ALBERT

Description: Introduction Essential thrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF) share the JAK2V617F mutation, but differ with regard to clinical phenotype, rate of disease progression, and risk of leukemic transformation. Variation in the JAK2V617F neutrophil allele burden does not account for these observed differences in clinical behavior. We therefore investigated JAK2V617Fallele burden and genotype in the stem/progenitor populations of MPN patients in chronic and leukemic phases. Methods We studied 39 JAK2V617Fpositive MPN patients evaluated between 2005 and 2013, including 8 patients at leukemic transformation. CD34+ cells isolated from peripheral blood were flow sorted based on CD34, CD38, and the stem cell marker aldehyde dehydrogenase (ALDH). JAK2V617F allele percentages were calculated using an allele specific real time PCR assay. Cells were sorted into 96 well plates and single cell JAK2V617Fgenotypes were obtained using a nested PCR assay. Additional genomic lesions and chromosomal copy number variation were investigated in the sorted fractions when applicable. Results In all MPN cases, the JAK2V617F mutation was detected in the CD34+CD38-ALDHhigh fraction – the same population in which the normal hematopoietic stem cell resides. Quantitative JAK2V617F allele burdens in this fraction were highest in MF 〉 PV 〉 ET. Single cell JAK2V617F genotyping revealed a higher proportion of JAK2V617F-/- cells in ET and PV than in MF, but JAK2V617F-/- cells were detectable in the CD34+CD38-ALDHhigh fraction of all cases. In most cases of PV and MF, this fraction contained a mixture of JAK2V617F-/-, JAK2V617F-/+, and JAK2V617F+/+ cells. Additional chronic phase lesions (including mutations of ASXL1 & TET2) were also found in the CD34+CD38-ALDHhighfraction. Two patterns of leukemic transformation were observed. The first pattern (in 7/8 patients) was identical to that of de novo AML (Gerber JM, Blood 2012), with emergence of a unique CD34+CD38-ALDHint fraction, which was clonal by JAK2V617F genotype and contained leukemia-specific lesions (e.g., 5q deletion). In contrast, the residual CD34+CD38-ALDHhigh population lacked the leukemic abnormalities and was oligoclonal with respect to JAK2V617F. In 3 of these AML cases, the CD34+CD38-ALDHint fraction was JAK2V617F-/-, while the JAK2V617F mutation remained detectable in the CD34+CD38-ALDHhigh fraction. Single cell genotyping performed during the leukemic phase of a PV patient revealed only JAK2V617F-/- CD34+CD38-ALDHint cells but identified JAK2V617F-/-, JAK2V617F-/+, and JAK2V617F+/+ CD34+CD38-ALDHhigh cells; JAK2V617F levels were barely detectable in the progenitors and neutrophils during this leukemic phase. Upon achievement of complete remission from AML, high JAK2V617F allele burdens were then found in the progenitors and neutrophils, as well as in the CD34+CD38-ALDHhigh fraction. A second pattern of leukemic transformation was seen in one patient, in whom no CD34+CD38-ALDHint population was present. The CD34+CD38-ALDHhigh population was expanded in this case and harbored JAK2V617F+/+ positive cells with the leukemia-specific lesion. Conclusions Unlike CML, in which the BCR/ABL oncogene is typically present in the majority of CD34+CD38-ALDHhigh cells at diagnosis (Gerber JM, Am J Hematol 2011), the JAK2V617F mutation was present in only a minority of CD34+CD38-ALDHhigh cells in JAK2V617F positive ET and PV. Moreover JAK2V617F-/- cells were detected even in longstanding, advanced phase PV and MF. Lower JAK2V617F clonal burdens in the primitive CD34+CD38-ALDHhigh compartment as compared to neutrophils in most cases of MPN suggest that the JAK2V617F mutation does not confer a significant advantage at the stem cell level and that other genetic lesions may drive expansion of this population. JAK2V617F negative leukemias occur in about 35% of PV patients, apparently arising from the residual JAK2V617F negative CD34+CD38-ALDHhigh reservoir. We conclude that primitive stem/progenitor cells are mosaic with regard to JAK2V617F mutation status in the majority of MPN patients. Furthermore, acquisition of JAK2V617F, development of JAK2V617F homozygosity, and accrual of other acquired lesions in chronic phase MPN all occur in the primitive CD34+CD38-ALDHhigh compartment. Lesions specific to post MPN AML segregate to a distinct CD34+CD38-ALDHint population. Disclosures: Jones: Cytomedix: Patent holder for Aldefluor reagent, which is licensed by Cytomedix. This relationship is managed by the Johns Hopkins Office of Policy Coordination., Patent holder for Aldefluor reagent, which is licensed by Cytomedix. This relationship is managed by the Johns Hopkins Office of Policy Coordination. Patents & Royalties.

Description: Background: Financial Toxicity (FT) is increasingly recognized as a major contributor to morbidity and mortality in a variety of cancers. Treatment of acute leukemia is associated with heavy healthcare utilization and high costs. The purpose of this study was to define rates, risk factors, and mortality implications for FT in patients with acute leukemia using patient reported data. Methods: All patients seen at the Levine Cancer Institute, a tertiary hospital-based leukemia practice, were surveyed prior to each visit over a six-month period. All patients were aged ≥18 years and were diagnosed with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL). 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." Demographic data and disease characteristics were abstracted from the medical record. Model selection was carried out using logistic regression to identify factors impacting the incidence of financial toxicity. Correlation of numerical financial toxicity scores with PROMIS scores and with mortality data was assessed using linear regression. Results: Of the 106 patients, 58 (54%) met the definition of exhibiting FT. The factors associated with incidence of FT included: age, race, and insurance type. The odds of FT in those patients 4 compared to patients with FT scores

Description: Introduction: Essential thrombocytosis (ET), polycythemia vera (PV), and myelofibrosis (MF; post ETMF, post PVMF and primary MF) share the JAK2V617F mutation, but differ with regard to clinical phenotype, rate of disease progression, and risk of transformation. Variation in the JAK2V617F neutrophil allele burden does not account for these observed differences in clinical behavior or natural history. We therefore investigated the JAK2V617F burden and JAK2 genotype composition in the hematopoietic stem cell (HSC) population of MPN patients. Methods: We studied 47 JAK2V617F-positive MPN patients during 51 distinct disease phases. Circulating CD34+ cells were flow-sorted based on the stem cell markers CD34, CD38 and aldehyde dehydrogenase (ALDH). CD34+ CD38- ALDH+ HSC were sorted into 96 well plates and single cell JAK2 genotypes (average 40 single cells genotyped/patient with 〉1000 total single cells genotyped) were obtained using a nested PCR assay. Additional genomic lesions and chromosomal copy number variation were investigated in the sorted, single cell fractions in informative patients by FISH or multiplex single cell PCR. Distribution of JAK2V617F stem cell genotypes were correlated with disease phenotype, neutrophil JAK2V617F allele burden, splenomegaly, white cell count, chemotherapy requirement and disease evolution. Results: In all MPN cases, regardless of disease class, the JAK2V617F mutation was detected in the CD34+ CD38- ALDH+ fraction - the same population in which normal HSC reside. All ET and MF patients, and the majority of PV patients, had three JAK2 genotypes coexisting in their respective HSC populations. ET was characterized by a high percentage of JAK2WT stem cells (〉75%) despite the concomitant presence of JAK2V617F homozygous clones and disease durations 〉15 years. Importantly, in the ET patients where JAK2WT clones fell to less than 50%, a PV phase followed. MF was characterized by a relatively low percentage of JAK2WT stem cells (median 24%), regardless of disease duration. PV had the most variable JAK2 genotypes with a wide range of JAK2WT stem cells (4%-92%) and a wide range of JAK2V617F homozygous stem cells (2-100%), and in 5/16 PV cases, only JAK2WT and JAK2V617F homozygous stem cells were identified. PV patients with JAK2V617F homozygous clones comprising more than 50% of their stem cells, regardless of disease duration, had higher white cell counts, higher neutrophil allele burdens, larger spleens and higher prevalence of chemotherapy compared to PV patients who had less than 50% JAK2V617F homozygous HSCs. The percentage of JAK2V617F homozygous HSC did not correlate with disease duration: some PV patients with a disease duration of 〉18 years had less than 10 % JAK2V617F homozygous HSC. A JAK2V617F - positive PV patient with a high JAK2V617F HSC burden and a high neutrophil JAK2V617F burden transformed to a JAK2V617F-negative chronic myelomonocytic leukemia (CMMoL); at the time of HSC analysis, the neutrophil JAK2V617F allele burden was 0% (previously 90%) and the HSC JAK2V617F homozygous percentage fell to 3% (previously 60%). While this patient's CMMoL was molecularly undefined, lesions identified in other JAK2V617F-positive patients (including mutations of ASXL1, TET2, deletion of 5q, 7q and 11q, trisomy 8 and 9), were also found in the CD34+ CD38- ALDH+ HSCs using single cell techniques, sometime coexistent with JAK2V617F-positive HSC, and sometimes in JAK2WT HSC. Conclusion: Driver and progression lesions in the JAK2V617F-positive MPN are acquired at the primitive HSC level. Despite decades of disease, the HSC pool in the MPN is mosaic for acquired lesions and also retains JAK2WT clones. Dominance of a particular JAK2 genotype at the primitive HSC level is variable, and distinguishes ET, where JAK2WT stem cells outnumber JAK2V617F-positive HSC, from MF, where JAK2WT HSC are the minority. PV is the most variable of the three MPN with regard to JAK2 genotype mosaicism. The allelic burden of HSC JAK2V617F in PV correlates with clinical disease burden. However, neither time nor JAK2V617F genotype determines the HSC burden in ET and PV, indicating that an undefined factor is a modifier of this important disease-defining process. Understanding the biology of HSC JAK2V617F homozygous clonal dominance may define an exploitable target to control disease burden, and to mitigate disease progression and evolution. Disclosures Moliterno: incyte: Membership on an entity's Board of Directors or advisory committees. Spivak:Incyte: Membership on an entity's Board of Directors or advisory committees.

Description: Recently, somatic mutations in the granulocyte colony-stimulating factor receptor (CSF3R) have been identified in the majority of patients with chronic neutrophilic leukemia (CNL). The T618I mutation is the most common of these mutations, and it has been suggested that this specific mutation be added to the current WHO criteria for the diagnosis of CNL. In vitro studies of cells transfected with the T618I mutation have demonstrated that the mutant receptor confers a hyperproliferative phenotype. We report here a case of congenital neutrophlia with an associated germline T618I CSF3R mutation. The patient, currently a 10 year old female, has had an elevated but stable leukocytosis (WBC 24,000 - 35,000) since birth, comprised of approximately 80% neutrophils. She has been healthy, with no increase in frequency of infections. Bone marrow studies performed at 5 months and 10 years of age have shown the marrow to be hypercellular, with normal karyotype/FISH (including BCR/ABL negative) and no dysplastic features. Additionally, no mutations have been detected in JAK2, MPL, CALR, PDGFA/B, and FGFR1. DNA was extracted from whole blood and buccal cells collected from the patient, and using next generation sequencing a T618I mutation in CSF3R was identified in both her buccal and blood cells, confirmed by Sanger sequencing. The T618I mutation was present at an approximately 50% allele frequency in both tissues. Using a combination of next generation and Sanger sequencing, the patient's DNA was also analyzed for the presence of mutations in ASXL1, SETBP1, and TET2; as these have been reported in combination with the T618I mutation in many cases of CNL. However, no such additional mutations were detected in our patient. Congenital neutrophilia arising from another activating mutation in CSF3R has previously been reported in a family from France (Plo et al., J Exp Med 2009). The mutation identified in that family was reported to be at amino acid position 617 (T617N) (numbering from the methionine 1, which includes the leader sequence, this correlates to a T640N mutation). Similar to the T618I mutation in our patient, none of the 12 affected family members (ages 8-80 years) progressed to an acute leukemia. Collectively, these observations suggest that activating CSF3R mutations, including the T618I mutation, may result in chronic neutrophilic leukemia but that subsequent disease progression may be due to other, cooperating mutations. Disclosures No relevant conflicts of interest to declare.

Description: 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.

Description: Abstract 240 Relapse of acute myeloid leukemia (AML) is hypothesized to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs) - the rare, resistant cells presumed responsible for maintenance of the leukemia. These cells have generally been reported to have a similar phenotype to normal hematopoietic stem cells (HSCs). However, despite the considerable research on LSCs over the past two decades, the clinical significance of these cells remains uncertain. We hypothesized that any minimal residual disease (MRD) present after therapy would be enriched for LSCs and that such persistence of LSCs would predict relapse. CD34+ cell populations from 27 AML patients and 10 normal donors were analyzed by flow cytometry for CD38 expression and for aldehyde dehydrogenase (ALDH) activity by Aldefluor. A total of 16 AML patients who achieved morphologic complete remission (CR) after induction chemotherapy were followed throughout their treatment course, and the flow cytometric staining patterns of their CD34+ cells at follow-up intervals were correlated with clinical outcomes. Cell subpopulations were sorted and then analyzed by fluorescence in situ hybridization (FISH) for leukemia-specific cytogenetic abnormalities (when applicable) and by transplantation into NOD/SCID-IL2Rgnull (NSG) mice to determine their in vivo self-renewal capacity. Normal bone marrow CD34+CD38− cells consistently exhibited two, discrete subpopulations by ALDH activity: one with low ALDH activity levels (CD34+CD38−ALDHlow) and another with high levels (CD34+CD38−ALDHhigh). As few as 1000 CD34+CD38−ALDHhigh cells generated normal hematopoiesis after transplantation into NSG mice. An additional population of CD34+CD38− cells with intermediate (int) levels of ALDH activity was found in the AML patients, but not in any of the normal donors studied. When present, even in patients in cytogenetic CR, this CD34+CD38−ALDHint population was at least 89% leukemic by FISH; and 1000 of these cells generated AML when transplanted into NSG mice. The CD34+CD38−ALDHhigh cells were invariably present in small numbers in newly-diagnosed AML patients. These cells did not harbor the AML-specific FISH abnormality, and 1000 generated normal hematopoiesis when transplanted into NSG mice, consistent with a residual population of normal HSCs. In those AML patients who achieved CR, any detectable MRD was enriched for the CD34+CD38−ALDHint leukemic cells. This population comprised 34% (range 9–51%) of the total leukemic burden when detectable in patients in cytogenetic CR, as compared to just 3% (range 0.5–4%) at initial diagnosis (p=0.02). Six of the seven CR patients with a detectable CD34+CD38−ALDHint population ultimately relapsed; the lone exception underwent allogeneic transplantation in first CR. Conversely, all nine of the patients with a consistently undetectable CD34+CD38−ALDHint population have remained in CR (p

Description: 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 compared to patients with FT scores 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.

Description: Background: The hypomethylating agents (HMAs) azacitidine and decitabine have been increasingly used in the frontline setting for elderly and/or unfit patients with acute myeloid leukemia (AML). While these therapies are oftentimes used in the palliative setting, HMAs have also been used with curative intent in some patients, as a bridge to allogeneic hematopoietic cell transplantation (HCT). It is well known that 4-6 cycles of HMA therapy can be necessary to achieve a response; however, it is still common in practice for treating physicians to stop HMAs earlier when a rapid response is not observed. Few studies have investigated time to response in the setting of frontline HMA treatment for AML. Methods: We retrospectively evaluated all patients who were initiated on frontline HMAs for AML at our institution from September 2013 to April 2018. HMAs were administered without dose reduction or treatment delays. Responses were evaluated and categorized as hematologic response (HR; defined by neutrophils 〉 1000/µL, platelets 〉 100k/µL, transfusion independence, and no peripheral blasts), complete remission (CR), CR with incomplete platelet recovery (CRp), CR with incomplete hematologic recovery (CRi), and no response. Patient, cytogenetic, and treatment characteristics were summarized and described. We evaluated patients exhibiting a response before receiving 4 cycles of HMA therapy ("early" responders) and compared these patients to those achieving a response after receiving at least 4 cycles of HMA ("late" responders). The Kaplan-Meier method estimated overall survival (OS). Odds of early response were estimated with logistic regression models. Results: During the study period, 137 patients received frontline HMAs. 122 (89.1%) patients received azacitidine, and 15 (10.9%) were treated with decitabine. Mean age at HMA start was 70.1 years (range 39.8-94.3). Most patients (62.8%) were male, and most (77.4%) were Caucasian. 21 (15.3%) patients were NCCN favorable-risk, 52 (38.0%) were intermediate-risk, and 64 (46.7%) were poor-risk. At first testing, 21.4% of the patients were positive for the FLT3/ITD mutation, 0.8% the FLT3/TKD mutation, and 21.4% the NPM1 mutation. Some patients received concomitant therapies along with the HMA; these included hydroxyurea, lenalidomide, and sorafenib. Median survival in the entire population was 11.6 (95% CI 8.3, 15.2) months. Overall response rate (ORR) was 60.6%. Among responders, 80.7% achieved HR as their first response; 19.3% were first noted to have marrow responses (1.2% CR, 4.8% CRp, and 13.3% CRi). Most patients did not undergo bone marrow evaluation to assess response. Among responding patients, 60.2% responded "early", whereas 39.8% responded "late". Median overall survival was 15.2 (9.3, 17.7) months in early responders, and 22.2 (11.7, 38.9) months in late responders. There was no difference in survival between the groups (p=0.108, log-rank test; Figure 1), although there was a trend toward improved survival in late responders. Nineteen patients underwent allogeneic HCT. Time to response was not associated with odds of receiving HCT (p=0.812). Conclusions: HMAs have a high ORR as frontline therapy in elderly and unfit AML patients. Among AML patients receiving frontline HMAs, later responders have equivalent survival to earlier responders. Physicians should consider exercising patience when treating AML patients with HMAs. These findings warrant validation in a larger, prospective study. Figure. Figure. Disclosures Avalos: Juno: Membership on an entity's Board of Directors or advisory committees. Grunwald:Alexion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Research Funding; Incyte Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forma Therapeutics: Research Funding; Janssen: Research Funding; Cardinal Health: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medtronic: Equity Ownership.

Description: Relapse of acute myeloid leukemia (AML) is thought to reflect the failure of current therapies to adequately target leukemia stem cells (LSCs), the rare, resistant cells presumed responsible for maintenance of the leukemia and typically enriched in the CD34+CD38− cell population. Despite the considerable research on LSCs over the past 2 decades, the clinical significance of these cells remains uncertain. However, if clinically relevant, it is expected that LSCs would be enriched in minimal residual disease and predictive of relapse. CD34+ subpopulations from AML patients were analyzed by flow cytometry throughout treatment. Sorted cell populations were analyzed by fluorescence in situ hybridization for leukemia-specific cytogenetic abnormalities (when present) and by transplantation into immunodeficient mice to determine self-renewal capacity. Intermediate (int) levels of aldehyde dehydrogenase (ALDH) activity reliably distinguished leukemic CD34+CD38− cells capable of engrafting immunodeficient mice from residual normal hematopoietic stem cells that exhibited relatively higher ALDH activity. Minimal residual disease detected during complete remission was enriched for the CD34+CD38−ALDHint leukemic cells, and the presence of these cells after therapy highly correlated with subsequent clinical relapse. ALDH activity appears to distinguish normal from leukemic CD34+CD38− cells and identifies those AML cells associated with relapse.

Description: 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.