Azacitidine in AML/MDS after allogeneic HSCT

1. Azacitidine in AML/MDS after allogeneic HSCT 台北榮總血液腫瘤科 楊元豪/高志平大夫

2. Background • Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only potentially curative treatment in patients with advanced myelodysplastic syndromes (MDS) or acute myeloid leukemia (AML) • Treatment for disease relapse after allo-HSCT is limited to conventional salvage chemotherapy, second allo-HSCT and donor lymphocyte infusion (DLI) • DLI induce sustained second remission in some patients but also severe graft-versus-host disease (GVHD)

3. Azacitidine • CALGB 9221 • A randomized controlled phase III trial of subcutaneous azacitidine in MDS • Patients: AML with marrow blasts 20-30% under current WHO criteria • Treatment: subcutaneous 75 mg/m2/d x7 days q28d x4 courses v.s. best supportive care (BSC) • Azacitidine improved response rate and time to leukemia transformation in MDS but not overall survival (OS) -Silverman LR, et al., JCO 2002

4. CALGB 9221: Azacitidine v.s. BSC Time to leukemia transformation OS P=0.10 P=0.007

5. Azacitidine • Fenaux P, JCO 2010 • Phase III randomized trial • Patients: elderly patients (median age 70 y) with AML with marrow blasts 20-30% under current WHO criteria • Treatment: subcutaneous azacitidine 75 mg/m2/d v.s. BSC only, low-dose cytarabine, or intensive chemotherapy • Azacitidine significantly prolongs OS compared with conventional care regimens (CCR)

6. Azacitidine v.s. CCR OS P=0.005

7. Azazitidine after failed allo-HSCT • Bolaños-Meade J, BBMT 2011 • Retrospective study • Between 2007 and 2009 at Johns Hopkins Hospital • Patients: 10 patients with myeloid malignancies that received 5-azacytidine after a failed allo-HSCT • Treatment: mostly 75 mg/m2/day for either 5 or 7 days

8. Outcomes of the patients

9. Discussions • In the study cohort, azacitidine results in sustained responses in many of the patients without exacerbation of GVHD • Hypomethylating agents including azacitidine may reverse the loss of tumor antigens and enhance graft-versus-tumor reactions

10. RELAZA trial • An open-label, single-center phase II trial • Patients: CD34+ MDS or AML after allo-HSCT • Treatment: azacitidine in the setting of minimal residual disease (MRD)-triggered pre-emptive therapy • Purpose: to prevent or delay hematologic relapse in patients -Platzbecker U, et al., Leukemia 2012

11. CD34+ donor chimerism • CD34+ donor chimerism analysis: <80% in the peripheral blood predicts almost unavoidable relapse in all patients, even in the presence of intervention of immediate interruption of immunosuppression or DLI in a median of 61 days

12. Patients • Inclusion • Aged >18 years • CD34+ MDS or AML • After allo-HSCT • CD34+ for leukemic blasts • Exclusion • Hematologic relapse • Severe hepatic impairment • Severe renal impairment

13. Patients • Screening • CD34+ donor chimerism in the PB • Monitored 3-4 weeks during the first 8 months, and 7-8 weeks during months 8-24 • Patients who experienced a drop in CD34+ donor chimerism below 80% without concurrent hematologic relapse (<5% bone marrow blats) entered the treatment phase

14. Methods • Treatment • 4 cycles of azacitidine 75 mg/m2/day subcutaneously on days 1-7 • Repeated cycle on day 29+/-2 • Major response: increase of CD34+ donor chimerism in PB >80% • Minor response: increase of CD34+ donor chimerism in PB but <80% • Additional 4 cycles in patients with minor response and stabilization or further decrease of CD34+ donor chimerisim

15. Methods • Dose adjustment • No adjustment: WBC >3x10^9/L, Plt >50x10^9/L • 67% in WBC 1-3x10^9/L, Plt 25-50x10^9/L • DC in WBC <1x10^9/L, Plt <25x10^9/L • Immunosupressions • Could be withdrawn to support relapse prevention • Antibiotics • Antibiotic prophylaxis is permitted

16. Results • A total of 59 patients entered the screening phase • A total of 20 patients experienced a drop of CD34+ donor chimerisim <80% and enrolled into the treatment phase

19. Summary of clinical responses

25. Disease course of a patient with repeated major response

26. Results • 13 patients (65%) in the intent-to-treat population had relapsed within a median of 231 days after first MRD detection • 8 patients (40%) were alive with a median follow-up of 487 days after the first detection of MRD • There was no GVHD reported in patients without a prior history of GVHD • Complete cessation of immunosuppressive treatment was possible in 4 of 6 patients without exacerbation of GVHD, even with history of GVHD

27. Discussions • After only 4 cycles of azacitidine, MRD was diminished or stabilized in 80% of patients • Response were continuous without any further treatment in 4 of these patients • But, for the majority, hematologic relapse finally occurred in 13 patients at a median of 231 days

28. Discussions • Studies in mice suggest azacitidine induced FOXP3 expression in naïve T-cells, which in turn induces a regulatory T-cell population that mitigate GVHD while preserving a GVL effect

29. Conclusions • MRD-triggerd treatment with azacitidine is an effective strategy to prevent or to delay hematologic relapse in patients with MDS or AML after HSCT. • Azacitidine may enhance GVL reaction and, conversely, may prevent GVHD. • The development of larger, prospective trials to evaluate the efficacy of azacitidine after allo-HSCT is necessary.