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

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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)


Azacitidine v s ccr

Azacitidine v.s. CCR

OS

P=0.005


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


Outcomes of the patients

Outcomes of the patients


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


Summary of clinical responses

Summary of clinical responses


Disease course of a patient with repeated major response

Disease course of a patient with repeated major response


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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