Background: Azacitidine (AZA) is effective in high risk MDS, CMML-2 and low blast count AML patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified. Aims: To evaluate efficacy and clinical predictors of OS and overall response rate (ORR) to AZA in a real life patient cohort. Methods: We retrospectively evaluated 94 consecutive patients treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. Statistical analysis was performed using Student’ t test for continuous variables, and chi-square test for categorical ones. OS was measured from the starting of AZA treatment. Median age at diagnosis was 72.5 years (range 39- 90); male to female ratio was 1.7 (58/34). The initial diagnosis according to WHO 2008 classification were low blast count AML in 15 cases (15.9%), AREB2 in 40 (42.6%), AREB1 in 25 (26.6%) CMML in 5 (5%) and RCUD/RCMD/MDS NOS in 9 (10%). The International Prognostic Scoring System (IPSS) risk for all MDS patients was int-2 (N=60) or high (N=20) at the onset of AZA therapy. Median number of cycles administered was 7 (range 1-44). Results: Seventy-nine patients (84%) receiving ≥4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-13), ORR was 47.8% (CR 23.1%, PR 14.1% and SD with hematologic improvement 10.3%), SD was 23.1%, and PD 29.5%. Median OS from the beginning of therapy was 19.9 months (range 4-75 months). AREB-1 and AREB-2 presented a lower OS (11.4 and 19 months) than AML (22 months) and CMML/RCUD/RCMD/MDS NAS (42 months). As expected, a statistically significant difference in median OS was observed between int-2 and high risk (31 versus 15 months respectively, p<0.005). In univariate analysis monocytosis, severe neutropenia, peripheral and marrow blasts percentage, and bone marrow cellularity did not influenced ORR. IPSS cytogenetic risk category (43 favourable, 10 intermediate, 41 poor) did not influence ORR, but it had an impact on OS that is significantly lower in poor than in intermediate risk (median OS 12 vs 26 months, p=0.05). OS in low risk cytogenetic category was 31 months. As regards the grade of marrow fibrosis, patients with MF-0 had significantly lower PD rate than those with any grade of fibrosis (25% vs 52%, p=0.01). Moreover, ORR was higher in patients with MF-0 versus the others (48% vs 40%), although not significantly (Figure 1). In our study, patients with any grade of fibrosis had worse median OS then patients with no fibrosis (15 months vs 26 months)Summary/Conclusions: Our results confirm effectiveness of AZA in patients with high risk MDS and AML with low marrow blast counts. To the best of our knowledge, this is the first report showing that bone marrow fibrosis negatively impacts response to AZA therapy. Further studies are needed to clarify the clinical significance of marrow fibrosis and its impact on OS and ORR among patients treated with hypomethylating agents.

Impact of bone marrow fibrosis in response to azacitidine in 94 patients with myelodisplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia / G. Reda, M. Riva, R. Cassin, B. Fattizzo, M. Deodato, A. Freyrie, A. Molteni, R. Cairoli, A. Cortelezzi. - In: HAEMATOLOGICA. - ISSN 0390-6078. - 101:suppl. 1(2016), pp. 241-242. ((Intervento presentato al 21. convegno Congress of the European-Hematology-Association tenutosi a Copenhagen nel 2016.

Impact of bone marrow fibrosis in response to azacitidine in 94 patients with myelodisplastic syndromes (MDS), chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia

G Reda;R Cassin;B Fattizzo;R Cairoli;A Cortelezzi
2016

Abstract

Background: Azacitidine (AZA) is effective in high risk MDS, CMML-2 and low blast count AML patients not suitable for more intensive treatment. Factors that may influence response to AZA are still under investigation. Bone marrow fibrosis is a potentially negative prognostic marker on overall survival (OS), but its clinical significance in this setting of patients remains to be clarified. Aims: To evaluate efficacy and clinical predictors of OS and overall response rate (ORR) to AZA in a real life patient cohort. Methods: We retrospectively evaluated 94 consecutive patients treated at two Institutions from June 2009 till February 2016 with AZA subcutaneously (5+2+2 schedule) every 28 days, outside clinical trials. We analyzed data from routine laboratory analysis, bone marrow histology, morphology and cytogenetics at diagnosis. Statistical analysis was performed using Student’ t test for continuous variables, and chi-square test for categorical ones. OS was measured from the starting of AZA treatment. Median age at diagnosis was 72.5 years (range 39- 90); male to female ratio was 1.7 (58/34). The initial diagnosis according to WHO 2008 classification were low blast count AML in 15 cases (15.9%), AREB2 in 40 (42.6%), AREB1 in 25 (26.6%) CMML in 5 (5%) and RCUD/RCMD/MDS NOS in 9 (10%). The International Prognostic Scoring System (IPSS) risk for all MDS patients was int-2 (N=60) or high (N=20) at the onset of AZA therapy. Median number of cycles administered was 7 (range 1-44). Results: Seventy-nine patients (84%) receiving ≥4 cycles of therapy were available for response evaluation according to International Working Group 2006 criteria. After a median of 6 cycles (4-13), ORR was 47.8% (CR 23.1%, PR 14.1% and SD with hematologic improvement 10.3%), SD was 23.1%, and PD 29.5%. Median OS from the beginning of therapy was 19.9 months (range 4-75 months). AREB-1 and AREB-2 presented a lower OS (11.4 and 19 months) than AML (22 months) and CMML/RCUD/RCMD/MDS NAS (42 months). As expected, a statistically significant difference in median OS was observed between int-2 and high risk (31 versus 15 months respectively, p<0.005). In univariate analysis monocytosis, severe neutropenia, peripheral and marrow blasts percentage, and bone marrow cellularity did not influenced ORR. IPSS cytogenetic risk category (43 favourable, 10 intermediate, 41 poor) did not influence ORR, but it had an impact on OS that is significantly lower in poor than in intermediate risk (median OS 12 vs 26 months, p=0.05). OS in low risk cytogenetic category was 31 months. As regards the grade of marrow fibrosis, patients with MF-0 had significantly lower PD rate than those with any grade of fibrosis (25% vs 52%, p=0.01). Moreover, ORR was higher in patients with MF-0 versus the others (48% vs 40%), although not significantly (Figure 1). In our study, patients with any grade of fibrosis had worse median OS then patients with no fibrosis (15 months vs 26 months)Summary/Conclusions: Our results confirm effectiveness of AZA in patients with high risk MDS and AML with low marrow blast counts. To the best of our knowledge, this is the first report showing that bone marrow fibrosis negatively impacts response to AZA therapy. Further studies are needed to clarify the clinical significance of marrow fibrosis and its impact on OS and ORR among patients treated with hypomethylating agents.
Settore MED/15 - Malattie del Sangue
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/758955
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