A phase 1b study was conducted to evaluate the safety and feasibility of ciprofloxacin and etoposide combination treatment in subjects with relapsed and refractory acute myeloid leukemia. Eleven subjects were enrolled in the study. Utilizing the standard '3 + 3' design, escalating ciprofloxacin doses (750 mg, 1000 mg) twice daily on D1-D10 in combination with a fixed dose (200 mg) of etoposide on D2-D8 were administered. Maximum tolerated dose was determined to be 1000 mg of ciprofloxacin in combination with 200 mg of etoposide. Serious adverse events occurred in 54.5% (n = 6) subjects and 91% (n = 10) subjects reported ≥ grade 3 toxicities. Nine subjects completed treatment, one had a dose-limiting toxicity, and one withdrew. One subject achieved complete remission with a duration of 111 days and one subject achieved morphologic leukemia-free state after cycle 1. While the combination demonstrated safety and an acceptable toxicity profile, only modest hematologic and clinical benefits were observed.This trial was registered at www.clinicaltrials.gov as #NCT02773732.

e19053 Background: Recent advances and approval of multiple targeted and non-targeted agents have significantly transformed care for Acute Myeloid Leukemia (AML) over the past 5 years, particularly for older/unfit patients. While this has provided clinicians with several treatment options in both upfront and relapsed/refractory setting, it has also increased the complexity of clinical decision making. Although several trials have shown immense promise of these therapies, the real-world outcomes have not been reported. The primary aim of this study is to compare survival outcomes in newly diagnosed and relapsed AML before and after the introduction of the novel AML treatments that were granted FDA approval over the past 5 years. Methods: We performed a retrospective single-center analysis on adult patients (≥ 18 years) with newly diagnosed and relapsed AML treated at University of Florida Cancer Hospital between January 2012 and December 2020. Patients were stratified according to the time of diagnosis and Overall survival (OS) was estimated using Kaplan Meier method. Survival between groups was compared using log-rank test. Results: A total of 1617 patients were included in this analysis. Median age was 61 years (range 18-83) and 54.4% of patients were men. 71.4% patients were of white race. Median OS was 71.5 months with 1-year OS of 67.4%. Women had significantly better survival than men (1-year OS: 72% vs 63.6%, p=0.0043). 1-year OS for patients diagnosed in 2012-14, 2015-17 and 2018-20 was 73.5%, 67.6% and 58.1% respectively (p < 0.0001). There were no significant differences in survival based on race. 21.4% (n=347) patients had relapse of AML. Median OS for AML relapse was 9.8 months with 1-year survival of 45.1%. There were no significant differences in survival of patients based on race, sex and year of diagnosis. Conclusions: Our study reports decline in 1-year survival of patients with AML in the modern era despite introduction of several novel therapies in recent years. Additionally, relapsed AML continues to have dismal outcomes despite the availability of multiple novel agents for R/R AML. These results are surprising given the reported good efficacy of these agents in clinical trials. Possible explanations include under-representation of real-life patients in clinical trials, poor tolerability of these therapies by the average patient, and/or barriers to access to these novel therapies in healthcare due to prohibitive high cost, inadequate insurance coverage, or limited availability. Larger-scale real-life population-based studies are needed to further investigate the validity of these findings. [Table: see text]

Introduction: Myelofibrosis (MF) is characterized by bone marrow (BM) fibrosis, ineffective hematopoiesis, splenomegaly, and debilitating symptoms. Expression of PIM-1 is significantly upregulated in MF hematopoietic cells, supporting exploration of PIM-1 as a potential therapeutic target in MF. TP-3654 is a highly selective oral investigational PIM-1 kinase inhibitor. When administered alone and in combination with ruxolitinib, TP-3654 reduced spleen size and BM fibrosis in JAK2V617F and MPLW515L murine MF models (Dutta, 2021). In addition, TP-3654 decreased cytokine response genes and serum TGF-b in progenitor cells and JAK2V617F mice, respectively. TP-3654 showed less hematopoietic inhibition than Janus kinase (JAK) inhibitors (ruxolitinib, pacritinib and momelotinib) in in vitro human megakaryocyte and erythrocyte cell colony formation. Methods: This Phase I/II study evaluates the safety and efficacy of TP-3654 monotherapy in patients with MF (NCT04176198). Key eligibility criteria include primary or secondary MF; intermediate or high-risk MF per DIPSS; previously treated with or ineligible for JAK inhibitor treatment; grade ≥2 BM fibrosis; platelet count ≥25x109/L; absolute neutrophil count ≥1x109/L; splenomegaly; and ≥2 measurable symptoms. The study aims to identify the maximum tolerated dose and/or recommended Phase II dose using a Bayesian logistic regression model (BLRM) with overdose control, and to assess clinical activity (spleen volume reduction [SVR], total symptom score [TSS] improvement, and BM fibrosis reduction), safety, pharmacokinetic, and pharmacodynamic markers in peripheral blood and BM biopsies. Results: As of 11 July 2022, 8 patients were enrolled across 5 dose levels in the dose escalation phase. At baseline, median age was 70 years (range, 61 to 77), median spleen volume was 2370 cm3 (range, 1189 to 4407), median total symptom score was 19 (range, 4 to 62), median platelet count was 120 x109/L (range 68 to 237), median hemoglobin was 10.1 g/dL (range, 5.9 to 13.7), and two patients were transfusion-dependent. All patients had received prior treatment with at least one JAK inhibitor. Median duration of prior JAK inhibitor treatment was 35 weeks (range, 13 to 269). Six patients had JAK2V16F mutation, 2 patients had CALR mutation. The median duration of TP-3654 treatment was 21 weeks (range, 1 to 45). No dose-limiting toxicities occurred. Treatment-related adverse events (TRAEs) occurring in >20% of patients included mild to moderate nausea, vomiting, and diarrhea. Grade ≥ 3 TRAEs included only 1 case of vomiting. No hematological TRAEs were reported. No discontinuation due to AE occurred. SVR was observed in 5 out of 6 evaluable patients (median best change -14%, range -3.2% to -35%) (Figure 1). Symptom improvement was observed in 5 out of 6 evaluable patients (median best change -70%, range -32 to -100%). A panel of cytokines were evaluated in plasma samples obtained at baseline and during TP-3654 treatment. Reductions in cytokines (TGF-b, IL-18, VEGF, RANTES, MMP-9, and TIMP-1) were observed after TP-3654 treatment (Figure 2). Patients with higher cytokine reductions correlated with higher reduction in total symptom score. Enrollment is ongoing, updated data will be presented. Conclusions: The preliminary clinical data in dose escalation show: 1) encouraging signs of clinical activity in spleen volume reduction, symptom improvement, and cytokine reduction with TP-3654 monotherapy in patients previously treated with JAK inhibitors, 2) TP-3654 is well tolerated with limited myelosuppressive adverse events. The non-clinical findings and preliminary clinical safety/efficacy data support accelerated development and assessment of TP-3654 as the optimal partner for combination with JAK inhibitors. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Administering myelosuppressive chemotherapy to patients with aggressive malignant hematologic disorders typically poses serious infectious complications, which can be exacerbated by the presence of active COVID-19 infection. We report on a case of a successfully treated fit elderly woman with refractory acute myeloid leukemia (AML) who also had mild COVID-19 infection and detectable viral load at the time she was found to have recurrent disease. Prior to initiation of reinduction treatment with cytarabine/idarubicin, this 2-dose COVID-19-vaccinated patient received antiviral therapy with remdesivir with resolution of upper respiratory symptoms. This was followed by sotrovimab on the third day of chemotherapy. Throughout her hospital course, she remained hemodynamically stable with one episode of neutropenic fever without other identified infections. Symptomatic reactivation of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing COVID-19 was not observed. After achieving biopsy-confirmed morphologic remission of AML and with neutrophil recovery, the patient gradually cleared the virus, eventually testing negative on polymerase chain reaction test of the nasopharynx. This case underlines the importance of considering initiation of timely chemotherapy, although myelosuppressive, in appropriate patients with aggressive hematologic malignancies and concomitant SARS-CoV-2. It demonstrates management of active COVID-19 infection in this group of patients and the dynamics of SARS-CoV-2 viral load during leukemia treatment.

Hematopoietic stem cell transplantation (HCT) survivors are burdened by a high prevalence and early onset of chronic diseases. Healthy dietary patterns have been associated with lower risks of chronic health conditions in the general population. HCT survivors are susceptible to multiple complications that may result in chronic illness. Unfortunately, no study to date has comprehensively documented the adherence of HCT survivors to the Dietary Guide-lines for Americans (DGA), which are designed specifically to provide guidance for making healthy food choices. The primary aim of this study was to evaluate diet quality and nutrient intake adequacy of HCT survivors. A secondary aim was to assess these survivors' willingness to take part in a future dietary intervention. The dietary intake of adults who had undergone autologous or allogeneic HCT for a hematologic disease and were at least 1 year posttransplantation was assessed using the Block 2014 food frequency questionnaire, and diet quality was estimated using the Healthy Eating Index 2015. Nutrient intake adequacies of the group were estimated by the estimated average requirement cutpoint method. Survivors' (n = 90) HEI-2015 scores averaged 61.6 +/- 1.1. Adherence to a good-quality diet was reported by only 10% of survivors. Intakes of vitamins A, C, and D, as well as magnesium and calcium, suggested inadequacy. Fiber intake at 8.9 g per 1000 kcal/day fell below the recommended adequate intake. "Change in taste" was associated with lower quality of diet (P = .02). HCT survivors within 2 years post-transplantation were more receptive than survivors beyond 2 years to participating in a dietary intervention (95% versus 65%; P = .0013). Adult HCT survivors reported less-than-optimal adherence to the 2015-2020 DGA and had numerous shortfall nutrient intakes; however, their willingness to participate in a dietary intervention was relatively high. These findings reinforce the need to incorporate nutrition into HCT survivor care. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.

IntroductionAbsolute lymphocyte count (ALC) recovery following autologous stem cell transplant(ASCT) has been shown to be an important factor for overall and progression free survival. This is thought to be mediated by improved immune reconstitution resulting in decreased adverse events.ObjectivesOur primary aim was to investigate the role of ALC recovery at day 30 (D30) following ASCT in the overall survival(OS) and progression free survival(PFS) in patients treated for multiple myeloma(MM). Our secondary aim was to evaluate the correlation between infused CD3 content and ALC D30.MethodsTwo hundred forty-six patients were identified from our center's CIBMTR database who underwent ASCT between 2000-2010 for MM. Following manual chart review one hundred twenty-five met criteria for inclusion in analysis. ALC D30 was defined as the closest ALC to D30 post ASCT +/- 7 days. Patients who did not have D30 ALC data (n= 87) or underwent tandem ASCT (n=25) were excluded. Descriptive data is available in Table 1. The cohort was split into two groups with ALC ≥ 500 cells x10^6/cu mm or ALC < 500 cells x10^6/cu mm. Albumin was categorized into high and low, consistent with R-IPSS. Descriptive statistics were summarized for all variables. Univariable and multivariable Cox Proportional Hazard regression models were fitted to examine the association between the ALC D30 and the PFS and OS.ResultsALC D30 failed to show an association with either PFS or OS in the univariable and multivariable analyses. The Median PFS time in ALC ≥500 group was 23.7 months (95%CI: 18.4 - 29.7) compared to 30.1 months (95% CI: 15.5 – 70.5) in the ALC < 500 group, p = 0.72. One year OS rates were 98%(CI: 92%-99%) and 96%(CI: 72%-99%) in ALC ≥ 500 and ALC < 500 groups, respectively (figure 2). Previously identified factors such as age at transplant and Karnofsky performance score also failed to show associations with both PFS and OS. In the multivariable analysis, albumin and disease response status following ASCT were significantly associated with improved OS but not with PFS, Table 2. Infused CD3+ showed a weak correlation to ALC D30, r = 0.25, p = 0.004.ConclusionsOur study failed to show an association between ALC D30 recovery and OS or PFS in patients with MM undergoing ASCT. Previously identified factors such as age also did not show an association with OS and PFS in our study. Data on induction regimens was not collected for this study and maintenance therapy was not administered or data was unavailable for a large portion of our dataset which may contribute to the discrepancy with previously reported studies. CD3+ dose of cells infused showed a weak but statistically significant correlation with ALC D30.

Patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) are generally older and have more comorbidities. Therefore, identifying personalized treatment options for each patient early and accurately is essential. To address this, we developed a computational biology modeling (CBM) and digital drug simulation platform that relies on somatic gene mutations and gene CNVs found in malignant cells of individual patients. Drug treatment simulations based on unique patient-specific disease networks were used to generate treatment predictions. To evaluate the accuracy of the genomics-informed computational platform, we conducted a pilot prospective clinical study (NCT02435550) enrolling confirmed MDS and AML patients. Blinded to the empirically prescribed treatment regimen for each patient, genomic data from 50 evaluable patients were analyzed by CBM to predict patient-specific treatment responses. CBM accurately predicted treatment responses in 55 of 61 (90%) simulations, with 33 of 61 true positives, 22 of 61 true negatives, 3 of 61 false positives, and 3 of 61 false negatives, resulting in a sensitivity of 94%, a specificity of 88%, and an accuracy of 90%. Laboratory validation further confirmed the accuracy of CBM-predicted activated protein networks in 17 of 19 (89%) samples from 11 patients. Somatic mutations in the TET2, IDH1/2, ASXL1, and EZH2 genes were discovered to be highly informative of MDS response to hypomethylating agents. In sum, analyses of patient cancer genomics using the CBM platform can be used to predict precision treatment responses in MDS and AML patients.

Introduction Long-term hematopoietic stem cell transplant (HCT) survivors are burdened by a high prevalence and early onset of chronic diseases. Healthy dietary patterns have been associated with lower risks of chronic health conditions in the general population, yet no study to date has comprehensively documented the adherence of HCT survivors to the Dietary Guidelines for Americans (DGA), specifically designed to provide guidance for making healthy food choices. The aims of this study were to evaluate the extent to which HCT survivors adhere to the DGA and to determine nutrient intake adequacy. A secondary aim was to assess their willingness to take part in a future nutritional program or dietary intervention. Methods The study population included adults (≥18 y), who had undergone autologous or allogeneic HCT for a hematologic disease and were at least 1-year post-transplantation. Dietary intake was assessed using the Block 2014 food frequency questionnaire and diet quality (adherence to the DGA) was estimated using the Healthy Eating Index-2015 (HEI-2015). A HEI score of ≤50 indicates "poor diet quality", 51-80 suggests a "diet that needs improvement", and >81 indicates "good diet quality" out of maximum of 100. HEI-2015 scores by patient and transplant characteristics were analyzed by ANCOVA. Nutrient intake adequacies of the group were estimated by determining the percentage of the group falling below the Estimated Average Requirement (EAR) of the Dietary Reference Intakes. Receptivity to participate in a dietary intervention to stay healthy was measured by the question, "How willing would you be to take part in a healthy nutrition program or diet intervention?" Response categories included, "not at all," "somewhat," and "definitely". Results Between December 2017 and September 2018, 124 survivors were invited to participate, of whom 90 (51 autologous and 39 allogeneic HCT survivors) completed the dietary intake assessment and were included in the analysis. Majority were male (56%), White (72%), married (81%) and completed some college education (57%). Most participants were overweight (34%) or obese (37%). The median time from the HCT was 5.2 years. Mean ±SE HEI-2015 scores were 61.6 ± 1.3 and 60.7 ± 2.2 for the 18-64 y and ≥65 y age groups, respectively, slightly higher than the US general population. Adherence to a good quality diet was reported by only 10% of survivors. The majority of the survivors reported a diet in need of improvement (82%) or a poor-quality diet (8%). Intakes of vitamin A (720 ± 447 mcg/d), vitamin C (82 ± 73 mg/d), vitamin D (4.4 ± 3.4 mcg/d), magnesium (253 ± 133 mg/d), and calcium (781 ± 430 mg/d) suggested inadequacy, as more than 50% of the group fell below the specific EARs. Sodium intake at 2834 ± 1345 mg/d exceeded the DGA recommendation of 2300 mg/d. Fiber intake at 8.9 g per 1000 kcal/d was significantly below the Adequate Intake of 14 g per 1000 kcal/d. "Change in taste" was the only variable associated with lower quality of diet (p=0.02). Interestingly, 29% of HCT survivors reported persistent altered taste sensation. No significant relationships were seen for participant's demographics and diet quality which may be due to a sample population skewed toward older, causations and socioeconomically advantaged individuals. More than two thirds of participants (73%) indicated an interest in participating in dietary intervention. HCT survivors within 2 years of transplant were more likely to be receptive to participation in a diet intervention study compared to survivors beyond 2 years (52% vs 28%, p=0.0013). Conclusion Adult HCT survivors report poor adherence to the 2015 Dietary Guidelines for Americans and have numerous short-fall nutrient intakes. However, the willingness to participate in a nutritional program or dietary intervention in this survivorship population was relatively high. These findings reinforce the need to incorporate nutrition into HCT survivor care. Disclosures Wingard: Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy; Ansun: Consultancy; Pluristem: Consultancy.

Abstract Droplet digital PCR (ddPCR) is a highly sensitive and rapid method for detecting mutant allele frequency (MAF). In preliminary work, our lower limit of detection for common myeloid gene mutations was 0.001% in peripheral blood and bone marrow compared to 0.1% with flow cytometry and 0.01% with real-time quantitative PCR, and turnaround time is 1 day. Furthermore, we detected leukemic mutant alleles in peripheral blood (PB), introducing the possibility of sparing painful bone marrow biopsy procedures to determine treatment response. Thus, we hypothesized that ddPCR is a feasible and accurate method for monitoring leukemic disease burden in PB for the prospective care of patients (pts) with AML. Eighteen patients (pts) with de novo, relapse/refractory, and secondary AML were recruited to an IRB-approved study (NCT02435550) and bone marrow (BM), peripheral blood (PB), and saliva were collected at standard clinical visits. Gene mutations were identified by whole-exome sequencing (WES) of BM specimens at study entry. For ddPCR interrogation, genomic DNA was isolated (Qiagen), and select primers and probes (Bio-Rad/IDT) were developed based on variants identified in WES data. Case-specific primers and probes were validated on archived specimens obtained at study entry. 12/18 pt mutanomes met criteria for primer/probe design. 8 pts are in the primer/probe design and validation stage and 4 have completed validation and serial analyses. WES identified, and ddPCR confirmed, at least 1 mutation per patient at the study entry timepoint. The mutations included NRAS G13R, NRAS G12A, CSF3R T618I, and IDH2 R172K. In 2 cases, we observed a reduction in both PB and saliva MAF that were consistent with the reduction in both BM and PB blasts after treatment, resulting in complete remissions. Although PB blasts were reduced in a third pt receiving ruxolitinib, the persistence of their CSF3R MAF in PB indicated a resistant AML clone. WES revealed the presence of NRAS G13R variant in a secondary AML pt; however, WES did not detect this NRAS G13R variant in a cryopreserved BM specimen obtained at the pts MDS diagnosis. Interestingly, ddPCR was able to detect NRAS G13R variant at 0.1% MAF in a PB sample obtained at MDS diagnosis, demonstrating the ultrasensitive detection of rare variants within a sample, and highlighting the subclonal evolution of this pt's malignancy. Rapid detection of myeloid-related somatic mutations in a variety of tissue sources (i.e., saliva, PB) will allow for noninvasive monitoring of AML tumor burden. ddPCR may be used to observe molecular response to treatment and to detect molecular residual disease and relapse prior to clinically indicated BM biopsies. Citation Format: Kimberly E. Hawkins, Cesia Salan, Madeleine Turcotte, Lauren T. Vaughn, Mei Zhang, Yanping Zhang, Barry Sawicki, Glenda G. Anderson, Nosha Farhadfar, Hemant S. Murthy, Biljana N. Horn, Helen L. Leather, Paul Castillo, Maxim Norkin, John W. Hiemenz, Randy A. Brown, William Slayton, Jack W. Hsu, John R. Wingard, Christopher R. Cogle, Leylah M. Drusbosky. Droplet digital PCR is a sensitive method for detecting refractory acute myeloid leukemia (AML) clones in peripheral blood and saliva [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3253.

e19504 Background: Autologous Stem Cell Transplant (ASCT) is considered as standard of care for patients (pts) with relapsed and refractory non-Hodgkin's lymphoma (NHL). In this study we evaluated delayed engraftment (DE) in large cohort of ASCT recipients with NHL. Methods: 1,162 pts undergoing ASCT at a single institution from 1996-2016 were retrospectively reviewed to determine DE, defined as platelet count ≤50,000/μl, hemoglobin ≤8 g/dL, or ANC ≤1000 mm3. Pts with prior ASCT or those lost to follow up were excluded. Results: NHL represented only 209/1162 (18.0%) of pts undergoing ASCT but accounted for 108/239 (45.2%) of pts with DE at 30 days (Table 1). By comparison, multiple myeloma (MM) represented 686/1162 (59.0%) of pts undergoing ASCT but accounted for only 69/239 (28.9%) of pts with DE at 30 days. This was statistically significant (p = 0.05, OR = 2.377 (95% CI 1.00, 5.65). Given this discrepancy for the engraftment of NHL pts, the 108 NHL pts with DE were analyzed further to determine clinical factors influencing development of DE in NHL pts. In univariate analysis NHL type (p = 0.99), stage (p = 0.95), disease status at transplant (p = 0.54), bone marrow or extranodular involvement (p = 0.54, 0.68), conditioning regimen (p = 0.39), EBV and CMV viral serologies (p = 0.51, 0.06), history of radiation therapy (p = 1.0), prior chemotherapy regimens, and CD34+ dose (p = 0.11) showed no statistically significant impact on development of DE in NHL pts. Conclusions: DE was identified in 52% of all pts with NHL and pts with NHL have a significantly higher risk for the development of DE as compared to MM pts. Disease stage, bone marrow or extranodular involvement, chemotherapy regimen, or other treatment related factors had no influence of DE indicating that this inherent characteristic of NHL and its impact of marrow microenvironment can be responsible for this discrepancy in DE Table 1: Demographics of NHL pts with DE Variable n = 108 (%) Stage 1 (1%) 2(14%) 3(17%) 4(69%) NHL subtype - DLBCL 57 (53%) Mantle cell 18 (17%) Follicular 11 (10%) T-cell 10 (9%) B-cell 6 (6%) Other 6 (6%) Disease status at transplant - CR 59 (55%) PR 49 (45%) Extranodular disease - Yes 67 (62%) No 41 (38%) Bone marrow involvement - Yes 40 (37%) No 68 (63%)

e20001 Background: Delayed engraftment (DE) is a well-described complication after allogeneic transplant, however the incidence and risk factors of DE in recipients of autologous stem cell transplant (ASCT) is not well studied. Methods: 1162 patients (pts) receiving ASCT at the University of Florida (UF) from 1996 to 2016 were retrospectively reviewed for DE, defined as platelet count ≤50,000 μl, hemoglobin ≤8 g/dL, or ANC ≤1000 mm3. Patients with prior ASCT or those lost to follow up were excluded. This study was approved by the UF IRB. Results: Of 1162 pts analyzed, 239 (20.6%) were found to have DE at 1 month after ASCT. These 239 pts were analyzed at 3, 6, and 12 month intervals with 107/239 (44.8%) engrafting by 3 months. For patients with DE, there was a statistically significant difference in pre-transplant platelet level (p < 0.0001), transfusion dependence (p = 0.0004), and CD34+ cell count (p = 0.0057). Pts were then subdivided into those with pre-transplant platelets ≥ 150,000/µl and those < 150,000/µl, and CD34+ cell count ≥3x106/kg and those < 3 x106/kg. Multivariate analysis showed that CD34+ cell count ≥3x106/kg, transfusion dependence, and platelets ≥150,000/µl were statistically significant predictors of DE (Table 1). Conclusions: DE is a frequent complication after ASCT, which often persists for > 3 months following ASCT. Pts with pre-transplant platelets ≥150,000/µl were 3 times less likely to have DE at 3 months compared to all others, and those who were transfusion dependent were significantly more likely to have DE at 3 months compared to all others (OR = 0.29). Based on this analysis, if CD34+ cell dose is ≥3x106/kg (as 85% of pts were), pre-transplant platelets and transfusion dependence may be used as an early predictive model to identify patients at risk for DE. Table 1. Multivariate analysis variable OR: 95% CI: P-value: CD34+ (≥3 vs < 3 x106/kg) 5.411 (1.907, 15.357) 0.0015 Pre-transplant Platelet Count (≥150 vs < 150 x103/µl): 3.114 (1.455, 6.663) 0.0034 Transfusion dependence (Yes vs No): 0.250 (0.093, 0.672) 0.0060

Relapsed acute myeloid leukemia (AML) is a significant challenge after allogeneic hematopoietic cell transplant (HCT). Multiparameter flow cytometry (MFC), conventional cytogenetics (CG), and fluorescence in situ hybridization (FISH) are routinely performed on bone marrow specimens prior to HCT to assess disease status. We questioned the extent by which pre-HCT evidence of minimal residual disease (MRD) detected by these standard assays, corresponded with post-HCT relapse. We conducted a single center, retrospective study of 166 AML patients who underwent HCT. Thirty-eight of one hundred sixty-six (23%) patients in complete remission (CR) or CR with incomplete count recovery (CRi) had MRD detectable by MFC, CG, or FISH. MRD was more frequently seen in patients with poor risk karyotype at diagnosis (P = 0.011). MRD-negative patients (MRDneg) had significantly longer overall survival (OS) and relapse-free survival than patients who were MRD positive (MRDpos) (P = 0.002 and 0.013, respectively). In patients with MRDpos prior to HCT, the presence of acute graft vs. host disease (GVHD) (grade ≥ 2) or chronic GVHD significantly improved progression free survival (PFS) (hazard ratio (HR) = 0.053 (95% confidence interval (CI): 0.01–0.279), P = 0.0005) and OS (HR = 0.211 (95% CI: 0.081–0.547), P = 0.0014).

Data from a phase II clinical trial of venetoclax in AML recently supported its FDA breakthrough therapy designation for use in combination with hypomethylating agents in untreated AML patients ineligible for standard induction chemotherapy. Venetoclax is currently FDA approved for use in chronic lymphoid leukemia (CLL) patients with a 17(p) deletion who have been treated with at least 1 prior therapy. Del17(p) leads to loss of the TP53 gene, encoding the key tumor suppressor p53. Loss of p53 results in BCL-2 overexpression, providing a target for venetoclax's mechanism of action. Approval of this BCL-2 inhibitor in CLL raises the question of mechanism of action in AML and patient selection for treatment. Unfortunately, no biomarkers or methods exist to predict venetoclax response in AML, making treatment selection challenging.

Hypomethylating agents (HMAs) (azacitidine (aza), decitabine (dec)) and lenalidomide (len) are approved agents and used to treat patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Despite their widespread use, HMAs fail in the majority of these patients, and len fails in 75% of non-del(5q) MDS. Currently, no method exists to predict disease response, thus the management of MDS and AML patients is challenging. Methods: Patients with AML or MDS were recruited to a clinical trial (NCT02435550) designed to assess predictive values by comparing computer predictions of drug response to actual clinical response. Genomic profiling was conducted by cytogenetics, whole exome sequencing, and array CGH. Genomic results were inputted into a computational software (Cellworks), which generates disease-specific protein network maps using PubMed and other resources. Digital drug simulations were conducted by quantitatively measuring drug effect on a cell growth score (proliferation + viability + apoptosis). Each patient-specific protein network was screened for the extent by which aza, dec or len reduced disease growth in a dose-respondent manner. Treatment was physician’s choice of SOC. Clinical outcomes were prospectively recorded. IWG criteria were used to define response. Western blot assays were performed to validate the predicted protein network perturbations. Fisher’s exact test was used to compare prediction values of the genomics-informed computer method versus empiric drug administration. Results: 88 patients have had all molecular tests and computational modeling performed. Lab validation of computer-predicted, activated protein networks in 19 samples from 13 different patients showed correct prediction of 5 activated networks (Akt2, Akt3, PIK3CA, p38, Erk1/2) in 17 samples, with 89% accuracy. At the time of this report, 26/88 patients were eligible for efficacy evaluation. 8/26 patients showed clinical response to SOC therapy, 18/26 did not. 24/26 outcome predictions were correctly matched to their clinical outcomes, and 2/20 were incorrectly matched, resulting in 92% prediction accuracy, 80% PPV, 100% NPV, 100% sensitivity, and 89% specificity. The accuracy of the genomics-informed computer method was significantly greater than empiric drug administration (p=1.664e-05). New genomic signature rules were discovered to correlate with clinical response after aza, dec or len. Summary: A computational method that models multiple genomic abnormalities simultaneously showed high predictive value of protein network aberrations and clinical outcomes after SOC treatments. The network method uncovered molecular reasons for drug failure and highlighted resistance pathways that could be targeted to recover chemosensitivity. This technology could also be used to establish eligibility criteria for precision enrollment in drug development trials Citation Format: Leylah Drusbosky, Kimberly E. Hawkins, Shireen Vali, Taher Abbasi, Ansu Kumar, Neeraj Kumar Singh, Kabya Basu, Chandan Kumar, Amjad Husain, Caitlin Tucker, Randy A. Brown, Maxim Norkin, John Hiemenz, Jack Hsu, John Wingard, Christopher R. Cogle. iCare 1: A prospective clinical trial to predict treatment response based on mutanome-informed computational biology in patients with AML and MDS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT085. doi:10.1158/1538-7445.AM2017-CT085

Introduction: A limited knowledge exists regarding the incidence and risk factors of poor graft function (PGF) following ASCT. There are multiple factors related to either quality of infused hematopoietic cells such as inadequate numbers or poor viability, or host factors such as chemotherapy induced stromal damage, bone marrow fibrosis, post-transplant infections, relapse, or drug-induced myelosupression which can contribute to development PGF in ASCT recipients.

Refractory disease remains a challenge in treating patients (pts) with MDS and AML. Despite their widespread use, cytotoxic agents (7+3, HiDAC) and hypomethylating agents (HMAs) fail in the majority of pts, and lenalidomide (LEN) fails in 75% of non-del(5q) MDS. 90% of MDS and AML pts harbor at least one somatic mutation, further contributing to disease complexity. Currently, no comprehensive method exists to predict disease response based on the entire mutational burden detected in malignant samples. Predicting response to treatment would improve effectiveness, limit treatment-related adverse events, and reduce health care costs. Hence, there is need to predict pt response based on disease biology. Aim: Determine the biological and clinical predictive values of a genomics-informed computational biology method (CBM) in pts who are treated with standard of care (SOC) therapy. Methods: Pts with AML or MDS were recruited in a prospective clinical trial (NCT02435550) designed to assess predictive values by comparing computer predictions of treatment response to actual clinical response. Genomic profiling was conducted by cytogenetics, whole exome sequencing (WES), and copy number variation (CNV) analysis. These genomic results were entered into a CBM software (Cellworks Group), which generates disease-specific protein network maps using PubMed and other online resources. Digital drug simulations were conducted by quantitatively measuring drug effect on a cell growth score, which is a composite of cell proliferation, viability and apoptosis. Each pt-specific protein network map was digitally screened for the extent to which each pt9s therapy reduced simulated disease growth in a dose-respondent manner. Treatment was physician9s choice of SOC. Before initiating treatment, treating physicians were masked to the results of WES and CBM predictions. Clinical outcomes were prospectively recorded by the physicians. To be eligible for efficacy assessment, MDS pts must have had at least 4 cycles of HMA treatment or 2 cycles of LEN treatment. For AML, CR+PR was used to define response (IWG 2003). For MDS, CR+PR+HI was used to define response (IWG 2006). AML pt response was determined at time of recovery bone marrow biopsy, post induction therapy and/or consolidation therapy. Western blot assays were performed to validate the predicted protein network perturbations. Comparisons of CBM versus actual responses were performed using 2x2 tables. Fisher9s exact tests were used to compare prediction values of the genomics-informed computer method versus empiric drug administration. Results: Between June 2015 and July 2017, 120 pts were recruited, and 81 have had all genetic tests performed. At the time of this report, 42 pts were eligible for clinical response evaluation. 25/42 (60%) had AML, 15/42 had MDS (36%), and 2 pts had myelofibrosis. The median age was 65 (range 47-90). 24/42 (57%) were treatment-naive and 18/42 (43%) were treatment-refractory. Laboratory validation study of computer-predicted, activated protein networks in 19 samples from 11 different pts showed correct prediction of 4 activated networks (Akt2, Akt3, PIK3CA, Erk1/2) in 17 samples, exhibiting 89% accuracy. At the time of this report, 42/81 pts received 52 treatments and were eligible for efficacy evaluation. 28/52 treatments resulted in clinical response to SOC therapy, while 24/52 did not achieve clinical response. 48 drug outcome predictions (92%) were correctly matched to their actual clinical outcomes, and 4/52 were incorrectly matched, resulting in 93% PPV, 92% NPV, 93% sensitivity, and 92% specificity (Table 1). Of note, CBM performed accurately in both treatment-naive and relapsed/refractory pts. The accuracy of the CBM was significantly greater than empiric drug administration (p=6.034 E-08). Additionally, new genomic signature rules were discovered to correlate with clinical response after HMA or len. Conclusions: CBM that models multiple genomic abnormalities simultaneously showed high predictive value of protein network perturbations and clinical outcomes after SOC treatments. The network method uncovered molecular reasons for drug failure and highlighted resistance pathways that could be targeted to recover chemosensitivity. This technology could also be used to establish eligibility criteria for precision enrollment in drug development trials, and will be used in upcoming precision medicine trials. Disclosures Singh: Cellworks Research India Pvt. Ltd: Employment. Radhakrishnan: Cellworks: Employment. Ullal: Cellworks Research India: Employment. Talawdekar: Cellworks: Employment. Sikora: Cellworks: Employment. Nair: Cellworks: Employment. Bhowmick: Cellworks: Employment. Abbasi: Cellworks Group Inc.: Employment. Vali: Cellworks Group Inc.: Employment. Norkin: Celgene: Honoraria, Research Funding. Cogle: Celgene: Other: Membership on Steering Committee for Connect MDS/AML Registry.

Background: Although virtually all patients (pts) with AML or MDS harbor at least one somatic mutation, a minority of pts possess genetic mutations considered directly targetable by a drug. Moreover, in pts with multiple gene mutations, single-gene/single-drug matching often produces conflicting drug recommendations. This lack of clinically relevant mutation-targeted therapy represents an unmet need in treating AML and MDS, and is a major limitation in personalized medicine. We hypothesized that genomic mutations from pts with AML or MDS could be used to generate pt-specific protein network maps for use in digital drug screening (DDS) even in cases when the gene mutations per se are not directly actionable. This would dramatically increase the percent of pts with actionable findings. Our primary goal was to establish a genomics and computational biology workflow that identified disease-relevant treatment options for every pt.

Although bone marrow evaluation on day 14 after initiation of induction chemotherapy (D14 BM) is a widely accepted practice in patients with acute myeloid leukemia (AML), it has suboptimal predictive value for predicting complete remission. We retrospectively analyzed pretreatment characteristics and post-induction response in a cohort of AML patients to determine if adding clinical and laboratory characteristics can improve the predictive value of the D14 BM evaluation. Among 297 patients treated for AML at the single institution 183 patients (61%) had leukemia-positive D14 BM. Of those, 94 were given reinduction chemotherapy and 89 were not. Of the 89 patients who did not receive reinduction, 32 (36%) subsequently achieved complete remission (CR) or complete remission with incomplete count recovery (CRi), and 57 (64%) had persistent disease. Persistent disease after positive D14 BM was more likely associated with higher percentage of D14 myeloblasts, a history of relapsed disease before induction, and higher risk disease compared to patients who subsequently achieved CR. Age, diagnostic white blood cell count, and the D14 BM cellularity did not influence the subsequent likelihood of achieving remission in patients with a positive D14 BM. A new mathematical equation was created and resulted in a positive predictive value of 83%, negative predictive value 90% and accuracy 88% for correctly identifying remission status after positive D14 BM in AML. The accuracy of predicting response using these additional parameters was significantly higher than without (0.88 vs. 0.80, P=0.002). Our new model provides better accuracy for predicting the likelihood of achieving remission and if validated in future studies may be useful for managing AML patients.

Abstract Introduction: High dose melphalan followed by autologous hematopoietic stem cell transplant (ASCT) is the standard of care in eligible multiple myeloma (MM) patients (pts). It is common practice to collect sufficient stem cells for two transplants, for the first ASCT immediately after induction, and for salvage ASCT following disease progression. We investigated the frequency of salvage second ASCT in the era of novel agents to determine if there has been a change in practice. Methods: We retrospectively reviewed medical records of MM pts who had stem cells collected for two ASCTs from 03/1996 to 12/2014. We then compared pts who received their first ASCT prior to January 2007 to those after this time. We excluded pts who received their second transplant as part of a clinical protocol, who received subsequent allogenic transplants, and pts who received 2 ASCT transplants as part of initial therapy. Fisher's exact test was used to assess significance of categorical independent variables and t-test was used to assess significance of continuous variables. Results: Forty of 506 pts (7.9%) received salvage second ASCT (Fig 1). Among 195 MM pts who received their first ASCT before 2007, 19 pts (9.7%) received salvage ASCT. After 2007, 21 of 311 MM pts (6.7%) received salvage ASCT (P= 0.24). When comparing salvage ASCT in the two time periods, no significant differences were noted, with the exception of a slightly lower KPS status (80% vs 70%, P=0.001), and the use of novel agents before the salvage therapy (0/19 (0%) vs 17/21 (81%), p <0.001). Otherwise the clinical characteristics, prior response and response duration, and initial stage were similar. Prior to 2007, 6 of 44 (14%) pts older than 65 years received salvage ASCT, whereas after 2007 only 3 of 110 (3%) patients received salvage ASCT (p = 0.017). Conclusions: Outside of clinical trials, the use of salvage second ASCT for relapsed MM is not frequent, and was noted to be decreasing further after 2007. We speculate that this 30% relative reduction in the frequency of salvage ASCT after 2007 is likely explained by the introduction of novel agents such as bortezomib and lenalidomde into the clinical practice, the use of maintenance therapy post-ASCT, and more non-ASCT options for salvage treatment after relapse. Further studies are needed to investigate the optimal timing for salvage ASCT and the patients who will best benefit from such treatment. Figure 1 Figure 1. Disclosures Wingard: Astellas: Consultancy; Gilead: Consultancy; Ansun: Consultancy; Fate Therapeutics: Consultancy; Merck: Consultancy.

Background: Hypomethylating agents (HMAs) (e.g., azacitidine (aza), decitabine (dec)) and lenalidomide (len) are approved agents and used in the treatment of patients with myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML). Despite their widespread use, HMAs fail in the majority of MDS and AML patients, and len fails in 75% of non-del(5q) MDS. Unfortunately, no method exists to predict disease response, thus the management of MDS and AML patients is challenging. Predicting treatment response would improve treatment effectiveness, restrict treatment-related adverse events to those who would benefit, and reduce health care costs. Ideally, patient prediction would be based on disease biology.