Is Azacitidine (AZA) Really Effective in High Risk MDS Patients with Chromosome 7 Abnormalities (Abn 7)? Results of a Retrospective Study From the GFM and GESMD Registries

Is azacitidine (AZA) really effective in higher risk MDS patients with chromosome 7 abnormalities (Abn 7)? Results of a retrospective study from the GFM and GESMD registries.

Cytogenetic alterations are the most discriminative prognostic variables in MDS, complex karyotype and abnormalities of chromosome 7 (Abn 7) having the poorest outcome. However, prognosis of isolated 7q- and to a lesser extent isolated −7 appears to be less severe than that of complex karyotypes at least in patients not receiving drugs with a potential effect on survival (Schanz et al, JCO, 2012, Cordoba et al, Cancer, 2012). It has been suggested in relatively small patients series that Abn 7 may be associated with relatively favorable response to AZA in MDS. We analyzed the outcome of a large series of higher risk MDS with Abn 7 treated with AZA.

Between 2005 and 2011, higher risk MDS pts were treated with AZA (75 mg/m2/d during 7 or less often 5 days / 4 weeks, scheduled for at least 6 cycles), in compassionate programs (prior to AZA approval by EU) or within AZA label (since 2008) and included in the French and Spanish MDS registries. We retrospectively analyzed, in those series, the outcome of pts with Abn 7.

123 pts with Abn 7 having received at least one cycle of AZA, including 82 (66%) de novo MDS and 69 males (55%), with a median age of 70y (range 33–89) were analyzed. At diagnosis, according to WHO 2008, 52% pts (n=65) had RAEB2, 16% (n=20) had RAEB1 and 10% (n=13) had AML with 20–30% marrow blasts (RAEB-T according to FAB). IPSS was high in 51% (n=64), int-2 in 43% (n=55), and not available (but at least int-2) in the remaining 25 pts. Karyotype distribution was: monosomy 7 (−7) (isolated or with 1 other abnormality, non complex −7) in 33 patients (27%), 7q- (isolated or with 1 other abnormality, non complex 7q-) in 19 patients (16%), del(7p) (isolated or with 1 other abn) in 1 patient (1%), and 69 patients (56%) had complex karyotype (>= 3 abn) with −7 or 7q-. Among 106 patients with this information available, 74% (n=78) were RBC and/or PLT transfusion dependent (TD). 86% (n=108) of the patients received the conventional 7 day schedule of AZA, the remaining 14% receiving reduced daily dosing or 5 day cycles. The median number of cycles administered was 5 (1–32). Among 110 patients with available information the overall response rate (IWG 2006 criteria) was 32% (35/110), including 12% CR and 20% SD with HI. Among non responders, 12% died prior to evaluation, 33% were in SD and 23% progressed. Among transfusion dependent patients, 16% became RBC transfusion independent (12 of 73 TD patients with available information). The overall response rate was 30% in pts with complex karyotype with −7 or 7q-, 33% in pts with non complex −7 and 31% in pts with non complex 7q- (p=0.1 for complex vs non complex Abn 7). At the time of last follow up, 66 patients (53%) had relapsed or progressed and 102 (83%) had died. Median event free survival(considering death, relapse or progression as events ) at 1 and 2 years was 32 and 8%, respectively. Median OS at 1 and 2 years was 40%, and 18%, respectively. OS was better for patients with response after 4–6 cycles (OS at 1 year 64%) when compared with SD (1y OS 47%) or progression (1y OS 12%), p<0.001. Patients with complex karyotype had poorer OS than those with non complex −7 and non complex 7q- (1 year OS of 32%, 57% and 57% respectively, p=0.012). Interestingly, patients with non complex −7 achieving SD had an OS comparable to that of responders, and better than that of patients who progressed (OS at 1 year 67% vs 64% vs 0%, in responders, stable and progressive patients, p<0.001). Though not reaching statistical significance, similar trends were noted in the other cytogenetic subgroups analyzed: 1y-OS was 80% vs 50% vs 33%, respectively among pts with non complex 7q-, (p=0.16) and 53% vs 31% vs 11% respectively among pts with complex karyotype (p=0.09).

In this large series of higher risk MDS with Abn 7, we confirm that Azacitidine yields significant response rates, translating in a survival benefit in patients with non complex monosomy 7 and non complex 7q- (ie isolated or with one additional cytogenetic abn) but is less effective in patients with −7 or 7q- included in a complex karyotype. In contrast to series of pts not receiving drugs with a potential effect on survival (Schanz et al, JCO, 2012, Cordoba et al, Cancer, 2012), patients with −7 and 7q- seemed to have similar outcomes when treated with azacitidine.

Díez-Campelo:CELGENE: Research Funding. Itzykson:CELGENE: Honoraria. Cañizo:CELGENE: Research Funding. Fenaux:CELGENE: Honoraria, Research Funding.