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Introduction: With the improvement in transplant practices during recent years, non-relapse mortality (NRM) following allogeneic hematopoietic cell transplantation (allo-HCT) has significantly improved. The use of reduced intensity conditioning has extended allogeneic transplants to older patients and those with comorbidities that preclude traditional myeloablative conditioning (MAC) albeit at the cost of higher rates of relapse. Busulfan (BU) has been used for approximatively four decades as a major component of chemotherapy-based conditioning before allo-HCT. At our center, IV-BU dose in MAC is 12.8 mg/kg (BU12.8) and in those not eligible for MAC, it is 9.6 mg/kg (BU9.6). The goal of BU9.6 is to improve tolerability without increasing disease recurrence. The choice of BU12.8 or 9.6 is determined by consensus based on patient age, Karnofsky score and comorbidities. Aims: The aim of this study was to compare the impact of BU9.6 to BU12.8 on outcomes in patients with acute leukemia (AL) or myelodysplastic syndromes (MDS) who received allo-HCT after BU-based conditioning from matched related or unrelated donors. Patients and methods: This study included 181 patients: 134 AL [122 (67%) AML, 10 (6%) ALL and 2 (1%) biphenotypic AL] and 47 (26%) MDS patients who received allo-HCT between Jan 2012 and Dec 2018 at the Ottawa Hospital. Median age at allo-HCT was 58 years (range: 18-73), 104 (57%) were males. Median time from diagnosis to transplant was 5 months. At time of conditioning, among AL patients, 99 (74%) were in CR1, 19 (14%) in CR2 and 16 (12%) not in CR, and among MDS patients, 22 (47%) were not treated and 25 (53%) had received azacytidine. All patients received PBSC from HLA matched related [N=68 (38%)] or unrelated [N=113 (62%)] donors. Patients were classified according to the refined Disease Risk Index (DRI): 94 (52%) intermediate, 81 (45%) high and 6 (3%) very high. Karnofsky score was 80% [N=59 (33%)]; HCT comorbidity index was 0 [N=70 (39%)], 1 [N=25 (14%)], 2 [N=24 (13%)] and >2 [N=62 (34%)]. GVHD prophylaxis consisted of tacrolimus and short course methotrexate for all patients. Rabbit antithymocyte globulin (rATG, Thymoglobulin) was used in all transplants from unrelated donors (n=113) and in BU12.8 transplants from related donors (n=28). rATG dose was 2.5 mg/kg in 85 (47%) patients and 4.5 mg/kg in 56 (31%). Bu dose was 9.6 mg/kg for 74 (41%) patients [Bu/Flu (N=73) and Bu/Flu/TBI (N=1)], and 12.8 mg/kg for 107 (59%) [Bu/Cy (N=79), Bu/Flu (N=19) and Bu/Flu/TBI (N=9)]. Results: Ninety-eight % of the patients engrafted; ANC>500/µL was achieved at a median of 16 days (range: 7-79) post-transplant and did not differ between BU9.6 and BU12.8. GVHD requiring systemic immunosuppressive therapy was observed in 26/74 (35%) patients (4 acute, 22 chronic) after BU9.6, and in 45/107 (42%) patients (13 acute, 32 chronic) after BU12.8. With a median follow-up of 22 months (range: 5-74) for survivors, no significant difference in survival, relapse incidence (REL) or NRM was observed between BU9.6 and BU12.8. Two-year OS, REL and NRM for the whole population were 65% (95%CI: 57-73), 29% (95%CI: 22-37) and 10.8% (95%CI: 6-16) respectively. When stratified according to DRI: intermediate, high and very high scores had 2-year OS of 76% (95%CI: 65-84), 53% (95%CI: 38-66) and 0% respectively, p=0.001; and 1-year REL rates of 12% (95%CI: 6-20), 31% (95%CI: 21-42) and 67% (95%CI: 12-92) respectively, p Conclusions: Our results validate the efficacy of a reduced 9.6 mg/kg BU-based conditioning regimen for patients not suitable for traditional 12.8mg/kg dose. Relapse was not increased, unlike what has been reported with BU6.4mg/kg. While NRM was not decreased, the BU9.6 group was older and had more comorbidities. In addition, we confirm the value of DRI in prognosticating both relapse and survival. We recommend the use of BU9.6 in patients not suitable to receive BU12.8. Further studies are needed to determine whether the BU9.6 can replace BU12.8 for all patients. Disclosures Sabloff: Astellas Pharma Canada: 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; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi Canada: Research Funding; Pfizer Canada: Honoraria, 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; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees; Actinium Pharmaceuticals, Inc: Membership on an entity's Board of Directors or advisory committees. Laferriere:Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Astra Zeneca: Honoraria; Teva Pharm: Honoraria; Taiho: Honoraria; ROCHE: Honoraria; Pfizer: Honoraria.

Objective Multiple myeloma (MM) is a B-lymphocyte neoplasia that is presently incurable because the tumor cells become resistant to currently available drugs. The growth and survival signals resulting from interactions between the malignant clones and the bone marrow microenvironment are mediated chiefly through the phosphoinositide 3′-kinase/Akt kinase signaling pathway. Thus agents that can abrogate this pathway have great potential as targeted therapies. A novel approach in this regard is through activation of the Src homology 2-containing inositol 5′-phosphatase (SHIP), using the small molecule agonist, AQX-MN100. Materials and Methods The SHIP agonist AQX-MN100 was tested in vitro for its ability to inhibit DNA synthesis, induce apoptosis in MM cell lines, as well as inhibit phosphorylation of the kinases in the phosphoinositide 3′-kinase/Akt kinase cascade. The ability of AQX-MN100 to enhance the cytotoxicity of the current MM therapeutic drugs dexamethasone and bortezomib was also examined. Results We demonstrate herein that activation of SHIP using AQX-MN100 is sufficient to prevent growth and induce cytotoxicity of MM cell lines, while having no significant effects on nonhematopoietic cells lacking SHIP. AQX-MN100 also augments the effects of the established agents dexamethasone and bortezomib. Conclusion These results provide the basis for the further study of small molecule SHIP activators to improve MM patient outcomes.

Introduction With routine use of autologous stem cell transplantation (ASCT) and novel agents, survival of patients with multiple myeloma (MM) has improved in recent years. Yet, MM remains incurable and long-term survivors (LTS) of ≥10 years from diagnosis remain uncommon. This study aims to identify patient, disease and treatment characteristics of MM LTS, with particular interest in the effect of novel therapies. Methods A retrospective analysis was conducted of MM patients diagnosed between 1998 and 2002 and treated at Princess Margaret Cancer Centre, a tertiary care institution. LTS were identified by survival of ≥10 years from diagnosis and were compared with patients diagnosed and followed contemporaneously at our institution with survival Results Seventy-five patients were identified as LTS, with a control group of 119 patients with survival Patient and disease characteristics: At diagnosis, LTS were younger (p = 0.0005) and at earlier ISS stage (p = 0.02) than non-LTS. At diagnosis, LTS had a higher baseline mean hemoglobin level (p = 0.02) and platelet count (p = 0.003), and less frequently had lytic bone lesions (p = 0.03), consistent with earlier stage at diagnosis. There were no significant differences in baseline mean leukocyte count, serum calcium and creatinine. Cytogenetics were not routinely performed during this time period. Treatment characteristics: Of the LTS, 95% received an ASCT, as compared to 86% of non-LTS (p = 0.77). Median age at transplant was younger in the LTS (p = 0.003). LTS experienced a longer time from transplant to disease progression (TTP) than non-LTS (p < 0.0001) despite achieving similar rates of complete response (CR) and very good partial response (VGPR). Exposure to novel agents was common in both the LTS and control groups (73% vs. 82%, p = 0.24). Length of exposure to thalidomide (p = 0.01) and lenalidomide (p = 0.002) was greater in LTS, leading to higher quality responses and longer TTP with both agents (p < 0.0001 and p = 0.002, respectively). Similarly, bortezomib exposure was longer in the LTS (p = 0.02) with a longer TTP over that achieved in non-LTS (p = 0.008), although the quality of response was not significantly different. In a multivariate analysis, a longer TTP after ASCT (OR = 1.004; 95% CI 1.002-1.006, p = 0.0008), thalidomide (OR = 34; 95% CI 1.7-690.6; p = 0.023) and bortezomib (OR = 28.2; 95% CI 3.5-228; p = 0.002) treatment, though not after lenalidomide, were independently predictive of LTS. Table 1. Comparison of characteristics between LTS and non-LTS Disease characteristics LTS (n=75) Non-LTS (n=119) p -value Age (y) 53.2 59.1 0.0005 ISS stage I 66 43 0.02 II 20 33 III 14 24 Hemoglobin (g/L) 109 102 0.03 Leukocytes (x 109/L) 5.97 6.29 0.45 Platelets (x 109/L) 255 218 0.003 Calcium (mmol/L) 2.41 2.46 0.39 Creatinine (umol/L) 107.5 148.6 0.16 Presence of lytic lesions (%) 55 70 0.03 Treatment characteristics Autologous stem cell transplant Age (median, years) 53.3 59.4 0.003 Response (CR or VGPR, %) 47 44 0.62 TTP (median, months) 59 19.9 0.001 Thalidomide Age (median, years) 11.4 8.2 0.01 Response (CR or VGPR, %) 40 23 0.02 TTP (median, months) 32.4 9.6 Conclusion LTS with MM received prolonged therapy and achieved higher quality responses to both transplant and novel agents. Our analysis suggests that LTS have baseline characteristics (age, early-stage disease, greater marrow reserve) that may enable them to tolerate more intensive or prolonged therapy. However, it is possible that LTS have disease more indolent or sensitive to therapeutic interventions. The retrospective nature of the study limits our ability to further characterize this. Regardless, these data suggest that the practice of continued exposure to novel agents may contribute to long-term survival in MM. Disclosures Reece: Otsuka: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Millennium: Honoraria, Research Funding; Merck: Research Funding; BMS: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria. Trudel:Celgene: Honoraria; Novartis: Honoraria; Glaxo Smith Kline: Honoraria, Research Funding; Oncoethix: Research Funding. Kukreti:Celgene: Consultancy, Honoraria. Tiedemann:Janssen: Honoraria. Chen:Celgene: Honoraria; Janssen: Honoraria.