Leukemia And Lymphoma Society Research Articles

Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx)

Five-Year Analysis of Murano Study Demonstrates Enduring Undetectable Minimal Residual Disease (uMRD) in a Subset of Relapsed/Refractory Chronic Lymphocytic Leukemia (R/R CLL) Patients (Pts) Following Fixed-Duration Venetoclax-Rituximab (VenR) Therapy (Tx)

Genetic Determinants and Evolutionary History of Richter's Syndrome

Genetic Determinants and Evolutionary History of Richter's Syndrome

Expression of Sf3b1-K700E accelerates the Development of Chronic Lymphocytic Leukemia in a Del(13q) Murine Model

Expression of Sf3b1-K700E accelerates the Development of Chronic Lymphocytic Leukemia in a Del(13q) Murine Model

The CLL-1100 Project: Towards Complete Genomic Characterization and Improved Prognostics for CLL

The CLL-1100 Project: Towards Complete Genomic Characterization and Improved Prognostics for CLL

AML Cells Alter Bone Homeostasis By Promoting the Formation of Immature Bone and Resorption of Mature Bone That Supports Leukemia Progression

Background: Genetic alterations in the osteoprogenitor cells has been shown to induce acute myeloid leukemia (AML) in several mouse models. Moreover, we have recently reported that AML cells induce osteogenic differentiation in mesenchymal stromal cells (MSC) to gain growth advantage in the bone marrow (BM; Battula et al., JCI Insight, 2017). However, the effect of AML cells on bone homeostasis/turnover and its impact on AML progression is unknown. Here, we hypothesize that AML cells expand osteoprogenitor cells and alter the balance between bone formation and resorption. Methods: To investigate the effect of AML cells on osteoprogenitor cells and mature osteoblasts, we used triple transgenic reporter mice with the genotype Osx-CreERt2;Ocn-GFP;ROSA-tdTomato. Murine AML cells with MLL-ENL translocation were implanted into these transgenic mice, and Osteoprogenitor (Osx+) cells and mature osteoblasts (Ocn+) in femurs were measured by confocal microscopy. To investigate the effect of human AML cells on bone composition, patient-derived xenograft (PDX) cells were implanted into non-obese diabetic scid interleukin-2Rγnull (NSG) mice and bone histomorphometry was performed using H&E and Goldner's trichrome staining. Computed tomography (micro-CT) was used to measure bone volume (BV) and mineral density (BMD) in mice. Tartrate-resistant acidic phosphatase (TRAP) staining was performed to measure osteoclast number/activation. Finally, bone density on the vertebral bone (T12) was measured in 263 de-novo AML patients and 23 normal individuals by CT imaging. Results: In transgenic mice implanted with syngenic AML cells, we found a 3-4 fold increase in Osterix+, but not Osteocalcin+ cells, suggesting AML cells expand osteoprogenitor cells in the BM during short term exposure (2-3 weeks). To investigate the effects of AML on bone during a long term exposure, we implanted 10 different AML-PDX models in NSG mice (3 mice per model) and analyzed femurs by micro-CT and bone histomorphometry analysis. Interestingly, we observed a dramatic increase in new web-like medullary bone formation in 5/10 of the PDX models tested. Moreover, higher bone volume is associated with less aggressive PDX models (which takes 4-6 months to reach 90% circulating leukemia), but not aggressive PDX models (only 4-8 weeks to reach 90% circulating cells). These findings were also confirmed by micro-CT of mouse femurs. Interestingly, in some PDX models, CT images revealed large cavities in cortical bones close to epiphysis and metaphysis areas in the femur and tibia of mice with AML suggesting bone resorption. To validate bone resorption, we performed TRAP staining and found a significant increase in osteoclast activity on the endosteal surface and massive bone resorption in AML bone compared to normal bone. These data indicate high bone turnover in mice with AML compared to control mice. Next, we measured bone densities in AML patients and normal individuals by chest CT imaging. We found bone densities were gradually decrease with age in both healthy individuals and AML patients. However, compared to healthy individuals, bone densities are significantly higher in majority of AML patients (~70%) (p<0.01). Interestingly, survival analysis revealed that higher bone density is associated with good prognosis in AML patients (p<0.01), suggesting high bone turnover alters patient outcomes. Conclusion: Our data suggest that AML cells expand osteoprogenitor-rich niche and alter BM microenvironment by high bone turnover. New bone induction by less aggressive AML-PDX models coupled with AML patient CT data suggests that high bone density and volume are associated with favorable prognostic factors in AML. Mechanisms underlying this observation are under investigation. Disclosures Andreeff: Amgen: Research Funding; Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees. Konopleva:Ablynx: Research Funding; AstraZeneca: Research Funding; Kisoji: Consultancy; Ascentage: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Rafael Pharmaceutical: Research Funding; Amgen: Consultancy; Agios: Research Funding; Sanofi: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Forty-Seven: Consultancy, Research Funding; Eli Lilly: Research Funding; Genentech: Consultancy, Research Funding; F. Hoffmann La-Roche: Consultancy, Research Funding. Battula:Leukemia Lymphoma Society: Research Funding; Tolero Pharmaceuticals: Research Funding; Golfers Against Cancer: Research Funding.

Editorial introductions

Editorial introductions

Potential Genetic and Immunologic Mechanisms of Therapeutic Resistance and Disease Progression in CNS Lymphoma Elucidated Via Whole Brain Autopsy Studies

While the genomic landscape of CNS lymphomas at diagnosis has largely been defined, there remains a significant gap in our understanding of the molecular pathways that mediate therapeutic resistance and disease progression. CNS lymphomas generally exhibit multifocal dissemination as an end-stage manifestation. To elucidate key genetic and pathophysiologic pathways of CNS lymphoma that mediate resistance, we have conducted what may be the first study to apply next generation sequencing to compare the genetic features of PCNSL and SCNSL at the time of diagnosis with multifocal lesions isolated from relapsed, treatment-refractory disease from matched patient specimens at final lymphoma progression, isolated from whole brain autopsy specimens. Whole-exome sequencing from diagnostic specimens (4 brain and 1 retinal biopsy) were compared with matched whole brain autopsy specimens in 5 patients: 4 with PCNSL and 1 with SCNSL. A median of 6 distinct anatomical CNS lymphoma-containing brain regions were analyzed/whole brain autopsy specimen. Median age was 57 (range 51-81 yrs). Two patients died after primary refractory disease to methotrexate-based induction and three died after median of four progressions; each of these later patients progressed after lenalidomide, and one also received pomalidomide followed by ibrutinib before final disease progression. Four cases were from UCSF and 1 from Stanford. Tumor tissue and uninvolved normal brain was microdissected from formalin-fixed, paraffin-embedded blocks of initial biopsy prior to therapy and multiple distinct tumor regions at time of autopsy. Multiplex library preparation was performed from extracted genomic DNA and hybridization-capture of pooled libraries performed using NimbleGen SeqCap EZ Human Exome Probes Bait Library. Captured libraries were sequenced as paired-end 100 base pair reads and sequence reads mapped to the reference human genome build GRCh37 (hg19) using Sentieon DNAseq. Somatic variant detection including single nucleotide variants and insertions/deletions was performed. Single nucleotide variants and insertions/deletions were verified using Integrated Genome Viewer. Copy number analysis was performed using CNVkit and visualized using Nexus. High-confidence somatic nonsynonymous mutations were identified and pathway analysis applied using gene sets for canonical pathways and Gene Ontology (GO) terms downloaded from Molecular Signatures Database) at http://www.broad.mit.edu/gsea/msigdb. Lymphoid-specific signatures were curated by Staudt lab (http://lymphochip.nih.gov/signaturedb/) or previous publications. Fisher's Exact test was used to calculate enrichment p values for each of those gene sets and the BH method used for False Discovery Rate (FDR) control. A mean of 214 lymphoma-specific mutations per specimen was identified (range 56-1,764). Notably, of the 283 distinct molecular pathways analyzed, only 1 pathway was significantly enriched for mutations in tumors from each of the 5 CNS lymphoma whole brain autopsy specimens compared to pre-treatment diagnostic biopsies: the Ikaros 1(IKZF1) in centroblast pathway (p<0.05). The 2 cases of CNS lymphoma that had been exposed to an IMiD most proximate to brain autopsy (< 6 weeks) exhibited the strongest enrichment for mutations in IKZF1 pathway (p<0.005). Genes recurrently mutated in the IKZF1 pathway in relapsed CNS lymphomas included CD79A/B, IGLL5, BTG2, and TMEM30A. Mutations in the BCL6 and BACH2 transcriptional repressor pathway were significantly enriched in CNS lymphomas at autopsy compared to diagnostic specimens in 3 out of 5 cases. We also detected marked regional heterogeneity in DNA copy number aberrations in lymphoma from whole brain autopsy specimens. High level focal amplification of 9p24.1 targeting PD-L1 was enriched in only one case: a highly refractory PCNSL that had been exposed to pomalidomide followed by ibrutinib within two months of autopsy; amplification of PD-L1 was not detected in the diagnostic specimen. While multiple genetic aberrations are associated with disease progression in CNS lymphoma, our study suggests that mutational activation of the IKZF1 pathway may be a unique canonical mechanism in the evolution of resistance to multiple interventions, including first-line methotrexate. This observation may have significant therapeutic implications. Supported by NCI and Leukemia Lymphoma Society. Disclosures Rubenstein: Genentech: Research Funding; Celgene: Research Funding; Bristol Myers Squibb: Research Funding.

Editorial introductions

Editorial introductions

Quantifying Patient Preferences for Treatment Outcomes in AML: A Discrete-Choice Experiment

▪Background: Treatment of acute myeloid leukemia (AML) remains a significant challenge: induction chemotherapy is associated with substantial toxicities, and most patients will eventually die related to their disease. While inducing complete remission (CR) has historically been the primary aim of most treatment regimens, it is unknown to what extent patients would be willing to trade-off the chance at remission for other outcomes such as a reduced toxicity profile. Clinicians routinely make such decisions for patients by selecting less intense regimens for elderly patients or those with significant comorbidities, or when remission may not be clinically relevant or likely achievable. Patient preferences for treatment outcomes often inform shared decision making at the bedside and are increasingly recognized by the FDA and industry as a critical aspect to incorporate into drug development. As part of a patient-focused drug development initiative led by The Leukemia & Lymphoma Society (LLS), we sought to quantify patient preferences for treatment outcomes in AML.Methods: In collaboration with diverse stakeholders (including patients, clinicians, industry representatives, and the LLS staff), a survey instrument was developed to quantify patient preferences for treatment outcomes in AML. A discrete-choice experiment (DCE), in which participants made choices between 9 pairs of hypothetical treatments, was utilized with five attributes: event-free survival, complete remission, time in hospital, short-term side effects, and long-term side effects. All attributes were tiered to three clinically relevant levels. A national survey was conducted and analyzed using a conditional logistic regression. Elicited preference weights, reflecting the desirability for individual attributes, were aggregated into preference estimates. Sub-group analysis compared outcomes based on remission status.Results: The survey was sent to 896 patients with AML who were identified through the LLS database. Three-hundred and twenty-two patients participated in the survey; 294 completed the DCE. Most patients were white (89.4%), married (74.7%), college-educated (74.4%), and privately-insured (76.9%). The majority of patients had received an allogeneic stem cell transplant (63.8%) and nearly all (95.0%) were in remission. The mean time since diagnosis was 8.0 years (range = 1 - 40). Mean age was 56.8 years (Standard Deviation = 12.4). Based on the DCE, CR was identified by patients to be the most important attribute (Preference estimates, 10% increase in CR = 1.05, Standard Error (SE) = 0.06), followed by severity of long-term side effects (1-step increase = -0.52, SE = 0.05), event-free survival (6 months increase = 0.29, SE = 0.02), severity of short-term side effects (1-step increase = -0.33, SE = 0.04), and time in hospital (1 month increase = -0.12, SE = 0.03). These preference estimates suggest that patients were willing to accept a 1-step increase in severity of short-term side effects for a 3% increase in chance at CR. Patients would be willing to accept a 5% decrease in the chance at CR for a 1-step decrease in long-term side effects. Patients equivalently valued an additional 3 more months in the hospital to a 3% increase in chance of CR. They valued a 10% increase in chance of CR as approximately the same as 22 months of event-free survival. No differences were seen between patients currently in remission and those not in remission. Patients found the questions easy to understand (79%), easy to answer (68%), and relevant to them (72%).Conclusions: In addition to demonstrating the feasibility of a DCE in eliciting patient preferences and creating the first large dataset of its kind, this study illustrates that AML patients are willing to make trade-offs regarding treatment outcomes. While patients most highly value the chance at CR, they were willing to forgo small increases in the probability of remission to improve other outcomes, especially long-term side effects. Demonstrating patients' willingness to make such trade-offs becomes critical as incremental gains in CR with novel treatments may come with significantly increased toxicities. These data will be important to inform shared decision making, drug development and approval. Prospective studies using DCE may be helpful to guide individual treatment recommendations. DisclosuresSeo:Evidera/PPD: Employment. O'Donoghue:The Leukemia & Lymphoma Society: Employment. Bridges:The Leukemia & Lymphoma Society: Research Funding.

Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial

Enasidenib Is Highly Active in Previously Untreated IDH2 Mutant AML: Early Results from the Beat AML Master Trial

Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 Studies

Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 Studies

Phase 1b Dose Escalation Study of BI 836858 and Azacitidine in Previously Untreated AML: Results from Beat AML S2

Phase 1b Dose Escalation Study of BI 836858 and Azacitidine in Previously Untreated AML: Results from Beat AML S2

Forty Percent of MDS Patients Wish They Received Red Blood Cell Transfusions at Higher Hemoglobin Thresholds Than They Currently Are: A Multinational Transfusion Audit

Background: Red blood cell transfusion dependence (RBC-TD) is a reality for most MDS patients at some point during their disease trajectory. RBC-TD has been associated with inferior quality of life, iron overload and inferior overall survival. Alongside a focus on new therapies to abrogate or diminish the dependence on RBC units, optimizing quality of life while on transfusions may also have value. Our objective was to better understand the transfusion experience and what patients value, in order to inform future research initiatives. Methods: We designed a web-based survey (using SurveyMonkey) in the USA, Canada and UK that was disseminated by the international MDS Foundation, the Leukemia Lymphoma Society of Canada, the Aplastic Anemia and MDS Association of Canada (AAMAC), the University of York, the MDS registry of Canada and the MDS UK Patient Support Group. The survey consisted of 57 questions and was completed by willing patients who received at least 1 unit of blood in the previous 8 weeks. The anonymized survey was completed from 8/27/17 to 2/18/2018.Results: Of 712 responses, 475 (67%) were RBC-TD and eligible for the survey. 55% were male with a median age of 72 years, 77% lived in urban or suburban communities. 75%, 12% and 12% of respondents were from USA, Canada and the UK; 93% were Caucasian. 45% and 27% reported lower and higher risk MDS respectively while 28% did not know. Patients reported having lived with MDS for a median of 3 years, 52% became transfusion dependent within 6 months of diagnosis and 37% > 12 months after diagnosis. 80% knew the haemoglobin (Hb) threshold at which they were transfused (Figure 1). 14%, 30% and 54% received 1, 1-2 or 2 units at a time and the median number of units/month was 2 (Figure 2). The most common symptoms pre-transfusion were fatigue (91%), weakness (69%), shortness of breath (SOB, 72%), dizziness (43%) and headache (22%) with fatigue and SOB having the most negative impact on their lives. 25%, 53% and 12% felt better after a transfusion within 1 day, 1-2 days and 3-4 days respectively and 20% felt worse for 1-2 days post transfusion. 64% reported feeling symptomatic for 5+ days before their next transfusion was organized, but 65% were able to organize a blood transfusion within 1-2 days of reaching their Hb threshold. 61% had a crossmatch on a different day from their transfusion and 30% of these patients indicated that they would have preferred to have a same day crossmatch even if it demanded more time at the transfusion centre. 42% were driven to their transfusions by friends or family. Travel time to the transfusion centre was < 1 hour for 93% of patients and did not have a negative impact on quality of life for 81% of respondents. 47% spent 4-6 hours at the clinic on the day of their transfusions and 19% spent 6-7+ hours. 31% faced economic hardship (‘significantly’ 12%, ‘somewhat’ 20%) due to their transfusion dependence. 24% experienced negative side effects consisting of, allergic reactions (32%), fever (16%), circulatory overload (9%), and other (39%). 57% patients reported iron overload. When presented with scenarios, 45% indicated that receiving less frequent transfusions (for example, by receiving 3 units at a time instead of 2) and 74% indicated that having home Hb point of care testing (to facilitate organizing transfusions before symptoms) would improve their QOL. Only 20% felt that receiving more frequent transfusions would improve their QOL, but 40% preferred to be transfused at a higher threshold than currently ordered by their physician. The ideal ‘aspired-to’ Hb thresholds for transfusion by these patients are indicated in figure 1, and 66% indicated a Hb of > 85g/L. Conclusions: It is well known that transfusion dependence has a negative impact on the QOL of MDS patients but this survey revealed that it also presents an economic hardship and significant time commitment. Patient feedback from this survey suggests some approaches that might improve the experience of TD MDS patients. These might include strategies to reduce the time for the transfusion pathway (eg. same day crossmatches) and point of care testing for Hb at home. Studies are needed to address a lack of evidence on optimal or higher Hb thresholds for red cell transfusion in outpatients as no trials have been conducted. 2 clinical trials (RBC-Enhance, NCT 02099669 and REDDS, ISRCTN26088319) are ongoing. More transfusion clinical trials with primary endpoints of patient reported outcomes are needed in MDS. [Display omitted] DisclosuresBuckstein:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Developing an instrument to assess patient preferences for benefits and risks of treating acute myeloid leukemia to promote patient-focused drug development

Objective Acute myeloid leukemia (AML) is a progressive blood cancer with few effective treatment options. As part of a patient-focused drug development (PFDD) initiative led by the Leukemia and Lymphoma Society (LLS), this study sought to use a community-centered approach to develop and pilot an instrument to measure patient preferences for the benefits and risks of treating AML.Methods Instrument development was informed by a literature review, engagement with expert stakeholders (n = 12), engagement with community stakeholders, and pre-testing. A discrete-choice experiment (DCE), in which participants made choices between 16 pairs of hypothetical treatments, was developed with five attributes: event-free survival, complete remission, time in hospital, short-term side-effects, and long-term side-effects. A pilot test was conducted and analyzed using conditional logistic regression. Results are presented using relative attribute importance (RAI) scores.Results Patients with AML and caregivers were engaged in developing (n = 15), pre-testing (n = 13), and pilot testing (n = 26) the instrument. The pilot included patients with AML (n = 18) and caregivers of living or deceased patients with AML (n = 8). Participants had a mean age of 50 years (range =24–81), and were mostly college educated (n = 22), privately insured (n = 21), and employed (n = 13). Based on the DCE, complete remission was identified as the most important attribute (RAI =10), followed by event-free survival (3.7), time in hospital (2.8), long-term side-effects (2.3), and short-term side-effects (2.1).Conclusion The mixed-methods approach to PFDD was welcomed by all stakeholders and there was strong endorsement to implement this DCE as part of a national survey.Key points for decision makersThe Leukemia and Lymphoma Society (LLS) initiated an independent effort to promote patient-focused drug development (PFDD). This study presents the development and piloting of a preference study as a first step in this initiative.Results of this pilot study were used to guide a PFDD meeting to discuss the lived experience of patients and caregivers affected by AML.Productive engagement by all patients, caregivers, and stakeholders throughout the process resulted in strong endorsement of the project’s approach and recognition of the need to conduct a national study.

A Foundation Funding Frontier

A Foundation Funding Frontier

Outcomes of Chronic Phase Chronic Myeloid Leukemia (CP-CML) after Sequential Treatment with Tyrosine Kinase Inhibitors (TKI)

Introduction: A change in TKIs is needed in 30-50% of CP-CML patients due to adverse events or suboptimal response/treatment failure. With 5 TKIs Currently available: imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) we sought to evaluate outcomes of CP CML following sequential TKI treatment. Method: Record of CP-CML referred to our center were reviewed. Patients who did not initiate TKI within 6 months after diagnosis were excluded. Results: Between January 2005 and April 2016, 206 patients with CP CML were identified. Clinical characteristics are summarized in table 1. With a median follow-up of 48.4 (1.4-183.7) months 36.9% received 1 TKI, 35.9% 2 TKIs and 27% received > 3 TKIs. Eighteen patients (8.7%) reused same TKIs in different treatment lines. IM was the most frequently used in 1st line treatment (n=145, 70.4%), DAS in 2nd line treatment (n=68, 52.3%), NIL in 3rd line treatment (n=21, 32.8%), and PON in 4th and 5th line treatment (n=10, 34.5%, and n=4, 40%), respectively. Reason for switching TKIs included resistance (50%), intolerance (43.3%), and others (insurance, clinical trial, or reason are not available, 6.7%). ABL domain mutations were detected in 25 patients (12.1%), of which 9 were T315I. Overall, 19 (9.2%) progressed to advanced phase (AP, n=6; myeloid BC (MBP), n=4; lymphoid BP (LBP), n=9). Eight patients underwent allogeneic HSCT due to TKI failure (n=2), presence of T315I mutation (n=1), irreversible IM-associated neutropenia (n=1), and progression to LBP (n=3) and AP (n=1). One underwent an autologous HSCT due to refractory leukemic meningitis. Ten patients expired because of complication of allogenic HSCT (n=3), refractory disease (n=6) and acute myocardial infarction (n=1). Estimated cumulative PFS at 5- and 10-year were 90% and 80%, and OS at 5- and 10-year were 94% and 90% respectively for the entire group. Curves depicting PFS and OS according to number of TKI exposure, are represented in the figure. OS at 10 years for patients exposed to 1 TKI was 100% (n=76), 2TKI, 95% (n=74), 3TKIs, 85% (n=33), 4 TKIs, 73% (n=16), and 5TKIs, 55% (n=7), respectively (p=0.001). Conclusion: CP CML tolerating and responding to first and second-line TKI had the best survival but survival of patients exposed to up to 5 TKIs was acceptable (10 years OS of 55%), suggesting that sequential use of TKI may be a reasonable approach in CP-CML. Disclosures Heffner: ADC Therapeutics: Research Funding. Arellano: Cephalon Oncology: Research Funding. Kota: Pfizer: Consultancy; Novartis: Consultancy; Xcenda: Consultancy; Incyte: Consultancy; Takeda Pharmaceuticals: Consultancy; Leukemia Lymphoma Society: Research Funding.

Editorial introductions

Current Opinion in Hematology was launched in 1994. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of hematology is divided into nine sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Section Editors for this issue. SECTION EDITORS Hal E. BroxmeyerHal E. BroxmeyerDr Hal E. Broxmeyer is a distinguished Professor, Professor of Microbiology and Immunology, Mary Margaret Walther Professor Emeritus, and Co-Leader Program on Hematopoiesis, Malignant Hematology, and Immunology, Indiana University Simon Cancer Center, and former Chairman of Microbiology and Immunology and Scientific Director, Walther Oncology Center, at the Indiana University School of Medicine, Indianapolis, IN, USA. From 1975 to 1983, he worked at the Memorial Sloan Kettering Cancer Center (MSKCC) in New York City rising from the rank of Associate Researcher to that of Associate Member. He was also Assistant Professor of Biology, Sloan Kettering Division of Cornell University Graduate School of Medical Sciences, New York, USA, before being recruited to the Indiana University School of Medicine in 1983 as an Associate Professor of Medicine. To date, he has published 764 scientific papers (527 refereed papers and 237 Reviews/Book Chapters). Dr Broxmeyer's laboratory studies mechanisms regulating hematopoietic stem and progenitor cell, embryonic stem cell and induced pluripotent stem cell: proliferation, self-renewal, survival, differentiation and migration (homing/mobilization) and he was involved in establishing the field of cord blood transplantation. Dr Broxmeyer has been the recipient of numerous awards since the 1970's. The more recently include Indiana University School of Medicine Alumni Association (2008); State of Indiana General Assembly House Resolution No. 46 (2008); Mission Advancement Award, Leukemia Lymphoma Society (2008); Cord Blood Pioneering Award, Int. Cord Blood Symposium (2008); Till and McCullough Award, Canadian Bone Marrow Transplant Group (2010); Donald Metcalf Award, Int. Soc. Expt. Hematol. (2011); Elected Fellow of the American Association for the Advancement of Science (AAAS) (2013); and Honorary Professorship, Peking Union Medical College, Beijing, China (2014). Dr Broxmeyer is a Past President of the American Society of Hematology (ASH; 2010), past President of the International Society for Experimental Hematology (ISEH, 1990, 1991), past Chairman, and member, Board of Scientific Councilors, National Space Biomedical Research Institute (NSBRI/NASA, 1998–2006), and Chairman Emeritus, Board of Directors, National Disease Research Interchange, Philadelphia, PA, USA. Ari MelnickAri MelnickAri Melnick, MD, is the Gebroe Family Professor of Hematology/Oncology and a Professor of Medicine and Pharmacology at Weill Cornell Medical College (WCMC) in New York City, USA. He is Chair of the Hematologic Malignancies Program of the Weill Cornell Cancer Center and is also Director of the Raymond and Beverly Sackler Center for Biomedical and Physical Sciences and Director of the Epigenomics Core Facility, both of which are at WCMC. Dr Melnick was raised in Argentina and received his medical degree from the University of Buenos Aires, Argentina. He completed a residency in internal medicine and a fellowship in hematology/oncology, as well as a postdoctoral fellowship at the Mount Sinai School of Medicine in New York City, USA. Dr Melnick's research interests include the biology and molecular targeting of B-cell lymphomas, targeting transcriptional and epigenetic repressors for cancer therapy, and identifying the epigenetic basis of hematologic malignancies. He and his research associates have also developed novel therapies to correct aberrant transcriptional regulation and signaling in these tumors. Dr Melnick has been Scientific Chair of the American Society of Hematology (ASH) annual meeting and has organized several meetings in the areas of epigenetics and hematologic malignancies. Dr Melnick is a past ASH Faculty Scholar and Kimmel Foundation Scholar, and he has been recognized for this work by the Leukemia & Lymphoma Society. He is also co-leader of the New York Leukemia Working Group. Dr Melnick has authored or coauthored more than 150 published manuscripts in journals such as Nature, Science, Cell, Cancer Cell, Nature Medicine, Nature Immunology, and the New England Journal of Medicine.

A Prospective Multi-Center Trial Shows Reduction of Early Deaths (ED) and Improved Survival in Elderly Acute Promyelocytic Leukemia (APL) Patients (>60 years). Results of Using a Simplified Treatment Algorithm and Expert Support in Georgia, South Carolina and Neighboring States

Background: APL is the most curable leukemia with reported survival above 90% in many large co-operative group studies. These excellent outcomes are not seen in elderly patients where early deaths in trials are 10-18%. Population based registry data shows that ED rate in elderly APL patients is even higher with reported incidence of 24-50%. We conducted a prospective trial using a set of simplified treatment guidelines along with support from a dedicated team of APL experts. Herein, we report outcomes of patients >60 years treated within the prospective trial. We compared these to our institutional experience prior to implementation of the trial. Methods: The protocol consisted of a two page simplified treatment algorithm with emphasis on preventing bleeding, infection and differentiation syndrome (DS); the most common causes of ED. A network of Leukemia treatment centers was established by visiting most of the leukemia treatment centers in Georgia, South Carolina and neighboring states. Communication was established between the treating community oncologist and APL expert early in the diagnosis and was continued until the end of induction. Five other large leukemia treating centers in Georgia and South Carolina were part of the study and IRB approval was obtained. After 6 months of intense publicity, the study was implemented in 7/2013 and patients were prospectively accrued. Induction deaths of elderly APL patients in our study were compared to historical results at our institution (with IRB approval for retrospective review) prior to the initiation of this program. The study was funded by the Leukemia Lymphoma Society. Statistics are descriptive. Results: Between 1/2007 and 5/2016, we treated or co-managed a total of 70 patients above the age of 60 years. 23 were in the early group (EG) and 47 after 7/2013 in the new group (NG). Comparing the EG and NG patients, median age was 66 years (range 61-80) vs 69 (61-83 years), median WBC was 1.9 vs 2.3/mm3 (range 0.3-132 vs 0.3-38), male to female ratio was 1:2 and 1:1 respectively. Risk stratification based on WBC counts at presentation (> vs Conclusions: By our observation, elderly patients tolerate full doses of ATRA and ATO poorly during induction. ATRA/ATO at reduced doses is better tolerated and use of a simplified treatment algorithm with expert support has the potential to decrease induction mortality (13.3%) and improve population wide survival (77.8%) (1 year survival in patients >60 years based on Swedish Registry data ~ 37%) in elderly APL patients. Disclosures Kota:Leukemia Lymphoma Society: Research Funding; Ariad Pharmaceuticals: Membership on an entity9s Board of Directors or advisory committees; Incyte: Membership on an entity9s Board of Directors or advisory committees; Pfizer: Membership on an entity9s Board of Directors or advisory committees. Heffner:Millennium: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Stuart:Bayer: Research Funding; Celator: Research Funding; Incyte: Research Funding; Agios: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Astellas: Research Funding. Gerber:Spectrum: Membership on an entity9s Board of Directors or advisory committees; Janssen: Research Funding; Alexion: Membership on an entity9s Board of Directors or advisory committees; Seattle Genetics: Membership on an entity9s Board of Directors or advisory committees. Grunwald:Forma Therapeutics: Research Funding; Medtronic: Equity Ownership; Ariad: Membership on an entity9s Board of Directors or advisory committees; Janssen: Research Funding; Alexion: Membership on an entity9s Board of Directors or advisory committees; Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity9s Board of Directors or advisory committees, Research Funding. Jillella:Leukemia Lymphoma Society: Research Funding.

A Multi-Center Prospective Study Utilizing a Simplified Treatment Algorithm Complemented By Expert Support Decreases Induction Mortality and Improves Survival in Acute Promyelocytic Leukemia (APL). Results of the APL Trial in Georgia, South Carolina and Neighboring States

Background: APL is a highly curable malignancy with reported survival above 90% in many co-operative group studies. However these spectacular results are not evident in the general population. US SEER data and other population based studies from Swedish Cancer Registry and Brazil showed that early deaths (ED) can be as high as 30%, leading to a considerably lower survival compared to clinical trials where ED is around 5-10%. Decreasing ED remains a global challenge and the highest priority at all leukemia treatment centers and will result in population wide survival in this most curable leukemia. We report results of our prospective trial using a set of simplified treatment guidelines along with expert support designed to decrease ED.Methods: A network of leukemia treatment centers was established in Georgia, South Carolina and neighboring states. An aggressive outreach effort was made by visiting most of the leukemia treatment centers to publicize the concept and educate treating physicians in the community about ED in APL. The protocol provides a simplified two page treatment algorithm that emphasizes quick diagnosis, prompt initiation of therapy and proactive and aggressive management of the major causes of death during induction. Expert and treating physician communication was established very early when a diagnosis of APL was suspected and was maintained until the completion of induction. Study was approved by local IRBs (if applicable) and funded by the Lymphoma Leukemia Society (LLS). Informed consent was obtained upon confirmation of a diagnosis of APL and there were no exclusion criteria. Patient accrual was initiated in July 2013 and continued till May 2016 when the accrual goal of 120 was met on an intent to treat basis. Statistics are descriptive.Results: Between 7/2013 and 5/2016, 120 patients were enrolled at 5 large leukemia centers (n=54, 45%) and 24 community hospitals (n=66, 55%). Only 3 hospitals treated more than 3 APL patients/year. Median age was 54 years (range 21-84 years). 68 were male. 84% were low risk (WBC < 10,000/mm3) and median WBC count was 4.3 (range 0.3-170,000/mm3). ATRA was initiated at suspicion of APL diagnosis in 100% of patients and was the only treatment in 2(1.5%) patients. Arsenic was combined with ATRA in 93 (81.5%) patients while the other 17% received chemotherapy. 15(13%) had bleeding complications at presentation. Treatment course was complicated by infection and differentiation syndrome (DS) in 31(28%) and 40(34%) patients respectively.There were 12 early deaths, of which 1 was a Jehovah's Witness who declined transfusions and 1 who enrolled 12 days after diagnosis while in multi-organ failure. Incidence of ED was 10/118 (8.5%). The cause of death was disseminated intravascular coagulation (DIC) (n=4), DS (n=2), infection (n=1), anemia (n=1), multi-organ failure (n=4). With a median follow-up of 10.6 months, 2 low risk patients relapsed: I due to non-compliance 1 year after diagnosis and 1 with CNS relapse 3 months after completing consolidation. With a median follow up of 320 days (range 1-965) overall survival (Figure 1) was 87%. There were four late deaths; relapse (n=1), second cancer (n=1) and non-APL related comorbidities (n=2).Conclusions: Results of this prospective trial showed that a simplified treatment algorithm along with support from experts and co-management with treating physicians in the community decreased induction mortality (8.5%) and improved survival (87%) compared to SEER data (1 year relative survival of 71%). We believe our experience warrants large scale implementation and is presently approved as an ECOG/ACRIN trial (EA9131). This model can be applicable to other cancers and life-threatening diseases. [Display omitted] DisclosuresJillella:Leukemia Lymphoma Society: Research Funding. Heffner:AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Millennium: Research Funding. Stuart:Astellas: Research Funding; Celator: Research Funding; Sunesis: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Agios: Research Funding; Bayer: Research Funding; Incyte: Research Funding. Gerber:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding. Grunwald:Medtronic: Equity Ownership; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Amgen: Research Funding; Janssen: Research Funding. Kota:Pfizer: Membership on an entity's Board of Directors or advisory committees; Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees.

Outcomes of Chronic Phase Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitors Dose-Reductions

▪Introduction: Tyrosine kinase inhibitors (TKI) are overall well tolerated in chronic myeloid leukemia (CML) s, but more than 30% require dose reduction or change to another TKIs due to intolerance. Impact of TKI dose-reduction on outcomes in a "real world" setting is unknown, thus, we evaluated the characteristics and outcomes of chronic phase (CP)-CML patients who received doses of TKI lower than the label/FDA recommendation.Method: CP-CML with at least 12 months of follow-up, with ISBCR/ABL1 available after dose reduction were selected. Last TKI was defined as TKI which were taken at the last follow up visit or before disease progression to accelerated (AP) or blast phase (BP). FDA approved doses of imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) were 400mg, 100mg, 600mg (300mg BID), 500mg, and 45mg, respectively .Results: Between January 2005 and April 2016, 173 CP-CML patients, started IM (75%), DAS (18%) NIL (5%) and PON, BOS on clinical trial in 2%. Overall Fifty-eight (33.5%) patients had TKI dose reduction. IM (n=15) dose was reduced to 75% (range, 25-75), DAS (n=15) to 50% (range, 20-80), NIL (n=15) to 50% (range, 13-67), BOS (n=15) to 80% (range, 40-80) and PON (n=15) to 33% (range, 33-67). Median age for patients that received dose-reduced TKI was 55 (range, 18-88), and 27% received > 3 prior TKIs. With a median follow up of 53.6 (range 13.4-183.7) months, only 1 progressed to AP, and none to BP. Overall 60% achieved MMR. Among 35 patients who achieved MMR before dose reduction, MMR was maintained in 25 (71.4%) for a median of 17.2 (2-97.9) months from dose-reduction. CMR was achieved in patients on a maintenance dose of IM, 100mg QD (n=8); DAS, 20mg QD (n=4); NIL 300mg QD (n=3) and BOS, 200mg QD (n=3).Conclusion: Similar to data reported from clinical trials, TKI dose reduction appears to be safe and associated with high response rates. This data confirms that the minimal effective dose for each TKI remains to be defined. DisclosuresHeffner:Pharmacyclics: Research Funding; AbbVie: Research Funding; Millennium: Research Funding; Celgene: Research Funding. Jillella:Leukemia Lymphoma Society: Research Funding. Kota:Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.