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台北榮總血液腫瘤科楊元豪 / 高志平大夫

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BackgroundAllogeneic 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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AzacitidineCALGB 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. BSCTime to leukemia transformation

OS

P=0.007 P=0.10

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AzacitidineFenaux P, JCO 2010

Phase III randomized trialPatients: 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. CCROS

P=0.005

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Azazitidine after failed allo-HSCTBolaños-Meade J, BBMT 2011

Retrospective studyBetween 2007 and 2009 at Johns Hopkins

HospitalPatients: 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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DiscussionsIn 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

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RELAZA trialAn open-label, single-center phase II trialPatients: CD34+ MDS or AML after allo-

HSCTTreatment: 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 chimerismCD34+ 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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PatientsInclusion

Aged >18 yearsCD34+ MDS or AMLAfter allo-HSCTCD34+ for leukemic blasts

ExclusionHematologic relapseSevere hepatic impairmentSevere renal impairment

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PatientsScreening

CD34+ donor chimerism in the PBMonitored 3-4 weeks during the first 8 months,

and 7-8 weeks during months 8-24Patients 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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MethodsTreatment

4 cycles of azacitidine 75 mg/m2/day subcutaneously on days 1-7

Repeated cycle on day 29+/-2Major 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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MethodsDose adjustment

No adjustment: WBC >3x10^9/L, Plt >50x10^9/L

67% in WBC 1-3x10^9/L, Plt 25-50x10^9/LDC in WBC <1x10^9/L, Plt <25x10^9/L

ImmunosupressionsCould be withdrawn to support relapse

preventionAntibiotics

Antibiotic prophylaxis is permitted

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ResultsA total of 59 patients entered the screening

phaseA 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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Results13 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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DiscussionsAfter only 4 cycles of azacitidine, MRD was

diminished or stabilized in 80% of patientsResponse were continuous without any

further treatment in 4 of these patientsBut, for the majority, hematologic relapse

finally occurred in 13 patients at a median of 231 days

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DiscussionsStudies 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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ConclusionsMRD-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.