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Natural killer (NK) cells are cytotoxic lymphocytes that play a major role in the innate immune system. NK cells exhibit potent cytotoxic activity against cancer cells and virally infected cells without antigen priming. These unique cytotoxic properties make NK cells a promising therapeutic against cancer. Limitations of NK cell therapy include deficiencies in high clinical efficacy often due to a need for a high NK cell to target cell ratio to achieve effective killing. In order to address the suboptimal efficacy of current adoptive NK cell therapy, a high throughput screen (HTS) was designed and performed to identify drug-like compounds that increase NK cytotoxic activity against tumor cells without affecting the normal cells. This screen was performed in a 384-well plate format utilizing an expanded primary NK cell product and ovarian cancer cells as a target cell (TC) line. Of the 8000 diverse small molecules screened, 16 hits were identified (0.2% hit rate) based on both a robust Z (RZ) score

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as < 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC >1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count >20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

Graft versus host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplantion (HCT) and a major cause of posttransplant morbidity and mortality. Despite recent advancements in our knowledge regarding pathophysiology of GVHD, success in treatment has been limited. Mesenchymal stem cells (MSC) have immunomodulatory and antiinflammatory properties that can be exploited for the prevention and treatment of GVHD, with established preliminary results in early-phase clinical trials. In this chapter, we briefly review HCT and GVHD, and evaluate the evidence for MSC therapy in GVHD.

Purpose The left ventricle (LV) undergoes physiologic remodeling in adaptation to the hemodynamic changes that occur in pregnancy. Speckle tracking echocardiography (STE) is a novel and reliable tool to evaluate subtle myocardial alterations that have been utilized to assess myocardial changes in patients with diabetes mellitus (DM) but not in patients with gestational DM (GDM). We seek to evaluate changes in LV function using STE in patients with GDM compared with women with normal pregnancy. Methods This was a single-center retrospective cohort study. A total of 312 pregnant patients that underwent transthoracic echocardiogram (TTE) between 2009 and 2014 were screened. After excluding patients with comorbidities or insufficient data, 90 women were included. TTE from the second and third trimester for each patient were then reviewed, and STE analysis was performed. Results Of the 90 subjects, 72 had normal pregnancies and 18 developed GDM. There was no difference in LV end-diastolic diameter (4.73 ± 0.40 versus 4.60 ± 0.56, p = 0.25), LV end-systolic diameter (3.12 ± 0.35 versus 2.91 ± 0.61, p = 0.152), or ejection fraction (62.26 ± 4.12 versus 63.50 ± 5.24, p = 0.314) between the two groups. Global longitudinal strain was lower (−19.8 ± 3.34 versus −17.2 ± 2.18, p < 0.001) in patients with GDM, while time-to-peak strain was greater (0.43 ± 0.05 versus 0.50 ± 0.06, p < 0.001). Circumferential and radial strains were preserved in both groups. Conclusions Although conventional TTE variables show preserved LV size and function, LV longitudinal strain suggests subclinical myocardial dysfunction in patients with GDM. © 2016 Wiley Periodicals, Inc. J Clin Ultrasound, 2016

e12571 Background: There is no approved drug therapy for CNS mets from mBC. Eribulin mesylate (eribulin) is a microtubule inhibitor approved for treatment of mBC patients (pts) who have received at least 2 prior chemotherapy regimens. Previously reported cases have demonstrated significant CNS responses in mBC pts treated with eribulin. This study evaluates the CNS response in pts with mBC treated with eribulin. Methods: CASE7113 was a prospective phase II single-arm study to evaluate the 12-week CNS progression free survival (12-wk CNS-PFS) of pts with mBC and CNS mets treated with eribulin. 20 pts were to be enrolled to demonstrate a 40% 12-wk CNS-PFS (95% CI, 8.5% - 61.5%). All pts had radiologically confirmed mBC CNS lesions with at least one lesion that did not receive prior radiation or surgical resection. Eribulin was administered at standard dose of 1.4mg/m2 IV on days 1 and 8 of a 21 day-cycle. Pts underwent baseline and 12-week brain MRI. The study was closed due to slow accrual; an analysis of enrolled pts was performed. Results: 9 female pts were enrolled; median age was 56 (32-82) years. 55% and 67% had ER+ and/or PR+ and Her2+ mBC respectfully. 1 pt had triple negative breast cancer (TNBC). Median number of prior therapies was 3 (0-12). The 12-wk CNS-PFS (95% CI) was 88.9% (51.8% - 99.7%), the median PFS (95% CI) was 22.6 (4.3 - 31.9) weeks, the median OS (95% CI) was 15.7 (4.0 - 27.3) months. 4 pts achieved stable disease and 1 pt had a partial response. There were no unexpected toxicities. Conclusions: For mBCa pts with CNS mets, this estimate of 12-wk CNS-PFS suggests activity of eribulin and merits further investigation in this population in the context of clinical trials. Clinical trial information: NCT02581839.

e18127 Background: Metformin, an oral hypoglycemic agent, has been linked to favorable outcomes among patients (pts) with cancer (Coyle et al. Ann Oncol 2016). Wu et al. demonstrated better overall survival (OS) with metformin use in pts with mm and Diabetes Mellitus (DM) (Br J Cancer 2014). They also found that patient with steroid-induced DM [SID] had worse outcomes than pts with pre-existing DM [PDM]. However, Keller et al. did not find these associations in a study of VA mm pts (Blood 2015 126:4502). We evaluated the impact of DM and metformin use on outcomes of pts with mm in the SEER-Medicare database. Methods: We used SEER-Medicare claims from 2007-2013 for pts with newly diagnosed MM. DM was identified using ICD-9 codes, antidiabetic medications by Medicare part D prescription claims. Multivariate analysis was performed by Cox proportional hazard modelling to evaluate (1) Association of DM type (PDM or SID) with mm outcomes and (2) Impact of metformin on outcomes of pts with mm and DM. Covariates included age, gender, transplant, CKD (chronic kidney disease), CCI (Charlson Comorbidity Index), and use of other antidiabetic medications. Potential smoldering mm cases in the dataset were controlled for using a pre-established algorithm (Fakhri, et al,Blood 2016 128:2348) Results: Out of 4708 mm pts, 45% had DM. Among the pts with DM, 28% were on metformin. Out of the 2112 pts with DM, 20% had SID. Median follow up was 26 months. We found no association between PDM (aHR 1.04, 95% CI 0.96-1.12) or SID (aHR 1.03, 0.91-1.17) with OS when compared to non-diabetic pts. Metformin use, female gender, transplant and CCI < 5 were significantly associated with improved OS. Metformin use was associated with an 18% decrease in mortality (aHR 0.82, 0.72-0.93, p = 0.002); controlling for CKD did not impact the association (aHR 0.83 (0.73- 0.94, p = 0.005). Other antidiabetic medications including insulin were not associated with OS. Conclusions: DM (PDM or SID) and insulin use were not associated with poorer outcomes. Metformin use was associated with improved OS among pts with mm and DM in the SEER-Medicare database. The impact of metformin on outcomes in mm pts should be further investigated in prospective clinical trials.

Introduction: Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Patients not in remission prior to undergoing allo-HCT continue to have a very poor prognosis. Complete remission with incomplete cell count recovery (CRi) following chemotherapy for acute myeloid leukemia (AML) has also been associated with reduced overall survival and increased risk of relapse. However, there is currently a paucity of data on transplant outcomes in AML patients with ablated marrows after prior chemotherapy. In these patients, waiting for count recovery for an extended time period leads to increased infectious complications, often making them ineligible for allo-HCT. We hypothesized that outcomes of AML patients with pre-transplant ablated marrows who undergo allo-HCT would be similar to those of patients who are in complete remission (CR) prior to allo-HCT. To answer this question, we retrospectively analyzed the outcomes of AML patients from a single institution who underwent allo-HCT in CR, CRi, or with an ablated marrow. Patient and methods: For this retrospective study, we analyzed the outcomes of 270 AML patients (median age 54 years, range 17 to 74 years, 146 males and 124 females) who underwent 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at Washington University School of Medicine in St. Louis between 2006 and 2013. Patients with persistent disease based on bone marrow biopsy immediately prior to transplant were excluded. Data was collected on baseline characteristics including patient and donor sex, AML type, induction therapy, conditioning regimen, stem cell source, and graft-versus-host disease (GVHD) prophylaxis. Based on their cell count and marrow recovery prior to allo-HCT, patients were divided into 3 categories: CR, CRi, and ablated marrow, using response criteria from the International Working Group. The primary outcomes were overall survival (OS) and disease-free survival (DFS), and the secondary outcomes were cumulative incidence of non-relapse mortality (NRM), cumulative incidence of relapse, acute graft vs. host disease (aGVHD), and chronic graft vs. host disease (cGVHD). Propensity-score matching was used to adjust for potential confounding effects of patient characteristics, and the between-group differences in OS or DFS were compared by Cox proportional hazards model. Results: Of the 270 patients, 206 were in CR, 45 in CRi, and 19 had ablated marrow prior to their allo-HCT. Median follow-up for the CR, CRi, and ablated groups were 524, 410, and 290 days, respectively. The patients with ablated marrows had a 3-year OS of 47% and DFS of 40%, as compared to patients in CR whose 3-year OS and DFS were 49% and 45%, respectively (Fig. 1). Using a 1:3 propensity-score matching (3 CR per 1 ablated), no significant differences were found in OS (HR=1.66, 95% CI 0.88-3.12; P = 0.12) or DFS (HR=1.39, 95% CI 0.75 - 2.58; P = 0.30). The cumulative incidence of NRM in our ablated marrow cohort was 58%, significantly higher than those in CR and CRi who had cumulative incidences of NRM of 22% (P = 0.0004) and 16% (P = 0.002), respectively (Fig. 2). The cumulative incidence of grade 2-4 aGVHD in patients with CR, CRi, and ablated marrow, were 38%, 38%, and 42%, respectively (P = 0.93). Likewise, the cumulative incidence of cGVHD in patients with CR, CRi, and ablated marrow, were 34%, 38%, and 16%, respectively (P = 0.22). Conclusions: Allo-HCT continues to be the curative therapy for patients with AML. Based on our results, overall survival and disease-free survival following transplant for patients with ablated marrows do not differ significantly from those in CR or CRi. Interestingly, there was a higher incidence of non-relapse mortality among patient with ablated marrows compared to those in Cr or CRi, which is most likely related to the use of myeloablative conditioning regimen in our ablated patients. These results could have an important bearing on patients with ablated marrows whom treating physicians might post-pone allo-HCT to wait for marrow recovery, thereby potentially putting them at increased risk for infectious and bleeding complications. Smaller cohort size is the major limitation of our study, and our results suggest investigating this important question in a large registry. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

7018 Background: Relapse and graft failure continue to be major challenges after allogeneic hematopoietic stem cell transplantation (alloHSCT). There is no standard treatment for either condition a...

Cytomegalovirus (CMV) reactivation after allogeneic hematopoietic cell transplant (allo-HCT) has been associated with a reduced risk of relapse in patients with acute myeloid leukemia (AML). However, the influence of the conditioning regimen on this protective effect of CMV reactivation after allo-HCT is relatively unexplored. To address this, we evaluated the risk of relapse in 264 AML patients who received T cell–replete, 6/6 HLA matched sibling or 10/10 HLA matched unrelated donor transplantation at a single institution between 2006 and 2011. Of these 264 patients, 206 received myeloablative (MA) and 58 received reduced-intensity conditioning (RIC) regimens. CMV reactivation was observed in 88 patients with MA conditioning and 37 patients with RIC. At a median follow-up of 299 days, CMV reactivation was associated with significantly lower risk of relapse in patients who received MA conditioning both in univariate (P = .01) and multivariate analyses (hazard ratio, .5246; P = .006); however, CMV reactivation did not significantly affect the risk of relapse in our RIC cohort. These results confirm the protective effect of CMV reactivation on relapse in AML patients after allo-HCT reported by previous studies but suggest this protective effect of CMV reactivation on relapse is influenced by the conditioning regimen used with the transplant.

Pre-transplant remission status in patients with acute myeloid leukemia (AML) is one of the most important factors determining their outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). Most patients are in complete remission with full hematologic recovery (CR) prior to undergoing allo-HCT. However, some patients achieve CR without recovery of platelet count (CRp) or a morphologic leukemia-free state (MLFS), defined as meeting all CR criteria without recovery of both neutrophil and platelet counts. Currently, there is a paucity of data regarding transplant outcomes in AML patients achieving MLFS after chemotherapy. To address this question, we evaluated transplant outcomes in 270 AML patients who received 6/6 HLA-matched sibling or 10/10 HLA-matched unrelated donor transplantation at a single institution between 2006 and 2013. Of our 270 patients, 206 were in complete remission (CR), 45 were in complete remission with incomplete platelet count recovery (CRp), and 19 were in MLFS prior to allo-HCT. Patients in CR, CRp, or MLFS had similar 3-year overall survival (49%, 46%, and 47%, respectively; P = 0.88) and 3-year event-free survival (45%, 36%, and 40%, respectively; P = 0.53). However, the cumulative incidence of non-relapse mortality (NRM) was significantly higher in patients in MLFS compared to those in CR (58% vs. 22%, P =0.0004), while the cumulative incidence of relapse in patients in MLFS was significantly lower compared to those in CR (11% vs. 36%, P = 0.03). Our results suggest that survival outcomes in AML patients are not influenced by degree of hematologic recovery prior to allo-HCT.