Summary of Key AML Abstracts Presented at the American Society of Hematology (ASH) December 2-6, San Diego CA

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1 Summary of Key AML Abstracts Presented at the American Society of Hematology (ASH) December 2-6, San Diego CA ASH 2016 ANNUAL MEETING: ABSTRACT SEARCH PAGE: DefeatAML had attended the following presentations during the 2016 ASH Annual Meeting. Please consult the ASH webpage above for a SEARCH of full list of AML abstracts. (Listing does not imply any endorsement of the investigational products cited or not cited) A. First-Line AML 590 Vadastuximab Talirine ( 33A ) Monotherapy in Older Patients with Treatment Naive CD33-Positive Acute Myeloid Leukemia (AML) Twenty-seven treatment naive patients (48% male) with a median age of 74 years (range, 67-89) were treated with 40 mcg/kg of 33A. Most patients had intermediate (70%) or adverse (26%) cytogenetic risk by MRC and 48% of patients had underlying myelodysplasia. Twenty-four patients were considered unfit for intensive therapy and 3 patients declined intensive therapy. At baseline, patients had a median of 47% BM blasts. Three patients remain on treatment. The most common Grade 3 or higher adverse events (AE) were thrombocytopenia (44%), febrile neutropenia (41%), anemia (33%), fatigue, and pneumonia (19% each). Other common treatment-emergent AEs regardless of relationship to 33A were decreased appetite, diarrhea, fatigue, peripheral edema, thrombocytopenia (44% each), febrile neutropenia (41%), dizziness (37%), anemia, chills, cough, dyspnea, and epistaxis (33% each). The 30- and 60-day mortality rates were 0% and 15%. Of the 26 efficacy evaluable treatment naive patients, 6 patients (23%) achieved a best clinical response of CR, 8 (31%) achieved CRi, and 5 patients (19%) achieved a morphologic leukemia-free state. Most remissions were achieved after 1 cycle and were observed in many patients with adverse risk including underlying myelodysplasia (6/12, 50%), FLT3/ITD+ (3/4, 75%), and in patients 75 years of age (8/12, 67%). Of the responding patients with available minimal residual disease (MRD) data, 6 of 13 (46%) achieved MRD negativity by flow cytometry.

2 #591 Vadastuximab Talirine ( 33A ) Plus Hypomethylating Agents: A Well-Tolerated Regimen with High Remission Rate in Frontline Older Patients with Acute Myeloid Leukemia (AML) [CD33-directed antibody conjugated to 2 molecules of a pyrrolobenzodiazepine (PBD) dimer] Dose escalation of 33A, in first line, high risk AML patients unfit for intensive therapy. The median treatment duration is currently 19.3 weeks (range, 2-86) with 13 patients remaining on treatment; no DLTs or infusion reactions were reported. G3 or higher AEs reported in 15% of patients were thrombocytopenia (55%), anemia (43%), febrile neutropenia (43%), neutropenia (38%), pneumonia (19%), and leukopenia (17%). A total of 37% (90/246) of doses were delayed due to AEs primarily related to myelosuppression (neutropenia 16%, thrombocytopenia 6%, febrile neutropenia 4%). Thirty-six of the 49 efficacy evaluable patients (73%) achieved CR (21, 43%) or CRi (15, 31%). Remissions were achieved after a median of 2 cycles (range, 1-4) and were observed in most of the patients with adverse risk disease including antecedent myelodysplasia (16/22, 73%), adverse cytogenetics (15/18, 83%), FLT3/ITD (5/5, 100%), and patients 75 years (17/26, 65%). Seventeen of 22 efficacy-evaluable patients with secondary AML (77%) achieved CR (11, 50%) or CRi (6, 27%). Of all responding patients, 17 of 36 (47%) achieved MRD negativity by flow cytometry. The median relapse-free survival was 9.1 months (range, ) and OS continues to evolve with 22 patients (42%) alive with a median follow-up of 10 months. #211 A Phase 1b Study of Vadastuximab Talirine in Combination with 7+3 Induction Therapy for Patients with Newly Diagnosed Acute Myeloid Leukemia (AML) To date, 42 patients (36% male) with a median age of 45.5 years (range, 18-65) have been treated with (n=4) and (n=38) mcg/kg of 33A. Most patients had intermediate (40%) or adverse (43%) cytogenetic risk by MRC criteria and 17% of patients had secondary AML. As expected, all patients experienced Grade 4 myelosuppression. In patients who achieved CR or CRi, the estimated median time to count recovery from Day 1 of therapy was 33 days for neutrophils ( 1K) and 35 days for platelets ( 100K). Three DLTs (lack of recovery of platelets [25K] and/or ANC [500] by Day 42) occurred at the mcg/kg dose level, which was determined to be the maximum tolerated dose (MTD) of 33A in combination with 7+3. Grade 1 or 2 non-hematologic AEs occurring in >15% of patients were nausea (55%), diarrhea (33%), constipation (31%), decreased appetite (19%), fatigue (19%), and vomiting (17%); no infusion-related reactions occurred. No veno-occlusive disease (VOD) or significant hepatotoxicity was observed. The 30- and 60-day mortality rates were 0% and 7%, respectively. Of the 40 efficacy evaluable patients, best responses include 24 CR (60%), 7 CRi (18%), and 4 morphologic leukemia-free state (10%) with a CR+CRi (CRc) rate of 78%; 94% of CR or CRi responses occurred with 1 cycle of induction therapy. Twenty-three of 31 (74%) patients attaining CR or CRi achieved MRD negative status.

3 #102 Safety and Efficacy of Venetoclax Plus Low-Dose Cytarabine in Treatment-Naive Patients Aged 65 Years with Acute Myeloid Leukemia [selective BCL-2 inhibitor] Median time on venetoclax was days (range: 8-455). Grade 3/4 AEs ( 10% patients) excluding cytopenias were febrile neutropenia (35%), hypertension (20%), hypophosphatemia (20%), decreased appetite, increased blood bilirubin, hyponatremia, hypoxia, hypotension, pneumonia, sepsis, syncope, urinary tract infection, and vomiting (10% each). No events of TLS occurred. 15/20 (75%) patients achieved an objective response (CR+CRi+PR). Of them, 14/20 (70%) patients had a CR+CRi; all 14 patients belonged to a subset of 18 patients with no prior myeloproliferative neoplasm (MPN). 16/19 (84%) patients with available data had their bone marrow blast percentage reduced to below 5%. The 12-month overall survival (OS) estimate for all patients was 74.7% (95% CI= ) and that for the responders (n=15) was 86.7% (95% CI= ). The median time to best response was 30 days (range: ). Only 2/14 patients who achieved CR/CRi have died [disease progression (n=1), acute hepatic failure (n=1)]. B. Consolidation and Relapsed/Refractory AML #215: Results from Ongoing Phase 2 Trial of SL-401 as Consolidation Therapy in Patients with Acute Myeloid Leukemia (AML) in Remission with High Relapse Risk Including Minimal Residual Disease (MRD) [Human IL3 (CD123) Fusion Dyptheria Toxin] Dose escalation of SL-401 in CR 1 or CR2. The most common treatment-related AEs, all grades, were thrombocytopenia (3/9; 33%) and hypoalbuminemia (3/9; 33%); the most common grade 3 treatment-related AE was thrombocytopenia (1/9; 11%); there was no DLT. Stage 1 is complete without DLT or MTD. For all 3 patients treated at 12 ug/kg (MRD+, n=1; MRD-, n=2), 2 patients remain on SL-401 and have received 1+ and 4+ cycles (both ongoing). Stage 2 (expansion) is open to enroll AML patients in CR1 or CR2 who are MRD+ at the highest tested dose of 12 ug/kg. DefeatAML note: The presentation by Dr. Andrew Lane noted early indication of efficacy in one MRD+ AML patient who sustained a decrease in MRD, determined locally, treated at 12 ug/kg/day who then went on to stem cell transplant Separately, in August 2016 FDA granted Breakthrough Therapy Designation to SL-401, a targeted therapy directed to the interleukin-3 receptor (CD123), for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN).

4 #1070 Determination of IDH1 Mutational Burden and Clearance Via Next-Generation Sequencing in Patients with IDH1 Mutation-Positive Hematologic Malignancies Receiving AG-120, a First-in-Class Inhibitor of Mutant IDH1 This is the first report of IDH1 mutation clearance assessed by variant allele frequency (VAF) analysis using next-generation sequencing (NGS) in patients treated on the dose escalation portion of the first-in-human phase 1 study. Seventy-eight patients were treated in the dose escalation portion, which is now closed to enrollment. As of the data cut-off of May 12, 2016, the median duration on treatment was 3.2 months and 9 (11.5%) patients remain on treatment, with an additional 8 (10.3%) patients transitioned to stem cell transplant. Doses ranged from mg QD with 1 cohort at 100 mg BID. Though the MTD was not reached, the recommended phase 2 dose was determined to be 500 mg QD. The majority of adverse events (AEs) were grade 1 and 2, the most common ( 30%) being diarrhea, fatigue, and nausea; the most common grade 3 AEs ( 15%) were febrile neutropenia, anemia, leukocytosis and pneumonia. The most common serious AEs were febrile neutropenia (16.7%) and pneumonia (12.8%). The overall response rate (ORR) was 38.5% (n=30), with 17.9% (n=14) achieving a complete remission (CR). Of the 63 patients with R/R AML, 21 (33%) achieved an objective response, including 10 (16%) CRs, eight CRi/CRp, two MLFS and one PR. Responses were durable, with a median response duration of 10.2 months (3.7- not estimable (NE)) overall and 6.5 months (3.7-NE) in the subset of patients with R/R AML. Median duration of treatment is 3.2 months (ranging from 0.1 to 24.2 months). Longitudinal midh1 VAF data were available for 51 patients; of these, 22% (n=11) achieved a CR. IDH1-MC was observed in 27.3% (3/11) patients who achieved CR (Figure 1). In contrast, only 1/40 patients who did not achieve CR experienced IDH1-MC. This occurred in a patient with an initially low midh1 VAF who had clinical progression despite IDH1-MC (Figure 1, bottom right). In all 3 patients with CR who achieved IDH1-MC, an initial increase in midh1 VAF, or early peak, was observed prior to IDH1-MC, suggesting that early clonal expansion might have occurred as part of the mechanism of action of AG-120.

5 #904 Long Term Survival and Clinical Complete Responses of Various Prognostic Subgroups in 103 Relapsed/Refractory Acute Myeloid Leukemia (r/r AML) Patients Treated with Guadecitabine (SGI-110) in Phase 2 Studies [next-generation hypomethylating agent (HMA] 103 RELAPASED/REFRACTORY AML patients were treated with guadecitabine (50 with 5-day regimen and 53 with the initial 10-day intensification regimen). Eight six patients (84%) received prior standard 7+3 induction. Median age was 60y (range 22-82y); PS 2 in 14%; poor risk cytogenetics 41%; prior Hematopoietic Cell Transplant (HCT) 18%, and median number of 2 prior regimens (range 1-10) including 11% with prior HMA treatment. After a median follow up of 29 months, the median OS was 6.6 months with 1-y and 2-y survival rates of 28 and 19% respectively. CRc was associated with statistically significant longer survival; median OS not reached for patients in CRc and was 5.6 months for patients with no CRc (p<0.01). OS was significantly worse in patients with PS 2 (p<0.001); patient with poor risk cytogenetics (p<0.001); and those with <6 months from last therapy (p=0.015). Safety was acceptable in all doses and schedules, the most common Grade 3 AEs regardless of relationship to therapy were febrile neutropenia (60%), pneumonia and thrombocytopenia (36% each), and anemia (31%). All-cause early mortality was 3.8% at 30 days and 11.6% at 60 days #4065 A Phase 1 Trial of MEC (Mitoxantrone, Etoposide, Cytarabine) in Combination with Ixazomib (MLN9708) for Relapsed/ Refractory Acute Myeloid Leukemia (AML) Of 23 pts enrolled, 22 are evaluable. The median age was 58 yrs. The median time from initial diagnosis to registration was 7.1 months (range ) and 7 pts (30%) had a history of an antecedent hematologic disorder. Thirteen pts were in 1st relapse and 10 pts were refractory to their last therapy. One pt had received a prior allogeneic hematopoietic cell transplant (AHCT), 7 pts had FLT3 ITD mutations and 7/ 21 pts (33%) had adverse cytogenetics. At DL1, 1 DLT occurred (grade 4 thrombocytopenia), so this DL was expanded to 6 pts. At DL2, 2 pts developed Grade 4 thrombocytopenia; therefore, the MTD of ixazomib was 1.0 mg. The most common grade 3-5 NHTs in the dose escalation phase were febrile neutropenia (100%), hypoalbuminemia (25%), hypokalemia (42%), hypotension (33%), and respiratory failure (33%). No adverse events in the dose escalation phase were attributed to ixazomib alone. The overall response rate was 55% [CR/ CR with incomplete count recovery (CRi)], and 9 pts proceeded to AHCT. Five of these 9 pts remain alive with a median follow-up of 12.8 months. Five pts had CD74 expression performed. Two pts had high levels of CD74 expression (> 80%); and both achieved CRi. Myeloid mutation panel data was available in 14 pts. Previous data has demonstrated the number of mutations in DNTMT3A, TP53, ASXL1, and NRAS (0, 1, >1) is associated with a worse response to salvage therapy (Advani et al, abstract 3825, ASH 2015). Seven pts had at least one of these mutations and 6 of the 7 achieved CR/ CRi.

6 C. Genomic Profiling #596 Comprehensive Clinical Genomic Profiling Defines Age-Associated Molecular Targets in Pediatric and Adult Acute Myeloid Leukemia [FHCRC & Seattle Children s] Diagnostic and relapse specimens from a total of 934 patients, comprised of 179 pediatric (age 0-18 years) and 755 adult (age years) specimens underwent clinical comprehensive sequencing. DNA and RNA integrated next-generation sequencing was performed in a CLIAcertified, CAP-accredited, NYS-approved laboratory for FoundationOne Heme. All captured libraries were sequenced to high depth averaging 569X for DNA (405 genes) and >3M unique pairs for RNA 9265 genes). Somatic variants identified included short variants (single nucleotides variants (SNVs) and short insertions, indels), and structural variants (fusions, amplifications, loss of whole genes, or truncations). The total variant prevalence was 571 in 131 genes in the pediatric cohort vs variants in 219 genes in the adult cohort. The average number of variants in the pediatric cohort was 3.2 vs. 4.0 in the adults (p<0.001). Overall, genomic alterations were less frequent in the youngest cohort of patients < 5 years of age compared to older patients (p<0.001). We subsequently analyzed the differences between the pediatric vs. adult cohorts based on the presence of short and structural variants. There were 404 somatic short variants detected in 146 samples (82%) of the pediatric cohort vs in 718 (95%) of adult specimens. The average number of the short variants/patient was lower in the pediatric cohort at 2.3 vs. 3.5 in the adult cohort (p<0.001). Although there was overlap between several of the commonly mutated genes such as N/KRAS and FLT3, there were some significant differences between the cohorts. Many of genes involved in epigenetic modification are highly prevalent in the adult cohort and absent or at a very low prevalence in the pediatric cohort (DNMT3A: 21% vs. 2%;p<0.001), IDH1/2 21% vs. 3%;p<0.001), TET2 16% vs. 3%;p<0.01). A total of 167 structural variants in 108 (60%) pediatric specimens were identified, compared to 375 variants in 292 (38%) adult specimens (p<0.001). Partial tandem duplications of KMT2A were more common in adults vs. pediatrics (9% vs. 2%;p<0.001), while KMT2A translocations were more common in the pediatric cohort (12% vs. 4%;p<0.001). Structural alterations involving the NUP family of genes were more common in the pediatric vs. adult cohort (15% vs. 2%; p<0.001). Alterations involving the CDKN2A/B genes were also more common in pediatric vs. adult AML (13% vs. 2%;p<0.001) (Figure 1). Genomic profiling also identified cryptic fusions across all ages, including novel fusions involving transcription factors, such as the ETS family, CREBBP, and NPM1. Within the

7 pediatric cohort, we identified several cryptic fusions that are becoming increasingly recognized as poor prognostic features (e.g. CBF2T3A-GLIS). AML has distinct age-associated biologic traits, with pediatric AML characterized by a lower prevalence of genomic alterations. We found that structural variants were very common in pediatric AML, occurring in 60% of patients. Importantly, a number of these variants may be important as prognostic markers, targets for therapeutic intervention, or used for disease monitoring. Genomic profiling identified significant biologic differences in pediatric vs. adult AML and advances understanding of age-dependent drivers of leukemogenesis and contribute to advancing therapeutic development that is based on strong biologic rationale. Patient specific CGP can further precision medicine efforts in AML across all age groups. -end-