Abstract: 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. Figure Overall Survival Figure. Overall Survival Disclosures Jillella: 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.

Abstract: Acute promyelocytic leukemia (APL) is a curable leukemia with 〉 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths. METHODS: In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place. RESULTS: Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% 〉 60 years and 25% with an age-adjusted Charlson comorbidity index 〉 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%. CONCLUSION: Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.

Abstract: Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Previous research has demonstrated patients with myeloproliferative neoplasms (MPNs) exhibit a substantial comorbidity burden and have an increased risk of mortality. The purpose of this study was to define rates of FT and the implications on morbidity and mortality in this population using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based specialty practice, were surveyed prior to their visit over a six-month period. All patients were aged ≥18 years and diagnosed with Philadelphia chromosome−negative classical MPNs including myelofibrosis (MF), polycythemia vera (PV), and essential thrombocythemia (ET). The survey consisted of the PROMIS Global-10 measure and two questions from the COST measure. FT was defined as scoring 4 or less (maximum: 10) in agreement with the COST questions: "I know that I have enough money in savings, retirement, or assets to cover the costs of my treatment" and "I am satisfied with my current financial situation." Patient disease and treatment characteristics were summarized with frequencies and proportions for categorical variables and medians and ranges for continuous variables. Correlation of numerical FT scores with PROMIS scores was assessed with Pearson correlation coefficients and ANOVA regression. Additionally, model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity (where FT score 〈 =4). Kaplan Meier methods were used to estimate overall survival distributions and log rank tests were used to compare between groups. Results: A total of 51 patients were surveyed. Disease type consisted of 45.1% MF, 31.4% PV, and 23.5% ET. Median age was 62 years. Most patients were high risk by disease specific scoring systems (58.8%), Caucasian (82.4%), and had commercial insurance (56.9%). Median distance from the clinic was 21 miles and median time from diagnosis was 2.2 years. Of the 51 patients surveyed, 20 (39.2%) met the predefined definition of exhibiting severe FT. Lower FT scores (indicating a higher degree of FT) were associated with lower global physical (p 〈 .001) and mental (p 〈 .002) scores by the PROMIS measures (Figure 1). There was no statistically significant difference in survival between patients with FT scores 〉 4 compared to patients with FT scores 〈 =4; however, there was a trend toward decreased survival in those with lower FT scores. The rate of mortality in those with FT score ≤4 was 15.0% compared to 3.2% in those with FT score 〉 4 (p =.287). There also appeared to be a separation of the survival curves when looking at both time from diagnosis and time from survey administration (Figures 2 and 3). Age, race, gender, insurance type, distance from the hospital, disease type, disease specific risk classification, medications utilized, and history of blood/marrow transplant were not found to be significantly different in the two groups. Conclusions: Patients with myeloproliferative neoplasms represent an extremely vulnerable population for financial toxicity with quantifiably increased distress related to this toxicity increasing morbidity and potentially mortality. These findings should be validated in a larger patient cohort and interventions devised to reduce financial distress. Disclosures Knight: Foundation for Financial Planning: Research Funding. Ai:InCyte: Speakers Bureau; Amgen: Speakers Bureau. Trivedi:Incyte: Speakers Bureau. Avalos:Best Practice-Br Med J: Patents & Royalties: receives royalties from a coauthored article on evaluation of neutropenia; Juno: Membership on an entity's Board of Directors or advisory committees. Symanowski:Boston Biomedical: Membership on an entity's Board of Directors or advisory committees; Carsgen Therapeutics: Membership on an entity's Board of Directors or advisory committees; Eli Lilly: Membership on an entity's Board of Directors or advisory committees; Immatics: Membership on an entity's Board of Directors or advisory committees. Grunwald:Amgen: Consultancy; Novartis: Research Funding; Genentech/Roche: Research Funding; Pfizer: Consultancy; Daiichi Sankyo: Consultancy; Trovagene: Consultancy; Agios: Consultancy; Incyte: Consultancy, Research Funding; Cardinal Health: Consultancy; Forma Therapeutics: Research Funding; Abbvie: Consultancy; Celgene: Consultancy; Merck: Consultancy; Medtronic: Equity Ownership; Janssen: Research Funding.

Abstract: Introduction Access to appropriate healthcare close to home is a national and global problem with huge geographic variation in availability of subspecialized care and specific therapies, as illustrated by hematopoietic cell transplantation rates [Gratwohl, et al. Lancet Hematol, 2015]. Disease-specific physician specialization appears to improve outcomes in hematologic malignancies [Go, et al. Mayo Clin Proc, 2015] . Charlotte is the 2nd largest city in the Southeastern United States and 17th largest in the US, yet subspecialized care in hematologic malignancies including a leukemia unit and hematopoietic cell transplantation (HCT) program were non-existent 3 years ago. The closest HCT program was a 90-minute drive from Charlotte. Many patients lacked the resources or willingness to travel to a transplant center and died of potentially curable diseases. Establishment of a transplantation program, in particular, requires a substantial upfront investment, broad infrastructure and highly specialized interdisciplinary care. Better transplant outcomes have been associated with higher numbers of procedures [Loberiza, et al. Blood, 2005], but programs established over the last decade have struggled to attract adequate numbers of patients to support the required investment. Methods In 2011 Carolinas HealthCare System (CHS), which serves as a healthcare safety net for the region, decided to develop the Levine Cancer Institute as a primary through quaternary referral and treatment center, integrated through more than 12 sites, with a key focus being a program in HCT. The Department of Hematologic Malignancies and Blood Disorders was established in September 2012. We envisioned that the development of specialized care in leukemia, lymphoma, and plasma cell disorders, as well as more complex non-malignant hematologic disorders, would improve the quality of care for patients with those diseases, attract larger volumes of patients, and serve to identify patients appropriate for HCT in a timely manner. A 16 bed hematologic malignancies unit housed in a protected environment was constructed and completed in January 2014. Results Starting with 4 general hematologists, the department has grown over 4 years to include 23 faculty members, 14 of whom provide subspecialized care in hematologic malignancies and HCT. Patient volumes have grown more than six-fold during this time. The HCT Program performed its first transplant in March 2014, with a total of 60 transplants performed in 2014 and 81 in 2015. The HCT Program is on pace to perform over 100 transplants in 2016. The program received FACT accreditation in 2016, a little more than 2 years after the first HCT was performed. The age range of patients undergoing transplantation is from 22 to 76 (median 58) years. Sixty-nine percent of transplants have been autologous and 31% allogeneic, of which 65% were from haploidentical related donors. The proportion of transplants which are allogeneic is steadily increasing. More than 90% of patients who have undergone transplantation were referred through a disease-specific section. Non-relapse mortality (NRM) at 1 year is 1.8% for autologous transplants and 9.4% for allogeneic transplants, with survival rates at 1 year of 95.6% and 80.8% respectively. Notably, there is no difference in NRM (P=0.86), relapse-free survival (P=0.85), or overall survival (P=0.47) between HLA-identical and haploidentical transplant recipients. Conclusions Three years ago, for patients in Charlotte, access to subspecialized care in hematologic malignancies and HCT required significant travel. The development and growth of a program that provides disease-specific care in hematologic malignancies has overcome this barrier and has provided a base for growth of a newly established program in HCT. These developments have elevated the quality of care in hematologic malignancies in the Charlotte area and permit patients to receive appropriate and complex care close to home. Disclosures Gerber: Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Usmani:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pharmacyclics: Research Funding; Novartis: Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Array: Research Funding; Amgen: Consultancy, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Britsol-Myers Squibb: Consultancy, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Grunwald:Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Medtronic: Equity Ownership; Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees. Ghosh:Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; SGN: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Gilead: Honoraria, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Genentech: Research Funding; TG Therapeutics: Research Funding. Bhutani:Prothena: Research Funding; Takeda Oncology: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Onyx, an Amgen subsidiary: Speakers Bureau. Symanowski:Endocyte: Consultancy; Eli Lilly & Co: Consultancy; Ra Pharma: Consultancy; Caris Life Sciences: Consultancy. Raghavan:Gerson Lehrman: Consultancy; Caris Life Sciences: Membership on an entity's Board of Directors or advisory committees. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

Abstract: Response to hypomethylating agents (HMAs) in patients (pts) with acute myeloid leukemia (AML) is variable. Data on biological predictors of response is limited. Cytidine deaminase (CDA) inactivates HMAs. Increased CDA activity may lead to HMA resistance. Using core pathway analysis, we identified nucleophosmin 1 (NPM1) indirectly influences CDA expression. We hypothesized that responses to HMAs occur in the setting of decreased CDA expression regulated by NPM1 and investigated the relationship between NPM1 status, CDA expression, single nucleotide polymorphisms (SNPs) in CDA, and HMA response in pts with AML. AML pts with banked samples who received HMA-based therapy between 1/2014 to 12/2018 were reviewed. Responses following at least 2 cycles of HMA were categorized as responders (R) or non-responders (NR). Pt, disease, NPM1 status, and treatment characteristics were summarized. CDA gene and protein expression was examined in bone marrow and peripheral blood samples at diagnosis using qRT-PCR and CDA sandwich ELISA, respectively. CDA gene expression levels were normalized to the housekeeping gene, 18s, and the comparative CT method was used to assess expression. Comparisons based on response and NPM1 mutation status were performed using the Mann-Whitney U test. 17 SNPs previously shown to alter CDA activity were selected for analysis. SNPs were determined using real-time PCR with allele specific probes; longer insertions/deletions were identified by sanger sequencing. Univariate logistic regression analysis was performed to discern the association between SNPs in CDA and response to HMAs. 54 pts had available blood, marrow, or buccal samples available for analysis. 33 pts provided blood or marrow samples for gene and protein analysis prior to HMA. 22 pts (67%) were classified as R in this cohort. 35 pts had available buccal swabs for genotyping, and 28 pts (80%) were classified as R. Median OS was 21 months (mo) for all pts, 23 mo among R, and 18 mo in NR. CDA expression was significantly decreased in NPM1 wild type pts compared to NPM1 mutant pts (p=0.02) but did not differ in R compared to NR. No significant differences were identified in CDA protein expression based on NPM1 status or response. No SNPs were significantly associated with response. Baseline CDA gene expression in bulk tumor cells was significantly lower in NPM1 wild type pts compared to NPM1 mutant pts but no different between pts responding to HMAs compared to NR. There was no clear correlation between CDA protein expression and NPM1 status or response. None of the CDA SNPs were predictive of response to HMAs. This analysis reveals feasibility of assessing CDA activity in this population. Our small sample size limits our ability to determine CDA activity as a biological predictor of response, and ongoing pt accrual will allow for further exploration of the role of CDA in HMA response. Citation Format: Brittany Knick Ragon, Issam S. Hamadeh, C Greer Vestal, Alicia Hamilton, Mathew L. Smith, Danielle Boselli, Jing Ai, Thomas G. Knight, Michael R. Grunwald, Jonathan M. Gerber, Edward A. Copelan, Lawrence J. Druhan, Belinda R. Avalos, Nury M. Steuerwald, Jai N. Patel. Response to hypomethylating agents based on cytidine deaminase expression, genetic polymorphisms, and NPM1 mutation status in acute myeloid leukemia [abstract] . In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1920.

Abstract: Introduction: Recent evidence supports the clinical significance of leukemia stem cells (LSCs) in acute myeloid leukemia (AML). However, the identification of LSCs in acute lymphocytic leukemia (ALL) has proved challenging, as transplantation studies in immunocompromised mice have yielded conflicting results. The distinction between Philadelphia chromosome-positive (Ph+) ALL and lymphoid blast crisis (LBC) chronic myeloid leukemia (CML) is also controversial. We previously identified a clinically relevant CD34+CD38- population of LSCs with intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity (CD34+CD38-ALDHint) in AML [Gerber, et al. Blood, 2012]. This population was not present in healthy controls and could be distinguished from normal hematopoietic stem cells (HSCs), which had higher levels of ALDH activity (CD34+CD38-ALDHhigh). We hypothesized that the same approach could be used to identify a putative LSC population in ALL. Furthermore, in contrast to most cases of AML, the chronic phase CML stem cell was found to reside in the same CD34+CD38-ALDHhigh population as normal HSCs [Gerber, et al. Am J Hematol, 2011] . We therefore also hypothesized that the presence of BCR/ABL mutations in the CD34+CD38-ALDHhigh population might help distinguish LBC CML from Ph+ ALL. Methods: Bone marrow and/or peripheral blood specimens were collected at diagnosis from patients with B cell ALL or LBC CML on an IRB-approved protocol. A total of 7 patients were evaluated: 2 Ph- ALL, 2 Ph+ ALL, and 3 LBC CML patients. CD34+ cells were isolated by magnetic bead and column selection, then analyzed by flow cytometry with respect to CD38 expression and ALDH activity. Sorted cell populations were analyzed by fluorescence in situ hybridization (FISH) for leukemia-specific abnormalities. Polymerase chain reaction was performed on clinical samples to determine the presence of a p190 vs. p210 transcript. Results: All patients harbored an aberrant CD34+CD38-ALDHint population, similar to that previously seen in AML. This population was ≥95% positive for BCR/ABL by FISH in all Ph+ ALL and LBC CML cases. It was similarly positive (≥75%) for other leukemia-specific FISH abnormalities (including trisomy 4, 8, 10, 12, and/or 21) in all four ALL cases, as well as one LBC CML case. Conversely, the CD34+CD38-ALDHhigh population (which typically contains the normal HSCs) lacked any of the other cytogenetic abnormalities in all of the cases, irrespective of Ph status or a diagnosis of ALL vs. CML. Notably, the CD34+CD38-ALDHhigh population was negative for BCR/ABL in the Ph+ ALL cases but was 〉 95% positive for BCR/ABL by FISH in the LBC CML cases. The B cell differentiation marker, CD19, was expressed on the CD34+CD38-ALDHint but not the CD34+CD38-ALDHhigh population in all ALL cases, both Ph- and Ph+. In contrast, CD19 expression was variable in the LBC CML cases. Both Ph+ ALL cases possessed a p190 BCR/ABL transcript, whereas all of the LBC CML cases contained a p210 transcript. Also of note, the CD34+CD38-ALDHint population was persistently detectable in one of the LBC CML patients while in complete remission after induction therapy; that patient subsequently relapsed. Conclusions: An abnormal CD34+CD38-ALDHint population was identified in all cases of B cell ALL and LBC CML. This population is analogous to a previously identified, clinically relevant LSC population in AML and may represent a putative LSC population in ALL. The CD34+CD38-ALDHhigh population was normal by FISH in the ALL cases but contained the BCR/ABL mutation in the LBC CML cases, thus permitting distinction between Ph+ ALL and LBC CML (which also differed based on the presence of p190 vs. p210 transcripts, respectively). Additionally, clonal evolution from chronic phase to lymphoid blast crisis CML was apparent, based on the acquisition of additional cytogenetic abnormalities unique to the CD34+CD38-ALDHint population as compared to the CD34+CD38-ALDHhigh population. The presence of CD19 on the putative LSCs in the four cases of ALL suggest that CD19-directed therapies may target the LSCs and thus may have curative potential in those cases. This assay may serve as a means to evaluate other possible therapeutic targets. Lastly, the detection of the abnormal CD34+CD38-ALDHint population may have utility as a minimal residual disease assay for monitoring response to treatment. These findings warrant validation in a larger patient cohort. Disclosures Gerber: Janssen: Research Funding; Alexion: Membership on an entity's Board of Directors or advisory committees; Spectrum: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees. Grunwald:Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medtronic: Equity Ownership; Janssen: Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding. Avalos:Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.