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)
 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)
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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
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CALGB 9221: Azacitidine v.s. BSC
Time to leukemia
transformation
P=0.007
OS
P=0.10
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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)
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Azacitidine v.s. CCR
OS
P=0.005
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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
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Outcomes of the patients
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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 graftversus-tumor reactions
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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
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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
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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
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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
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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
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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
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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
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Summary of clinical responses
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Disease course of a patient with
repeated major response
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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
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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
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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
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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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