optical imaging of AML disease dissemination illustrated lower disease burden in Ara-C + DAN treated mice than controls (p<0.05), those treated with ELA+DAN demonstrated significantly reduced disease progression, both in comparison to controls (p<0.001) and Ara-C+DAN (p<0.01) treated NSG mice. Flow cytometry analysis of bone marrow aspirates revealed similar reductions in ELA treated mice. Ultimately, combination of ELA+DAN exhibited significant increases in mean survival time (45 ± 4.6 days) over control (31.6 ± 1.7 days; p<0.0001) and Ara-C+DAN treated NSG mice (39 ± 3.2 days; p<0.039). ELA is more effective preclinically than Ara-C in combination with DAN in primary patient xenografts of refractory AML. ELA was found to be well tolerated and significantly increased survival in combination with Daunorubicin. Despite withdrawal of Elacytarabine as a single agent (following Phase III clinical trial earlier this year in relapsed and refractory AML versus investigators choice of treatment) our preclinical results demonstrate combined therapy of ELA+DAN may promise enhanced survival advantages over current standard therapy for AML patients. Disclosures: Popa: KinN Therapeutics AS: Employment. Gjertsen:KinN Therapeutics AS: Membership on an entity’s Board of Directors or advisory committees. McCormack:KinN Therapeutics AS: Membership on an entity’s Board of Directors or advisory committees.

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