Oral Azacitidine in AML maintenance.pptx

Oral Azacytidine in AML Maintenance

1. Oral Azacitidine in AML maintenance Dr.Abhijit Baheti , DM,DNB ( Hematology , Pune )

2. FDA/DCGI Approval (Oral Azacitidine) Indicated for continued treatment of adult patients with acute myeloid leukemia who achieved first complete remission ( CR ) or complete remission with incomplete blood count recovery ( CRi ) following intensive induction chemotherapy and are not able to complete intensive curative therapy Continue until disease progression or unacceptable toxicity Approval was based out of a Phase-III QUAZAR AML-001 trial

3. QUAZAR AML-001 Trial was conducted at 148 sites in 23 countries Study Type  : Interventional  (Clinical Trial): Oral Azacitidine (CC-486) Actual  Enrollment   : 472 participants Allocation: Randomized Intervention Model: Parallel Assignment Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

4. Oral Azacitidine Phase 3 study QUAZAR AML-001: Background Although induction chemotherapy results in remission in many older patients with acute myeloid leukemia (AML), relapse is common and overall survival is poor . Effective AML maintenance therapy strategies are needed to reduce relapse rates and prolong survival, without causing significant toxicity or reducing QoL To date, no AML maintenance therapy has demonstrated improvement in OS [4-6] Results from an open-label phase 2 study suggest that CC-486 (Oral Azacitidine) provided effective maintenance therapy after HSCT Current study assessed safety and efficacy of Oral Azacitidine in patients with de novo or secondary AML in first remission following IC [10] 1. Ramos. J Clin Med. 2015;4:665. 2. Chen. Medicine (Baltimore). 2016;95:e4182. 3. McMahon. Semin Hematol . 2019;56:102. 4. Buyse . Blood. 2011;117:7007. 5. Goldstone. Blood. 2001;98:1302. 6. Boumber . Leukemia. 2012;26:2428. 7. Laille . PLoS One. 2015;10:e0135520. 8. Garcia- Manero . Leukemia. 2016;30:889. 9. Savona. Am J Hematol . 2018;93:1199. 10. Wei. ASH 2019. Abstr LBA_3.

5. Key Inclusion Criteria: Male or female participants ≥ 55 years of age Newly diagnosed , histologically confirmed de novo acute myeloid leukemia (AML) or AML secondary to prior myelodysplastic disease or CMML (Chronic myelomonocytic leukemia) First complete remission (CR)/ complete remission with incomplete blood count recovery ( CRi ) with induction therapy with intensive chemotherapy with or without consolidation therapy within 4 months (+/- 7 days) of achieving CR or CRi

6. Key Exclusion Criteria: AML with inversion ( inv )(16), translocation = t(8;21), t(16;16), t(15;17), or t(9;22) or molecular evidence of such translocations Prior bone marrow or stem cell transplantation Have achieved CR/ CRi following therapy with hypomethylating agents Diagnosis of malignant disease within the previous 12 months Proven central nervous system (CNS) leukemia

7. Study Design

8. Baseline Demographic and Disease Characteristics

9. Baseline Demographic and Disease Characteristics

10. QUAZAR AML-001: Survival 1-yr relapse rate was 53% vs 71% (in CC-486 arm vs placebo arm) Wei. ASH 2019. Abstr LBA_3. Overall survival Relapse free survival HR - 0.69 (0.55, 0.86) HR - 0.65 (0.52, 0.81) Median follow up: 41.2 months % of patients surviving at 1 yr  72.8% (CC-486 grp) and 55.8% ( placebo grp) at 2 yrs  50.6% ( CC-486 grp) and 37.1% ( placebo grp) OS benefit regardless of any consolidation therapy or MRD

11. Univariate Analyses of Overall Survival at 2 Years in Patient Subgroups 

12. QUAZAR AML-001: Safety AEs ≥ 15% in either arm, n (%) CC-486 (n = 236) Placebo (n = 233) All Grades Grades 3/4 All Grades Grades 3/4 Any AE 231 (98) 169 (72) 225 (97) 147 (63) GI Nausea 153 (65) 6 (3) 55 (24) 1 (0.4) Vomiting 141 (60) 7 (3) 23 (10) Diarrhea 119 (50) 12 (5) 50 (22) 3 (1) Constipation 91 (39) 3 (1) 56 (24) Wei. ASH 2019. Abstr LBA_3. AEs ≥ 15% in either arm, n (%) CC-486 (n = 236) Placebo (n = 233) All Grades Grades 3/4 All Grades Grades 3/4 Hematologic Neutropenia 105 (45) 97 (41) 61 (26) 55 (24) Thrombocytopenia 79 (34) 53 (23) 63 (27) 50 (22) Anemia 48 (20) 33 (14) 42 (18) 30 (13) Other AEs Fatigue 70 (30) 7 (3) 45 (19) 2 (1) Asthenia 44 (19) 2 (1) 13 (6) 1 (0.4) Pyrexia 36 (15) 4 (2) 44 (19) 1 (0.4) Cough 29 (12) 39 (17) GI AEs most common during first 2 cycles of treatment Serious AEs reported for 34% of patients in CC-486 arm vs 25% of patients in the placebo arm No treatment-related deaths

13. QUAZAR AML-001: Safety dose-reduction discontinuation

14. Escalated Dosing: On identification of AML relapse with 5 to 15% blasts Among the 78 patients who had central confirmation of at least 5% blasts in their bone marrow, 10/43 patients (23%) in the CC-486 group had “Restoration of CR status” 4/35 patients (11%) in the placebo group had restoration of CR status while receiving the escalated 21-day dosing regimen.

15. QOL: FACIT-Fatigue and EQ-5D-3L health utility scores across treatment Patients reported relatively low levels of fatigue and physical impairment. FACIT Fatigue Scale and EQ-5D-3L scores were similar in the two treatment groups.

16. Conclusion CC-486 maintenance therapy was associated with significantly longer overall and relapse-free survival than placebo among older patients with AML who were in remission after chemotherapy. Side effects were mainly gastrointestinal symptoms and neutropenia. Quality-of-life measures were maintained throughout treatment.

17. Comparative Efficacy Of Oral Azacitidine Vs Injectable Azacitidine In Patients With AML In First Remission After Intensive Chemotherapy: An Indirect Treatment Comparison Chen C. et al . Comparative efficacy of oral versus injectable azacitidine in patients with AML in first remission after intensive chemotherapy: an indirect treatment comparison (sub-analysis update). EHA Library . 2021. 325200; EP446. AML, Acute myeloid leukemia ; AZA, Azacitidine; HOVON97, Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients; IV, intravenous; OS, Overall survival; QoLESS , Azacitidine for post-remission therapy in elderly patients with Acute Myeloid Leukemia; QUAZAR AML-001, Maintenance Trial: Oral Azacitidine in patients with AML in first remission; SC, Subcutaneous. Conclusion: CC-486 had a longer duration of follow-up than injectable AZA and an earlier and more durable relative OS benefit , which was maintained beyond 60 months. This analysis demonstrates that CC-486 was associated with a meaningful improvement in mean survival time , and that maintenance treatment with CC-486 provides a long-term survival benefit compared with the relative short-term benefit observed with injectable AZA . Trials Study groups QUAZAR AML-001 (CC-486) Oral AZA vs placebo HOVON97 SC AZA vs control QoLESS SC/IV AZA vs control Relative OS benefit over time

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