azacitidine in aml mds after allogeneic hsct
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Azacitidine in AML/MDS after allogeneic HSCT. 台北榮總血液腫瘤科 楊元豪 / 高志平大夫. 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)

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azacitidine in aml mds after allogeneic hsct

Azacitidine in AML/MDS after allogeneic HSCT

台北榮總血液腫瘤科

楊元豪/高志平大夫

background
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)
azacitidine
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

calgb 9221 azacitidine v s bsc
CALGB 9221: Azacitidine v.s. BSC

Time to leukemia transformation

OS

P=0.10

P=0.007

azacitidine1
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)
azazitidine after failed allo hsct
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
discussions
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
relaza trial
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

cd34 donor chimerism
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
patients
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
patients1
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
methods
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
methods1
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
results
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
results1
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
discussions1
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
discussions2
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
conclusions
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.
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