ALBERT

Description: Introduction Core-binding factor (CBF) acute myeloid leukemias (AML) are characterized by the chromosomal abnormalities t(8;21) or inv(16)/t(16;16) and their fusion proteins RUNX1/RUNX1T1 and CBFB-MYH11, respectively. Despite their relatively favorable prognosis, it has been reported that up to 45% of patients with CBF-AML relapse. Current guidelines recommend monitoring the peripheral blood (PB) or bone marrow (BM) for molecular evidence of residual disease (RD) every 3 months for 2 years following remission. By monitoring patients for rising molecular transcripts, those at risk of impending relapse can be identified and treated prior to the emergence of overt disease. However, the relapse kinetics of CBF-AML are poorly-understood, and it is unknown if serial RD monitoring can detect molecular relapses with sufficient lead-time to intervene and prevent morphologic relapse. Methods After local REB approval, we identified patients with CBF-AML treated at the Princess Margaret Cancer Centre in Toronto, Canada between 2000 and 2017. Patients underwent induction and consolidation chemotherapy according to standard protocols followed by RD monitoring with polymerase chain reaction (qPCR) of RUNX1/RUNX1T1 or CBFB-MYH11 transcripts in a CAP/CLIA certified lab every 3 months for a median of 1.2 years (range 0-5.3). RD assessment was performed on BM aspirates, but PB could be tested in patients who could not tolerate repeat BM aspirates. Morphologic relapse was defined as emergence of 〉5% blasts in the PB or BM, and molecular relapse as a positive transcript PCR (if previous PCR measurements were undetectable) or an increase by 1 log (if previous PCR measurements were detectable) on 2 successive samples without morphologic relapse. Rapid relapse was defined as

Description: INTRODUCTION: Despite accumulating evidence supporting the efficacy of hypomethylating agents in patients with AML and 〉 30% bone marrow blasts as well as in relapsed/refractory AML, this therapy is not yet funded by National Health Plans / Healthcare Funding Agencies in a number of countries including Canada. The assistance of an industry-sponsored compassionate program has enabled provision of azacitidine for this group of patients at The Ottawa Hospital. We report here our local "real-world" experience of azacitidine efficacy in this diverse group of AML patients and identify a sub-group whose outcomes are equivalent to that of patients with higher-risk Myelodysplastic Syndrome (MDS) and AML with 20-30% blasts for whom azacitidine therapy has funding approval in Canada. METHODS: All patients who received azacitidine at The Ottawa Hospital between 2009 and 2016 were included in this single-center, retrospective analysis. Azacitidine was administered at a dose of 75mg/m2 subcutaneously daily for 7 consecutive days every 28 days. Response was evaluated with a repeat bone marrow aspirate and trephine biopsy after the 6th cycle. In those patients confirmed to have stable or responsive disease, azacitidine was continued until progression of disease, intolerable side-effects of the drug or the patient chose to discontinue therapy. Overall survival curves were generated using the Kaplan-Meier method and log-rank tests were used to compare subgroups of patients. Actuarial median survival months were calculated with 95% confidence intervals (CI). P-values less than 0.05 were considered statistically significant. RESULTS: During the study period, 109 patients received azacitidine: 54 had MDS /AML with 20-30% blasts (the 'funded' group) and 55 had either AML with 〉 30 % blasts (n=23), AML relapsed post-intensive chemotherapy (n=14), AML relapsed post-allogeneic stem cell transplant (n=10) or primary refractory AML (n=8) (the 'unfunded' group). Median survival of the 'funded' group was 12.2 months while median survival of the 'unfunded' group was 5.6 months (95% CI 3.3-7.7; p=0.0058). Of the AML patients in the 'unfunded' group, 24% completed more than 6 cycles of azacitidine compared to 52% of patients in the 'funded' group. In both the 'funded' and 'unfunded' groups, patients who completed more than 6 cycles of azacitidine had similar survival outcomes (p=0.7277): the 'funded' group had a median survival of 19 months (95% CI 14.4-25.3) while the median survival of this sub-population of the 'unfunded' AML group was 22 months (95% CI 11.7-24.9). Patients in both groups who failed to complete more than 6 cycles of azacitidine also had a similar outcome (p=0.39), with a median survival of 5.7 months (95% CI 4.0-6.3) for patients with MDS/AML 20-30% blasts and 3.6 months (95% CI 2.2-5.1) for AML patients with 〉 30% blasts or relapsed/refractory disease. Reasons for patients not completing at least 6 cycles of azacitidine included progression of disease (25%), bacterial infections most commonly pneumonia (53%) and patient preference (7%). CONCLUSION: A significant sub-population of AML patients with 〉 30% blasts or refractory/relapsed AML can achieve a meaningful survival benefit with the hypomethylating agent, azacitidine. A higher proportion of this AML patient population discontinued azacitidine as a result of infective complications. The provision of routine prophylactic antibiotics may enable more patients with AML to receive an adequate amount of azacitidine to achieve therapeutic benefit and warrants further investigation. Our results add to the growing body of 'real-world' evidence that supports healthcare funding agencies to provide coverage of azacitidine for patients with AML who in some countries at present do not fulfill government funding criteria. Disclosures Bredeson: Otsuka: Research Funding. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; ASTX: Membership on an entity's Board of Directors or advisory committees, Research Funding; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas Pharma Canada: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding.

Description: Background Graft-versus-host disease (GVHD) is a leading cause of morbidity and mortality in allogeneic hematopoietic stem cell transplantation (HSCT). Prophylactic in-vivo T-Cell depletion with antithymocyte globulin (ATG) has recently been reported as leading to decreased GVHD rates in matched unrelated and related donor HSCT, without increases in relapse or death. Understanding that higher rates of GVHD are observed with matched unrelated versus matched related donor HSCT, we have always had a local policy to give ATG as part of GVHD prophylaxis in patients undergoing HSCT from an unrelated donor. Here we report and compare clinical outcomes of patients who did and did not receive ATG at our transplant center using a unique, substantially lower ATG dose than previously reported. Methods We conducted a retrospective single-center database study comparing outcomes in 110 matched unrelated donor (MUD; ATG-exposed) and 78 matched related donor (MRD; ATG-unexposed) HSCT patients transplanted for any malignant indication at The Ottawa Hospital from 2009 to 2014. Patients were exposed to a rabbit ATG formulation (Thymoglobulin ®) at 0.5 mg/kg on day -2 and 2.0 mg/kg on day -1 prior to stem cell infusion, to total 2.5 mg/kg. Primary outcomes assessed were incidence of acute and chronic GVHD, defined as new-onset GVHD requiring systemic immunosuppressive therapy at less or more than 100 days post HSCT, respectively. Secondary outcomes included disease relapse and survival. Results At baseline there were no significant differences in median age at transplant, sex, disease indication or risk index, graft source, conditioning regimen and intensity between ATG exposed (MUD) and unexposed (MRD) cohorts. The majority of patients in both cohorts had intermediate or high disease risk index. There were significant baseline differences between the ATG exposed and unexposed cohorts with respect to proportion of 7/8 mismatched unrelated donor transplants (14 v 6% respectively, p = 0.015) and median CD34+ dose (4.9 v 7.6 x 108 cells; p 〈 0.001). No differences were noted in platelet engraftment. ATG exposed patients had significantly shorter time to neutrophil engraftment than the unexposed cohort (16 v 19 days respectively; p=0.007). ATG exposed patients had significantly lower rates of GVHD compared to the unexposed cohort (57 v 79%; p=0.005), with differences noted predominantly in rates of chronic GVHD (18 v 44%, p= 0.009). The proportion of patients off immune suppression one year after HSCT was not significantly different between the cohorts.At median follow-up of 13 (1-73) months for the ATG exposed cohort and 20 (0-69) months for the ATG unexposed cohort, no significant differences in overall survival (median overall survival not met for either cohort), cumulative incidence of relapse (26 v 29%; p=0.73) or relapse-free survival (not met in ATG exposed; 26.2 months in ATG unexposed, p=0.22) were observed between groups (Figure 1). Significant differences were observed with respect to GVHD-Free Relapse-Free Survival (GRFS) between ATG exposed and unexposed cohorts, with a two-year GRFS of 23 v 3% respectively (p = 0.003). There were no significant differences between cohorts in proportion of patients with post HSCT infectious episodes or ICU admissions. Conclusions Here we report significantly lower rates of chronic GVHD and significant improvement in GVHD-free relapse-free survival in our ATG exposed MUD HSCT cohort compared to our ATG unexposed MRD. These findings were observed without differences in relapse or survival outcomes, infectious complications or ICU admissions. While in keeping with other recent reports on ATG use for GVHD prophylaxis, our findings indicate that a lower dose of ATG may be effective in preventing GVHD. Our study suggests that a broader exploration into the optimal dosing of this prophylactic GVHD agent is warranted. Disclosures Bence-Bruckler: Lundbeck: Membership on an entity's Board of Directors or advisory committees. Sabloff:Novartis Canada: Membership on an entity's Board of Directors or advisory committees; Lundbeck: Research Funding; Alexion: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Research Funding.

Description: Mixed phenotype acute leukemia (MPAL) is a heterogeneous disease consisting of acute leukemia expressing markers of both myeloid and lymphoid lineage. The role of hematopoietic stem cell transplantation (alloHSCT) remains uncertain due to lack of prospective trials . Several studies have retrospectively examined its role in pediatric and younger adult subgroups. Myeloablative conditioning (MAC) can result in an overall survival (OS) of 56% at 3 years, but is not suitable for older and frail patients. With expanding transplant availability and alternative donors, we sought to evaluate the outcomes of our cohort of MPAL patients, including older adults unfit for MAC, in a heterogeneous, real-world scenario compared with the outcomes of patients who were consolidated with chemotherapy only. Methods: Seventy four patients, aged 18 years or older, at the Princess Margaret Cancer Center between January 1, 2000 and December 31, 2018 were evaluated. All patients included in analysis met the WHO 2016 classification criteria for MPAL. Overall survival and relapse free survival rates were calculated using the Kaplan-Meier product-limit method. The log-rank test was used to compare the two groups with respect to OS and relapse free survival. Results: Baseline characteristics of the patient cohorts are shown in Table 1. Among the 74 MPAL patients included in this study, 59 (79%) received induction chemotherapy. Complete remission (CR) was achieved in 47 (79%) treated patients. Twenty-five of 36(80%) achieved a CR using ALL protocols (DFCI Protocol, Hyper-CVAD), while 9 of 23 (39%) achieved a CR using AML protocols (3+7, FLAG-Ida). Consolidation treatment post CR was evenly split, with 24(51%) receiving chemotherapy followed by an alloHSCT and 23 (49%) receiving chemotherapy only. In the alloHSCT group, RIC was used in 20 (81%) patients while MAC was used in four younger patients with a median age of 51 and 30 respectively. Donor types included sixteen matched unrelated donors, five sibling donors, two haploidentical donors, and one double umbilical cord. The median age of the transplant cohort was 50 years with a median OS of 21 months. In the chemotherapy only group, the median age was 57 with a median OS of 18 months. ALL-type treatment was used for consolidation in 74% of patients with 83% using the asparaginase-containing DFCI protocol. Univariate analysis demonstrated no difference in outcomes with several parameters including age, induction chemotherapy, donor source, and conditioning intensity. The sole predictor of poor OS on univariate analysis was acute graft versus host disease (aGVHD) with a hazard ratio of 3.3 (95% CI 0.9-11). In total, 12 patients (50%) had aGVHD with a median OS of 16 months. However, when Grade 1/2 and Grade 3/4 aGVHD were compared, median OS was not reached in patients with G1/2, compared with an OS of 11 months in those patients with G3/4 aGVHD. Chronic GVHD was present in 6 patients and did not impact OS (HR 0.9892 CI 95% 0.2-2.9). Post-transplant relapses occurred solely in the RIC group and were early, occurring within a median of 124 days (range 87-188). Although, there was no relapses in the MAC group, the non-relapse mortality (NRM) was 75%, with patients dying from either aGVHD or infection. The NRM in the RIC group was 17.65%. The 3 year OS and relapse free survival (RFS) for the entire cohort were 30% and 32%, respectively. When comparing those patients that had undergone alloSCT and those that who received chemo alone, survival in the two groups were similar with a 1 year OS of 75% vs. 68% and a 3 year OS of 29% vs 32%, respectively (Figure 1). The 3 year RFS was also similar at 29% and 34%, respectively. Subgroup analysis between the two groups was performed for patients with specific poor prognostic factors (older age, complex cytogenetics, higher WCC, conditioning regimen used), but results showed no significant survival differences. Conclusions Older patients with MPAL have an inferior prognosis and worse outcomes with alloHSCT compared with those of younger adults or children. Despite the increase in access to alloHSCT and an expanding pool of alternative donors, outcomes with RIC remain similar to consolidation with chemotherapy alone. There may be some evidence to suggest that the graft versus leukemia effect can be harnessed to improve outcomes in selected patients. Further research towards optimizing patient outcomes is clearly required to address the needs of older patients unfit for MAC. Disclosures Gupta: Sierra Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Honoraria, Research Funding. Mattsson:Gilead: Honoraria; Celgene: Honoraria; Therakos: Honoraria. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Michelis:CSL Behring: Other: Financial Support. McNamara:Novartis Pharmaceutical Canada Inc.: Consultancy. Schimmer:Jazz Pharmaceuticals: Consultancy; Otsuka Pharmaceuticals: Consultancy; Medivir Pharmaceuticals: Research Funding; Novartis Pharmaceuticals: Consultancy. Schuh:Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees; Agios: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Jazz: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Teva Canada Innovation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Yee:Astex: Research Funding; MedImmune: Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Hoffman La Roche: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Millennium: Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Research Funding. Minden:Trillium Therapetuics: Other: licensing agreement.

Description: INTRODUCTION: Acute myeloid leukemia (AML) is a rare hematologic cancer primarily affecting older people, with a median age at diagnosis of 67 years old (Almeida & Ramos, 2016). Heterogeneity in the presentation, functional status and presence of comorbidities among AML patients presents unique challenges for treatment. Intensive chemotherapy (IC), although the best option for prolonging survival, carries a risk of early death and other trade-offs, including significant time spent in the hospital. The toxicity of IC treatment and the requirement for prolonged hospitalizations may negatively affect patients' physical functioning and health-related quality of life (HRQoL). Novel, low-intensity treatments can be administered in the clinic and may pose less risk of immediate toxicities but may be associated with reduced efficacy. Each patient and family will approach these trade-offs differently, yet few studies examine the process of shared decision-making in AML. We aimed to better understand this process by eliciting patient/family and physician narratives about expectations and attitudes towards AML treatments. METHODS: Ten physicians in the US (n=4), UK (n=3) and Canada (n=3) and 12 AML patients (all US) and a member of their family took part in an individual, 60-minute qualitative telephone interview. Further interviews are scheduled and any additional data at the time of presentation will also be reported. The interviews followed a semi-structured guide comprising open-ended questions. The overarching aim of the interviews was to understand the value of living longer for AML patients who are not candidates for standard IC and to explore the treatment decision process from the patient, family and physician perspective. During the interviews, each participant (patient, family member or physician) completed a rating exercise in which they were asked to rate a list of pre-defined factors (9-10 factors) on a scale of 0 (not at all important) to 3 (very important) to determine their importance in AML treatment decisions. As well as providing a numerical rating for each factor, each participant was asked why they selected their rating and which three factors they would consider the most important. RESULTS: Across all three groups, relief in AML symptoms (namely fatigue and pain), longer survival and better QoL were equally considered the three most important factors when making a treatment decision. All three groups described the interaction between QoL and longer survival, explaining that any increase in survival would be important, but only if QoL (time spent with family, maintaining hobbies/interests) was maintained or improved. Physician's advice was also important to AML patients when making decisions regarding treatment. Other treatment-related factors within the rating task were rated as very important for at least a subset of patients, with no factors widely considered to be of limited importance. All participants noted that while relief of AML symptoms, longer survival and quality of life were all important, these had to be considered in light of treatment side effects and risk of infection. Likelihood of being hospitalized was important to family members, as they wanted to spend quality time at home with their loved ones, while patients and physicians considered hospitalization as an inevitable consequence of the disease and treatment. All participants reported that AML patients would consider taking any form of treatment if suitable and effective, regardless of the mode of administration. However, it was acknowledged that oral treatments would be more convenient and less invasive. The relative importance of location of care/treatment delivery was influenced by proximity to resources and whether the participant was based in an urban or rural setting. The ability to receive treatment at home was considered beneficial. CONCLUSIONS: The results from this rating exercise and qualitative interviews showed convergence across all stakeholders, indicating that AML patients, family and physicians have similar priorities regarding treatment decisions, prioritizing symptom relief, survival, and quality of life. The predominant treatment pathways in AML each require trade-offs in these factors, demonstrating the importance of shared decision making in ensuring the most appropriate treatment is selected for a given individual, in accordance with their values, goals, and preferences. Figure Disclosures LeBlanc: Jazz Pharmaceuticals: Research Funding; Daiichi-Sankyo: Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Heron: Membership on an entity's Board of Directors or advisory committees; Helsinn: Consultancy; Flatiron: Consultancy; NINR/NIH: Research Funding; Duke University: Research Funding; Astra Zeneca: Consultancy, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Medtronic: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Research Funding; Celgene: Honoraria; AbbVie: Membership on an entity's Board of Directors or advisory committees; Pfizer Inc: Consultancy; American Cancer Society: Research Funding; Agios: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CareVive: Consultancy. Walter:Seattle Genetics: Research Funding; Agios: Consultancy; Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; New Link Genetics: Consultancy; Pfizer: Consultancy, Research Funding; Race Oncology: Consultancy. Hernandez-Aldama:Pfizer Inc: Consultancy. Sully:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Bell:Pfizer Inc.: Employment, Equity Ownership. Johnson:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Peloquin:Pfizer Inc: Employment, Equity Ownership. Gater:Pfizer Inc: Consultancy; Adelphi Values Ltd: Employment. Welch:Pfizer Inc: Employment, Equity Ownership. O'Hara:Adelphi Values Ltd: Employment; Pfizer Inc: Consultancy. Russell:Astellas: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; Jazz: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau. Horikoshi:Pfizer Inc: Consultancy. Maze:Pfizer Inc: Consultancy; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees.

Description: Acute myeloid leukemia (AML) is a clinically and biologically heterogeneous disease. Traditionally, cytogenetic analysis has been the backbone for prognostication and treatment decisions. Outcomes vary between age groups with older adults generally having a poorer prognosis. Next Generation Sequencing (NGS) has expedited the discovery of novel genetic lesions in AML to better predict response to intensive chemotherapy and overall survival (OS). The aims of our study were to describe the genetic profile of older adults with AML and to determine its impact on treatment response and survival. We included all new patients with a diagnosis of AML (≥20% blasts in peripheral blood or bone marrow; acute promyelocytic leukemia and myeloid sarcoma were excluded), treated at Princess Margaret Cancer Centre between February 2015 and August 2017. NGS was performed on DNA isolated from peripheral blood or bone marrow samples at diagnosis. Analysis was performed using the TruSight Myeloid Sequencing Panel (Illumina; San Diego, CA) on the MiSeq benchtop genome sequencer (Illumina). Of the 54 genes included in the panel, the complete coding region was sequenced in 15, with hotspot region coverage provided for 39. Demographic and clinical data were obtained from the Princess Margaret Cancer Centre Registry. We identified 454 patients with a new diagnosis of AML in whom frontline NGS was performed. Of these, 300 were 60 years (range 60-92) or older. Demographic and clinical data are shown in Table 1. The median age overall at presentation was 67 yrs (range 18-92) and 57% were male. de novo AML was diagnosed in 329 patients (72%), secondary AML in 17%, and therapy related myeloid neoplasm in 11%. Secondary AML (sAML) was more frequently seen in the ≥60 vs the 1% of patients, and 11 genes were mutated in 〉10% of patients. The most commonly mutated genes included DNMT3A (25%), NPM1 (21%), TET2 (19%), RUNX1 (16%), TP53 (16%), ASXL1 (15%), IDH2 (15%), SRSF2 (15%), NRAS (12%), and IDH1 (11%). Older patients had a greater number of mutations overall compared to younger adults (median: 3 vs 2; P = 0.001). In total 986 oncogenic variants were identified in the older group (median 3, range 1-12), while 367 oncogenic variants (median 0, range 0-2) were present in patients 〈 60 years old (P 〈 0.001). The older group more commonly harbored mutations in TET2 (25 vs 10%), ASXL1 (21 vs 4%), RUNX1 (20 vs 8 %), SRFS2 (20 vs 6 %), STAG2 (11 vs 6%) and U2AF1 (8 vs 2%). Patients with PTPN11 and NPM1 mutations had longer OS, while patients carrying mutations in ASXL1, JAK2, RUNX1, TP53 and SRSF2 had a shorter OS (Table 2). No differences in OS between age groups (P= 0.2). Multivariate Cox regression analysis showed that male sex (P= 0.0057), sAML (P

Description: Background: Intracranial hemorrhage (ICH) is a common complication in acute leukemia that is associated with significant morbidity and mortality. While evidence supports prophylactic platelet transfusions at a threshold 〈 10 x 109/L to reduce the risk of bleeding in acute leukemia, there is little data to guide platelet transfusion practice in patients following ICH. The objectives of this study were to characterize the clinical features and outcomes of acute leukemia patients with ICH and to understand current platelet transfusion practice following ICH. Methods: This was a retrospective study conducted at a large, quaternary, academic cancer centre. We included all adult patients with a diagnosis of acute leukemia who had a documented ICH at our centre between January 1, 2009 and December 31, 2016. We assessed demographics, medications, infection and bleeding history in the week preceding ICH, characteristics of ICH including site of bleed, acute management, transfusion practice in the first 90 days, and clinical outcomes. Radiologic scans were re-assessed by neuroradiology to determine if the ICH was stable or if new or progressive bleeding had developed. Transfusion practice following the ICH was compared between the two groups with longitudinal data analysis using platelet counts as outcome. Kaplan-Meier product limit method was used to estimate overall survival (OS) rates as well as to obtain median survival; log-rank test was used to compare OS among those without new or progressive ICH vs. those with progression. Results: During the study period, of 2576 patients diagnosed with acute leukemia, 101 suffered from ICH and were included in the study. Most patients (94) had AML, of which 9 had APL, 6 had ALL, and 1 had MPAL. At the time of ICH, 61 patients were newly diagnosed or receiving induction chemotherapy, 33 had relapsed disease and 7 were in complete remission. Spontaneous ICH occurred in 76 patients. Within the week preceding ICH, 7 patients were on medications known to increase bleeding risk and 39 were on tranexamic acid. Sixty-four patients had clinical evidence of bleeding elsewhere and 22 had evidence of infection. On the day of ICH, the median platelet count was 16 x 109/L (range 0- 433 x109/L). Thirty-one patients had a platelet count 〈 10 x 109/L and 10 of these patients received a platelet transfusion prior to the bleed. Seventy patients had a platelet count ≥10 x109/L and 17 of these received a platelet transfusion prior to the bleed. Six patients (6%) exhibited evidence of platelet transfusion refractoriness. In the 90 days following ICH, 21% of platelet transfusions were given for a platelet count 〈 10 x 109/L, 55% were given with a platelet count between 10-29 x109/L, and 24% were given with a platelet count ≥ 30 x 109/L. New or progressive ICH occurred in 28 patients. The median platelet transfusion threshold was 19 x 109/L (range 0-114 x 109/L) for those without new or progressive ICH and 21 x 109/L (range 0-93 x 109/L) for those with progression (p=0.04; Figure 1). Of the 101 study patients, 79 have died. Median OS was 5.6 months for those without new or progressive ICH and 2.9 months for those with progression (p=0.002) (Figure 2). Cause of death was attributed to non-ICH causes in the majority of patients 65/79 (82%). Conclusions: In this retrospective study, we evaluated the outcomes of 101 patients with acute leukemia and ICH. At the time of the bleed, the majority of patients had active disease and more than two thirds had platelet counts of 10 x 109/L or higher. During 90 days of follow-up, nearly one third of patients developed new or progressive ICH. Platelet transfusion practice was variable and the median threshold was, in fact, higher in those who subsequently developed new or progressive bleeding. The reasons for this were unclear from our chart review, but we hypothesize that these patients may have had additional risk factors, e.g. fever, infection. The outcomes of patients with acute leukemia and ICH are poor. Factors other than platelet transfusion threshold likely contribute to secondary ICH events and the overall poor prognosis. Disclosures Maze: Novartis: Consultancy, Honoraria.

Description: Background/Objective: Mobilized peripheral blood hematopoietic progenitor cells are the most common stem cell source for autologous hematopoietic stem cell transplantation (auto-HSCT). Successful short-term stem cell engraftment requires collection of at least 2x106 CD34+ cells/kg. The American Society of Bone Marrow Transplantation (ASBMT) recommends a stem cell infusion target of 3-5 x106 cells/kg (Giralt et al. 2014). However, the number of CD34+ cells to reinfuse to ensure long-term engraftment has not been established. Plerixafor, a reversible CXCR4 antagonist, increases CD34+ cell yield at collection even in patients who are predicted poor mobilizers (PPM). Although plerixafor could be used universally for all collections, this may not be the most cost-effective strategy (Veltri et al. 2012). This study sought to determine the minimum number of CD34+ cells/kg required for adequate long-term hematopoiesis, identify factors associated with poor long-term hematopoiesis, and determine if plerixafor mobilization improved long-term peripheral blood counts. Methods: A retrospective chart review was conducted on patients who underwent auto-HSCT between January 2004 and September 2013 at The Ottawa Hospital, for management of hematological malignancies. Peripheral blood cell counts were collected from 1 to 5 years after auto-HSCT, or until disease relapse. Poor long-term hematopoiesis was defined as an ANC

Description: Introduction Essential thrombocythemia (ET), polycythemia vera (PV) and myelofibrosis (MF) are a group of hematopoietic stem cell-derived clonal disorders collectively known as the classical, Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although MPN diagnoses are typically made in the sixth or seventh decade of life, approximately 20% of ET patients and 15% of PV patients are under the age of 40 years. Pregnancy with an MPN is associated with maternal thrombosis, hemorrhage and placental dysfunction leading to fetal growth restriction or loss. The aims of this systematic review were to determine the risk of maternal and fetal complications in pregnancy complicated by MPN and to quantify the benefit of commonly used interventions. Methods A systematic search was conducted using MEDLINE (1946 to July 2018), EMBASE (1947 to July 2018), Cochrane Database of Systematic Reviews (2005 to July 2018), CCRCT (inception to June 2018), and Epub Ahead of Print & Other Non-Indexed Citations (inception to July 2018). Bibliographic references were reviewed for additional studies. There were no date or language restrictions and the review was registered with PROSPERO (CRD42018090680). Studies were included if they reported on maternal or fetal outcomes of pregnancy in patients with an MPN. Case reports and series including fewer than 10 patients were excluded. Duplicate reports were excluded, with only the most recent or most informative included. Data were extracted independently by two investigators (D.M. and S.K.). The primary outcome was live birth. Secondary outcomes included fetal complications (e.g. intrauterine growth restriction) and maternal complications (e.g. pre-eclampsia, thrombosis, hemorrhage). Study quality was assessed using the Newcastle-Ottawa Scale. Analyses were performed using Open Meta-Analyst version 10.12 and Review Manager version 5.3. Results The search strategy resulted in 4191 records of which 22 met the inclusion criteria (Figure 1). The studies included a total of 779 women and 1226 pregnancies. Fifteen of the studies included patients with ET, 3 included patients with PV, and 4 included patients with any classical MPN. There were no studies of MF patients that met our inclusion criteria. Most of the studies were retrospective cohort studies (19) and 3 were prospective cohort studies. Among 1226 pregnancies, the live birth rate was 70%. Of 821 pregnancies with ET and 171 with PV, the live birth rate was 71% and 51%, respectively. The live birth rate was higher in patients with ET who received low dose aspirin during pregnancy than those managed with observation alone (OR 5.0; 95% CI 2.2 - 11.3; I226%; Figure 2). There was no further improvement with the addition of low molecular weight heparin (LMWH) to aspirin (OR 2.8; 95% CI 0.67 - 11.7; I20%). Interferon alpha (INF) during pregnancy was also associated with a higher live birth rate (OR 3.9; 95% CI 1.5 - 10.4; I22.5%; Figure 3). The presence of the JAK2 mutation resulted in a lower live birth rate (OR 0.58; 95% CI 0.4 - 0.9; I26%; Figure 4). Maternal events were unaffected by the addition of aspirin (OR 0.48; 95% CI 0.16 - 1.4; I20%) or INF (OR 0.1; 95% CI 0.01 - 1.5; I20%). Risk of bias assessment was performed using the Newcastle-Ottawa scale. Most studies included a representative cohort and follow up was generally adequate to at least 6 weeks postpartum. Only 3 studies included a control group. Conclusions The preliminary results of our systematic review determined that the live birth rate is lower in pregnant patients with MPN as compared to the general population. The chance of a successful pregnancy was higher in patients with ET than PV and the presence of the JAK2 mutation increased the risk of fetal loss. Patients who received low-dose aspirin during pregnancy had a 5-fold higher odds of a successful pregnancy than those managed with usual care and observation alone. Cytoreduction with INF improved the odds of live birth by nearly 4-fold. Maternal events were uncommon overall and no intervention was found to be beneficial. Our review is limited by generally small sample sizes and the retrospective nature of most studies. Additionally, given that the studies span up to 4 decades, our results may be affected by changing standards of care. Pregnancy in patients with MPN is uncommon and this is the only systematic review to determine the chance of successful pregnancy and quantify the benefit of commonly used interventions. Disclosures Maze: Novartis: Consultancy, Honoraria. Kazi:Shire: Other: Vonvendi was provided by Shire. Gupta:Novartis: Consultancy, Honoraria, Research Funding; Incyte: Research Funding.

Description: Introduction:Induction chemotherapy debulks the leukemic burden in AML patients. Blood count recovery usually occurs during the fourth week of starting chemotherapy in patients who achieve a morphologic remission in bone marrow. However, a subset of patients experience significantly delayed recovery. The relevance of delayed recovery on long-term clinical outcomes and its contributing factors have not been well studied. Specifically, the association between recurrent mutations in AML and hematologic recovery is unknown. Methods:We studied a total of 262 newly diagnosed adult AML patients treated between September 2014 and December 2017 at Princess Margaret Cancer Centre who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) after one cycle of induction chemotherapy. The regimens consisted of 3+7 (N=194) and FLAG-IDA (N=68). We collected information on disease characteristics and blood count results at baseline and during chemotherapy. Mutation profiling of diagnostic samples was performed using a 54-gene next generation sequencing panel (TruSight Myeloid Sequencing Panel, Illumina). Detection of persistent mutations in remission samples was performed using a custom 37-gene duplex sequencing platform with a lower detection limit of ~0.05% variant allele frequency (VAF). Results:Of the cohort of 262 patients, 256 patients (97.7%) achieved neutrophil recovery (defined as 〉 1x109/L), with time to recovery ranging from 17 to 84 days. Two hundred forty-four (93.1%) patients achieved platelet recovery (defined as 〉 100x109/L); time to recovery ranged from 17 to 117 days. The percentage of patients who achieved neutrophil and platelet count recovery before day 35 was 82.4% and 84.0% respectively (Fig. 1). To evaluate the prognostic significance of delayed recovery, we categorized patients who achieved CR into two groups, "normal" or "delayed" recovery, according to whether they achieved recovery before or after day 35, respectively. Relapse-free survival (RFS) of patients with delayed recovery was significantly worse than those with normal recovery and only marginally better than those with CRi (P=0.02; Fig. 2). Analysis restricted to 3+7 treated patients showed the same trend (P=0.02), excluding the possibility that the inferior outcome was due to treatment of higher risk patients with more intensive regimens. To study the factors associated with delayed recovery, we performed multivariable Cox regression analysis that included clinical factors and mutations identified at the time of diagnosis as covariates. Four factors were found to be independently correlated with delayed recovery: treatment with FLAG-IDA, truncating ASXL1mutations, SRSF2mutations, and DNMT3AR882 mutations (Table 1). Because FLAG-IDA is the preferred frontline regimen for higher risk patients at our institution, we performed a secondary analysis restricted to patients treated with 3+7 to exclude chemotherapy regimen as a potential confounding variable. This analysis identified six independent factors: AML with myelodysplasia-related changes, lower hemoglobin levels at presentation, truncating ASXL1mutations, TET2mutations, CEBPAmutations, and DNMT3AR882 mutations (Table 1). Somatic mutations in DNMT3A, TET2, ASXL1, and SRSF2(DTAS) mutations are associated with preleukemic conditions, such as myelodysplastic syndrome and age-related clonal hematopoiesis, and frequently persist in remission. These mutations are acquired in hematopoietic stem cells resulting in their propagation to progenitors and terminally differentiated blood cells. We hypothesized that the persistence of DTAS mutations in progenitors might compromise their capacity for reconstitution of normal hematopoiesis resulting in delayed recovery. To test this hypothesis, we performed duplex sequencing on peripheral blood DNA samples collected from a random subset of 43 patients during remission. The detection of DTAS mutations in remission above a VAF of 2% was strongly associated with delayed recovery (P=0.0004; Fig. 3). Conclusion:Delayed hematologic recovery in AML patients after induction chemotherapy is associated with inferior RFS and persistence of preleukemic mutations (i.e., DTAS mutations). Our results support a model in which progenitors harboring DTAS mutations have reduced repopulation capacity leading to delayed hematologic recovery after induction chemotherapy. Disclosures Gupta: Incyte: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Schimmer:Otsuka Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medivir AB: Research Funding. Yee:Agensys, Astex, GSK, Onconova, Genentech/Roche: Research Funding; Celgene, Novartis, Otsuka: Membership on an entity's Board of Directors or advisory committees. Maze:Novartis: Consultancy, Honoraria. Bratman:Roche: Other: SVB is a co-inventor on a patent describing methods for circulating tumor DNA analysis, which has been licensed to Roche Molecular Diagnostics.. Schuh:Shire: Consultancy; Jazz: Consultancy; Novartis: Consultancy; Otsuka: Consultancy; Teva: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; Amgen Inc.: Consultancy.