High-risk Acute Myeloid Leukemia Patients Research Articles

Advances in therapeutic options for newly diagnosed, high-risk AML patients.

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by clonal proliferation of neoplastic immature precursor cells. AML impacts older adults and has a poor prognosis. Despite recent advances in treatment, AML is complex, with both genetic and epigenetic aberrations in the malignant clone and elaborate interactions with its microenvironment. We are now able to stratify patients on the basis of specific clinical and molecular features in order to optimize individual treatment strategies. However, our understanding of the complex nature of these molecular abnormalities continues to expand the defining characteristics of high-risk mutations. In this review, we focus on genetic and microenvironmental factors in adverse risk AML that play critical roles in leukemogenesis, including those not described in an European LeukemiaNet adverse risk group, and describe therapies that are currently in the clinical arena, either approved or under development.

Improved Outcome for High-Risk Acute Myeloid Leukemia Patients Using Autologous Bone Marrow Transplantation and Monoclonal Antibody-Purged Bone Marrow

AbstractWe have conducted a 9-year multicenter trial of autologous bone marrow transplantation (ABMT) for acute myeloid leukemia (AML). Remission BM was purged in vitro using monoclonal antibodies (MoAbs; PM-81, AML-2-23) and complement targeting myeloid differentiation antigens (CD15, CD14). In 1988, the preparative regimen changed from 60 mg/kg/d cyclophosphamide × 2 and fractionated total body irradiation (TBI) total dose, 1,200 cGy (Cy/fTBI), to 4 mg/kg/d busulfan × 4 and 60 mg/kg/d Cy × 2 (Bu/ Cy2). Recent analysis (October 1, 1993) shows that the Bu/Cy2 regimen along with the same MoAb purging method yields an improved outcome. Seven first complete-remission (CR) (CR1), 45 second- orthird-CR (CR2/3), and 11 first-relapse (R1) patients were treated with chemotherapy and TBI or chemotherapy alone followed by ABMT with MoAb-purged BM. Median age at ABMT for those patients in CR 2/3 and R1 patients was 36 years. Twenty-nine CR 2/3 and R1 patients were conditioned with Cy/ fTBI, and 27 CR2/3 and R1 patients were conditioned with Bu/CY. Using the Kaplan-Meier method, the CY/fTBI, CR2/3, and R1 patients have a 3-year disease-free survival (DFS) of 21 %. On the other hand, the Bu/Cy2, CR2/3, and R1 patients have a 3-year DFS of 48%. Nineteen CR2/3 and R1 patients relapsed post-ABMT. On analysis by conditioning regimen, those treated with Cy/fTBI have a 3-year relapse rate (RR) of 58%, whereas the patients conditioned with Bu/Cy2 have a 39% 3-year RR. Long-term DFS can be achieved in about 50% of patients with advanced remissions and relapsed AML using Bu/Cy2 with MoAb-purged BM.

The Molecular Characteristics and Clinical Relevance of NUP98-Other Translocations in Pediatric Acute Myeloid Leukemia

Background Cytogenetic and molecular aberrations are important prognostic factors in pediatric acute myeloid leukemia (AML). NUP98 translocations with more than 30 different partner genes have been identified in pediatric AML. The 2 most common fusions, NUP98-NSD1 and NUP98-KDM5A, have been shown to have distinct characteristics and are both associated with adverse outcomes. Although NUP98 fusions with less common fusion partners have been identified, the biological and clinical implications of these variants are unknown. Methods To determine the biological and clinical implications of the less common "other" NUP98 translocations (NUP98-X), we evaluated the clinical characteristics and transcriptome and genome sequencing data from 2396 children and young adults with AML within 4 consecutive Children's Cancer Group (CCG) and Children's Oncology Group (COG) trials CCG-2961, AAML03P1, AAML0531 and AAML1031. All NUP98-X translocations were confirmed by RNA sequencing. Results Of the 2396 patients screened, 164 patients (6.8%) had a NUP98 translocation. We identified 20 patients with a NUP98-X fusion (0.83%) and compared them with those with NUP98-NSD1 (n=110, 4.5%), NUP98-KDM5A(n=34, 1.4%), and a reference cohort without NUP98 translocations (n=2232). Translocation partners identified in the NUP98-X group were HOXA9 (n=4), HOXD13 (n=3), PHF15 (n=2), PHF23 (n=2), and single cases of BPTF, BRWD3, DDX10, HMGB3, HOXA13, KAT7, PRRX1, SET and TOP1. Besides the distinct characteristics of NUP98-NSD1 and NUP98-KDM5A, the NUP98-X group showed high inter-patient variance in clinical characteristics compared to our reference cohort. NUP98-X patients showed a clear bimodal age distribution with half of the patients being in the older age category and a similar number in the category <3 years (Figure 1). White blood cell count and blast percentages were in line with those of the reference cohort. We investigated the co-occurrence of common pediatric AML mutations within our cohort (Figure 2). There was a lack of additional driving mutations with the exception of WT1 mutations that are significantly more prevalent in the NUP98-X group compared to the reference cohort (25% vs 8%, p=0.018). NUP98-X patients with a WT1 mutation have a median age of 16.3 years compared to 2.3 years for those without a WT1 mutation. Also, in contrast to NUP98-NSD1 translocated patients, the co-occurrence of FLT3-ITD did not occur in NUP98-X translocated patients. Further, NUP98-X patients had a more varied transcriptome profile than did patients with NSD1 or KDM5A translocations (Smith J, et al. ASH abstract 2020). We evaluated the impact of NUP98-X translocations in response to the initial induction therapy. The morphological complete remission (CR) rate after course 1 was 65% in the NUP98-X cohort versus 76% in the reference cohort (p=0.266). NUP98-NSD1 patients had an inferior CR rate (36%, p<0.001), but the CR rate in NUP98-KDM5A patients was similar (77%) to the reference cohort. Of all NUP98-X patients, 11% underwent stem cell transplantation (SCT), compared to 17% in the reference cohort, 40% in the NUP98-NSD1 and 23% in the NUP98-KDM5A cohort. Outcome analysis for NUP98-X patients demonstrated that despite differences in disease characteristics, they have similar adverse outcomes as patients with NSD1 or KDM5A translocations (Figure 3). Overall survival (OS) at 5 years from diagnosis was 35% compared to 65% in the group without NUP98 translocations (p=0.006, Figure 3). Event-free survival was 35% for NUP98-X patients, compared to 48% for those without NUP98 translocations (p=0.282). These adverse outcome rates are comparable to those reported in studies on high-risk pediatric AML patients. Conclusion NUP98-X translocated pediatric AML patients represent a rare cohort with a high variability in both translocation partners and other clinical characteristics. Despite this heterogeneity, the OS of these patients is comparable to high-risk pediatric AML patients, which justifies a high-risk stratification of these patients and emphasizes the need for developing new treatment strategies. Further research within large patient cohorts is needed to investigate the biologic and clinical characteristics of these rare translocations and potential differences between the different NUP98-X fusion partners. Disclosures Kaspers: AbbVie: Ended employment in the past 24 months; Helsinn Healthcare: Ended employment in the past 24 months; Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees; Janssen R&D: Ended employment in the past 24 months. Cooper:Celgene: Other: Spouse was an employee of Celgene (through August 2019).

Comparison of FLU-BU12 Conditioning with the Standard BU-CY Myeloablative Regimen in High-Risk Pediatric ACUTE Myeloid Leukemia Patients Undergoing Allogeneic STEM Cell Transplantation

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for high-risk acute myeloid leukemia (AML).The preparative regimen consisting of busulfan and cyclophosphamide (BuCy) is considered as one of the classical myeloablative conditioning regimens (MAC); however, it is associated with significant early and long-term toxicities, leading to a high rate of transplant-related mortality (TRM). P urpose: To compare toxicities and outcomes of BuCy and FluBu12 conditioning in the pediatric population. Methods: We retrospectively analyzed 71 pediatric high-risk AML patients in CR1/2 (n=51, 71,8%) and R/R disease (n=20, 28,2%) received allo-HSCT from MSD (n=16, 22,5%), MUD (n=43, 60,6%) and Haplo donor (n=12, 16,9%). BuCy and FluBu conditioning regimens were used in 47 (66,2%) and 24 (33,8%) patients respectively. Median age was 6 years (0-17). GVHD prophylaxis was PTCy±CNI±m-TOR inhibitor in 32 (45%) or ATG±CNI in 39 (55%) patients. The primary end points were TRM, relapse-free survival (RFS), graft-versus-host disease (GVHD) free, relapse free survival (GRFS) and overall survival (OS). Secondary end points included neutrophil engraftment, sinusoidal obstruction syndrome (SOS), acute and chronic GVHD. Patient were censored at the time of death or last follow-up. Probabilities of OS, RFS and GRFS were estimated using Kaplan-Meier curves. TRM was defined as any death that occurred in the absence of disease relapse; relapse was a competing risk for this event. Results: Engraftment rate was 91% and 87,5% in patients received BuCy and FluBu, respectively (p=0,4). There was a trend to lower day 100 TRM after FluBu (4,1% vs 14,9% after BuCy, p=0,07). Overall survival at 2 years did not differ as well (BuCy 48,9%, FluBu 56%, p=0,5). BuCy showed borderline higher RFS at 2 years (70,2% vs 52%, p=0,06). The composite endpoint GRFS did not differ between two study cohorts being 31,8% and 29,2% at 2 years for BuCy and FluBu (p=0,7). We observed a tendency towards a higher incidence of III0-IV0 aGVHD and cGVHD following BuCy when compared with FluBu: 57,1% vs 41% (p=0,06) and 46,5% vs 28,5% respectively (p=0,2). No significant differences were found between the BuCy and FluBu groups in risk of SOS (6% and 8%, respectively). Conclusions: The optimal conditioning regimen for children with AML is still a matter of debate. Our results suggest that FluBu represents a valid myeloablative regimen, able to provide lower TRM, aGVHD and cGVHD. This conditioning might become an alternative approach in patients with a high risk of severe post-transplant complications. Disclosures No relevant conflicts of interest to declare.

Safety and Efficacy of Pembrolizumab Prior to Allogeneic Stem Cell Transplant in Patients with Acute Myeloid Leukemia

Introduction Up-regulation of inhibitory receptors, such as programmed death-1 (PD-1), is an integral component of acute myeloid leukemia (AML) immune evasion, chemotherapy resistance, and disease progression. Early phase clinical trials investigating immune checkpoint inhibitors (ICIs) in patients with AML have demonstrated promising findings. We previously reported that pembrolizumab administration on day 14 after high-dose cytarabine (HiDAC) salvage chemotherapy in patients with relapsed/refractory (R/R) AML was safe, feasible, and associated with encouraging clinical outcomes. PD-1 blockade prior to allogeneic stem cell transplant (alloSCT) has been associated with increased risks of alloSCT-related toxicity in lymphoma. AlloSCT remains the most established treatment paradigm for curative intent in AML patients who achieve a complete response (CR); however, there are limited data on the clinical outcomes and safety of ICI prior to alloSCT in AML. We set out to compare clinical outcomes of AML patients receiving pembrolizumab prior to alloSCT versus a control group of AML patients receiving alloSCT without prior ICI exposure. Methods We assessed clinical outcomes of patients who enrolled on a phase II clinical trial of HiDAC followed by pembrolizumab 200 mg IV on day 14 (NCT02768792) for R/R AML and subsequently underwent an alloSCT. Date of alloSCT was required to be >30 days from last dose of pembrolizumab. We matched each trial participant who underwent an alloSCT in a 1:2 ratio with controls who received alloSCT at our institution since 2016. Patients were matched on age, sex, age-adjusted hematopoietic cell transplantation-comorbidity index (HCT-CI), donor type, and conditioning intensity. The nonparametric Jonckheere-Terpstra test was used to test for a difference in the ordered severity categories of acute graft versus host disease (aGVHD) within 100 days of transplant. The time-to-event estimates for overall survival (OS) and relapse-free survival (RFS, event is either death or relapse) were calculated using the Kaplan-Meier method and compared using a log rank test. Results Nine out of 37 (24.3%) R/R AML patients treated with HiDAC followed by pembrolizumab received an alloSCT. Baseline characteristics of the R/R AML patients who received pembrolizumab versus R/R AML controls who underwent alloSCT are described in Table 1. One patient in each cohort received an alloSCT with evidence of active disease by flow cytometry (>5% blasts) or hematopathology IHC evaluation, whereas all other patients in both arms were in CR/CRi or MLFS at the time of alloSCT. The pattern of aGVHD severity was similar with the exception of 3 control patients (3/18 or 17%) having grade III-IV aGVHD versus 0/9 pembrolizumab patients (p = 0.92). Notably, 7/9 (78%) patients in the pembrolizumab cohort had no evidence of chronic GVHD. There was a nonsignificant increase in relapses (6/9: 67% vs. 6/18: 33%; p = 0.22) and deaths (6/9: 67% vs. 8/18: 44%, p = 0.42) in pembrolizumab versus control patients, respectively. The median follow-up for survivors was 23 months. Median OS was 21 months for pembrolizumab cohort versus 25 months for control patients. One-year OS was 67% (95% CI, 28%-87%) for pembrolizumab patients versus 78% (95% CI, 51%-91%) for control patients, p = 0.34. One-year RFS was 44% (95% CI, 14%-72%) for pembrolizumab patients versus 67% (95% CI, 40%-83%) for control patients, p = 0.14. Conclusion Treatment with ICI represents a promising therapeutic strategy for AML. Among a cohort of patients treated with HiDAC followed by pembrolizumab for R/R AML, alloSCT appeared to be feasible without increased risk of GVHD or early mortality. Although a small number of patients received alloSCT after pembrolizumab, OS appeared comparable to R/R AML controls who did not receive ICI. The increase in relapse rates seen in the pembrolizumab cohort may have been impacted by the higher proportion of patients with measurable residual disease (MRD) prior to alloSCT (78% vs. 39%, respectively). These data warrant further investigation of ICI prior to and after alloSCT in high-risk AML patients. Disclosures Tschernia: AstraZeneca: Research Funding. Vincent:GeneCentric Therapeutics: Consultancy. Coombs:Abbvie: Consultancy, Honoraria; Genentech: Honoraria; AstraZeneca: Honoraria; MEI Pharma: Honoraria; LOXO Oncology: Honoraria; Octapharma: Honoraria; Novartis: Honoraria. DeZern:MEI: Consultancy; Celgene: Consultancy, Honoraria; Abbvie: Consultancy; Astex: Research Funding. Luznik:WindMil Therapeutics: Patents & Royalties: Patent holder; Genentech: Research Funding; AbbVie: Consultancy; Merck: Research Funding, Speakers Bureau. Riches:Biointelect: Consultancy. Gojo:BMS: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Merck: Research Funding; Amphivena: Research Funding; Genentech: Research Funding. Zeidner:AbbVie: Honoraria, Other: Independent Review Committee; Agios: Honoraria; Daiichi Sankyo: Honoraria; Genentech: Honoraria; Pfizer: Honoraria; Takeda: Consultancy, Honoraria, Other: Travel Reimbursement, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; AsystBio Laboratories: Consultancy; AROG: Research Funding; Forty-Seven: Other: Travel Reimbursement, Research Funding; Merck: Research Funding; Sumitomo Dainippon Pharma Oncology, Inc.: Research Funding.

MDS1-EVI1 Complex (MECOM) Activation Promotes Leukemic Stem Cell Quiescence By Upregulating CDKN1C/P57Kip2

Background: Activation of MDS1-EVI1 Complex (MECOM) via proviral insertion at its gene locus (Morishita et al., 1988) or through chromosomal rearrangements at 3q26 (Suzukawa et al., 1994; Tang et al., 2019) results in marked overexpression of EVI1, and is predominantly associated with myeloid malignancies (Secker-Walker et al., 1995), especially high-risk acute myeloid leukemia (AML) (Barjesteh van Waalwijk van Doorn-Khosrovani et al., 2003). We previously showed that EVI1 overexpression skews hematopoiesis toward the myeloid lineage via the upregulation of a master regulator of myelopoiesis PU.1 encoded by SPI1 (SFPI1) (Ayoub et al., 2018), which explains the high cooccurrence of 3q abnormalities in myeloid malignancies. However, the role of EVI1 in reduced survival and high rates of relapse in AML patients is still unknown, and therapies specific for EVI1+ AML are absent due to the lack of EVI1 specific targets. Here we describe a novel mechanism of action of EVI1 in controlling leukemic stem cell quiescence by upregulating an essential member of the cyclin-dependent kinase inhibitor (cip/kip) gene family: CDKN1C/P57Kip2. Results: We first identified the upregulation of CDKN1C in the presence of EVI1 overexpression using RNA-seq on sorted hematopoietic stem and progenitor leukemia cells from our previously published EVI1+ leukemia mouse model (EVI1TO) (Ayoub et al., 2018). Since CDKN1C/ P57 expression has been linked to high relapse rates in AML patients following chemotherapy (Radujkovic et al., 2016), we confirmed the upregulation of CDKN1C using RNA-seq on sorted populations (mononucleated cells (MNCs), leukemia stem cells (LSCs), and minimal residual disease (MRD)) from activated-MECOM AML patients in comparison to nonactivated-MECOM high risk AML patients (67 samples from 27 patients). Additionally, we found EVI1 overexpression produces a reversible block in differentiation and engraftment that can be rescued by ablating EVI1 overexpression or by additional mutations. In an effort to identify EVI1-induced transcriptional regulations for CDKN1C, we performed chromatin immunoprecipitation and sequencing (ChIP-seq) and assayed for transposase accessible Chromatin (ATAC-seq) using our in vivo and in vitro EVI1 overexpression models. ChIP-seq for EVI1 showed a binding site for EVI1 located 300 kb from CDKN1C transcription start site (TSS), and ATAC-seq in EVI1 overexpressing AML showed an open chromatin pattern at the CDKN1C TSS only in the presence of EVI1 overexpression. We are presently investigating the molecular mechanism involved in the transcriptional regulation of CDKN1C in the presence of EVI1 overexpression. Conclusions: Our data suggest a correlation between EVI1 and CDKN1C expression in high risk AML with 3q abnormalities and provide insights into a potential molecular mechanism for MECOM activation in controlling leukemic stem cell quiescence and resistance to chemotherapy by upregulating CDKN1C. Disclosures Andreeff: Daiichi-Sankyo; Jazz Pharmaceuticals; Celgene; Amgen; AstraZeneca; 6 Dimensions Capital: Consultancy; Daiichi-Sankyo; Breast Cancer Research Foundation; CPRIT; NIH/NCI; Amgen; AstraZeneca: Research Funding; Centre for Drug Research & Development; Cancer UK; NCI-CTEP; German Research Council; Leukemia Lymphoma Foundation (LLS); NCI-RDCRN (Rare Disease Clin Network); CLL Founcdation; BioLineRx; SentiBio; Aptose Biosciences, Inc: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding.

Comparable outcomes of haploidentical transplant with TBF conditioning versus matched unrelated donor with fludarabine/busulfan conditioning for acute myeloid leukemia.

We compared transplant outcomes of 708 acute myeloid leukemia (AML) patients receiving haploidentical allogeneic hematopoietic-cell transplantation using thiotepa/busulfan/fludarabine (TBF) conditioning with posttransplant cyclophosphamide (ptCy), to 2083 patients receiving matched unrelated donor (MUD) transplantation using fludarabine/busulfan (FB) conditioning and in vivo T-cell depletion. For intermediate cytogenetic risk AML transplanted in first complete remission (CR1), multivariate analysis revealed that haplo-TBF significantly increased nonrelapse mortality (NRM) (HR 2.1; p = 0.0006) but did not affect relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS), or graft-versus-host disease-free, relapse-free survival (GRFS). For high cytogenetic risk AML transplanted in CR1, haplo-TBF significantly increased NRM (HR = 2.7; p = 0.02), decreased RI (HR = 0.45; p = 0.03) but had no influence on LFS, OS, or GRFS. For AML transplanted in CR2, haplo-TBF significantly increased NRM (HR = 2.36; p = 0.008), decreased RI (HR = 0.38; p = 0.005), but had no influence on LFS, OS, or GRFS. Finally, for AML patients transplanted with active disease, haplo-TBF had no influence on transplant outcomes. In conclusion, compared to MUD-FB, haplo-TBF increased NRM, reduced RI in high-risk AML in CR, resulting in similar LFS, OS, and GRFS. These results comparing two different approaches support the use of a haploidentical family donor for high-risk AML patients lacking a matched sibling donor.

Effect of rhG-CSF Combined with Decitabine Prophylaxis on Relapse in High-Risk Acute Myeloid Leukemia Patients after Hematopoietic Stem Cell Transplantation: An Open-Label, Multicenter, Randomized, Controlled, Phase 2 Trial

Background: Recurrence is a major cause of treatment failure after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for high-risk acute myeloid leukemia (HR-AML). Recent studies have indicated that granulocyte colony-stimulating factor (G-CSF) and DNA methyltransferase inhibitor Decitabine (Dec) have regulatory effects on T/B/NK lymphocytes and could help enhance the graft versus leukemia (GVL) effect after allo-HSCT. The aim of this study was to prove G-CSF combined with minimal-dose Dec could effectively prevent AML relapse after allo-HSCT. Methods: We did an open-label, multicenter, randomized, controlled, phase 2 trial. 204 HR-AML patients 60-100 days after allo-HSCT were randomized 1:1 to either rhG-CSF combined with minimal-dose decitabine (G-Dec: G-Dec group: 100 µg/m2 of rhG-CSF subcutaneous injection on days 0-5 and 5 mg/m2 of Dec infusion on days 1-5) or no intervention (non-G-Dec) groups. The primary outcome of the trial was relapse after transplantation, and the secondary outcomes were chronic graft-versus-host disease (cGVHD), the safety of the treatment, leukemia-free survival and overall survival. Findings: Between Apr 1, 2016, and Mar 21, 2019, 220 patients from 12 transplant centers were included in the clinical study, and 204 patients were randomly assigned to the study groups (102 patients in the G-Dec group and 102 patients in non-G-Dec group). Median follow-up was 30 months (IQR 6-38). Of 204 evaluable patients, the estimated cumulative incidence of 2-year relapse in the G-Dec group was 15.1 (95% CI 8.0-22.2) %, compared with 38.3 (95% CI 28.9-47.7) % in the non-G-Dec group (P<0.001). There was no difference between the two groups in the incidence of cGVHD without relapse (23.8[95% CI 15.4-32.2] % and 25.6[95% CI 16.2-35.0] %, p=0.844). The most common treatment-emergent adverse event (TEAE) was hypoleukocytosis. After rhG-CSF combined with minimal-dose Dec maintenance, increasing numbers of NK, CD8+ T and regulatory T (Treg) cells were observed. Interpretation: Our findings suggest that rhG-CSF combined with minimal-dose Dec maintenance after allo-HSCT can reduce the incidence of relapse, accompanied by changes in the numbers and subtypes of lymphocytes, leading to the acquisition of graft-versus-leukemia and immune tolerance. Trial Registration: This study is registered with www.chictr.org.cn, number ChiCTR-IIR-16008182. Funding Statement: This research was supported by the National Key Research and Development Program of China (2016YFA0202104 and 2017YFA0105504), the Chinese National Natural Science Foundation (No. 81370593, No. 81570131 and No. 81570097), the Chongqing Social Undertakings, People's Livelihood Guarantee and Technology Innovation Foundation (cstc2016shms-ztzx10003), the Chongqing Key Project of Basic and Frontier Research Program (cstc2015jcyjBX0077), the Chongqing National Natural Science Key Foundation (cstc2019jcyj-zdxmX0023), the Research Fund from the Clinical Foundation of Army Medical University (2018JSLC0034) and Xinqiao Hospital (2018YQYLY007). Declaration of Interests: All authors have agreed to the submission of this manuscript and have no conflicting financial interests to disclose. Ethics Approval Statement: The protocol and all amendments were approved by the China Registered Clinical Laboratory Ethics Committee and the institutional review boards at each of the 12 participating institutions.

Maintenance Therapy with Decitabine after Allogeneic Hematopoietic Stem Cell Transplantation to Prevent Relapse of High Risk Acute Myeloid Leukemia

Background: Relapse remains the main cause of treatment failure post transplantation. Relapse prevention is an important strategy for acute myeloid leukemia (AML) patients. M ethods: We retrospectively analyzed the results of21 high risk AML patients who received a median number of 3 courses (range, 2 - 8) of decitabine (DAC) maintenance treatment (20mg/m2/d ×5d every 3 months for 1 year). Meanwhile, another 63 high risk AML patients without any prophylactic treatment after transplantation were included as a control group for 1:3 pair matched study. Results: With median follow-up of 23 months, 20 out of 21 (95.2%) patients maintained complete molecular remission (CMR) in DAC group, while 35 out of 63 (55.6%) patients maintained CMR in control group. Comparing with control group, the patients of DAC group had higher 3-year overall survival (OS) rates and 3-year leukemia free survival (LFS) rates (92.9% vs 51.8%, P =0.003; 94.1% vs 54.7%, P=0.002 respectively). Moreover, DAC maintenance was well tolerated in all patients and grade 3/4 or 4/4 hematological toxicities were observed in 11 of 21 (52.4%) patients. Conclusion: Our results suggested that DAC maintenance therapy was an effective and safe treatment option to prevent relapse after transplantation for high risk AML patients. Disclosures No relevant conflicts of interest to declare.

Durable Responses and Survival in High Risk AML and MDS Patients Treated with an Allogeneic Leukemia-Derived Dendritic Cell Vaccine

Background. Maintenance of induced responses remains a significant unmet medical need in patients with acute myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS) not eligible for allogeneic hematopoietic stem cell transplantation (HSCT). The allogeneic leukemia-derived dendritic cell vaccine, DCP-001, has shown to generate both humoral and cellular immune responses and is safe for clinical practice (van de Loosdrecht et al., Cancer Immunol. Immunother. 2018). In this study we show additional data on long-term follow up and patient-related risk factors from the phase 1 study. Methods. AML- or MDS-patients (n=12), ineligible for HSCT, were included in a post-hoc clinical analysis of the DCP-001 phase I trial, receiving DCP-001 vaccination at the Amsterdam University Medical Center, VU University Medical Center, Amsterdam, the Netherlands (NCT01373515). All clinical data, including baseline characteristics as cytogenetics, pre-and post-vaccination treatment and morphologic blast counts in follow up, were retrospectively collected from corresponding patient files. Targeted next generation sequencing (NGS) gene panel data and cytogenetics were utilized to determine (cyto-)genetic risks following the European Leukemia Net (ELN) 2017 criteria. We defined 'response' as decreased or stable morphologic blast counts in bone marrow at day 126 (last day of official study evaluation) compared to study entry. Results. Seven out of twelve patients responded to treatment, the other patients showed progressive disease (data are summarized in table 1). The median relapse free survival (RFS) for the responding patients was 420 days (range 90-1849) and overall survival (OS) was 1090 days (90-2160); two patients died early in complete remission (CR) due to infection (respectively at 90 and 184 days). Notably, three of these patients were intermediate risk and four were poor risk patients based on the ELN risk classification for AML or Revised International Prognostic Scoring System (IPSS-R) for MDS. The median OS for the non-responders was 144 days (range 59-209). These five patients had relapsed or refractory disease at start of vaccination with detectable circulating peripheral blasts; four of them received additional azacitidine (AZA) therapy prior to vaccination. Moreover, they were vaccinated after induction and consolidation therapy with a median time between diagnosis and first vaccination of 611 days (219-2310) compared to 240 days (105-1398) for the seven responding patients. Of the latter, all were in complete remission (CR) (n=5) or had morphologic marrow blast counts &amp;lt;10% (n=2) at the start of vaccination. Two responders that progressed and two that relapsed after vaccination were treated with AZA, resulting in one complete remission and two partial responses (one non-evaluable due to sample failure), see figure 1. Conclusion/discussion. Clinical data of the phase 1 trial show that DCP-001 may prolong duration of remission or smoldering disease in intermediate and high risk AML or MDS patients. Response was associated with treatment by vaccination shortly after achieving CR. This should be taken into account in selection criteria of future vaccination studies. Hence, an international multi-center phase 2 study (ADVANCE II; NCT03697707) is currently being conducted to determine the effect of DCP-001 on measurable residual disease (MRD) in AML patients, aiming to convert them to a MRD negative state. Furthermore, we demonstrated that AZA can be applied as rescue therapy upon progression after vaccination. Disclosures Rovers: DCprime: Employment. Cloos:Daiicchi Sankyo: Speakers Bureau; Glycomimetics: Research Funding; Takeda: Research Funding; Novartis: Other: MRD assessments of clinical trials, Research Funding; Merus: Other: MRD assessment of a clinical trial , Research Funding; Genentech: Consultancy, Research Funding; Helsinn: Other: MRD assessment of a clinical trial; DCPrime: Other: MRD assessment of a clinical trial. de Gruijl:DCprime: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Decitabine As Part of a Modified Bu-Cy Conditioning Regimen Significantly Improved the Outcome of High-Risk AML Patients Undergoing Allogeneic Hematopoietic Stem Cell Transplantation

Background :Relapse remains a major cause of death after allogeneic hematopoietic stem cell transplantation (allo-HSCT), especially in patients with high-risk acute myeloid leukemia (AML). Therefore, how to eradicate the minimal residual disease and prevent of relapse are of great importance to improve the outcome of allo-HSCT for these high risk AML patients. M ethods :We retrospectively investigated decitabine (DAC) as part of a modified Bu-Cy regimen for high-risk AML patientsundergoing allo-HSCT. Fifty-nine patients received DAC (20 mg/m2/d,i.v.) for 5 days, followed by modified Bu-Cy (DAC group). A control (CON) of 177 patients (pair-matched 1:3) received modified Bu-Cy only. Results:Median follow-up was 402 (85-1504) days. There was no difference in graft versus-host disease occurrence. Treatment-related mortality (day 100) was 0% (DAC) and 6.2% (CON). The DAC group had better 2-year overall survival (OS, 77% versus 64%, P=0.018) and leukemia-free survival (LFS, 73% versus 56%, P=0.007). The differences were more substantial among patients with active disease: OS, 83% (DAC) versus 47% (CON), P=0.01 and LFS, 77% (DAC) versus 34% (CON), P=0.002. Median time to relapse was 187 days (DAC) versus 86 days (CON) and two-year relapse rates were 10% (DAC) and 49% (CON) for patients with active disease. Patients with cytogenetic monosomy 7 or 7q- abnormality responded better. Conclusions: Our data indicate that novel conditioning regimen containing DAC may be an effective and well-tolerated strategy and confer a subgroup-specific survival advantage in high-risk AML patients undergoing allo-HSCT. Disclosures No relevant conflicts of interest to declare.

In-Hospital Morbidity and Mortality Among Acute Myeloid Leukemia Patients Admitted for Hematopoeitic Stem Cell Transplants between 2002-2014

Introduction: Acute myeloid leukemia (AML) is a disease with poor overall prognosis, about 4.3 per 100,000 men and women per year are diagnosed with AML with a deaths rate of 2.8 per 100,000. The incidence of AML increases with age which leads to an older population with multiple comorbidities and inferior prognosis. Hematopoietic stem cell transplant (HCT) remains the standard of care in most intermediate and high-risk AML patients. However, HCT puts these patients at risk of severe cytopenia, opportunistic infections, acute graft versus host disease and financial stress, especially in the early phases of transplant. The purpose of this study is to identify the annual trends in in-hospital mortality and morbidity associated with patients with AML admitted for HCT and impact of comorbid conditions on the likelihood of death during admission. Method Data was collected from the National Inpatient Sample from the years of 2002 to 2014. Admissions for HCT for acute myeloid leukemia patients were identified using a procedural clinical classification software code for bone marrow transplants in combination with ICD 9 codes for acute myeloid leukemia. Annual trends in mortality, hospital length of stay, and costs of admission were assessed with a linear regression analysis. Univariate logistic regression analysis was used to test for associations between chronic medical conditions and mortality among these patients. Co-morbid conditions were identified using the Agency for Healthcare Research and Quality comorbidity measures for underlying chronic conditions in patients in 2013 to 2014. Results: Between and including the years of 2002 to 2014, a total weighted estimate of transplants for acute myeloid leukemias in the United States totaled 31,811 (N=6,102). Annual transplants increased from 1,761 in 2002 to 3,030 in 2014. In-hospital mortality decreased from 8.4% in 2002 to 4.8% in 2014 (p=0.02). The mean length of stay remained unchanged from 32.8 days in 2002 to 32.7 days in 2014. Costs of admission increased from $226,280 to $474,106. In-hospital mortality in the years 2013 and 2014 were most strongly associated with comorbid conditions of congestive heart failure (Odds ratio (OR)=5.93), weight loss (OR=4.32), coagulopathy (OR=3.84), liver cirrhosis (OR=3.41). Any two of these conditions increased the OR to 8.34. Conclusions: HCTs have traditionally been associated with high upfront including in-hospital mortality. Our data demonstrates that in the last two decades mortality has been reduced by almost 50% while the length of hospital stay has not changed. This could be related to improvements in supportive care and better selection of conditioning regimens for the patients. It also shows that the costs of hospitalization has doubled. Congestive heart failure, weight loss, underlying coagulopathy and liver cirrhosis are most strongly associated with worse outcomes with any combination of these further potentiating risk of death. Careful selection of patients with special attention to the pre-existing comorbidities is the key to improving early outcomes in HCT. Consideration should also be given to expanding infrastructure to perform outpatient transplants to bend the cost curve. Disclosures No relevant conflicts of interest to declare.

Superior Graft-Versus-Leukemia Effect in Haploidentical Transplantation Compared with HLA-Matched Sibling Transplantation for High-Risk Acute Myeloid Leukemia in First Complete Remission: A Prospective Multicentre Cohort Study

This study aimed to investigate graft-versus-leukemia (GVL) of haploidentical donor (HID) compared with HLA-matched sibling donor (MSD) for high-risk acute myeloid leukemia (H-AML) in first complete remission (CR1). One hundred and eighty-nine patients with H-AML in CR1 were enrolled in this multicentre prospective cohort study. Patients were assigned to groups transplanted with HID (n=83) or MSD (n=106) based on donor availability (biological randomization). The primary endpoint was the incidence of MRD positivity post-transplantation (post-MRD+). All post-MRD+ patients received preemptive interventions. The cumulative incidences of post-MRD+ were 18% and 42% in HID and MSD groups, respectively, (p&lt;.001). Fifty-two patients received preemptive DLI, including 13 (16%) in HID and 39 cases (37%) in MSD groups (p=.001). Among HID and MSD groups, the 3-year cumulative incidence of relapse were 14% and 24% (p=0.101); the 3-year cumulative incidence of treatment-related mortality were 15% and 10% (p=0.368); the 3-year overall survival rates were 72% and 68% (p=0.687); the 3-year disease-free-survival were 71% and 66% (p=0.579); the 3-year graft-versus-host disease and relapse free survival were 63% and 43% (p=0.035), respectively. HID has a stronger GVL than MSD in H-AML patients. HID transplantation as post-remission therapy should be recommended as one of the optimal choices for H-AML in CR1. Disclosures No relevant conflicts of interest to declare.

Influence of alternative donor type on early survival after hematopoietic stem cell transplantation for acute myeloid leukemia lacking a sibling donor.

Allogeneic hematopoietic stem cell transplantation is the only potentially curative therapy for acute myeloid leukemia. In the absence of an HLA-matched related or unrelated donor (MRD or MUD), the best alternative donor source remains controversial. Umbilical cord blood and haploidentical donors offer a shorter delay from indication to transplantation. This retrospective multicentre study of a French registry compares overall survival in the 18 months following registration in the absence of a MRD between four types of donors. Between 2012 and 2016, 1302 patients were transplanted using MUD (control, n = 803), mismatched MUD (n = 219), umbilical cord blood (n = 153) and haploidentical (n = 127) donors. Multivariate analyses were conducted for overall survival after registration, after transplant, and transplant-related mortality. After adjustment for variables, the type of donor did not influence any of the three end points. Our results confirmed the significant negative impact of longer time between registration and transplant: HR = 1.04 [1.02-1.06] (p < 0.0001). This indicates a positive correlation between better survival and shorter registration-to-transplantation wait time. In the absence of a sibling donor, the alternative stem cell source does not impact early survival in acute myeloid leukemia patients. The minimization of registration-to-transplantation time should be considered when weighing the alternative donor options.

A Sampling of Highlights from the Literature

New clonotypes recruited (by Staff Sergeant K. Brasier via U.S. Air Force)To identify which tumor-specific T cells are active after anti–PD-1 therapy of basal cell carcinomas, single cells from biopsies before and after treatment were analyzed for gene expression and TCR usage. T cells already exhausted before anti–PD-1 therapy were not reactivated. Instead, novel clonotypes (only a small fraction of which had previously expressed TCF7) replaced those, transiting from memory to activated states. This was also true of squamous cell carcinoma, suggesting that checkpoint blockade prompts a new wave of immunoevolution and that the tumor's ability to constantly attract new T cells may be key to successful responses.Yost KE, …, Chang HY. Nat Med 2019 Aug 1;25:1251–9.CD163+ TAMs infiltrating melanomas (from Fig. 1C Etzerodt et al. J Exp Med 2019)Tumor-associated macrophages (TAMs) can contribute to tumor cell immune evasion, which is dependent on their phenotype and the tumor microenvironment (TME). Barkal et al. show that ovarian and breast cancers overexpress CD24, which relays “don't eat me” signals to TAMs via interaction with Siglec-10. Etzerodt et al. demonstrate that in melanomas refractory to anti–PD-1, CD163+ TAMs are elevated. Immunotherapies that target either surface molecules (such as CD24) or cell types (such as CD163+ TAMs) that promote immune evasion can alter the TME, resulting in enhanced antitumor immunity.Barkal AA, …, Weissman IL. Nature 2019 Aug 15;572:392–6.Etzerodt A, …, Lawrence T. J Exp Med 2019 Aug 2. DOI: 10.1084/jem.20182124.Optimizing the anti–PD1 schedule (by Best Picko via Flickr)Optimizing the efficacy of combination therapies involves determining their ideal schedule. In anti–PD-1–resistant murine tumor models, peptide vaccination plus anti–PD-1 slows tumor growth, whereas exposure to anti–PD-1 before combination treatment abrogates effectiveness. Anti–PD-1 causes suboptimal antigen priming of intratumoral CD8+ T cells, leading to increased dysfunction, higher PD-1+ CD38hi frequency, and more death. Anti–PD-1 responder patients have fewer intratumoral PD-1+ CD38+ CD8+ T cells compared to nonresponders, suggesting a predictive biomarker for anti–PD-1. Thus, T-cell priming prior to anti–PD-1 therapy is crucial for its efficacy.Verma V, …, Khleif SN. Nat Immunol 2019 Sep 1;20:1231–43.IFN opposing itself (via Max Pixel)Resistance to immune checkpoint blockade (ICB) is complex. Tumor-produced IFNγ sets up feedback loops that promote intrinsic tumor resistance and inhibit innate and adaptive immunity. Blocking IFN-stimulated gene expression from MHC class Ilow tumors can restore ICB responsiveness, stimulating tumor killing via TRAIL by NK and type 1 innate lymphoid cells (ILC1s). ICB treatment enhances IFNγ produced by CD8+ exhausted T (TEX) cells (that had been inactivated through PD-1 engagement), which supports NK/ILC1 cell maturation; TEX cells can also kill those tumor cells with adequate MHC class I, via the granzyme B/perforin pathway.Benci JL, …, Minn AJ. Cell 2019 Aug 8;178:933–48.e14.Engineering increased functionality (by N. Pawar via MotorsGarage)The affinity of a TCR for its target can affect antileukemia responses in patients with acute myeloid leukemia (AML) treated by hematopoietic cell transplantation (HCT). Engineered T cells bearing a high-affinity TCR targeting antigen WT1 (called TCRC4) can kill AML cells, are polyfunctional, and have increased persistence in vivo. When infused into patients after HCT, TCRC4 T cells reduced AML relapse. Thus, these engineered T cells could extend antileukemia T-cell persistence and reduce relapse in high-risk AML patients after HCT or other standards of care.Chapuis AG, …, Greenberg PD. Nat Med 2019 Jul 3;25:1064–72.Conditioning of hosts (by didkog via Pixabay)The efficacy of adoptive cell therapy (ACT) for cancer depends on prior lymphodepletion of recipients: IL-1β increases after this “conditioning.” Adding IL-1β to ACT therapy greatly improves therapeutic responses by increasing the number of effector CD8+ T cells in tumors and tumor-draining lymph nodes compared to ACT alone, in an IL-2/IL-15–mediated manner. IL-1β improves the trafficking of CD8+ T cells into peripheral organs and primes the host to better support effector CD8+ T-cell survival in these organs. Thus, treating patients with IL-1β may improve ACT efficacy.Lee P-H, …, Restifo NP. J Exp Med 2019 Aug 12. DOI: 10.1084/jem.20181218.

Maintenance therapy in AML: The past, the present and the future.

Curative treatment in acute myeloid leukemia (AML) depends on successful induction therapy to achieve a complete remission (CR), and subsequent post-remission therapy to prevent relapse. High relapse rates after consolidation therapy and after allogeneic stem cell transplant contribute to suboptimal outcomes in AML patients, and continue to represent a difficult challenge. Effective maintenance therapy could play an important role in prolonging the remission interval in the post-consolidation setting, especially in high risk AML patients. Maintenance treatment approaches based on conventional chemotherapy, immunotherapy, hypomethylating agents, and targeted small molecules have been explored in this setting, but no data so far have been convincing enough to establish this approach as the standard of care. However, ongoing and future studies including novel targeted therapies may demonstrate promising efficacy that could facilitate incorporation of maintenance therapy into clinical practice. In this review we summarize previous and ongoing approaches of maintenance therapy in AML and discuss the most promising strategies.

Haploidentical, Unmanipulated Granulocyte Colony-Stimulating Factor (G-CSF)-Primed Peripheral Blood Stem Cell Transplants for Acute Myeloid Leukemia (AML) in Remission: A Single Center Experience.

BackgroundData about application of related haploidentical allogeneic hematopoietic stem cell transplantation (haplo-HSCT) on patients with high-risk or intermediate-risk acute myeloid leukemia (AML) in the first complete remission (CR1) are lacking. In this study, we report the outcomes of using unmanipulated haploidentical allogeneic peripheral blood stem cell transplantation (haplo-PBSCT) as post-remission therapy for patients with high-risk or intermediate-risk AML in CR1.Material/MethodsFrom January 2008 to July 2016, 33 patients diagnosed as high-risk or intermediate-risk AML in CR1 undergoing haplo-PBSCT in our institution were enrolled for analysis. The cumulative incidence of platelet and neutrophil recovery, the occurrence of acute graft-versus-host-disease (GVHD) and chronic GVHD, relapse and non-relapse mortality were assessed. Patients’ survival rates were estimated using the Kaplan-Meier method.ResultsThe cumulative incidence of grade 2–4 acute GVHD, overall and extensive chronic GVHD was 18.2%, 9.1%, and 6.1%, respectively. 2-year probability of relapse was 9.1%. Disease-free survival and overall survival at 2 years were 72.7% and 75.8%, respectively.ConclusionsOur results showed that unmanipulated haploidentical transplantation with G-CSF primed PBSC alone as a graft source could be an acceptable alternative post-remission treatment for high-risk or intermediate-risk AML patients in CR1 lacking a matched donor.

Efficacy of All-Trans-Retinoic Acid in High-Risk Acute Myeloid Leukemia with Overexpression of EVI1

IntroductionEVI1 (MECOM)-positive acute myeloid leukemia (AML) cells have shown in vitro sensitivity to all-trans-retinoic acid (ATRA) by inducing differentiation, cell death, and decreased leukemic engraftment.MethodsIn this pilot study, we investigated the response to ATRA in 13 high-risk AML patients with overexpression of EVI1.ResultsSeven of the 13 patients (53.8%) achieved complete remission (CR), and response can be combined with a decreased of the leukemia stem cell pool.ConclusionThese primary results tend to confirm in vitro results and suggest that addition of ATRA might be of benefit in the treatment of patients with EVI1-positive AML.

Effect of rhG-CSF Combined with Decitabine Prophylaxis on Relapse in High-Risk Acute Myeloid Leukemia Patients after Hematopoietic Stem Cell Transplantation: An Open-Label, Multicenter, Randomized, Controlled, Phase 2 Trial

Effect of rhG-CSF Combined with Decitabine Prophylaxis on Relapse in High-Risk Acute Myeloid Leukemia Patients after Hematopoietic Stem Cell Transplantation: An Open-Label, Multicenter, Randomized, Controlled, Phase 2 Trial

Lenalidomide Plus Hypomethylating Agent for Acute Myeloid Leukemia (AML) with Recurrent Genetic Abnormalities -AML with Inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, Mecom

Intro: Acute myeloid leukemia (AML) is a heterogeneous clonal hematopoietic neoplasm. The cytogenetic changes associated with AML impact response rate and survival, and is one of the most important independent prognostic factors. AML with inv(3)(q21.3q26.2) or; GATA2, MECOMaccounts for 1-2% of all forms of AML. This form is associated with a younger age at diagnosis, poor response to standard induction chemotherapy, and very poor long-term prognosis with an overall survival of <10%. Unfortunately, traditional intensive induction chemotherapy has a reported remission rates of 10-20% (Raya et al. Hematology 2015;20(8):435-441). Clearly, alternative chemotherapy approaches are needed to effectively treat AML with inv(3). We previously presented a case report of a patient with inv(3) receiving induction chemotherapy with a combination of a hypomethylating agent (HMA) with lenalidomide and achieving remission (Platzbecker, et al. Leukemia 2013;27:1813-1819, Foucar et al. American Journal of Clinical Pathology2015; 144(1): 6-18). To further address the effectiveness of this regimen, we performed a retrospective cohort study comparing outcomes with HMA plus lenalidomide to standard intensive induction therapies in newly diagnosed and relapsed/refractory AML with inv(3).Methods: We conducted a single-center, IRB-approved, retrospective cohort analysis of 939 patients who received therapy for AML at the University of Michigan between March 2005-June 2018. 15/939 (1.6%) patients tested positive for inv(3)(q21.3q26.2), and they were divided into two cohorts: a lenalidomide-based regimen or other chemotherapy induction approaches. Data abstraction of patient, disease and treatment-related variables was performed through manual chart review. The primary outcome was overall response rate (ORR), reported as the combination of complete remission (CR) and complete remission with incomplete count recovery (CRi). Secondary endpoints included overall survival (OS), 30- and 60-day mortality, event free survival (EFS), and duration of response. All data were analyzed using SPSS software, version 24.0 (SPSS, Inc., Chicago, IL).Results: In total, 15 patients were positive for inv(3)(q21.3q26.2) and underwent treatment at the University of Michigan. 4/16 (25%) received lenalidomide and HMA as primary therapy. Patient demographics and lab values at diagnosis are shown in Table 1. 4/4 (100%) of patients receiving lenalidomide with HMA as first line therapy achieved CR/CRi while 3/11 (27.3%) of patients receiving other chemotherapeutic agents initially achieved CR/CRi (p=0.0256). Duration of response was numerically longer in patients receiving lenalidomide-based therapies (7.4 months vs. 1.45 months; p=0.057). Primary and secondary outcomes in patients receiving lenalidomide plus HMA and other chemotherapies are shown in Table 2. 2/13 patients requiring salvage therapy received lenalidomide with HMA. Both of these patients achieved CR/CRi, while 3/11 (27.3%) of patients receiving other chemotherapy achieved CR/CRi. Combining initial and salvage inductions, 6/6 (100%) achieved CR/CRi with lenalidomide with HMA versus 6/22 (27.3%) with other chemotherapy (p=0.0025).Discussion: AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOMis notorious for a poor response to standard induction chemotherapy and a reported remission rate of 10-20% with traditional chemotherapy (Raya et al. Hematology 2015;20(8):435-441).In this cohort, all patients who received lenalidomide with or without a HMA achieved CR/CRi compared to 27% of patients receiving other chemotherapy. Importantly, the median duration of response with lenalidomide and HMA was longer than traditional chemotherapy, although not statistically significant, likely due to the small sample size. The high ORR and reasonable duration of response could allow for potentially curative alloHCT in these high-risk AML patients. Our study is limited by the small sample size due to the rarity of this AML subtype, but the initial data suggests that lenalidomide plus HMA is a promising approach for patients with AML with inv(3)(q21.3q26.2) or t(3;3)(q21.3;q26.2); GATA2, MECOM. A multicenter, prospective trial should be considered to compare the efficacy of traditional cytotoxic chemotherapy approaches versus lenalidomide plus HMA to improve outcomes in this subtype of AML. [Display omitted] DisclosuresBixby:GlycoMimetics: Research Funding.