research paper
Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes
John F. Seymour,1 John M. Bennett,2 Alan F. List,3 Ghulam J. Mufti,4 Steven D. Gore,5 Pierre Fenaux,6 Valeria Santini,7 Joel Hetzer,8 Stephen Songer,8 Barry S. Skikne8 and Charles L. Beach8 1
Peter MacCallum Cancer Centre, University of
Melbourne, Melbourne, Vic., Australia, 2Medical Center, University of Rochester, Rochester, NY, 3
Moffitt Cancer Center, Tampa, FL, USA,
4
King’s College Hospital, London, UK, 5The
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA, 6Hospital Avicenne APHP University Paris XIII, Bobigny, France, 7University of Florence, Florence, Italy and 8Celgene Corporation, Summit, NJ, USA Received 22 August 2013; accepted for publication 1 November 2013 Correspondence: John Seymour, MD, Peter MacCallum Cancer Centre, Department of Haematology, Locked Bag 1, A’Beckett St., Melbourne, Vic. 8006, Australia. E-mail: [email protected]
Summary The efficacy and tolerance of azacitidine in higher-risk myelodysplasia with hypocellular bone marrow (BM) are unknown. This post hoc AZA-001 trial analysis assessed whether baseline BM cellularity affected the overall survival (OS) advantage demonstrated with azacitidine versus conventional care regimens (CCR). Baseline BM biopsies of 30% cellularity)
Response*
AZA n/N† (%)
CCR n/N† (%)
AZA n/N† (%)
CCR n/N† (%)
CR + PR Any HI HI-E HI-P HI-N
0/21 11/21 7/17 7/16 2/19
1/18 7/17 2/15 2/14 3/10
10/133 63/131 47/119 33/102 21/91
1/127 36/127 11/114 14/88 15/82
(0) (52) (41) (44) (11)
(6) (41) (13) (14) (30)
(8) (48) (40) (33) (23)
(1) (29) (10) (16) (18)
AZA, azacitidine; CCR, conventional care regimens; CR, complete remission; PR, partial remission; HI, haematological improvement; HI-E, major HI – erythroid; HI-P, major HI – platelet; HI-N, major HI – neutrophil. Patients must have been eligible for a haematological response in an individual cell line at baseline to be included in analyses. *IWG-2000 criteria (Cheson et al, 2000). †n, number of responders/N, number of patients who met evaluability criteria for the respective measure of response.
Table IV. Response in baseline hypocellular patients who had a post-treatment bone marrow (BM) assessment.* Azacitidine (n = 9*)
Response† HI-E major HI-P major HI-N major CR + PR TI RBC Platelet Overall (CR + PR + HI)
CCR (n = 3*)
Became non-hypocellular n/N‡
Remained hypocellular n/N‡
Became non-hypocellular n/N‡
Remained hypocellular n/N‡
3/4 (75) 3/4 (75) 1/3 (33) 0/5
2/3 (67) 0/3 0/4 0/4
0/1 0/1 0/0 0/1
0/2 0/2 1/2 (50) 0/2
2/3 (67) 1/1 (100) 4/5 (80)
2/2 (100) 0/0 2/4 (50)
0/1 0/0 0/1 (0)
0/1 0/0 1/2 (50)
CCR, conventional care regimens; HI, haematological improvement; HI-E, HI–erythroid; HI-P, HI – platelet; HI-N, HI – neutrophil; CR, complete remission; PR, partial remission; TI, transfusion independence; RBC, red blood cell. *Hypocellular patients with at least one post-baseline BM cellularity assessment. †IWG-2000 criteria (Cheson et al, 2000). ‡n, number of responders/N, number of patients who met evaluability criteria for the respective measure of response. Table V. Baseline grade 0–2 cytopenias that progressed to grade 3 or 4 during treatment.* Hypocellular (≤30% cellularity) (n = 39)
Thrombocytopenia Neutropenia Anaemia
Non-hypocellular (>30% cellularity) (n = 244)
AZA N = 21 (%)
CCR N = 18 (%)
AZA N = 129 (%)
CCR N = 115 (%)
12/15 (80) 7/8 (88) 13/21 (62)
11/12 (92) 6/8 (75) 10/16 (63)
49/70 (70) 51/63 (81) 57/115 (50)
46/64 (72) 32/53 (60) 56/87 (64)
AZA, azacitidine; CCR, conventional care regimens. *National Cancer Institute’s Common Toxicity Criteria toxicities based on laboratory data.
the current analysis, 90–100% of all patients had 2–3 cytopenias at baseline. During treatment, shifts of cytopenias from grade 0–2 to grade 3–4 occurred with similar frequency in the hypocellular and non-hypocellular patients receiving 54
azacitidine, demonstrating that haematological tolerance of azacitidine treatment was not impaired due to the baseline BM hypocellularity. Haematological response to azacitidine was also similar in both cellularity groups. ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 165, 49–56
Azacitidine in Hypocellular MDS Clinical practice guidelines typically utilize prognosis as a determinant of appropriate therapy (Feng et al, 2011), with the treatment goal in higher-risk MDS of prolonging OS. However, a number of studies suggest that prognosis in hypocellular MDS is not consistent with IPSS scores (Tuzuner et al, 1995; Calado, 2011; Tong et al, 2012). The recent revision to the original IPSS includes the addition of several prognostic variables; however, BM cellularity is not one of them (Greenberg et al, 2012). In an analysis of prognostic and disease variables in hypocellular MDS at the MD Anderson Cancer Center, 253 patients with hypocellular MDS (5% BM blasts, unfavourable cytogenetics, haemoglobin level < 100 g/l, serum lactate dehydrogenase > 600 iu/l, and performance status > 2 (Tong et al, 2012). Other studies investigating the survival of patients with MDS and hypocellularity have produced conflicting results. Some studies have suggested that hypocellularity might be an independent factor for a more favourable outcome, whereas others show no differences in OS (Marisavljevic et al, 2005; Yue et al, 2008; Tong et al, 2012). In the MD Anderson study mentioned above, there was no significant difference in OS between hypocellular and non-hypocellular patients; however, when only patients with de novo MDS were evaluated, there was a significant survival benefit in hypocellular patients (Tong et al, 2012). Interestingly, patients who had secondary MDS and hypocellular BM had an inferior survival to patients with secondary MDS with normocellular or hypercellular BM. A potential weakness of our analysis is that absolute cellularity as a percent value was not collected. At entry to the AZA-001 study, bone marrow biopsies were categorized as hypocellular (
Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes
John F. Seymour,1 John M. Bennett,2 Alan F. List,3 Ghulam J. Mufti,4 Steven D. Gore,5 Pierre Fenaux,6 Valeria Santini,7 Joel Hetzer,8 Stephen Songer,8 Barry S. Skikne8 and Charles L. Beach8 1
Peter MacCallum Cancer Centre, University of
Melbourne, Melbourne, Vic., Australia, 2Medical Center, University of Rochester, Rochester, NY, 3
Moffitt Cancer Center, Tampa, FL, USA,
4
King’s College Hospital, London, UK, 5The
Sidney Kimmel Cancer Center, Johns Hopkins University, Baltimore, MD, USA, 6Hospital Avicenne APHP University Paris XIII, Bobigny, France, 7University of Florence, Florence, Italy and 8Celgene Corporation, Summit, NJ, USA Received 22 August 2013; accepted for publication 1 November 2013 Correspondence: John Seymour, MD, Peter MacCallum Cancer Centre, Department of Haematology, Locked Bag 1, A’Beckett St., Melbourne, Vic. 8006, Australia. E-mail: [email protected]
Summary The efficacy and tolerance of azacitidine in higher-risk myelodysplasia with hypocellular bone marrow (BM) are unknown. This post hoc AZA-001 trial analysis assessed whether baseline BM cellularity affected the overall survival (OS) advantage demonstrated with azacitidine versus conventional care regimens (CCR). Baseline BM biopsies of 30% cellularity)
Response*
AZA n/N† (%)
CCR n/N† (%)
AZA n/N† (%)
CCR n/N† (%)
CR + PR Any HI HI-E HI-P HI-N
0/21 11/21 7/17 7/16 2/19
1/18 7/17 2/15 2/14 3/10
10/133 63/131 47/119 33/102 21/91
1/127 36/127 11/114 14/88 15/82
(0) (52) (41) (44) (11)
(6) (41) (13) (14) (30)
(8) (48) (40) (33) (23)
(1) (29) (10) (16) (18)
AZA, azacitidine; CCR, conventional care regimens; CR, complete remission; PR, partial remission; HI, haematological improvement; HI-E, major HI – erythroid; HI-P, major HI – platelet; HI-N, major HI – neutrophil. Patients must have been eligible for a haematological response in an individual cell line at baseline to be included in analyses. *IWG-2000 criteria (Cheson et al, 2000). †n, number of responders/N, number of patients who met evaluability criteria for the respective measure of response.
Table IV. Response in baseline hypocellular patients who had a post-treatment bone marrow (BM) assessment.* Azacitidine (n = 9*)
Response† HI-E major HI-P major HI-N major CR + PR TI RBC Platelet Overall (CR + PR + HI)
CCR (n = 3*)
Became non-hypocellular n/N‡
Remained hypocellular n/N‡
Became non-hypocellular n/N‡
Remained hypocellular n/N‡
3/4 (75) 3/4 (75) 1/3 (33) 0/5
2/3 (67) 0/3 0/4 0/4
0/1 0/1 0/0 0/1
0/2 0/2 1/2 (50) 0/2
2/3 (67) 1/1 (100) 4/5 (80)
2/2 (100) 0/0 2/4 (50)
0/1 0/0 0/1 (0)
0/1 0/0 1/2 (50)
CCR, conventional care regimens; HI, haematological improvement; HI-E, HI–erythroid; HI-P, HI – platelet; HI-N, HI – neutrophil; CR, complete remission; PR, partial remission; TI, transfusion independence; RBC, red blood cell. *Hypocellular patients with at least one post-baseline BM cellularity assessment. †IWG-2000 criteria (Cheson et al, 2000). ‡n, number of responders/N, number of patients who met evaluability criteria for the respective measure of response. Table V. Baseline grade 0–2 cytopenias that progressed to grade 3 or 4 during treatment.* Hypocellular (≤30% cellularity) (n = 39)
Thrombocytopenia Neutropenia Anaemia
Non-hypocellular (>30% cellularity) (n = 244)
AZA N = 21 (%)
CCR N = 18 (%)
AZA N = 129 (%)
CCR N = 115 (%)
12/15 (80) 7/8 (88) 13/21 (62)
11/12 (92) 6/8 (75) 10/16 (63)
49/70 (70) 51/63 (81) 57/115 (50)
46/64 (72) 32/53 (60) 56/87 (64)
AZA, azacitidine; CCR, conventional care regimens. *National Cancer Institute’s Common Toxicity Criteria toxicities based on laboratory data.
the current analysis, 90–100% of all patients had 2–3 cytopenias at baseline. During treatment, shifts of cytopenias from grade 0–2 to grade 3–4 occurred with similar frequency in the hypocellular and non-hypocellular patients receiving 54
azacitidine, demonstrating that haematological tolerance of azacitidine treatment was not impaired due to the baseline BM hypocellularity. Haematological response to azacitidine was also similar in both cellularity groups. ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 165, 49–56
Azacitidine in Hypocellular MDS Clinical practice guidelines typically utilize prognosis as a determinant of appropriate therapy (Feng et al, 2011), with the treatment goal in higher-risk MDS of prolonging OS. However, a number of studies suggest that prognosis in hypocellular MDS is not consistent with IPSS scores (Tuzuner et al, 1995; Calado, 2011; Tong et al, 2012). The recent revision to the original IPSS includes the addition of several prognostic variables; however, BM cellularity is not one of them (Greenberg et al, 2012). In an analysis of prognostic and disease variables in hypocellular MDS at the MD Anderson Cancer Center, 253 patients with hypocellular MDS (5% BM blasts, unfavourable cytogenetics, haemoglobin level < 100 g/l, serum lactate dehydrogenase > 600 iu/l, and performance status > 2 (Tong et al, 2012). Other studies investigating the survival of patients with MDS and hypocellularity have produced conflicting results. Some studies have suggested that hypocellularity might be an independent factor for a more favourable outcome, whereas others show no differences in OS (Marisavljevic et al, 2005; Yue et al, 2008; Tong et al, 2012). In the MD Anderson study mentioned above, there was no significant difference in OS between hypocellular and non-hypocellular patients; however, when only patients with de novo MDS were evaluated, there was a significant survival benefit in hypocellular patients (Tong et al, 2012). Interestingly, patients who had secondary MDS and hypocellular BM had an inferior survival to patients with secondary MDS with normocellular or hypercellular BM. A potential weakness of our analysis is that absolute cellularity as a percent value was not collected. At entry to the AZA-001 study, bone marrow biopsies were categorized as hypocellular (
