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Adolescents and young adults (AYAs) with acute lymphoblastic leukemia have improved outcomes when treated with pediatric-inspired regimens. CALGB 10403 was the largest prospective study to evaluate the feasibility of using a pediatric regimen in AYAs with acute lymphoblastic leukemia up to 40 years of age. This article presents the toxicity events observed in the CALGB 10403 study and compares these toxicities vs those observed among AYAs treated on the same arm of the companion Children’s Oncology Group (COG) AALL0232 study. Toxicities in CALGB 10403 were similar to those observed in COG AALL0232. Some grade 3 to 4 adverse events were more often reported in CALGB 10403 compared with COG AALL0232 (hyperglycemia, hyperbilirubinemia, transaminase elevation, and febrile neutropenia). Adverse events correlated with body mass index ≥30 kg/m2 and some with increasing age. The mortality rate in CALGB 10403 was low (4%) and similar to that in the COG AALL0232 trial. A caveat to this analysis is that only 39% of CALGB 10403 patients completed all planned protocol treatment. In COG AALL0232, although 74% of patients aged

Background Patients with relapsed/refractory (R/R) Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) have a poor prognosis and limited treatment options. Methods The efficacy of inotuzumab ozogamicin (InO), a humanized anti‐CD22 monoclonal antibody conjugated to the cytotoxic antibiotic calicheamicin, was evaluated in R/R ALL patients in the phase 1/2 study 1010 (NCT01363297) and open‐label, randomized, phase 3 study 1022 (INO‐VATE; NCT01564784). This analysis focused specifically on Ph+ R/R ALL patients. In study 1022, Ph+ patients were randomly assigned 1:1 to InO (n = 22) or standard intensive chemotherapy (SC) (n = 27) and 16 Ph+ patients in study 1010 received InO. Results In study 1022, rates of complete remission/complete remission with incomplete hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity (patients achieving CR/CRi) were higher with InO (CR/CRi = 73%; MRD = 81%) versus SC (CR/CRi = 56%; MRD = 33%). The corresponding rates in study 1010 were 56% (CR/CRi) and 100% (MRD). The hematopoietic stem cell transplantation (HSCT) rate in study 1022 was 41% versus 19% for InO versus SC; however, there was no benefit in overall survival (median OS: 8.7 vs 8.4 months; hazard ratio, 1.17 [95% CI, 0.64‐2.14]). The probability of being event‐free (progression‐free survival) at 12 months was greater with InO versus SC (20.1% vs 4.8%). Conclusion Given the substantial improvement in responses and rates of HSCT, InO is an important treatment option for patients with R/R Ph+ ALL. Future studies need to consider better characterization of disease characteristics, more sensitive MRD measurements, MRD‐directed therapy before HSCT, and potentially combination therapies, including tyrosine kinase inhibitors., An analysis of 65 patients with relapsed/refractory Philadelphia chromosome‐positive acute lymphoblastic leukemia shows that patients receiving inotuzumab ozogamicin (InO) have higher rates of complete remission/complete remission with incomplete hematologic recovery, minimal residual disease negativity, and subsequent hematopoietic stem cell transplantation than those receiving standard intensive chemotherapy (SC). Although this does not result in prolonged progression‐free survival or overall survival compared with SC, InO remains an important treatment option for patients with resistant and difficult‐to–treat disease.

FF-10501-01 potently inhibits inosine-5-monophosphate dehydrogenase (IMPDH), inducing anti-proliferative and pro-apoptotic effects in acute myeloid leukemia (AML) human cell lines resistant to hypomethylating agents. In this Phase 1/2a study, Phase 1 enrolled 38 patients with relapsed/refractory AML (

Introduction: CRS is a potentially life-threatening toxicity observed following T cell-redirecting therapies. CRS is associated with elevated cytokines, including IL6, IFNγ, TNFα, IL2 and GM-CSF. Glucocorticosteroids (GC) and the IL6 receptor blocking antibody tocilizumab (TCZ) can reduce CRS severity; however, CRS may still occur and limit the therapeutic window of novel immunotherapeutic agents. Disruption of cytokine signaling via Janus kinase (JAK) pathway interference may represent a complementary approach to blocking CRS. Ruxolitinib (RUX), an oral JAK1/2 inhibitor approved for the treatment of myelofibrosis and polycythemia vera, interferes with signaling of several cytokines, including IFNγ and IL6, via blockade of the JAK/STAT pathway. We hypothesized that RUX may reduce the frequency and severity of CRS in R/R AML patients (pts) undergoing treatment with flotetuzumab (FLZ), an investigational CD123 x CD3 bispecific DART® molecule. Methods: Relapse/refractory (including primary induction failure, early relapse and late relapse) AML pts were included in this study. RUX pts were treated at a single site, Washington University, St. Louis, MO. RUX was dosed at 10 mg or 20mg BID days -1 through 14. Comparator (non-RUX) pts (n=23) were treated at other clinical sites. FLZ was administered at 500 ng/kg/day continuously in 28-day cycles following multi-step lead-in dosing in week 1 of cycle 1. CRS was graded per Lee criteria1. Results: As of July 1st, 2020, 10 R/R AML pts, median age 65 (range 40-82) years, have been enrolled and treated in the RUX cohort (6 at 10mg, 4 at 20 mg of RUX). All pts had non-favorable risk by ELN 2017 criteria (8 adverse and 2 intermediate); 1 (10.0%) pt had secondary AML; pt characteristics in the RUX and non-RUX cohorts were balanced, except for median baseline BM blasts which was higher in non-RUX pts: 15% (range 5-72) vs (40% (range 7-84), RUX and non-RUX pts respectively. Cytokine analysis showed statistically significant (p Conclusion: Prophylactic RUX produced a clear difference in cytokine profiles but no discernable improvement in clinical CRS or response rates in FLZ treated patients. A larger study may be required to determine the prophylactic role of RUX in CRS. References: 1. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014; 124(2): 188-195. doi: 10.1182/blood-2014-05-552729 Disclosures Uy: Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Daiichi Sankyo: Consultancy; Astellas Pharma: Honoraria. Aldoss:abbvie: Consultancy, Research Funding; kite: Consultancy; agios: Honoraria; autolus limited: Consultancy; JAZZ: Honoraria, Speakers Bureau; Amgen: Consultancy; Agios: Consultancy. Arellano:Cephalon Oncology: Research Funding; Gilead Sciences, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; Hanmi: Research Funding. Foster:Daiichi Sankyo: Consultancy; Bellicum Pharmaceuticals: Research Funding; Macrogenics: Consultancy, Research Funding. Ravandi:Celgene: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; AstraZeneca: Consultancy, Honoraria; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Advani:Takeda: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding. Wieduwilt:Macrogeneics: Research Funding; Amgen: Research Funding; Leadiant: Research Funding; Merck: Research Funding; Shire: Research Funding; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees. Emadi:Genentech: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Jazz Pharmaceuticals: Research Funding; KinaRx: Other: co-founder and scientific advisor; Servier: Membership on an entity's Board of Directors or advisory committees. Michaelis:Jazz Pharmaceuticals: Research Funding. Stiff:Macrogenics: Research Funding; Kite, a Gilead Company: Research Funding; Delta-Fly: Research Funding; Unum: Research Funding; Atara: Research Funding; Gamida Cell: Research Funding; Amgen: Research Funding. Wermke:MacroGenics: Honoraria. Topp:Amgen, Boehringer Ingelheim, KITE, Regeneron, Roche: Research Funding; Amgen, KITE, Novartis, Regeneron, Roche: Consultancy. Muth:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Collins:MacroGenics: Current equity holder in publicly-traded company, Other: I currently work as a contractor for MacroGenics; IQVIA: Other: I have worked as a contractor for IQVIA in the past, within the past 24 months.. Guo:Macrogenics: Current Employment. Tran:MacroGenics: Current Employment. Kaminker:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Patel:MacroGenics: Current Employment. Bakkacha:MacroGenics: Current Employment. Jacobs:MacroGenics: Current Employment. Seiler:MacroGenics: Current Employment. Rutella:MacroGenics Inc.: Research Funding; Kura Oncology: Research Funding; NanoString Technologies Inc.: Research Funding. Walter:Aptevo Therapeutics: Research Funding. Bonvini:MacroGenics, Inc.: Current Employment, Current equity holder in publicly-traded company. Davidson-Moncada:Macrogenics: Current Employment. DiPersio:Magenta Therapeutics: Membership on an entity's Board of Directors or advisory committees.

Retrospective studies have suggested that older adolescents and young adults (AYAs) with acute lymphoblastic leukemia (ALL) have better survival rates when treated using a pediatric ALL regimen administered by pediatric treatment teams. To address the feasibility and efficacy of using a pediatric treatment regimen for AYA patients with newly diagnosed ALL administered by adult treatment teams, we performed a prospective study, CALGB 10403, with doses and schedule identical to those in the Children’s Oncology Group study AALL0232. From 2007 to 2012, 318 patients were enrolled; 295 were eligible and evaluable for response. Median age was 24 years (range, 17-39 years). Use of the pediatric regimen was safe; overall treatment-related mortality was 3%, and there were only 2 postremission deaths. Median event-free survival (EFS) was 78.1 months (95% confidence interval [CI], 41.8 to not reached), more than double the historical control of 30 months (95% CI, 22-38 months); 3-year EFS was 59% (95% CI, 54%-65%). Median overall survival (OS) was not reached. Estimated 3-year OS was 73% (95% CI, 68%-78%). Pretreatment risk factors associated with worse treatment outcomes included obesity and presence of the Philadelphia-like gene expression signature. Use of a pediatric regimen for AYAs with ALL up to age 40 years was feasible and effective, resulting in improved survival rates compared with historical controls. CALGB 10403 can be considered a new treatment standard upon which to build for improving survival for AYAs with ALL. This trial was registered at www.clinicaltrials.gov as #NCT00558519.

Karyotype is frequently used to predict response and outcome in leukemia. This post hoc exploratory analysis evaluated the relationship between baseline cytogenetics and outcome in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO), a humanized CD22 antibody conjugated to calicheamicin, in the phase 3, open-label, randomized INO-VATE trial. Data as of March 8, 2016, are presented in this analysis. Of the 326 patients randomized, 284 had screening karyotyping data (144 in the InO arm and 140 in the standard care [SC] arm). With InO, complete remission or complete remission with incomplete hematologic recovery (CR/CRi), minimal residual disease negativity rates, and overall survival (OS) were not significantly different between cytogenetic subgroups. CR/CRi rates favored InO over SC in the diploid with ≥20 metaphases, complex, and "other" cytogenetic subgroups. The OS hazard ratio favored InO over SC in the diploid with ≥20 metaphases, complex, and other cytogenetic subgroups. Generally, InO is effective and provides substantial clinical benefit in patients with R/R ALL who have specific baseline karyotypes.

To the Editor,The myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic conditions characterized by dysplastic changes and ineffective hematopoiesis [1]. Almost all patients with...

Uproleselan (GMI-1271) is a novel E-selectin antagonist that disrupts cell survival pathways, enhances chemotherapy response, improves survival in mouse xenograft and syngeneic models, and decreases chemotherapy toxicity in vivo. A phase 1/2 study evaluated the safety, tolerability, and antileukemic activity of uproleselan (5-20 mg/kg) with MEC (mitoxantrone, etoposide, and cytarabine) among patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). Among the first 19 patients, no dose-limiting toxicities were observed. The recommended phase 2 dose (RP2D) was 10 mg/kg twice daily. An additional 47 patients with R/R AML were treated with uproleselan at the RP2D plus MEC. At the RP2D, the remission rate (complete response [CR]/CR with incomplete count recovery [CRi]) was 41% (CR, 35%), and the median overall survival (OS) was 8.8 months. In a separate cohort, 25 newly diagnosed patients age ≥60 years received uproleselan at the RP2D plus cytarabine and idarubicin (7 + 3). In these frontline patients, the CR/CRi rate was 72% (CR, 52%), and the median OS was 12.6 months. The addition of uproleselan was associated with low rates of oral mucositis. E-selectin ligand expression on leukemic blasts was higher in patients with relapsed vs primary refractory AML and in newly diagnosed older patients with high-risk cytogenetics and secondary AML. In the R/R cohort, E-selectin expression >10% was associated with a higher response rate and improved survival. The addition of uproleselan to chemotherapy was well tolerated, with high remission rates, low induction mortality, and low rates of mucositis, providing a strong rationale for phase 3 randomized confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02306291.

Purpose: TTI-621 (SIRPα-IgG1 Fc) is a novel checkpoint inhibitor that activates antitumor activity by blocking the CD47 “don't eat me” signal. This first-in-human phase I study (NCT02663518) evaluated the safety and activity of TTI-621 in relapsed/refractory (R/R) hematologic malignancies. Patients and Methods: Patients with R/R lymphoma received escalating weekly intravenous TTI-621 to determine the maximum tolerated dose (MTD). During expansion, patients with various malignancies received weekly single-agent TTI-621 at the MTD; TTI-621 was combined with rituximab in patients with B-cell non-Hodgkin lymphoma (B-NHL) or with nivolumab in patients with Hodgkin lymphoma. The primary endpoint was the incidence/severity of adverse events (AEs). Secondary endpoint included overall response rate (ORR). Results: Overall, 164 patients received TTI-621: 18 in escalation and 146 in expansion (rituximab combination, n = 35 and nivolumab combination, n = 4). On the basis of transient grade 4 thrombocytopenia, the MTD was determined as 0.2 mg/kg; 0.1 mg/kg was evaluated in combination cohorts. AEs included infusion-related reactions, thrombocytopenia, chills, and fatigue. Thrombocytopenia (20%, grade ≥3) was reversible between doses and not associated with bleeding. Transient thrombocytopenia that determined the initial MTD may not have been dose limiting. The ORR for all patients was 13%. The ORR was 29% (2/7) for diffuse large B-cell lymphoma (DLBCL) and 25% (8/32) for T-cell NHL (T-NHL) with TTI-621 monotherapy and was 21% (5/24) for DLBCL with TTI-621 plus rituximab. Further dose optimization is ongoing. Conclusions: TTI-621 was well-tolerated and demonstrated activity as monotherapy in patients with R/R B-NHL and T-NHL and combined with rituximab in patients with R/R B-NHL.

Safety and efficacy of allogeneic hematopoietic stem cell transplantation (alloHCT) consolidation after blinatumomab is largely undetermined. To address this issue, we assembled multi-center data of relapsed refractory (RR) acute lymphocytic leukemia (ALL) patients who received alloHCT after blinatumomab. From December 2014 to May 2019, 223 patients who received blinatumomab for RR ALL outside clinical trials were identified. Among them, 106 (47%) patients transplanted post blinatumomab were evaluated for response and toxicity. Ninety-two (87%) patients received alloHCT after achieving CR, while remaining received subsequent salvage prior to undergoing alloHCT. Progression free survival (PFS) and overall survival (OS) at 2 years post alloHCT was 48% (95% CI: 36–59%) and 58% (95% CI: 45–69%), respectively. The cumulative incidence of GIII–IV aGVHD at 3 months was 9.9% (95% CI: 5.0–16.6%). Similarly, cumulative incidence of moderate to severe cGVHD at 2 years was 34.4% (95% CI: 23.7–45.3%). The overall survival at 2 years was not significantly different in patient who achieved CR with MRD negative (68.4% [95% CI: 28.5–89.1%]) compared to CR with MRD positive (63.4% [95% CI: 47.8–75.4%]) prior to alloHCT (p = 0.8). Our real-world analysis suggests that alloHCT is feasible and effective post blinatumomab in patients with RR ALL.

Adults with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) have a poor prognosis, especially if disease burden is high. This post hoc analysis of the phase 3 INO-VATE trial examined the efficacy and safety of inotuzumab ozogamicin (InO) vs. standard of care chemotherapy (SC) among R/R ALL patients with low, moderate, or high disease burden, respectively, defined as bone marrow blasts (BMB) 90% (n = 30 vs. 30). Patients in the InO vs. SC arm with low, moderate, and high BMB%, respectively, had improved rates of complete remission/complete remission with incomplete hematologic recovery (74% vs. 46% [p = 0.0022], 75 vs. 27% [p, Plain language summary Acute lymphoblastic leukemia (ALL for short) is a type of blood cancer where the body makes too many immature white blood cells called lymphoblasts. This study involved people with ALL whose cancer had returned after, or stopped responding to, previous treatment. These people received either inotuzumab ozogamicin (InO for short) or standard chemotherapy. Researchers divided people into groups, based on the level of lymphoblast cells they had in their bone marrow (called disease burden): low, medium, or high disease burden. In this study, compared with people who received standard chemotherapy, people who received InO were more likely to have no signs of their cancer (called remission), live to the end of the study, and/or reach the end of the study without their cancer getting worse. The researchers saw these results across all disease burden groups. For people who received InO, those with high disease burden were equally as likely as those with low disease burden to achieve remission, and/or experience medical problems. For people who received standard chemotherapy, those with high disease burden were less likely than those with low disease burden to achieve remission. Further information in a plain language format is available in Supplementary Information (SI) Fig. S1.

The availability and use of blinatumomab symbolizes a paradigm shift in the management of B-cell acute lymphoblastic leukemia (ALL). We conducted a retrospective multicenter cohort analysis of 239 ALL patients (227 relapsed refractory [RR], n = 227; minimal residual disease [MRD], n = 12) who received blinatumomab outside of clinical trials to evaluate safety and efficacy in the “real-world” setting. The median age of patients at blinatumomab initiation was 48 years (range, 18-85). Sixty-one (26%) patients had ≥3 prior therapies and 46 (19%) had allogeneic hematopoietic cell transplantation before blinatumomab. The response rate (complete remission/complete remission with incomplete count recovery) in patients with RR disease was 65% (47% MRD−). Among 12 patients who received blinatumomab for MRD, 9 (75%) patients achieved MRD negativity. In patients with RR disease, median relapse-free survival and overall survival (OS) after blinatumomab was 32 months and 12.7 months, respectively. Among patients who received blinatumomab for MRD, median relapse-free survival was not reached (54% MRD− at 2 years) and OS was 34.7 months. Grade ≥3 cytokine release syndrome, neurotoxicity, and hepatotoxicity were observed in 3%, 7%, and 10% of patients, respectively. Among patients who achieved complete remission/complete remission with incomplete count recovery, consolidation therapy with allogeneic hematopoietic cell transplantation retained favorable prognostic significance for OS (hazard ratio, 0.54; 95% confidence interval, 0.30-0.97; P = .04). In this largest “real-world” experience published to date, blinatumomab demonstrated responses comparable to those reported in clinical trials. The optimal sequencing of newer therapies in ALL requires further study.

Anthracyclines used in the treatment of acute myelogenous leukemia (AML) inhibit the activity of the mammalian topoisomerase II (topo II) isoforms, topo II α and topo IIβ. In 230 patients with non-M3 AML who received frontline ara-C/daunorubicin we determined expression of topo IIα and topo IIβ by RT-PCR and its relationship to immunophenotype (IP) and outcomes. Treatment outcomes were analyzed by logistic or Cox regression. In 211 patients, available for analysis, topo IIα expression was significantly lower than topo IIβ (P

Background Inotuzumab ozogamicin (InO) is an anti-CD22 monoclonal antibody–drug (calicheamicin) conjugate that has shown superior efficacy compared to conventional chemotherapy in relapsed/refractory (RR) B-cell acute lymphocytic leukemia (ALL) patients. We sought to find the safety and efficacy of InO in a real-world setting. Patients and Methods A multicenter cohort analysis on 84 RR ALL patients who received InO outside of clinical trials was conducted to evaluate response and toxicity. Results The median (range) age of patients at InO initiation was 50 (20-87) years. Forty patients (48%) had ≥ 3 therapies and 23 patients (27%) underwent allogeneic hematopoietic stem-cell transplantation (allo-HCT) before InO. The median (range) number of cycles of InO provided was 2 (1-6), and cumulative dose was 3.3 (1.8-9.3) mg/m2. Overall response rate (complete remission/complete remission with incomplete count recovery) was 63%; 44% had complete remission with minimal residual disease negativity. Twenty-three patients (27%) with response received allo-HCT. The median duration of response was 11.5 months and when censored at allo-HCT was not reached (51% in remission at 2 years). The median overall survival after InO was 11.6 months and when censored at time of allo-HCT was 13.6 months. The most common grade 3 or higher adverse events observed were transaminitis (16%), hyperbilirubinemia (5%), bleeding (4%), veno-occlusive disease (2%), and hyperglycemia (2%). In multivariate analysis, allo-HCT after InO did not retain favorable significance for duration of response (hazard ratio = 1.27; 95% confidence interval, 0.89-1.61; P = .2) or overall survival (hazard ratio = 1.10; 95% confidence interval, 0.37-3.25; P = .85). Conclusion InO was well tolerated and had significant efficacy in RR B-cell ALL patients.

Approximately 50% of acute myeloid leukemia (AML) patients do not respond to induction therapy (primary induction failure [PIF]) or relapse after

Purpose To investigate the risk and outcomes of second hematologic malignancies (SHMs) in a population-based cohort of patients with well-differentiated thyroid cancer (WDTC) treated or not with radioactive iodine (RAI). Methods Patients with WDTC were identified from SEER registries. Competing risk regression analysis was performed to calculate the risks of SHMs that occurred after WDTC treatment and outcomes after SHM development were assessed. Results Of 148,215 patients with WDTC, 53% received surgery alone and 47% received RAI. In total, 783 patients developed an SHM after a median interval of 6.5 years (interquartile range, 3.3 to 11.2 years) from WDTC diagnosis. In multivariable analysis, compared with those undergoing thyroidectomy alone, RAI treatment was associated with an increased early risk of developing acute myeloid leukemia (AML; hazard ratio, 1.79; 95% CI, 1.13 to 2.82; P = .01) and chronic myeloid leukemia (CML; hazard ratio, 3.44; 95% CI, 1.87 to 6.36; P < .001). This increased risk of AML and CML after RAI treatment was seen even in low-risk and intermediate-risk WDTC tumors. Occurrence of AML but not CML in patients with WDTC was associated with shorter median overall survival compared with matched controls (8.0 years v 31.0 years; P = .001). In addition, AML developing after RAI trended toward inferior survival compared with matched controls with de novo AML (median overall survival, 1.2 years v 2.9 years; P = .06). Conclusion Patients with WDTC treated with RAI had an increased early risk of developing AML and CML but no other hematologic malignancies. AML that arises after RAI treatment has a poor prognosis. RAI use in patients with WDTC should be limited to patients with high-risk disease features, and patients with WDTC treated with adjuvant RAI should be monitored for myeloid malignancies as part of cancer surveillance.

Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukemia (AML) blasts to chemotherapy. A Phase 2 study of high dose pravastatin given in combination with idarubicin and cytarabine demonstrated an impressive response rate [75% complete remission (CR), CR with incomplete count recovery (CRi)]. However, this population was a favorable risk group as eligible patients had to have a CR/CRi lasting ≥3 months following their most recent chemotherapy. Therefore, the study was amended to treat patients with poor risk disease including those with CR/CRi < 6 months following their last induction regimen or with refractory disease. Here, we present results in this poor risk group. This trial included a significant number of patients with poor risk cytogenetics (43%) and poor risk molecular mutations. The response rate was 30% and approximately one-fourth of patients were able to proceed to allogeneic hematopoietic stem cell transplant (HSCT). The median overall survival for patients proceeding to allogeneic HSCT is 27.1 months. Although this trial did not meet criteria for a positive study based on the response rate (p=0.062), these results are encouraging given the poor risk population and suggest that targeting the cholesterol pathway may have therapeutic benefit in AML.

Tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Many older patients (pts) are not good candidates for intensive chemotherapy and are treated with TKIs plus corticosteroids or low intensity chemotherapy. Although the remission rates with this approach have been high, the median disease-free survival (DFS) has been short. Therefore, novel treatment strategies are needed. This trial evaluated the feasibility of combining the TKI dasatinib with prednisone and blinatumomab in older pts with Ph+ ALL. Methods: This trial was activated through the NCTN in January 2015 and closed to accrual in April 2021. Pt eligibility included: age ≥ 65 years; Ph+ or Ph-like ALL (with dasatinib-sensitive fusions or mutations); newly diagnosed or relapsed/ refractory; no evidence of central nervous system (CNS) disease; and adequate organ function. Treatment: For induction, pts received dasatinib 140 mg/d orally (PO) Days 1-56 along with prednisone 60 mg/m 2/d PO Days 1-24. Pts achieving complete remission (CR) or CR with incomplete count recovery (CRi) (Day 28 or Day 56) continued dasatinib until Day 84 followed by 3 cycles of post-remission therapy (PRT) with blinatumomab/ dasatinib. Pts not achieving CR or CRi by Day 56 received re-induction with blinatumomab. Response was assessed at Day 35 of blinatumomab. Pts not achieving CR/ CRi could receive a second cycle of blinatumomab. This was followed by 3 cycles of PRT with blinatumomab/ dasatinib. Maintenance therapy consisted of prednisone 60 mg/m 2/d x 5 days every 28 days for a total of 18 cycles along with dasatinib 140 mg po qd indefinitely. CNS prophylaxis included intrathecal (IT) methotrexate every 4-6 weeks x 8 doses. IT methotrexate was given at least 2 days apart from blinatumomab. Response was assessed at Days 28, 56, 84 and additional time points were dependent on response. Minimal residual disease (MRD) was assessed centrally by multi-color flow cytometry at Day 28. Statistics: 9 eligible/ evaluable pts receiving PRT were to be evaluated before enrolling additional pts. Dose-limiting toxicities (DLTs) were defined as: > Grade 3 non-hematologic toxicities with the exception of nausea, vomiting, or diarrhea (if manageable with supportive care measures) or Grade 4 neutropenia lasting > 42 days with possible relationship to dasatinib or blinatumomab. If due to unexpected accrual, 12 pts were evaluable for DLT, the following rules would apply. If > 4 of the 12 pts experienced a DLT, the study would be temporarily closed pending review. Upon re-opening, 8 additional eligible and evaluable pts would be enrolled for a total of 20 pts receiving blinatumomab. Results: Due to rapid accrual, 16 pts enrolled before accrual was paused to assess feasibility and safety. Twelve pts were evaluable for DLT and 4 experienced a DLT: Grade 3 dyspnea and gastrointestinal pain (n=1), Grade 3 hypertension (n=1), Grade 3 dyspnea (n=1), Grade 3 hyperglycemia (n=1). These adverse events were deemed acceptable by the NCI and FDA and the study re-opened. A total of 25 eligible pts were accrued. The median age was 73 years (range 62-87). All pts were newly diagnosed. One pt was Ph-like, with the remainder being Ph+; 89% of Ph+ pts had additional cytogenetic abnormalities. During induction, 2 pts experienced treatment-related non-hematologic Grade 4 toxicities. No Grade 4 or higher treatment-related non-hematologic toxicities occurred during post-remission therapy or maintenance. Twenty-three out of 25 pts (92%) achieved a CR during dasatinib-based and prednisone induction therapy. Four did not receive PRT (2 due to adverse events, 1 to receive transplant, 1 because of insurance issues). Sixteen pts who achieved CR had MRD data. Five out of 16 pts (31%) were MRD negative at Day 28. One pt remains on PRT and 10 are on maintenance. The median follow up for pts who are alive is 1.7 years. The median overall survival (OS) and DFS have not been reached as of July 8, 2021. Kaplan-Meier 3-year estimates of OS and DFS are 85% (95% CI 58%-95%) and 80% (95% CI 55%-92%), respectively (Figure). Conclusions: This trial demonstrates the feasibility of combining dasatinib and blinatumomab in Ph+ ALL. In addition, with 1.7 years of follow up, outcomes are encouraging with high estimated 3-year DFS and OS. Longer follow up will be needed to determine the durability of these results. Figure 1 Figure 1. Disclosures Advani: Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Research Funding; Glycomimetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunogen: Research Funding; OBI: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Moseley: BioSight Ltd: Consultancy. Wood: Pfizer, Amgen, Seattle Genetics: Honoraria; Juno, Pfizer, Amgen, Seattle Genetics: Other: Laboratory Services Agreement. Park: Intellia: Consultancy; Kura Oncology: Consultancy; BMS: Consultancy; Affyimmune: Consultancy; Curocel: Consultancy; Novartis: Consultancy; Artiva: Consultancy; PrecisionBio: Consultancy; Servier: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy; Minerva: Consultancy; Autolus: Consultancy; Amgen: Consultancy. Wieduwilt: Gilead: Membership on an entity's Board of Directors or advisory committees; Reata: Current holder of stock options in a privately-held company. Jeyakumar: Jazz: Research Funding; Pfizer: Research Funding. Atallah: Abbvie: Consultancy, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Takeda: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy. Gerds: PharmaEssentia Corporation: Consultancy; CTI BioPharma: Research Funding; Sierra Oncology: Consultancy; AbbVie: Consultancy; Celgene/Bristol Myers Squibb: Consultancy; Constellation: Consultancy; Novartis: Consultancy. O'Brien: Amgen, Astellas, Celgene, GlaxoSmithKline, Janssen Oncology, Aptose Biosciences Inc., Vaniam Group LLC, AbbVie, Alexion, Verastem, Juno Therapeutics, Vida Ventures, Autolus, Johnson and Johnson, Merck, Bristol Myers Squibb, NOVA Research Company, Eli Lill: Consultancy; Kite, Regeneron, Acerta, Caribou, Gilead, Pharmacyclics, TG Therapeutics, Pfizer, Sunesis: Research Funding. Othus: Celgene: Other: Data safety monitoring board; Merck: Consultancy; Biosight: Consultancy; Glycomimetics: Other: Data safety monitoring board; Daiichi Sankyo: Consultancy. Litzow: Jazz: Other: Advisory Board; Pluristem: Research Funding; Amgen: Research Funding; Actinium: Research Funding; Omeros: Other: Advisory Board; Astellas: Research Funding; AbbVie: Research Funding; Biosight: Other: Data monitoring committee. Stone: Actinium: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Arog: Consultancy, Research Funding; Astellas: Membership on an entity's Board of Directors or advisory committees; BerGen Bio: Membership on an entity's Board of Directors or advisory committees; Boston Pharmaceuticals: Consultancy; Bristol Myers Squibb: Consultancy; Elevate Bio: Membership on an entity's Board of Directors or advisory committees; Foghorn Therapeutics: Consultancy; Gemoab: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Consultancy; Innate: Consultancy; Janssen: Consultancy; Jazz: Consultancy; Novartis: Consultancy, Research Funding; Onconova: Consultancy; Syndax: Membership on an entity's Board of Directors or advisory committees; Syntrix/ACI: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Aprea: Consultancy; Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy; Agios: Consultancy, Research Funding; Celgene: Consultancy; Macrogenics: Consultancy. Erba: AbbVie Inc; Agios Pharmaceuticals Inc; ALX Oncology; Amgen Inc; Daiichi Sankyo Inc; FORMA Therapeutics; Forty Seven Inc; Gilead Sciences Inc; GlycoMimetics Inc; ImmunoGen Inc; Jazz Pharmaceuticals Inc; MacroGenics Inc; Novartis; PTC Therapeutics: Research Funding; AbbVie Inc; Agios Pharmaceuticals Inc; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Incyte Corporation; Jazz Pharmaceuticals Inc; Novartis: Speakers Bureau; AbbVie Inc: Other: Independent review committee; AbbVie Inc; Agios Pharmaceuticals Inc; Astellas; Bristol Myers Squibb; Celgene, a Bristol Myers Squibb company; Daiichi Sankyo Inc; Genentech, a member of the Roche Group; GlycoMimetics Inc; Incyte Corporation; Jazz Pharmaceuticals Inc; Kura Oncology; Nov: Other: Advisory Committee.

Exposure to ionizing radiation increases the risk of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN), but such risks are not known in well-differentiated thyroid cancer (WDTC) patients treated with radioactive iodine (RAI). A total of 148 215 WDTC patients were identified from Surveillance Epidemiology and End Results (SEER) registries between 1973 and 2014, of whom 54% underwent definitive thyroidectomy and 46% received adjuvant RAI. With a median follow-up of 6.6 years, 77 and 66 WDTC patients developed MDS and MPN, respectively. Excess absolute risks for MDS and MPN from RAI treatment when compared to background rates in the US population were 6.6 and 8.1 cases per 100 000 person-years, respectively. Compared to background population rates, relative risks of developing MDS (3.85 [95% CI, 1.7-7.6]; P=0.0005) and MPN (3.13 [1.1-6.8]; P=0.012) were significantly elevated in the second and third year following adjuvant RAI therapy, but not after thyroidectomy alone. The increased risk was significantly associated with WDTC size >2 cm or regional disease. Development of MDS was associated with shorter median overall survival in WDTC survivors (10.3 vs 22.5 years; P

Aurora kinases are involved in the pathophysiology of several cancers including acute myeloid leukemia (AML). In this phase 1 study, we investigated the safety and efficacy of AMG 900, an orally administered, highly potent, selective, small-molecule inhibitor of both Aurora kinase A and B, in patients with AML. Patients with pathologically documented AML who either declined standard treatments or had relapsed from or were refractory to previous therapies were enrolled. Two every-2-week dose-escalation schedules using a modified 3 + 3+3 design were used: AMG 900 given daily for 4 days with 10 days off (4/10 schedule), and AMG 900 given daily for 7 days with 7 days off (7/7 schedule). Thirty-five patients were enrolled at 9 different dose levels: 22 patients on the 4/10 schedule (doses from 15 to 100 mg daily), and 13 patients on the 7/7 schedule (doses from 30 to 50 mg daily). Both schedules were tolerated; nausea (31%), diarrhea (29%), febrile neutropenia (29%), and fatigue (23%) were the most common treatment-related adverse events. Three patients (9%) achieved complete response with incomplete count recovery. Patients with higher baseline expression of a set of specific pathway-related genes (BIRC5, AURKA, TTK, CDC2, and CCNB1) were more likely to respond in an exploratory biomarker analysis. AMG 900 was tolerated in a general AML population, and pathway-specific biomarkers identified a potential target population. Future research efforts will be directed toward further exploration of biomarkers of response and combination of AMG 900 with other anticancer agents. This article is protected by copyright. All rights reserved.

Background Cytarabine resistance is a major reason for compromised treatment efficacy in acute myeloid leukemia (AML). This may be due to leukemic cells being at different stages in their cell cycle, with some at G0/G1, others in M phase, and only a limited number of cells in the S phase necessary for cytarabine susceptibility. Palbociclib, is a selective CKD4/6 inhibitor that arrests cancer cells in the G0/G1 stage. Preclinical studies have shown that the administration of palbociclib to AML cells in vitro for 48 hours can arrest 91% of the cells in the G0/G1 phase. When these cells proceed to S phase after the cessation of palbociclib, cytarabine-based (S phase dependent) chemotherapy has 30-50% enhanced cytotoxic activity. We hypothesize that the sequential administration of palbociclib and CPX-351 can enhance its efficacy without added toxicity. Methods This is a phase 1 (dose escalation of palbociclib) /II single arm trial of the sequential administration of palbociclib and CPX-351. The trial consists of two components: a phase I, 3+3 design to evaluate the safety with dose escalation of palbociclib in combination with CPX-351 (for patients [pts] with relapsed/primary refractory [R/R] AML, or higher risk newly diagnosed AML); and a phase II to evaluate the overall response rate (ORR) of the combination in newly diagnosed AML pts. Palbociclib was given at dose level 1 (75 mg po) (Figure 1) on day -1 and -2, day 0 rest, followed by CPX-351 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) on day 1, 3, and 5 along with palbociclib on day 2, 4, and 6 followed by a rest/monitoring period (days 7-35). Patients received 1-2 induction courses of the combination of palbociclib and CPX-351. Inclusion criteria: age 18-65, ECOG performance status (< 2), and adequate organ function. Pts with active infections or malignancies that prevented them from enrollment or with cardiac ejection fractions Results: In this pre-specified analysis, 9 pts competed phase I (3 received palbociclib at 75 mg, 3-100 mg, and 3- 125 mg). The median age was 48 (range, 30-69), 44% females, and median WBC was 3.5 (range, 0.27-39.7). Cytogenetic analysis included: 2 pts with normal karyotype, 4 pts with complex karyotype, 1 pt with inversion 3, 1 pt with Trisomy 8, and 1 pt (no growth). Four pts had TP53 mutations. There were no reported deaths during induction. Common adverse events were similar to those was observed in pivotal CPX-351 trials. Common grade 3 / 4 side effects possibly related to therapy included: febrile neutropenia in 6 pts, elevated bilirubin in 1 pt, epistaxis in 1 pt, electrolyte abnormalities in 1 pt, and atrial fibrillation in 1 pt. All toxicities resolved during the study period. One pt also experienced grade 2 pericarditis/pericardial effusion (possibly related), which resolved. The ORR among the 8 evaluable pts (1 pt had persistent disease at day 14 and refused to receive re-induction and was taken off the study) was 75%: 5 pts (63%) achieved a CR and 1 pt (12%) had a morphological leukemia-free state. A total 5 pts enrolled in the phase II trial. Three are evaluable for response, 1 withdrew from the study during induction therapy (pt choice), and one is still receiving therapy. Among the three evaluable pts one (unfavorable cytogenetics with a TP53 mutation) achieved CR, one (unfavorable cytogenetics achieved) CRp, and one (unfavorable cytogenetics) achieved CRi. No induction mortality has occurred to date. The phase II portion of the study is still ongoing. Conclusions The sequential combination of palbociclib and CPX-351 is highly effective in pts with R/R and newly diagnosed AML enrolled to this trial. The combination was well tolerated and no added toxicity was observed from palbociclib. The trial is ongoing and an updated enrollment of phase II pts will be presented at the meeting. Figure Disclosures Nazha: MEI: Other: Data monitoring Committee; Jazz: Research Funding; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Mukherjee:Aplastic Anemia and MDS International Foundation: Honoraria; Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squib: Honoraria; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy. Carraway:BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; ASTEX: Other: Independent Advisory Committe (IRC); Takeda: Other: Independent Advisory Committe (IRC); Abbvie: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau. Gerds:Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Pfizer: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding. Patel:Alexion: Other: educational speaker. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Maciejewski:Alexion, BMS: Speakers Bureau; Novartis, Roche: Consultancy, Honoraria. Sekeres:Pfizer: Consultancy; BMS: Consultancy; Takeda/Millenium: Consultancy. OffLabel Disclosure: Palbociclib in AML CPX-351 in newly diagnosed AML

The landscape of acute lymphoblastic leukemia (ALL) has evolved significantly over the last few years. Identification of specific recurrent genetic alterations and of minimal residual disease (MRD) guides prognostic classification and management. Novel agents (eg, blinatumomab) have demonstrated encouraging results in relapsed/refractory (R/R) and MRD+ patients and are currently incorporated into upfront treatment in specific settings. Other new strategies include the incorporation of tyrosine kinase inhibitor-based therapy for patients with Philadelphia chromosome–like ALL and the use of DOT inhibitors and bcl-2/bcl-xl inhibitors in R/R disease. These innovations promise to improve management and outcome in this disease.

Background Inotuzumab ozogamicin (InO) is an antibody‐drug conjugate used for adults with relapsed/refractory B‐cell precursor (BCP) acute lymphoblastic leukemia (ALL). The INotuzumab Ozogamicin trial to inVestigAte Tolerability and Efficacy (INO‐VATE) previously reported improved outcomes with InO versus standard‐of‐care (SoC) chemotherapy. This article reports the final INO‐VATE results (≥2 years of follow‐up) and additional analyses of patient characteristics associated with improved outcomes. Methods Between August 27, 2012, and January 4, 2015, this multicenter, parallel, open‐label, phase 3 trial randomized 326 adults with relapsed/refractory ALL to InO (n = 164) or SoC (n = 162); 307 received 1 or more doses of the study drug (164 in the InO arm and 143 in the SoC arm). Results The complete remission (CR)/complete remission with incomplete hematologic recovery (CRi) rate was higher with InO versus SoC (73.8% vs 30.9%; 1‐sided P, All key subgroups of patients with relapsed or refractory CD22‐positive B‐cell precursor acute lymphoblastic leukemia have the potential to benefit from inotuzumab ozogamicin in comparison with the standard of care (intensive chemotherapy). In the future, the combination of inotuzumab ozogamicin with other therapies may provide improved outcomes.

Peripheral neuropathy is a major toxicity of vincristine, yet no strategies exist for identifying adult patients at high-risk. We used a case-control design of 48 adults receiving protocol therapy for acute lymphoblastic leukemia (ALL) who developed vincristine-induced neuropathy (NCI grade 2-4) during treatment, and 48 matched controls who did not develop grade 2-4 neuropathy. Peripheral neuropathy was prospectively graded by National Cancer Institute (NCI) criteria. CEP72 promoter genotype (rs924607) was determined using polymerase chain reaction (PCR)-based single nucleotide polymorphism (SNP) genotyping. Frequency of the CEP72 T/T genotype was higher in cases (31% vs. 10%, P = 0.0221) and the incidence of vincristine-induced neuropathy (grades 2-4) was significantly higher in patients homozygous for the CEP72 T/T genotype. 75% of the 20 patients homozygous for the CEP72 T allele developed grade 2-4 neuropathy, compared to 44% of patients with CEP72 CC or CT genotype (P = 0.0221). The CEP72 polymorphism can identify adults at increased risk of vincristine-induced peripheral neuropathy.

EphA3 is an Ephrin receptor tyrosine kinase that is overexpressed in most hematologic malignancies. We performed a first-in-human multicenter phase I study of the anti-EphA3 monoclonal antibody KB004 in refractory hematologic malignancies in order to determine safety and tolerability, along with the secondary objectives of pharmacokinetics (PK) and pharmacodynamics (PD) assessments, as well as preliminary assessment of efficacy. Patients were enrolled on a dose escalation phase (DEP) initially, followed by a cohort expansion phase (CEP). KB004 was administered by intravenous infusion on days 1, 8, and 15 of each 21-day cycle in escalating doses. A total of 50 patients (AML 39, MDS/MPN 3, MDS 4, DLBCL 1, MF 3) received KB004 in the DEP; an additional 14 patients were treated on the CEP (AML 8, MDS 6). The most common toxicities were transient grade 1 and grade 2 infusion reactions (IRs) in 79% of patients. IRs were dose limiting above 250mg. Sustained exposure exceeding the predicted effective concentration (1ug/mL) and covering the 7-day interval between doses was achieved above 190mg. Responses were observed in patients with AML, MF, MDS/MPN and MDS. In this study, KB004 was well tolerated and clinically active when given as a weekly infusion.

Adults with relapsed/refractory acute lymphoblastic leukemia have an unfavourable prognosis, which is influenced by disease and patient characteristics. To further evaluate these characteristics, a retrospective analysis of 1,706 adult patients with Ph-negative relapsed/refractory B-precursor acute lymphoblastic leukemia diagnosed between 1990-2013 was conducted using data reflecting the standard of care from 11 study groups and large centers in Europe and the United States. Outcomes included complete remission, overall survival, and realization of stem cell transplantation after salvage treatment. The overall complete remission rate after first salvage was 40%, ranging from 35%-41% across disease status categories (primary refractory, relapsed with or without prior transplant), and was lower after second (21%) and third or greater (11%) salvage. The overall complete remission rate was higher for patients diagnosed from 2005 onward (45%, 95% CI: 39%-50%). One- and three-year survival rates after first, second, and third or greater salvage were 26% and 11%, 18% and 6%, and 15% and 4%, respectively, and rates were 2%-5% higher among patients diagnosed from 2005. Prognostic factors included younger age, longer duration of first remission, and lower white blood cell counts at primary diagnosis. This large dataset can provide detailed reference outcomes for patients with relapsed/refractory Ph-negative B-precursor acute lymphoblastic leukemia. clinicaltrials.gov identifier: 02003612.

Skin diseases are very common in places where the society lives in a crowded area. Pesantren is anIslamic school with a dormitory for its students, thus making the spread of skin infection easier to occur. Theobjective of this research was to identify the association between the prevalence of skin diseases with the hygienebehavior and level of education of santris (students of pesantren). This cross-sectional study was conducted in apesantren in South Jakarta. Data collection was carried out through a questionnaire consisting of ten questionsabout hygienic behaviors and history of previous dermatological examinations from July until September 2013.Results showed that out of 98 santris, 88 of them had skin diseases (89.7%). The most frequent skin infectionwas scabies with 67 cases (49.3%). Furthermore, 78 (88.6%) out of all santris who had skin diseases, werecategorized to have poor hygienic behaviors. There were only 10 santris that did not have any skin disease, 3of them had good hygienic behaviors. There was no significant difference between hygienic behaviors of santrisand the prevalence of skin disease (p=0.350). Associated with the level of education, ibtidaiyah had the highestnumber of santris (51.2%) affected by skin diseases. There was a significant difference between the level ofeducation and the prevalence of skin diseases (p

The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors’ suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 23-year-old man was urgently referred for evaluation of rapidly enlarging cervical lymphadenopathy, progressive dyspnea, fatigue, night sweats, and an unintentional weight loss of 25 pounds. A computed tomography scan of the neck performed 30 days before referral revealed bilateral cervical and supraclavicular lymphadenopathy (6 × 5 cm). A fine-needle aspirate of nasopharyngeal tissue demonstrated fibroadipose tissue. Tissue collected by core needle biopsy of a left internal jugular lymph node demonstrated a reactive lymph node but no malignancy. The patient was admitted to an academic medical center hospital. His physical examination was remarkable for bulky cervical and supraclavicular lymphadenopathy. A testicular examination was normal. The patient’s lactate dehydrogenase concentration was 327 U/L (normal range, 118-225 U/L). A positron emission tomography scan revealed bilateral cervical and supraclavicular lymphadenopathy (6 × 5 cm with a standardized uptake value [SUV] of 14), a 1.3-cm subcutaneous nodule in the left thigh (SUV 16), and two 2.7-cm liver lesions (SUV 14). He underwent an excisional lymph node biopsy. The lymph node revealed effacement of the architecture by an interfollicular infiltrate of lymphoid cells ( Fig 1 ). Mitotic figures were abundant (Ki-67 stain 80% to 90% positive) and there were multiple foci of tissue necrosis. The lymphoblasts were examined by flow cytometry and immunohistochemistry and expressed the T-cell markers CD2, CD3, CD4, and terminal deoxynucleotidyl transferase. A subpopulation of T cells was positive for both CD4 and CD8. Polymerase chain reaction studies revealed a clonal rearrangement of the T-cell receptor γ gene. A marrow aspirate and biopsy revealed normal trilineage hematopoiesis with no evidence of lymphoma and a normal male karyotype (46, XY). A lumbar puncture sample did not contain lymphoma cells. The patient’s diagnosis was T-lymphoblastic lymphoma.

Adding molecular data to prognostic models can improve predictive power in treated patients with myelodysplastic syndromes

Treatment options are limited for patients (pts) diagnosed with MDS at the time of hypomethylating agent (HMA) failure. One goal is to introduce another line of therapy to reduce tumor burden and enable patients to undergo hematopoietic stem cell transplant (HSCT), which may prolong survival for a subset. CPX-351, has shown better overall response rates and improved overall survival in patients with acute myeloid leukemia with underlying MDS changes compared to 7+3, suggesting that CPX-351 can be used in an MDS patient population. We hypothesized that treating MDS pts, who were failed by HMAs or were intolerant with CPX-351 would overcome HMA resistance. This is a phase II study of single agent CPX-351 administered at the standard FDA approved dose of 44 mg/m2 (daunorubicin 44 mg/m2 and cytarabine 100 mg/m2) intravenously on days 1, 3, 5 of the induction cycle. If patients achieve complete remission (CR), marrow CR, partial remission or hematologic improvement per 2006 IWG criteria they will be eligible to continue on to consolidation therapy, which consists of CPX-351 at a dose of 15.4 mg/m2 (daunorubicin 15.4 mg/m2 and cytarabine 35 mg/m2) every 28 days. Pts can receive up to 4 cycles of consolidation therapy in the absence of toxicity. The primary objective of the trial is to evaluate the efficacy of CPX-351 as measured by overall response rate (ORR) by IWG 2006 criteria. Secondary objectives include: ,1) determine the time to response (TTR), 2) evaluate the duration of response (DOR), 3) evaluate the event-free survival and the overall survival probability during trial period. Pts are risk stratified into lower vs higher-risk prior to enrollment using the Post-HMA model (Nazha A, et al. Hematologica 2016). Eligibility includes: pts >18 years with primary or secondary resistance to HMA, ECOG performance status < 2 and adequate organ function. Pts are excluded if they have uncontrolled infection or active malignancy. A total of 18 pts will be enrolled to each arm (lower and higher risk). To date, three pts were enrolled. One with MDS refractory to HMA who achieved complete remission and proceeded with 4 cycles of consolidation. The pt remained in remission 6+ months after the completion of consolidation. Another patient achieved a marrow CR but had a fungal pneumonia and then was taken off the trial (patient choice for going to hospice). The third patient had MDS/MPN, completed induction and achieved stable disease with improvement in platelets and neutrophils. All patients were lower-risk per the stratification model. No unexpected toxicity was observed. In conclusion, preliminarily CPX-351 is effective in MDS patients after HMA failure who are eligible to receive intensive chemotherapy. The treatment was well tolerated and toxicities were similar to what was observed in pivotal CPX-351 trials. The trial is ongoing and the results will be updated in the meeting. Disclosures Nazha: MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Incyte: Speakers Bureau; Jazz: Research Funding. Mukherjee:Celgene/Acceleron: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; EUSA Pharma: Consultancy; Partnership for Health Analytic Research, LLC (PHAR, LLC): Honoraria; Bristol Myers Squib: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Aplastic Anemia and MDS International Foundation: Honoraria. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Other: Steering committee/ honoraria, Research Funding; Immunogen: Research Funding; Seattle Genetics: Other: Advisory board/ honoraria, Research Funding; Amgen: Consultancy, Other: steering committee/ honoraria, Research Funding; Kite: Other: Advisory board/ honoraria; Pfizer: Honoraria, Research Funding; Novartis: Consultancy, Other: advisory board; OBI: Research Funding; Takeda: Research Funding. Carraway:Jazz: Consultancy, Speakers Bureau; BMS: Consultancy, Other: Research support, Speakers Bureau; Stemline: Consultancy, Speakers Bureau; Takeda: Other: Independent Advisory Committe (IRC); Novartis: Consultancy, Speakers Bureau; Abbvie: Other: Independent Advisory Committe (IRC); ASTEX: Other: Independent Advisory Committe (IRC). Gerds:AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding; Roche/Genentech: Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Apexx Oncology: Consultancy; Pfizer: Research Funding. Patel:Alexion: Other: educational speaker. Sekeres:Takeda/Millenium: Consultancy; Pfizer: Consultancy; BMS: Consultancy. OffLabel Disclosure: CPX-351 in MDS

Minimal residual disease (MRD) negativity is a key prognostic indicator of outcome in acute lymphocytic leukemia. In the INO-VATE trial (clinicaltrials.gov identifier: NCT01564784), patients with relapsed/refractory acute lymphocytic leukemia who received inotuzumab versus standard chemotherapy achieved greater remission and MRD-negativity rates as well as improved overall survival: hazard ratio 0.75, one-sided P = 0.0105. The current analysis assessed the prognostic value of MRD negativity at the end of inotuzumab treatment. All patients who received inotuzumab (n = 164) were included. Among patients with complete remission/complete remission with incomplete hematologic response (CR/CRi; n = 121), MRD-negative status (by multiparametric flow cytometry) was defined as

Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 μg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

Patients may be deemed ineligible for a clinical trial for reasons that do not directly impact efficacy or safety. We identified and categorized reasons for ineligibility and compared outcomes of ineligible with eligible patients treated on SWOG Leukemia Committee protocols. Patients enrolled in SWOG phase II, II/III, or III protocols open since 2005 were analyzed for eligibility status, reasons for ineligibility, baseline characteristics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), serious adverse events (SAEs), and outcomes, including complete remission (CR) status and overall survival (OS). A total of 2,361 patients were enrolled in the 13 included studies. Of these, 247 (10%) were deemed ineligible: 78 were excluded from analyses while 169 were included. Of the 78 patients excluded from analyses, the majority (73%; 57/78) did not have the disease of interest. Of the 169 included in analyses 60% (101/169) were excluded due to missing baseline documentation. Baseline characteristics comparing ineligible to eligible patients were similar, with the exception of ECOG PS, for S0325 (p=0.02) and S0530 (p=0.002). In multivariable analyses, neither the proportion of patients with ECOG PS 2 or higher (p=0.12) nor the rate of grade 5 SAEs: (p=0.62) differed between groups. There was no difference in survival between the eligible and ineligible patients (p=0.25), and CR rates were similar, with the exception of S0325 (p

For young adults with acute lymphoblastic leukemia, pediatric-based regimens are likely to provide the following when compared to hyper-CVAD regimens: better disease control, less hospitalization time, diminished acute toxicities, decreased financial cost, more quality-adjusted life years, and fewer adverse late effects, such as infertility, myelodysplasia, and second malignant neoplasms. There are also reasons to expect less cardiac and cognitive dysfunction after pediatric regimens. The improved quality and quantity of life associated with pediatric regimens renders them preferable to hyper-CVAD regimens for the treatment of Philadelphia-negative B-precursor or T-cell acute lymphoblastic leukemia and lymphoblastic lymphoma in young adults.

Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 µg/kg) or on days 1 and 4 (20 µg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years [range, 26-89 years]) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/µL) and 10.6 weeks for platelets (≥100 × 109/L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.

Intermediate-risk acute myeloid leukemia (IR-AML) is a clinically heterogeneous disease, for which optimal post-remission therapy is debated. The utility of next-generation sequencing information in decision making for IR-AML has yet to be elucidated. We retrospectively studied 100 IR-AML patients, defined by European Leukemia Net classification, who had mutational information at diagnosis, received intensive chemotherapy and achieved complete remission (CR) at Cleveland Clinic (CC). The Cancer Genome Atlas (TCGA) data were used for validation. In the CC cohort, median age was 58.5 years, 64% had normal cytogenetics, and 31% required >1 induction cycles to achieve CR1. In univariable analysis, patients carrying mutations in DNMT3A, U2AF1, and EZH2 had worse overall and relapse-free survival. After adjusting for other variables, the presence of these mutations maintained an independent effect on survival in both CC and TCGA cohorts. Patients who did not have the mutations and underwent hematopoietic cell transplant (HCT) had the best outcomes. HCT improved outcomes for patients who had these mutations. RUNX1 or ASXL1 mutations did not predict survival, and performance of HCT did not confer a significant survival benefit. Our results provide evidence of clinical utility in considering mutation screening to stratify IR-AML patients after CR1 to guide therapeutic decisions.

Comprehensive quantitative proteomic profiling of the pharmacodynamic changes induced by MLN4924 in acute myeloid leukemia cells establishes rationale for its combination with azacitidine

This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic leukemia. In phase 1, patients received InO 1.2 (n = 3), 1.6 (n = 12), or 1.8 (n = 9) mg/m2 per cycle on days 1, 8, and 15 over a 28-day cycle (≤6 cycles). The recommended phase 2 dose (RP2D) was confirmed (expansion cohort; n = 13); safety and activity of InO were assessed in patients receiving the RP2D in phase 2 (n = 35) and in all treated patients (n = 72). The RP2D was 1.8 mg/m2 per cycle (0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15), with reduction to 1.6 mg/m2 per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi). Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two VOD/SOS events occurred during treatment without intervening transplant; of 24 patients proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%) patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8) months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity was associated with higher InO exposure. InO was well tolerated and demonstrated high single-agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as #NCT01363297.

Approximately 40% of patients (pts) with newly diagnosed (AML) either fail to achieve complete remission with intensive induction therapy or experience disease recurrence after a short remission duration (< 6 months). These pts, herein considered to have primary refractory disease, are an extremely challenging population to treat, with only 14% achieving remission following conventional chemotherapy and with subsequent salvage attempts being nearly universally ineffective (1). Increased immune infiltration of the tumor microenvironment (TME) and high CD123 expression on AML blasts have been associated with primary induction failure and poor prognosis (2, 3). Flotetuzumab (FLZ), a CD123 x CD3 bispecific DART molecule, is currently being tested in a phase 1/2 study in pts with either relapsed or refractory (R/R) AML. We have previously reported FLZ activity in primary refractory AML (4); herein, we provide additional scientific rationale supporting the investigation of FLZ in this patient population. The recommended Phase 2 dose (RP2D) of FLZ identified in an ongoing Phase 1/2 study is 500 ng/kg/day administered as a 7 -day/week continuous infusion. Pts receive a lead-in dose during week (W) 1, followed by 500 ng/kg/day during W2-4 of Cycle 1, and a 4-day on/3-day off schedule for Cycle 2 and beyond. Disease status was assessed by modified IWG criteria; bone marrow (BM) samples were collected to investigate biomarkers, including CD123 receptor density (RD), and gene expression profiling using the NanoString PanCancer IO 360™ panel, which measures the expression of 770 genes, including 14 immune cell types and 32 immuno-oncology biological signatures. Gene expression comparisons are presented at fold change (FC) and a t-test was used for statistical analysis. Fifty pts with R/R AML received FLZ at the RP2D. Thirty (60%) pts had primary refractory AML: 24 failed ≥2 induction attempts and 6 recurred after remission of 30% decrease in BM blasts) was associated with increased baseline immune gene signatures, including significantly higher IFNγ scores (1.8 FC, p=0.0212; AUROC=0.74), and an increased tumor inflammation signature (TIS) score (1.658 FC, p=0.00827, AUROC=0.847 compared to non-responders. FLZ was well tolerated, with no increased cytokine release syndrome events in primary refractory pts (30% G1, 67% G2, 3% G3) compared to relapse pts (26% G1, 58% G2, 16% G3), notwithstanding the increased CD123 RD in the former. In conclusion, we show that FLZ elicits clinical response in heavily treated patients with poor response rates to primary therapy. We also show that increased IFNγ signaling gene expression scores in baseline BM appears to associate with response to FLZ therapy. Enrollment has been expanded to further define FLZ's activity specifically in pts with primary refractory AML, and candidate biomarkers to enable identification of pts more likely to respond to FLZ. Estey E, et al. Blood (1996), 88 (2) 756Vadakekolathu J, et al. Blood (2017) 130:3942Vergez F, et al. Haematologica (2011), 96(12):1792-8Uy GL, et al. Blood (2018) 132:764Duong V, et al. Leukemia (2013),13(6):711-5 Disclosures Uy: Astellas: Consultancy; Pfizer: Consultancy; Curis: Consultancy; GlycoMimetics: Consultancy. Aldoss:Agios: Consultancy, Honoraria; AUTO1: Consultancy; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses. Foster:Bellicum Pharmaceuticals, Inc: Research Funding; Daiichi Sankyo: Consultancy; MacroGenics: Research Funding; Celgene: Research Funding. Sallman:Celgene: Research Funding, Speakers Bureau; Celyad: Membership on an entity's Board of Directors or advisory committees; Incyte: Speakers Bureau; Jazz: Research Funding; Novartis: Speakers Bureau; Abbvie: Speakers Bureau. Sweet:Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Speakers Bureau; Stemline: Consultancy; Pfizer: Consultancy; Jazz: Speakers Bureau; Incyte: Research Funding. Rizzieri:AbbVie, Agios, AROG, Bayer, Celgene, Gilead, Jazz, Novartis, Pfizer, Sanofi, Seattle Genetics, Stemline, Teva: Other: Advisory Board; AROG, Bayer, Celgene, Celltron, Mustang, Pfizer, Seattle Genetics, Stemline: Consultancy; Celgene, Gilead, Seattle Genetics, Stemline: Other: Speaker; Stemline: Research Funding. Advani:Amgen: Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy. Emadi:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; NewLink Genetics: Research Funding; Genentech: Consultancy, Honoraria; KinaRx: Membership on an entity's Board of Directors or advisory committees, Other: Co-Founder and Scientific Advisor, Patents & Royalties; Jazz Pharmaceuticals: Research Funding. Wieduwilt:Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen, Leadiant, Merck, Servier: Research Funding; Reata Pharmaceuticals: Equity Ownership. Vey:Novartis: Consultancy, Honoraria; Janssen: Honoraria. Church:NanoString Technologies, Inc.: Employment, Equity Ownership. Rettig:WashU: Patents & Royalties: Patent Application 16/401,950. Arellano:Gilead: Consultancy. Löwenberg:Up-to-Date", section editor leukemia: Membership on an entity's Board of Directors or advisory committees; Frame Pharmaceuticals: Equity Ownership; Elected member, Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees; Editorial Board "European Oncology & Haematology": Membership on an entity's Board of Directors or advisory committees; Clear Creek Bio Ltd: Consultancy, Honoraria; Abbvie: Membership on an entity's Board of Directors or advisory committees; Agios Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; Astex: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; CELYAD: Membership on an entity's Board of Directors or advisory committees; Chairman Scientific Committee and Member Executive Committee, European School of Hematology (ESH, Paris, France): Membership on an entity's Board of Directors or advisory committees; Chairman, Leukemia Cooperative Trial Group HOVON (Netherlands: Membership on an entity's Board of Directors or advisory committees; Supervisory Board, National Comprehensive Cancer Center (IKNL), Netherland: Membership on an entity's Board of Directors or advisory committees; Hoffman-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees; Royal Academy of Sciences and Arts, The Netherlands: Membership on an entity's Board of Directors or advisory committees. Ravandi:Selvita: Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cyclacel LTD: Research Funding. Muth:MacroGenics, Inc.: Employment, Equity Ownership. Tran:MacroGenics: Employment. Timmeny:MacroGenics, Inc.: Employment, Other: Stock Ownership. Topp:Boehringer Ingelheim: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Regeneron Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Guo:Macrogenics: Employment. Zhao:MacroGenics, Inc.: Employment. Wigginton:MacroGenics, Inc.: Employment, Equity Ownership; Western Oncolytics: Other: clinical advisory board. Bonvini:MacroGenics, Inc.: Employment, Equity Ownership. Rutella:NanoString Technologies, Inc.: Research Funding; MacroGenics, Inc.: Research Funding. Walter:Seattle Genetics: Research Funding; Race Oncology: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy; Kite Pharma: Consultancy; 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. Davidson-Moncada:MacroGenics, Inc.: Employment, Equity Ownership. DiPersio:Amphivena Therapeutics: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Macrogenics: Research Funding, Speakers Bureau; Magenta Therapeutics: Equity Ownership; WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Celgene: Consultancy; Incyte: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Karyopharm Therapeutics: Consultancy.

Acute myeloid leukemia (AML) with t(8;21) or inv(16) chromosomal rearrangements are distinct heterogeneous disease entities within AML that are classified together as core binding factor AML (CBF-AML). Given the nature of the chromosomes involved, these rearrangements lead to the production of leukemogenic chimeric transcripts (RUNX1-RUNX1T1 and CBFB-MYH11) which disrupt the physiologic activity of the heterodimeric transcription factor CBF complex. Although CBF-AML patients have a favorable prognosis and good response to treatment compared to other AML subtypes, survival outcomes are not uniform. Indeed, 30-50% of patients with CBF-AML eventually relapse, and the 5-10 yr survival ranges between 55-61% for patients < 60 yr in MRC/NCRI AML trials. Studies have analyzed the clonal architecture of CBF-AML patients and identified cooperating mutations independently of receptor tyrosine kinases (FLT3, KIT) mutations while others have found a 30% occurrence of KIT mutations. Studies of murine models of Runx1 and Cbfb have demonstrated that inactivation of both genes does not lead to leukemia, suggesting that other factors are necessary to recapitulate the leukemia phenotype fully. Although mutations in RAS family of genes (NRAS/KRAS) are among the most frequently observed mutations described in CBF-AML [54% in inv(16) and 30% in t(8;21)], no associations between those mutations and survival outcomes have been found. Because of the lack of association between RASMT and clinical outcomes, their role in CBF-AML is still unknown. Here, we focused on dissecting the impact of RAS mutations (NRAS/KRAS; RASMT) on the clinical characteristics, survival outcomes, and the molecular associations among CBF-AML patients by evaluating the clonal succession of RASMT. In total, 284 CBF-AML patients were identified, in whom inv(16) and t(8;21) represent 61% (n=173) and 39% (n=111) of the cases, respectively. Thirty-five % (99/284) of the patients carried RAS mutations (NRAS=78; KRAS=21) with 8 patients harboring 2 mutations comprising NRAS, KRAS, or both NRAS/KRAS genes. RAS mutations were point mutations affecting known hotspots in NRAS and KRAS. Both RASMT and RASWT had a median age < 60 years (55 (14-83) vs. 49 (7-83) years, P=0.9) and sex was equally distributed among the two groups. Leukopenia, defined as white blood cell count In sum, our study of the frequency, clonal architecture and impact on survival of RASMT in CBF-AML patients points out the unique characteristics of this specific disease subgroup in which sole RASMT might represent, in addition to KITMT, a mutational lesion cooperating with inv(16) and t(8;21) rearrangements in driving leukemic evolution. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Advani:Glycomimetics: Consultancy, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Kite Pharmaceuticals: Consultancy. Nazha:Abbvie: Consultancy; Incyte: Speakers Bureau; Jazz Pharmacutical: Research Funding; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Daiichi Sankyo: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

Background: For patients (pts) with AML undergoing induction chemotherapy (IC), incomplete platelet (plt) recovery can lead to an increased risk of bleeding, prolonged dependence on plt transfusions, plt alloimmunization, as well as delay in post-remission therapy. Eltrombopag is a thrombopoietin receptor agonist that stimulates megakaryopoiesis and has anti-leukemic effects. Herein, we present the final results of a phase 2 trial evaluating the efficacy of eltrombopag in accelerating plt count recovery in older AML pts receiving IC (NCT02071901). Methods: All newly diagnosed FLT3-negative AML pts > 60 years (yrs) with ECOG scores of 0-2, no active second malignancy, and no evidence of marrow fibrosis at the time of AML diagnosis were included. Acute promyelocytic (AML-M3), megakaryocytic (AML-M7), and AML arising from myeloproliferative neoplasms were excluded. Pts with any arterial or venous thrombotic event (excluding line thrombosis) within the past 12 months were excluded. IC consisted of an anthracycline (daunorubicin at 45 mg/m2 x 3 days) and infusional cytarabine (100 mg/m2 x 7 days). Eltrombopag was administered starting day 15 (range, day 15-18) of IC in pts who had marrow blasts 50000/µL by day 24 of IC. In a historical cohort of 220 older AML pts (excluding APL and AML-M7) treated with IC between 2004 and 2011 at Cleveland Clinic, 60% achieved a plt count > 50,000/µL by day 24. Eltrombopag was administered at a dose of 200 mg with a one-time maximal dose escalation to 300 mg daily if plts remained < 50,000/µL after 2 weeks on treatment. Eltrombopag was discontinued once plts exceeded 100,000/µL. Informed consent was obtained prior to start of IC, and eligibility was determined on day 14. Results: Between 9-2014 and 9-2018, 93 pts were consented, of whom 31 met the eligibility criteria. Sixty seven percent of pts were ineligible as they had >5% blasts on day 14 marrow and the remaining met one or more of the following exclusion criteria: acute clinical worsening; use of supraphysiologic dose of steroids (n=1); marrow fibrosis (n=1); active second malignancy (n=1); elevated transaminases (n=5), and elevated serum creatinine (n=1). Median age was 67 years (range, 60-78), 38% were female, and 81% had a good ECOG status (ECOG 0 or 1). Most pts (84%) had de novo AML, 16% had secondary AML. By CALGB/Alliance criteria, 82% had intermediate cytogenetics, 9% had adverse karyotype and in 9% cytogenetic analysis was unsuccessful. The median eltrombopag treatment duration was 10 days (range, 8-11 d), and no dose escalations were required. Trends in the levels of plt count over time are shown in Figure 1. Median times from the start date of eltrombopag to plt >50,000/µL, and >100,000/µL were 7 d (range, 6-8) and 10 d (range, 8-11), respectively (Figure 2). By day 24 of IC, 30 of 31pts (97%) had plt >50,000/µL. The median peak plt count reached on eltrombopag was 606,000/µL (range, 280- 1,935,000/µL). The median time to reach peak plt count from start date of eltrombopag was 14 d (range, 13-36). Pts received a median of 4 units of plt transfusions (range, 3-11) in the first 14 days of induction (1 unit every 3.6 days), while during the eltrombopag treatment period, the median requirement decreased to 2 units (range, 0-6) or 1 unit every 4.8 d (P=.04). Ninety percent of pts achieved complete remission at a median time of 30 d [95% confidence interval (CI), 25-34d] from IC. No death occurred during treatment. The most common any grade toxicities (incidence > 15%) were maculopapular rash (28%), nausea (24%), increased alkaline phosphatase (24%), anorexia (20%), headache (20%), increased aspartate aminotransferase (16%), hypocalcemia (16%), and hypokalemia (16%). Grade 3/4 toxicities were reported at 4% (n=1) for febrile neutropenia, fever, pain, decreased white blood cell count, hypocalcemia, hypokalemia, generalized muscle weakness, maculopapular rash, and thromboembolic event. Median overall survival time from IC was 11.2 months (95% CI, 1.9, 14.8 m). Conclusion: In this study, eltrombopag appeared to hasten plt recovery and reduce plt transfusions without increasing rates of refractory disease in older FLT3-negative AML pts undergoing IC, without any limiting toxicities. Additional analyses are currently underway to evaluate durability of platelet responses, responses in other cell lineages and survival. Disclosures Mukherjee: Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; McGraw Hill Hematology Oncology Board Review: Other: Editor; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy. Hobbs:Amgen: Research Funding; SimulStat Inc.: Consultancy. Gerds:Celgene Corporation: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Sierra Oncology: Research Funding; Roche: Research Funding; Imago Biosciences: Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding. Advani:Abbvie: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Saunthararajah:EpiDestiny: Consultancy, Equity Ownership, Patents & Royalties; Novo Nordisk: Consultancy. Maciejewski:Novartis: Consultancy; Alexion: Consultancy. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees.

Genetic studies have been early introduced for the classification of acute myeloid leukemia (AML), but specific molecular lesions [e.g., t(8;21), inv(16), t(15;17)] define only a fraction of patients. In the genomic era, many mutations and cytogenetic abnormalities and their combinations have been described in AML; their diversity contributes to the heterogeneity of pathomorphologic presentations. While certain mutations are restricted to individual classical morphologic subtypes, pathognomonic lesions are difficult to find. Therefore, to date, molecular mutations or cytogenetic abnormalities have been used to assess prognosis rather than define disease sub-entities according to molecular pathogenesis, likely a future standard in AML diagnosis. Balanced translocations are prototypic founder lesions, however, founder somatic vs. subclonal mutations have not been used to define subtypes of AML. Molecular classification may better reflect the pathogenesis of AML than morphologic/clinical subtypes e.g., secondary (sAML) vs. primary AML (pAML) or AML with normal (ncAML) vs. abnormal cytogenetics (acAML). This work describes the results of a large and comprehensive analysis of genomic landscape and cytogenetics in AML. Initially, 6788 cases were analyzed, including 4867 from our institutions (Cleveland Clinic Foundation and Munich Leukemia Laboratory, n=4862) fortified by publically deposited cases (n=1926) to define gene signatures and succession of mutations distinguishing pAML vs. sAML. While data for core-binding factor AML, MLL gene rearrangement leukemia, acute promyelocytic leukemia and therapy-related AML have also been analyzed (n=1094), we focused on remaining sAML (n=876) vs. pAML (n=4808) and within these entities (ncsAML, n=367; acsAML, n=509 vs. ncpAML, n=2856 and acpAML, n=1952). Although, sAML and pAML showed usual clinical differences, a reliable diagnostic algorithm could not be constructed using supervised analytic approaches and thus we aimed at identification of molecular biomarkers with prognostic and diagnostic value. Abnormal cytogenetics were present in 57% of AML including complex: 13%, +8; 11%: -5/del(5q): 8%; and -7del7q: 8%. Deep NGS for the 25 top mutated genes was applied and correlated with clinical and cytogenetic parameters (Fig.1A-B). We then defined/compared mutational landscape in acAML and ncAML separately. AcsAML showed more complex karyotypes (58% vs. 40% in acpAML, P Using combined data sets of mutations and cytogenetic abnormalities and clinical parameters, we then constructed supervised and unsupervised analyses to identify signatures of pAML vs. sAML: discordant cases between the molecular and the classic diagnostic assignment of sAML vs. pAML were investigated and a novel molecular classification irrespective of the pAML and sAML derivation has been created to include founder and secondary mutations combinations and concordance of the outcomes. Disclosures Advani: Abbvie: Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Nazha:Daiichi Sankyo: Consultancy; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Incyte: Speakers Bureau; Abbvie: Consultancy; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

Introduction While the hypomethylating agents (HMAs) azacitidine (AZA) and decitabine (DAC) improve cytopenias and prolong survival in MDS patients (pts), response is not guaranteed. Timely identification of non-responders could prevent prolonged exposure to ineffective therapy, thereby reducing toxicities and costs. Currently no widely accepted clinical or genomic models exist to predict response or resistance to HMAs. We developed a clinical model to predict response or resistance to HMA after 90 days of initiating therapy based on changes in blood counts using time series analysis technology similar to the kind used in Apple's Siri or Google Assistant. In the setting of voice recognition, the sequence and context of words determines the meaning of a sentence; similarly, we hypothesized that the pattern of changes in MDS pts' blood counts would predict response or resistance early during treatment. Methods We screened a cohort of 107 pts with MDS (per 2016 WHO criteria) who received HMAs at our institution between February 2005 and July 2013 and had regular CBCs drawn during treatment. Mutations from a panel of 60 genes commonly mutated in myeloid malignancy were included. Responses were assessed after 6 months of therapy per International Working Group (IWG) 2006 criteria. Pts were divided randomly into training (80%) and validation (20%) cohorts. To address the potential for bias due to a small sample size, an oversampling algorithm was used to cluster similar pts based on their CBC data, Revised International Prognostic Scoring System (IPSS-R) score, and % bone marrow blasts at the time of diagnosis. CBC data from the first 90 days of treatment were fed into deep neural network (recurrent neural network) and decision tree algorithms, which were trained to predict whether pts would achieve a response (defined as complete remission (CR), partial remission (PR), or hematologic Improvement (HI)). Area under the curve (AUC) was used to assess model performance. Important features that impact the algorithm's predictions were extracted and plotted. Results 20747 unique data points were used, including CBC, clinical and genomic data. Among 107 pts, 61 (57.0%) received AZA only, 19 (17.8%) DAC only, 4 (3.7%) received both DAC and AZA, and 23 (21.5%) received HMA with an additional agent. Median age was 69 years (range: 37-100 years), and 27 (26.4%) were female. Forty pts (37.4%) were very low/low risk, 32 (29.9%) intermediate, 19 (17.8%) high, and 16 (14.9%) very high risk per IPSS-R. Responses included 23 (22.5%) CR, 2 (1.9%) marrow CR, 4 (3.9%) PR, and 20 (19.6%) HI. The most commonly mutated genes were ASXL1 (17.6%), TET2 (16.7%), SRSF2 (15.7%), SF3B1 (11.8%), RUNX1 (10.8%), STAG2(10.8%), and DNMT3A (10.8%). The median number of mutations per sample was 1 (range, 0-11), and 40 pts (39.2%) had > 3 mutations per sample. When trained using absolute values and changes in CBC values, the model's AUC was 0.95 in the training cohort and 0.83 in the validation cohort. When the cohort was oversampled to 1000 pts, the validation cohort AUC increased to 0.89. Feature extraction algorithms identified increases in MCV and RDW during weeks 2-8 of treatment, increased proportion of lymphocytes, decreased proportion of monocytes, and increased platelet counts during weeks 6-8 as factors favoring response to HMA. The model provides personalized, patient-specific predictions that correlate with blood counts (Figure 1). Conclusions We describe a machine learning model that monitors changes in blood counts during therapy with HMA to predict response or resistance to HMA in MDS pts. Such a model can be used to develop novel trial designs wherein pts predicted to not respond after 90 days of HMA treatment could be assigned to an investigational agent. Conversely, it would help inform the decision to continue HMA therapy in pts predicted to respond. Increasing sample size with oversampling dramatically increased model accuracy; a larger cohort of pts treated at different institutions is currently under development. Disclosures Sekeres: Millenium: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Mukherjee:Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria; McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau. Advani:Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Abbvie: Research Funding. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Nazha:Novartis: Speakers Bureau; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; MEI: Other: Data monitoring Committee.

Chromosomal abnormalities can be founder lesions (e.g., t (8; 21), inv (16), inv (3)), initiate or advance disease progression (both founder and secondary hits e.g., ASXL1, TP53, RUNX1) or can be obligatory secondary hits (FLT3, NPM1). Hence, the rank of these mutations may determine the biological properties and clinical outcomes. However, while many mechanistic studies have been undertaken without identifying the key pathogenetic factors resulting from SF3B1 mutations, important biological clues can be derived from the consequences of SF3B1 alterations in the context of the clonal architecture of myeloid neoplasia (MN). SF3B1 mutant patients often have a homogeneous phenotype with isolated erythroid dysplasia, ring sideroblasts (RS) and favorable prognoses. Studies in primary MDS cells have suggested that SF3B1 mutations are initiating lesions and provide a marked clonal advantage to MDS-RS cells by propagating from rare lympho-myeloid hematopoietic stem cells. However, there is significant diversity of clinical phenotypes and outcomes including the observation that the disappearance of RS can be observed during the disease course of clonal MN and might suggest cellular shifts due to acquisition of additional hits. In such scenarios, the cell's fate in the context of SF3B1 mutations is pre-defined by the predominance of expanded hits. We took advantage of our detailed database of molecularly and clinical annotated cases with MN to study the SF3B1 mutatome and describe whether the clonal nature (ancestral vs. secondary) might change the clinical and phenotypic trajectories of MDS cells and whether the concatenation of mutations decreases the competitiveness of SF3B1 clones, leading to the dominance of other driver genes and subsequently to clonal evolution. The clonal hierarchy was resolved using our in-house designed VAF-based bioanalytic method and confirmed by the PyClone pipeline, which showed a high level of concordance. We first assigned clonal hierarchy to SF3B1 mutations by using VAFs (adjusted for copy number and zygosity) and classifying the mutations into dominant (if a cutoff of at least 5% difference between VAFs existed), secondary (any subsequent sub-clonal hit) and co-dominant hits (if the difference of VAFs between two mutations was In conclusion, our study of the clonal architecture of SF3B1 mutations highlights that clonal progression of cases with MN harboring SF3B1 mutations might be inferred by the rank of additional genetic lesions cooperating with SF3B1. Disclosures Meggendorfer: MLL Munich Leukemia Laboratory: Employment. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Glycomimetics: Consultancy, Research Funding; Kite Pharmaceuticals: Consultancy. Nazha:Tolero, Karyopharma: Honoraria; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Daiichi Sankyo: Consultancy; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Abbvie: Consultancy. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

One strategy to improve precision medicine in acute myeloid leukemia (AML) is to further our understanding of the biological factors that influence pharmacologic efficacy. In a recent study, whole transcriptome analysis was conducted using pre- and post-treatment samples from a cohort of relapsed or refractory (R/R) AML patients treated with mitoxantrone, etoposide, cytarabine (MEC), and ixazomib. Logistic regression and linear discriminant analysis identified RORa as a predictor of response to treatment (Advani, et al., Clin Cancer Res, 2019, 4231-4237). RORa is not frequently mutated in AML but is described to be a tumor suppressor in patients with solid tumors. In the latter patient population, increased RORa expression is also associated with improved survival. We first retrospectively evaluated the prognostic significance of RORa in a larger cohort of R/R patients with AML (BeatAML). Second, we characterized RORa expression in cellular models of AML and sought to determine whether a commercially available RORa/RORγ agonist, SR1078, has anti-proliferative capacity in leukemia cell lines. For the correlative survival analyses, RORa mRNA expression and clinical information was downloaded from the BeatAML cohort (Tyner, et al., Nature, 2018, 526-531). Patients were categorized into high expressers (≥ median) and low expressers ( During normal hematopoiesis, we observed that RORa expression decreased with the stages of cellular maturation and is highly expressed in cells of AML patients with complex karyotype (BloodSpot, 2018). We noted that RORa mRNA expression varied across patients suggesting differences between AML subtypes. Expression levels were also confirmed to be different across AML subtypes in vitro by using cell line models (K-562, KG-1, OCI-AML3, U-937, THP-1, MOLM-13). In particular, analysis of TCGA data showed higher mean RORa expression in DNMT3A mutant (MT) (626 RPKM) compared to mean RORa expression in CEBPAMT (243 RPKM; P=0.026), NPM1MT (167 RPKM; P=0.012), and FLT3MT (236 RPKM; P=.003) AML patients. We then analyzed the sensitivity of cell lines to the commercially available synthetic RORa /RORγ ligand, SR1078. Myeloid lineage cells U-937 and KG-1 were used as a cellular model. Cells in logarithmic phase were treated with increased concentrations of the RORa /RORγ agonist SR1078 (from 3 nM to 30 mM) for 24 hours. Cell viability was measured by MTT tetrazolium reduction assay. Maximal growth inhibition was reached at 30 µM for U-937 (80%) and KG-1 (75%), respectively. We then combined SR1078 with MEC to evaluate whether in vitro SR1078 increased MEC growth inhibition. The addition of SR1078 to MEC significantly decreased cell viability in KG-1 cells compared to MEC alone (82% vs. 19%, P=.029). Our study suggests that increased RORa expression may be associated with improved survival in patients with R/R AML and that RORa may be a potential therapeutic target in AML. Figure 1 Disclosures Gerds: Celgene Corporation: Consultancy, Research Funding; Imago Biosciences: Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Roche: Research Funding; Sierra Oncology: Research Funding. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Projects in Knowledge: Honoraria. Nazha:Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Novartis: Speakers Bureau; MEI: Other: Data monitoring Committee; Tolero, Karyopharma: Honoraria; Abbvie: Consultancy; Daiichi Sankyo: Consultancy. Maciejewski:Alexion: Consultancy; Novartis: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees. Advani:Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Macrogenics: Research Funding; Kite Pharmaceuticals: Consultancy.

Mutations (MT) in the 5' untranslated region (UTR) of ANKRD26 (A26) are implicated in ANKRD26- related thrombocytopenia (A26-RT), an autosomal dominant disorder of mild to moderate thrombocytopenia (TP) often presenting in adulthood, although severe and pediatric cases are reported. Erythrocyte and leukocyte counts are normal to increased, with unremarkable morphology. Platelet (plt) size is usually normal, as with ETV6- and RUNX1-mutated TP. Together, A26, ETV6, and RUNX1 germline (GL) MT comprise a separate 2016 WHO category of myeloid neoplasms (MN) with GL predisposition and preexisting platelet disorders. Normal plt size separates A26-RT from other familial TPs with giant plts. No consistent morphological plt aberrations have been reported. Bleeding history is absent or mild, and while TP is not life threating, 8-10% of patients (pts) develop a MN, including a 30-fold increased risk for AML relative to the general population. A26 is an inner membrane adaptor protein with 2 major domains: ankyrin repeats (ANKR) and coil-coil (C-C), both of which interact with signaling and cytoskeletal proteins. A26-RT MT are almost exclusively in the 5'UTR, however, rare A26 coding variants (A26-CV) are reported to segregate with familial TP. Still, some studies on A26-RT limit sequencing to the 5'UTR. As such, A26-CV are not well represented or described. We performed whole-exome sequencing (WES) on 195 pts with MN seen at Cleveland Clinic between 2004 and 2012, and downloaded WES .bam files from online sources, totaling 653 MN cases. Using a standard pipeline for discovery of rare GL variants ( Complete clinical description was available for 8 A26-CV pts, all diagnosed with MDS or MDS/MPN at med age of 64. Two pts had antecedent bruising 1 year prior to diagnosis (dx). No prior bleeding was noted. Three pts had prior TP, two of whom had bicytopenia and pancytopenia. First degree family history (FH) was positive for cancer in 6 pts (75%), including 2 pts with FH of hematologic neoplasms. One pt had a 2nd-degree relative with a non-malignant hematologic condition requiring transfusions. At dx, cytogenetics were normal and complex in 2 pts each (25%). Deletions in chromosomes 5, 17, 20, and Y were observed in 1 pt each, and monosomy 7 in 2 pts. On bone marrow aspirate, 6 pts (75%) had dysmegakaryopoiesis, found in interstitial patterns and clusters. Mild to moderate dyserythropoiesis was observed in 5 pts (63%), and 5 pts had dysgranulopoiesis. The med blast percentage was 1.5% (range 0-8%), with 5 pts having hypercellular marrow, med 65% (range 40-95%). On corresponding CBC, pts were anemic (med hemoglobin of 9.5 g/dL), with the majority (n=5) showing signs of erythroid dysplasia, and also thrombocytopenic (med plt of 99 k/μL), with giant plts observed in 3 pts. Two pts had both giant plts and abnormal erythroid morphology. Hypo and monolobate, hyposegmented, and hypogranular forms were observed in the 3 lineages, as well as detached nuclear lobes, budding, segmentation, and nuclear-cytoplasmic dyssynchrony. On next generation sequencing, co-occurring SRSF2 and ASXL1 MT were observed in 3 and 2 pts, respectively. In sum, we have identified 22 A26-CV in MN, suggesting a role in predisposition as with A26-RT. We have seen in our cohort that A26-CV pts present differently from those with A26-RT. They have a variable past medical history and limited FH of TP, are anemic, with multilineage dysplasia observed not just in bone marrow, but also on peripheral blood smear, especially in megakaryocytes and erythrocytes. This is not surprising, as A26 is expressed in both lineages. The presence of giant plts is noteworthy. The mechanism for hypomorphic A26-CV may differ from that of the A26 5' UTR, which increase A26 levels in late-stage megakaryopoiesis by abrogating RUNX1/FLI1 binding, leading to aberrant proplatelet formation. Given the plt size and presence of nuclear phenotypes, altered interactions with signaling and cytoskeletal proteins could be involved, and may represent a novel A26 phenotype. Further investigation and association of A26-CV with MN ontogeny is under way. Disclosures Mukherjee: Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor; Bristol-Myers Squibb: Speakers Bureau. Advani:Kite Pharmaceuticals: Consultancy; Amgen: Research Funding; Macrogenics: Research Funding; Glycomimetics: Consultancy, Research Funding; Pfizer: Honoraria, Research Funding; Abbvie: Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Gerds:Imago Biosciences: Research Funding; Sierra Oncology: Research Funding; Roche: Research Funding; Incyte: Consultancy, Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; CTI Biopharma: Consultancy, Research Funding. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Maciejewski:Alexion: Consultancy; Novartis: Consultancy.

Background: Clinical trial recruitment is hindered by patient (pt), provider, and organizational barriers. The prohibitory impact of specific comorbidity/organ function criteria, however, has not been studied in the AML pt population. While intended to protect pts, trial eligibility criteria, when excessive, exclude pts irrespective of expected toxicities (Statler et al. Leukemia 2017). Yet, research demonstrates adverse events and outcomes are similar among eligible and ineligible AML pts (Statler et al. Blood 2018). We characterized the multi-morbidity prolife of AML pts prior to induction chemotherapy and compared outcomes among those with and without baseline comorbidities/organ dysfunction that have been used in clinical trial eligibility criteria. Methods: Adult (≥18 years) AML pts who received chemotherapy at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic/renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Univariate associations between dose modifications and pt characteristics were tested using logistic regression. Cox proportional hazards and logistic regression were used to identify significant prognostic factors for overall survival (OS) and complete remission (CR) status per International Working Group criteria. Kaplan-Meier method was used to estimate median OS. Results: Of 1,082 AML pts analyzed, the median age was 60.6 years (IQR: 50.2, 69.1), 53.1% (n=574) were male, 86.8% (n=939) were white, and 45.7% (n=494) had Medicare insurance. A majority (n=680, [62.9%]) had de novo AML, and 55.3% (n=598) had intermediate-risk disease. Pts were treated with: intensive cytarabine-based (n=901 [83.3%]), or non-intensive (low-dose cytarabine or hypomethylating agents (n=181 [16.7%]). Of those with comorbidities, the most common were vascular (n=540 [49.9%]), endocrine (n=272 [25.1%]), and neurological (n=220, [20.3%]) (Tables 1 and 2). With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). In multivariate analyses controlling for treatment, age, sex, insurance, number of comorbidities, AML etiology, and ELN risk, the only comorbidity associated with OS was liver disease (HR=1.90, P=.004). However, baseline AST (3xULN vs. normal: HR=1.02, P=.94; >3-5x ULN vs. normal: HR=1.42, P=.30.), ALT (3xULN vs. normal: HR=0.76, p=0.45, >3-5xULN vs. normal: HR=1.58, P=.23) and bilirubin (1.5xULN vs. normal: HR=1.34, P=.08) were not associated with a worse OS. Minor renal dysfunction was also not associated with OS, when measured by creatinine (1.5xULN vs. normal: HR=1.06, P=.52) or creatinine clearance by Cockcroft-Gault (CrCl 84-60 ml/min: HR=0.95, P=.62). Baseline LVEF abnormalities, though, were associated with increased mortality, and as severity increased the effect size increased in a dose-response fashion (50-40%: HR=1.38, P=.04; 480ms: HR=1.36, P=.04; ≥501: HR=1.72, 95%, P=.001). With the exception of liver comorbidities (OR=0.26, P=.03), our analysis failed to identify significant evidence of association between response and comorbidities/organ dysfunction. Comorbidities and liver function abnormalities were also not associated with dose modifications during AML treatment, while pts with clinically significant renal (CrCl ≤ 30 ml/min) and/or cardiac (LVEF ≤50%) abnormalities at baseline did have a higher odds of a dose reduction in univariate analysis. Conclusions: The majority of AML pts within this cohort (n=953 [88.1%]) presented with at least 1 comorbidity and/or 1 clinically insignificant liver or renal abnormality that could have excluded them from clinical trials. Yet, survival, response, and dose modification outcomes did not significantly differ between pts with and without comorbid conditions or minor liver/renal abnormalities. These results suggest future AML trials may liberalize comorbidity and organ function eligibility criteria, which will likely improve recruitment rates and provide equitable access to investigational products. Disclosures Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; McGraw Hill Hematology Oncology Board Review: Other: Editor. Advani:Abbvie: Research Funding; Macrogenics: Research Funding; Pfizer: Honoraria, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Gerds:Sierra Oncology: Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding; CTI Biopharma: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Pfizer: Consultancy; Celgene Corporation: Consultancy, Research Funding. Nazha:Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Daiichi Sankyo: Consultancy; Abbvie: Consultancy. Sekeres:Syros: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees.

Background: Determining which AML patients (pts) are "fit" for intensive chemotherapy (IC), both in real-world scenarios and for clinical trial eligibility (particularly as it relates to regulatory indications) is challenging. While age, AML etiology, and cardiac function have been invoked, these oversimplify the clinical assessment and recommendation for IC vs. Non-IC (NIC). We compared baseline characteristics among pts receiving IC and NIC, and evaluated associations between treatment receipt and pt characteristics. Adjusting for treatment received, pts' attributes were further evaluated for association with overall survival (OS). Methods: Adult (≥18 years) AML pts who received IC or NIC at Cleveland Clinic from 2003 to 2019 were included. The following characteristics were analyzed: age, sex, self-reported race, insurance, etiology of AML, comorbidities, hepatic and renal function tests, left ventricular ejection fraction (LVEF), and corrected QT interval (QTc). AML risk was categorized according to the 2017 European LeukemiaNet (ELN) risk stratification. Fisher's exact and Welch's t-tests were performed to compare baseline characteristics. Multivariate logistic and Cox regression were used to identify significant prognostic factors for treatment receipt and OS, respectively. The Kaplan-Meier method estimated distributions of OS, which were compared among pt cohorts using the log-rank test. Classification and regression tree (CART) analysis was performed to characterize the best decision process used to select pts for NIC. Results: Of 1,082 AML pts analyzed, 901 (83.2%) were treated with intensive, cytarabine-based chemotherapy, and 181 (16.8%) with non-intensive (low-dose cytarabine or hypomethylating agents) regimens. As expected, baseline characteristics were significantly imbalanced between groups; pts receiving NIC were more likely to be older (P Multivariable stepwise regression revealed independent associations with the following attributes (favoring NIC over IC): older age (OR=1.10, P1.5xULN vs. normal; OR=3.04, P=.02), renal (CrCl With a median follow-up of 12.9 (IQR: 4.67-43.13) months, the median OS for the cohort was 15.1 months (range 0.03-189.25). OS was significantly different between groups (median OS, NIC vs. IC: 4.9 vs. 20.4 months, P1.5xULN: HR=1.70, P=.01), renal (creatinine >1.5xULN: HR=1.55, P=.001; CrCl480-500ms: HR=1.36, P=.04; LVEF 50-40%: HR=1.38, P=.04) were, however, associated with worse survival. Conclusions: Age, comorbidities, and organ dysfunction are associated with AML treatment determination. Pts who presented with cancer/renal/myocardial comorbidities and renal/liver dysfunction were more likely to receive NIC, despite the comorbid conditions not having an impact on OS. Further research needs to elucidate the extent to which NIC is the optimal treatment decision for pts exhibiting varying severities of cancer/renal/myocardial comorbidities. Disclosures Hobbs: SimulStat Inc.: Consultancy; Amgen: Research Funding. Mukherjee:McGraw Hill Hematology Oncology Board Review: Other: Editor; Partnership for Health Analytic Research, LLC (PHAR, LLC): Consultancy; Celgene Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Projects in Knowledge: Honoraria; Bristol-Myers Squibb: Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria. Advani:Glycomimetics: Consultancy, Research Funding; Amgen: Research Funding; Kite Pharmaceuticals: Consultancy; Macrogenics: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding. Gerds:Sierra Oncology: Research Funding; Celgene Corporation: Consultancy, Research Funding; Pfizer: Consultancy; Incyte: Consultancy, Research Funding; CTI Biopharma: Consultancy, Research Funding; Imago Biosciences: Research Funding; Roche: Research Funding. Nazha:Daiichi Sankyo: Consultancy; Tolero, Karyopharma: Honoraria; MEI: Other: Data monitoring Committee; Novartis: Speakers Bureau; Jazz Pharmacutical: Research Funding; Incyte: Speakers Bureau; Abbvie: Consultancy. Sekeres:Millenium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Syros: Membership on an entity's Board of Directors or advisory committees.