Litzow, Mark

Background Blinatumomab is a bispecific T cell antibody construct, that binds and allows CD-3 positive cytotoxic T cells to recognize and eradicate CD19-positive acute lymphocytic leukemia (ALL) blasts. The drug is approved for patient (pts) with relapsed/ refractory (RR) B-cell ALL and those with minimal residual disease (MRD) based on efficacy in clinical trials. We sought to evaluate the safety and efficacy of blinatumomab in the "real world" setting. Methods We conducted a retrospective multicenter study in collaboration with 11 U.S. academic institutions, and evaluated the outcome of RR B-cell ALL pts, who received blinatumomab outside of clinical trials. These pts were evaluated for response, duration of response (DOR), overall survival (OS) from the time of blinatumomab initiation and toxicity. DOR was estimated among pts who had achieved complete remission (CR)/CR with incomplete count recovery (CRi). Survival curves were estimated using the Kaplan-Meier method and compared via log-rank test. Results From December 2014 to May 2019, 239 pts with B-cell ALL were identified. Baseline characteristics are summarized in Table 1. The median age of pts at blinatumomab initiation was 48 years (yrs) (range, 18-85). Sixty-one (26%) pts had Philadelphia chromosome [t(9;22)] positive (Ph+ve) disease. Sixty-one (26%) pts had ≥ 3 prior therapies and 46 (19%) pts had allogeneic stem cell transplantation (allo-HCT) prior to blinatumomab. Twenty-two (9%) pts received inotuzumab ozagamicin prior to blinatumomab. Twenty-nine (12%) pts received blinatumomab in combination with tyrosine kinase inhibitor (TKI). Twelve (5%) pts received blinatumomab for MRD. Response rate (CR/CRi) in pts with RR disease was 61%; 44% had CR with MRD negativity by flow cytometry. Rate of CR/CRi in Ph+ve B-cell ALL was 74.5%. Among 12 pts who received Blinatumomab for MRD, 9 (75%) pts achieved MRD negativity. Overall 113 (48%) pts were successfully bridged to allo-HCT. Median DOR in pts with RR disease was 32.1 months (95% CI; 9.5-not reached [NR]) (Fig. 1a) and when censored at allo-HCT was 14.8 months (95% CI; 5.2-NR) (Fig. 1b). Median OS in pts with RR disease after blinatumomab was 12.7 months (95% CI; 9.2 -17.9) (Fig. 1c) and when censored at allo-HCT was 8.6 months (95% CI; 6.4-11.6) (Fig.1d). Median OS after blinatumomab in RR B-cell ALL Ph+ve pts was NR (59% alive at 2 yr). Among pts who received blinatumomab for MRD, median DOR was NR and 54% sustained MRD negativity at 2 yrs. Median OS was 34.7 months (95% CI; 8.8-34.7) in group of pts who received blinatumomab for MRD. Seven (3%) pts discontinued blinatumomab due to adverse events and 40 (21%) pts had dose interruptions. Cytokine release syndrome (CRS) of any grade (G) was reported in higher number of pts (93 [39%]) compared to clinical trials, though G3-4 CRS appears to be similar (G1-2 [36%], G3-4 [3%]). Forty-four (44%) pts were treated with steroids and 8 (8%) pts required tocilizumab with steroids for CRS. Ninety-three percent of pts had complete resolution of CRS. CNS toxicities were observed in 31 (13%) pts, among them 60% (n= 19) had G3-4 toxicities. Hepatic toxicities were observed in 84 (35%) pts as outlined in Table 1. Six (2.5%) pts died due to blinatumomab induced toxicities. Conclusion: Our real-world data with multicenter collaboration suggest that overall blinatumomab was well tolerated and had led to significant response in pts with RR B-cell ALL. Disclosures Advani: Amgen: Research Funding; Abbvie: Research Funding; Pfizer: Honoraria, Research Funding; Macrogenics: Research Funding; Kite Pharmaceuticals: Consultancy; Glycomimetics: Consultancy, Research Funding. Aldoss:AUTO1: Consultancy; Helocyte: Consultancy, Honoraria, Other: travel/accommodation/expenses; Agios: Consultancy, Honoraria; Jazz Pharmaceuticals: Honoraria, Other: travel/accommodation/expenses, Speakers Bureau. Podoltsev:Agios Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; Astellas Pharma: Research Funding; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Research Funding; Sunesis Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Pfizer: Research Funding; Astex Pharmaceuticals: Research Funding; CTI Biopharma: Research Funding; Celgene: Other: Grant funding, Research Funding; Genentech: Research Funding; AI Therapeutics: Research Funding; Samus Therapeutics: Research Funding; Arog Pharmaceuticals: Research Funding; Kartos Therapeutics: Research Funding. Curran:Incyte: Research Funding; Merck: Research Funding; Gilead: Research Funding. Yang:Agios: Consultancy; AstraZeneca: Research Funding. Mattison:Pfizer: Membership on an entity's Board of Directors or advisory committees. Liedtke:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Atallah:Helsinn: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Pfizer: Consultancy; Helsinn: Consultancy; Novartis: Consultancy; Jazz: Consultancy.

Background MDS is a heterogeneous disease and the revised International Prognostic Scoring System (IPSS-R) is utilized in prognostication. The percentage (%) of blasts in the bone marrow is determined in the aspirate morphologically. Though the former is the standard of care the blast percentage is also reported by flow cytometry and biopsy which can many times be inconsistent. We previously presented the utilization of biopsy based blast percentage which showed meaningful prognostic groups compared to aspirate. In this study we compare the blasts as reported by the aspirate and flow cytometry in MDS-EB in calculating IPSS-R. Methods The MDS database was reviewed for cases of MDS-EB after due IRB approval at the Mayo clinic. We calculated IPSS-R scores based on the aspirate blast % (IPSS-RAsp) and flow blast% (IPSS-Rfl). The aspirate blast percentage was reported morphologically. Suboptimal aspirates were excluded from the study. The flow blast percentage was determined by immunophenotyping. The overall survival (OS) was determined by IPSS-RAsp and IPSS-RFl. OS estimates were calculated by Kaplan-Meier curves and log-rank testing using JMP v.13. Uno's concordance statistic was used to compare the 2 risk scoring systems. Results Of 1322 patients, 431 (33%) cases were identified with MDS-EB out of which 120 (29%) cases had blasts reported in the aspirate and flow. Based on aspirate MDS EB1: 54% (n=65), MDS EB2 46% (n=55). The hematological, cytogenetic and R-IPSS categories were compared between MDS-EB1 and MDS- EB 2. The blast percentage and hemoglobin levels was significantly different between MDS-EB1 and EB2 as seen in table 1, however the IPSS-R risk groups were not significantly different. The flow cytometry was concordant with aspirate in 66/120 (55%) cases. Out of the dis-concordant cases only 20% (11/54) was upstaged by flow cytometry with most of the patients being down staged as expected by the techniques used in processing the blood and hence not reliable when reported low (Figure 1). The OS outcomes based on the IPSS- R asp, IPSS-Rfl areshown in figure 2A,2B .The p value with aspirate based R-IPSS was more significant than flow cytometry based R-IPSS (p= 0.0007 vs 0.0174). We compared the two models for observed OS differences using the Uno model which was not statistically significant. (p= 0.6) Conclusions Both models did not show a difference which is likely due to the very small sample size. However flow cytometry did down stage more patients when disconcordant and may have less value in that setting. It would be ideal to compare all 3 models aspirate, biopsy and flow cytometry however we did not have enough number of patients to do the comparison. Disclosures Patnaik: Stem Line Pharmaceuticals.: Membership on an entity's Board of Directors or advisory committees. Al-Kali:Astex Pharmaceuticals, Inc.: Research Funding.

Abstract Abstract 3555 Background: Although treatment-related acute myeloid leukemia (tr-AML) has been identified as an independent marker of poor prognosis, it is important to determine how characteristics of the patient, primary malignancy, or treatment regimen affect the development and outcome of tr-AML. Taxane therapy has become essential in the management of breast cancer in light of its favorable effect on survival in short term studies. However, clinical trials fail to capture acute leukemias related to recently introduced agents since development of tr-AML occurs years after chemotherapy. Aim: To examine the effect of taxane therapy on clinical outcome of patients who were treated for breast cancer and subsequently developed tr-AML. Methods: This retrospective chart review considers patients diagnosed with AML at Mayo Clinic between 1990 and 2011. Patients were included if they had previously received chemotherapy for breast cancer, or if they had never received any chemotherapy. Demographic data, previous diagnosis and treatment regimen, CBC at diagnosis, pathology and cytogenetic information, therapy used, and response were collected for each patient. IRB approval was obtained. Comparison between two groups was done using t-test; survival estimates using Kaplan-Meier curves were constructed with software JMP 9. Results: A total of 88 adult females with AML were identified. Median age at AML diagnosis was 58 years (range 19–86). Median hemoglobin was 8.9 g/dL (4–14.5), white blood cell count (WBC) 9.7 x109/L (0.6–237), platelets 67 x109/L (1–361), peripheral blood (PB) blasts 13%, bone marrow blasts (BM) 44%, and BM cellularity 90%. Of the 88 patients, 23 (26%) had previously received treatment for breast cancer (tr-AML), the remainder had de novo AML. Taxanes were included in the initial treatment for breast cancer in 14 (61%, median age 57, group 1), compared to 9 (39%) patients with no history of taxane exposure (median age 58, group 2). Median hemoglobin was 9.7 g/dL, WBC 4.5×109/L, platelets 72×109/L, PB blasts 2%, BM blasts 40% in group 1, compared to 8.3, 7.1, 50, 28%, 47%, respectively, in group 2. Cytogenetic analysis of group 1 showed diploidy in 8%, complex karyotypes in 8%, and chromosome 11 abnormalities in 38%, compared to 50%, 0%, 33%, respectively, in group 2. In group 1, 14% had good risk cytogenetics, 57% had intermediate risk, and 29% had poor risk, compared to 17%, 83%, and 0%, respectively, in group 2. Cytogenetic analysis of de novo AML showed diploidy in 71%, complex karyotypes in 14%, and chromosome 11 abnormalities in 0%. Complete remission (CR) was achieved in 79% of group 1 and 83% of group 2 (p 0.8). Differences in survival of group 1 (375 days) and group 2 (222 days) did not reach statistical significance (p 0.12). Median survival was 584 days for patients with de novo AML, 375 days in group 1 (p 0.47), and 222 days in group 2 (p<0.001). Conclusion: In agreement with previous reports, we found that tr-AML is a poor prognostic factor overall (p 0.04). However, patients with a history of breast cancer who had been treated with taxanes as a part of their initial chemotherapy regimen demonstrated similar survival as patients with de novo AML (p 0.47). Tr-AML patients only did significantly worse than patients with de novo AML if they had never received taxanes as part of their breast cancer therapy (p<0.001). Disclosures: No relevant conflicts of interest to declare.

Abstract Background: Eastern Cooperative Oncology Group trial E1900 (E1900) showed that induction therapy with a high daily dose of daunorubicin (90 mg/m2) (DNR 90) improves survival in younger patients (pts) (<50 yrs) and intermediate (int) cytogenetic risk AML, but at 2 years of follow-up no benefit was seen in older pts (50-60 yrs), or in those with unfavorable cytogenetic risk or FLT3-ITD mutant AML (Fernandez et al. N Engl J Med 2009). Here we update results of E1900 with longer follow-up, focusing on the benefit of DNR 90 in cytogenetic and common molecular subgroups. Methods: Overall survival (OS) was measured from randomization for induction therapy to death from any cause (censored at last contact). Hazard ratios (HR) for death were computed using univariate and multivariable Cox proportional hazards models; multivariable Cox models were adjusted for sex, age, hemoglobin level, leukocyte count, platelet count, and cytogenetic profile. All conclusions regarding the impact of DNR 90, unless noted, are similar based on univariate and multivariable analysis. Results: Overall, 657 pts were enrolled with a median follow-up of 80.1 months. The HR for death in the DNR 90 group as compared with the standard-dose daunorubicin (45 mg/m2) (DNR 45) group was 0.74 (p=0.001). Pts <50 yrs benefited from DNR 90 (p = 0.002) while those >=50 yrs were not proven to benefit (p = 0.12). Pts with favorable (fav) and int. cytogenetic risk benefited from DNR 90 (p = 0.03 and p = 0.02, respectively). A benefit for pts with unfavorable cytogenetic risk was seen on multivariable analysis (p = 0.04). Impact of DNR 90 by mutation status: The 3 most common mutations were FLT3-ITD (24%), NPM1 (26%), and DNMT3A (24%). AML pts with any of these 3 mutations benefited from DNR 90 (p = 0.009, p = 0.002, and p = 0.02, respectively). FLT3-ITD pts who received DNR 90 had a 4-yr OS of 31%. Benefit was seen in pts age 50-60 with FLT3-ITD or NPM1 mutation (p = 0.02 and p = 0.04, respectively). No benefit of DNR 90 was seen in a small cohort of pts with MLL-PTD (p = 0.06). Benefit of DNR 90 in FLT3-ITD, NPM1, and DNMT3A mutant AML was confirmed in the int. cytogenetic risk group. Impact of DNR 90 on prognostic impact of NPM1: The presence of an NPM1 mutation conferred an improvement in OS in the DNR 90 group which was not seen in the DNR 45 group (p = 0.01 vs p = 0.3). This finding was confirmed in the int. cytogenetic risk group. Conclusion: With median follow-up of over 6 years on E1900, we confirm that DNR 90 improves outcome in pts with fav/int cytogenetic risk, DNMT3A or NPM1 mutant AML, or age < 50 (Patel et al. N Engl J Med 2012). Additionally, we now demonstrate that DNR 90 additionally benefits pts with FLT3-ITD AML, and pts with unfavorable cytogenetic risk, regardless of age. Moreover, we show that the favorable prognostic impact of the NPM1 mutation is only present when pts receive DNR 90. Given the benefit of DNR 90 across all cytogenetic risk groups as well as common molecularly defined subgroups of AML, DNR 90 should be the standard for all pts up to age 60 who are candidates for induction chemotherapy. Table HR for death by AML cohort. Subgroup N Univariate Model DNR 45 DNR 90 HR (DNR 90/DNR 45) & 95% CI Wald P All patients (n=657) Overall 330 327 0.74 (0.61, 0.89) 0.001 Age < 50 yrs³ 50 yrs 188 142 172 155 0.66 (0.50, 0.85) 0.81 (0.62, 1.06) 0.002 0.12 Cytogenetic Favorable Intermediate Unfavorable 38 232 59 51 212 63 0.51 (0.28, 0.93) 0.76 (0.61, 0.96) 0.79 (0.54, 1.16) 0.03 0.02 0.22 FLT3-ITD WT MUT 215 83 241 64 0.74 (0.59, 0.92) 0.61 (0.42, 0.89) 0.008 0.009 MLL-PTD WT MUT 290 16 296 15 0.70 (0.58, 0.86) 0.46 (0.21, 1.04) 0.0004 0.06 NPM1* WT MUT 180 65 192 65 0.70 (0.55, 0.89) 0.50 (0.32, 0.78) 0.003 0.002 DNMT3A WT MUT 177 61 194 58 0.66 (0.52, 0.85) 0.62 (0.41, 0.94) 0.001 0.02 * Statistically significant test of interaction (p<0.2) Figure 1A: Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1A:. Overall Survival by NPM1 Mutation Status and Treatment Arm Figure 1B: Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Figure 1B:. Overall Survival of FLT-ITD Mutant AML Patients by Treatment Arm Disclosures No relevant conflicts of interest to declare.

AbstractThe prognostic importance of genetic information in primary myelofibrosis (PMF) was recently highlighted in a study of over 1000 cytogenetically‐annotated patients; 5‐year survival rates were 8% for very high risk (VHR), 27% “unfavorable” and 45% “favorable” karyotype. The current study addresses the practice‐relevant question of whether or not allogeneic hematopoietic stem cell transplant (HCT) can overcome the detrimental survival effect of VHR or unfavorable karyotype. The study included 67 patients with PMF or secondary MF who received HCT at the Mayo Clinic and in whom pretransplant cytogenetic information was available. Dynamic international prognostic scoring system (DIPSS) risk distribution was 13% high, 66% intermediate‐2 and 21% intermediate‐1. Cytogenetic risk distribution was 11% VHR, 34% unfavorable and 55% favorable. At median post‐HCT follow‐up of 60 months for living patients (range 34‐170), 28 (42%) deaths were recorded. Five‐year survival was 62% and was not affected by VHR or unfavorable karyotype (P = .68). The salutary effect of HCT in patients with VHR or unfavorable karyotype was also apparent during analysis of a combined dataset that included a nontransplant cohort of 383 patients with PMF; multivariable analysis of the combined dataset (n = 450) resulted in HRs (95% CI) of 2.4 (1.6‐3.6) for absence of transplant, 3.3 (2.2‐4.8) for VHR karyotype, 1.6 (1.2‐2.1) for unfavorable karyotype, 2.9 (2.0‐4.2) for DIPSS high and 1.7 (1.4‐2.2) for DIPSS intermediate‐2. These observations were further confirmed by analysis of more stringently matched case‐control subset cohorts and provide the evidence for the therapeutic preference of HCT in cytogenetically high risk patients with MF.