Myelodysplastic syndromes ◦ Clonal hematopoetic disorder in which ineffective or dysplastic cell production leads to peripheral cytopenias ◦ Variable risk of transformation to acute myeloid leukemia ◦ French American British classification (FAB) refractory anemia (refractory cytopenia) (RA) refractory anemia with ringed sideroblasts refractory anemia with excess blasts (RAEB) refractory anemia with excess blasts in transformation chronic myelomonocytic leukemia (CMML) Acute myeloid leukemia ◦ Presence of > 20% blasts from myeloid cell line by bone marrow aspirate or in the peripheral blood ◦ t(8,21), inv (16), t(15,17), myeloid sarcoma
Current Therapies for MDS and AML ◦ Azacitidine, decitabine ◦ 7+3 (cytarabine + daunorubicin) ◦ Hematopoetic stem cell transplantation (HSCT) Standard therapies for post transplant relapse ◦ withdrawal of immunosuppressive regimens (WIS) ◦ donor lymphocyte infusion (DLI) ◦ re-induction chemotherapy ◦ retransplantation
Mielcarek et al. BBMT 2007; 13: 1160-1168 2 year OS: 3-19% Complete remission rate: 30% Median survival prolongation with remission: 9.5 months
Cytidine analogue cytoxic activity at high doses. In malignant cells, tumor suppressor genes, growth-regulatory genes, and adhesion molecules have been demonstrated to have undergone epigenetic inactivation via DNA hypermethylation of specific promoter regions. Azacitidine promotes hypomethylation of DNA by irreversibly inhibiting DNA methyltransferases allowing transcription of tumor suppression genes in malignant cells.
Azacitidine alone ◦ the only non-transplant therapy shown to prolong overall survival in patients with MDS (Silverman 2002, Fenaux 2009). ◦ shown to be beneficial in patients with AML when used alone as induction or maintenance therapy Demonstrated hematologic response (60%) in patients unsuitable for other therapies when used as induction therapy (Sudan 2006). Prolonged duration of remission and improved survival for patients Aza as maintenance therapy: 13.5 months (2–49+) and median survival time: 20 months. (Grovdal 2008). Azacitidine + gemtuzumab ◦ Monoclonal anti CD 33 antibody ◦ Aza differentiation and enhanced expression of CD 33 on leukemic cell surface. 70% CR rate among elderly patients (median 76), median duration of CR 8 months, median survival of 10 months with minimal toxicity (Nance 2008).
Increased HLA-DR2 expression by leukemic blasts 1 Demethylation of killer cell immunoglobulin-like receptor (KIR) regions on donor NK cells 2 Modulate T-cell function post-engraftment and reduce GVHD 3 Mitigates GVHD while preserving GVL in mice receiving mismatched allogeneic transplants 4 Lower side effect profile -rash, nausea/vomiting -immunosuppression and infection Administered as outpatient 1 Pinto et al. Lancet 1984;2(8407):867-868 2 Santourlidis et al. J Immunol. 2002;169(8):4253-4261 3 Sanchez-Abarca Blood. 2010;115:107-121 4 Choi et al. Blood, Jul 2010; 116: 129 - 139.
To compare survival among patients with relapsed or persistent MDS or AML after HSCT who were treated with azacitidine to historical control population treated with standard therapies. Historical controls were obtained from the FHCRC database* and included 307 patients with recurrent/ persistent acute leukemia disease (AML, MDS or CMML) after allogeneic HSCT and who received at least 1 relapse-directed intervention between 1995 and 2004. *Mielcarek et al. 2007
Inclusion criteriaPatient characteristics Patients receiving an allogeneic HCT for primary or secondary AML, advanced/high risk MDS and CMML with blast transformation FHCRC between 2004 and 2009. Persistent or relapsed disease was defined as any evidence of disease in the bone marrow matching the cytologic characteristics of the pre- transplant diagnosis as identified by flow cytometry. Treated with azacitidine alone or in combination with gemtuzumab for persistent or relapsed disease. No of patients25 Age range (median), yrs 20.2-69.2 (47.6) Gender M14 F11 Diagnosis AML19 (76) MDS 6 (24) Cytogenetics Low risk 12 (48) Intermediate risk 3 (12) High risk 10 (40) Time of relapse/persistence < 100 days19 (76) 100-200 days0 (0) >200 days 6 (24) Gemtuzumab therapy? Y13 (52) N12 (48)
Cox regression models to evaluate overall survival at 3, 9 and 12 months among patients with relapse 200 days after HSCT. Generation of survival curves for each subgroup. Intention to treat analysis: patients were NOT excluded if they received additional standard therapies for persistent/recurrent disease. For study population, survival was calculated from the initiation of azacitidine therapy, as opposed to time of relapse for historical controls. Univariate analysis examining risk factors for decreased survival after initiation of therapy.
Overall survival among patients with early relapse (<100 days after transplant) Overall survival among patients with late relapse (>200 days after transplant) 3, 9, and 12 mos OS: 74%, 36% and 15%. 3, 9, and 12 mos OS: 83%, 33% and 33%.
HR (95% CI)P Time from HCT to relapse 0-100 days (n=19)1.0 200+ days (n=6)0.8 (0.3-2.3)0.71 Time from relapse to AZA 0-28 days (n=18)1.0 29+ days (n=7)1.2 (0.4-3.1)0.73 Blast count at AZA start per 5% increase1.6 (1.1-2.2)0.006 Gemtuzumab? No (n=13)1.0 Yes (n=12)1.1 (0.5-2.7)0.84 Achieved remission? No (n=14)1.0 Yes (n=11) (time-dep)0.5 (0.2-1.4)0.20
First to include patients with persistent disease Retrospective analysis with small numbers Comparison made to historical controls ◦ Unable to make a statistical comparison between two populations. Potential for lead time bias among study population ◦ Survival addressed from the beginning of the start of azacitidine therapy.
Azacitidine therapy may be an effective therapy for patients with early relapsed or persistent AML or MDS after HCT. Among patients with early relapse (< 100 days post HCT), median survival from time of azacitidine initiation was 163 days as opposed to 64 among historical controls treated with standard therapies. Among patients with late relapse (> 200 days post HCT) improved survival was not demonstrated, although this was likely limited by reduced numbers. Concomitant gemtuzumab therapy was not associated with improved survival among patients treated with azacitidine. Reduced blast count at time of initiation of azacitidine therapy appears to be associated with better outcomes.
Ongoing, prospective trial examining the efficacy of azacitidine plus gemtuzumab among patients with relapsed or persistent AML, MDS or CMML after HSCT ◦ Primary endpoint: 6 month survival ◦ Secondary endpoints Rate of response by IWG criteria. Red Blood cell and platelet transfusion requirements Incidence of Grades II-IV GVHD
UW Department of Medicine ◦ Dr. Scott Weigle ◦ Dr. Ken Steinberg FHCRC ◦ Dr. Marco Mielcarek et al. ◦ Dr. Barry Storer ◦ Dr. Bart Scott (!!!)