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Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics: Outcomes of prolonged therapy
Leukemia Research 36 (2012) e78–e80
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics: Outcomes of prolonged therapy
1. Introduction Acute myeloid leukemia (AML) is predominantly a disease of the elderly, with over half of patients aged >60 years at diagnosis [1]. Prognosis in this age group is typically poor, and use of intensive therapies is limited by factors such as comorbidities and poor performance status, often resulting in inferior response to treatment and pronounced toxicities compared with younger patients [2]. Azacitidine (Vidaza® ; Celgene) has recently been approved in the European Union for the treatment of patients with AML with 20–30% bone marrow (BM) blasts and multi-lineage dysplasia, according to World Health Organization (WHO) criteria. In a recent phase III study (AZA-001), azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCR) in patients with higher-risk myelodysplastic syndromes (MDS) (p = 0.001) [3]. In this trial, patients had intermediate-2- or high-risk MDS according to French–American–British (FAB) classification, including 113 patients with refractory anemia with excess blasts in transformation (RAEB-t; 20–30% BM blasts), who would now be considered as having AML according to revised WHO criteria [4]. A subsequent analysis demonstrated a median OS of 24.5 months with azacitidine versus 16.0 months with CCR (p = 0.005) in these patients [4]. Here we report the case of an elderly patient with WHO AML, initially randomized to receive azacitidine in the AZA-001 trial in July 2006, and who has continued to receive azacitidine therapy to present day.
2. Case report A 78-year-old female Caucasian patient with newly diagnosed AML was referred to our hospital in June 2006 for treatment. Physical examination showed the patient was pale with bruising and petechiae over her trunk and extremities. She had no significant comorbidities. Laboratory analysis of peripheral blood showed hemoglobin (Hb) level of 9 g/dL, a platelet count of 12 × 109 L−1 , an absolute neutrophil count (ANC) of 0.15 × 109 cells/L and a white blood cell (WBC) count of 1 × 109 cells/L (Fig. 1). A BM aspirate was hypocellular with dysplastic features in the granulocytic and erythroid lineages. The number of megakaryocytes was severely reduced and there were 24% myeloblasts present. Karyotype analysis revealed complex cytogenetic aberrations (Table 1). Virology, coagulation tests and blood biochemistry were normal. A diagnosis of MDS, RAEB-t (equivalent to WHO AML) was made, and an International Prognostic Scoring System (IPSS) classification of high-risk (score: 3.5) was assigned. The patient declined chemotherapy and was enrolled in the AZA-001 trial following informed consent. The 0145-2126/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2011.11.022
patient was randomized to receive azacitidine 75 mg/m2 administered subcutaneously (s.c.) from days 1 to 7 of a 28-day cycle. During the first azacitidine cycle, the patient experienced an injection site reaction, which was resolved without treatment. The patient received three units of red blood cells (RBC), and 30 multiple-donor and 5 single-donor platelet units. During this cycle, no granulocyte colony-stimulating factor (G-CSF) was administered, as per the AZA-001 trial protocol. Blood counts on day 14 of cycle 1 showed WBC 0.48 × 109 cells/L, ANC 0.2 × 109 cells/L, platelets 24 × 109 L−1 and Hb 9.5 g/dL. The kinetics of WBC, ANC and platelet counts is described in Fig. 1. At cycles 2 and 3 the patient again received azacitidine 75 mg/m2 s.c., days 1–7 of a 28-day cycle. No hematological toxicities were observed and no transfusions or additional medications were required. Follow-up blood counts for cycle 2, in August 2006, showed WBC 1.54 × 109 cells/L, ANC 0.6 × 109 cells/L, platelets 131 × 109 L−1 and Hb 8.7 g/dL (Fig. 1). Blood counts at the start of cycle 3 in September 2006 showed WBC 2.1 × 109 cells/L, ANC 1 × 109 cells/L, platelets 184 × 109 L−1 and Hb 11.6 g/dL (Fig. 1). By November 2006 the patient had achieved complete remission (CR) confirmed by BM smear, BM biopsy and cytogenetics. Subsequently the patient received monthly azacitidine dosing for 15 months and thereafter has received a reduced dose of azacitidine 75 mg/m2 s.c. 5 days every 2 months, following the patient’s request. She became RBC transfusion independent in July 2006. Karyotype analysis showed a change in karyotype from 46, XX[20] in November 2006 (at time of CR) to an abnormal karyotype after 8 months’ azacitidine treatment in April 2007, which persisted to the most recent analysis in December 2009 (41 months; Table 1). In November 2009, blood counts showed WBC 3.55 × 109 cells/L, ANC 1.85 × 109 cells/L, platelets 227 × 109 L−1 and Hb 11.1 g/dL (Fig. 1). The most recent BM aspirate (April 2010) revealed recurrent disease with a 12% blast count. She became RBC and platelet transfusion dependent in June 2010. At the time of writing (June 2011) she is alive with stable disease and is continuing azacitidine treatment.
3. Discussion In this elderly patient with AML and 24% BM blasts, azacitidine was well tolerated, adverse events were predictable and transient, and a durable response to therapy was obtained. Our patient experienced a sustained CR following initiation of azacitidine therapy, and remains alive more than 4 years later. This reflects the median OS of 24.5 months and 2-year OS rate of 50% obtained with azacitidine in elderly patients (median age, 70 years) with WHO AML in study AZA-001 [4]. In contrast, a median OS of 5 months has been reported for patients with RAEB-t treated with best supportive care [5]. In a meta-analysis of 36 trials in elderly AML patients, treatment with intensive chemotherapy resulted in an averaged median OS of approximately 7 months [6].
Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics / Leukemia Research 36 (2012) e78–e80
e79
Table 1 Karyotype analysis from initiation of azacitidine treatment to December 2009. Date
Time after azacitidine treatment initiation
Karyotype
08 June 2006
0 months
12 November 2006 12 April 2007
4 months 9 months
16 December 2008
29 months
16 December 2009
41 months
46, XX[3] 46, XX, −5, +mar 1 [16] 46, XX, t(3;3) (q21;q26), −5, +mar 1 [1] 46, XX [20] 46, XX [12] 46, XX, −5, +mar 1 [8] 46, XX [9] 46, XX, −5, +mar 1 [10] 47, XX, +8 [1] 46, XX [2] 46, XX, –5, +mar 1 [18]
study, which was supported by funding from Celgene International. Contributions. VP and KG, with ID, TE, GD, conceived, designed and carried out the case study; KG, SP, and PT were in day to day clinical charge of the case study; VP, with KG and SP, analyzed the data; CS performed cytogenetic analysis. All authors reviewed the article critically and approved the final manuscript for submission. References
Fig. 1. Blood counts from initiation of azacitidine treatment to November 2009.
Cytogenetic analysis showed normalization of an initially complex karyotype concurrent with achievement of CR 4 months post-azacitidine therapy. It is notable that, despite the reemergence of an abnormal karyotype in April 2007, the patient continued to achieve clinical benefit from azacitidine and remained transfusion independent more than 3 years later. Our patient tolerated azacitidine well, and experienced only mild toxicities. The patient has shown a long-term hematological improvement, and has remained transfusion independent from July 2006 until June 2010 and has reported an improvement in quality of life (QoL). The favorable toxicity profile and apparent improvement in QoL obtained in this 78-year-old patient is of particular relevance given the need for well-tolerated treatment options for AML in the elderly. Several ongoing studies are further investigating the potential of azacitidine in AML, including higher blast-count disease, especially as first-line therapy, and promising preliminary efficacy findings have been reported [7,8]. The good tolerability observed in our patient over a period of >4 years adds to the rationale for assessment of azacitidine as maintenance therapy, which has been investigated in a number of recent and ongoing studies in various settings [9,10]. Further studies are needed to provide valuable data on the potential utility of azacitidine across the whole spectrum of patients with AML, but particularly for elderly patients with poor prognosis, for whom current treatment options are limited. Conflict of interest No potential conflicts of interest were declared by any author. Acknowledgments The authors would like to acknowledge writing assistance of Lynn Pritchard of FireKite during the development of this case
[1] Ferrara F, Annunziata M, Copia C, Magrin S, Mele G, Mirto S. Therapeutic options and treatment results for patients over 75 years of age with acute myeloid leukemia. Haematologica 1998;83:126–31. [2] National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. V. 2.2010. http://www.nccn.org/professionals/physician gls/f guidelines.asp; accessed 01.06.10. [3] Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223–32. [4] Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562–9. [5] Germing U, Gattermann N, Strupp C, Aivado M, Aul C. Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 2000;24:983–92. [6] Deschler B, de Witte T, Mertelsmann R, Lübbert M. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 2006;91:1513–22. [7] Thépot S, Itzykson R, Seegers V, Recher C, Quesnel B, Delaunay J, et al. Azacytidine (AZA) as first line therapy in AML: results of the French ATU program. Blood 2009;114:347 [abstract 843]. [8] Cross M, Jaekel N, Krahl R, Junghanss C, Maschmeyer G, Tran T, et al. Low levels of global (LINE) and CDH13 methylation at diagnosis and rapid clearance of marrow blasts correlate with a better haematological response to azacitidine in patients with newly diagnosed and refractory/relapsed AML not eligible for or resistant to chemotherapy: a multi-centre phase I/II-study of the East German Haematology and Oncology Study Group (OSHO). Blood 2009;114:1036 [abstract 2642]. [9] Gardin C, Prébet T, Bouabdallah K, Caillot D, Guerci A, Raffoux E, et al. A phase II study of post-remission therapy with azacitidine (AZA) in patients with AML post-MDS and high-risk MDS: a GFM group study. Blood 2009;114:348 [abstract 344]. [10] Jabbour E, Giralt S, Kantarjian H, Garcia-Manero G, Jagasia M, Kebriaei P, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer 2009;115:1899–905.
Vasiliki Pappa ∗ Konstantinos Girkas Haematology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University General Hospital, University of Athens, Athens, Greece Constantina Sambani Laboratory of Cytogenetics, NCSR “Demokritos”, Athens, Greece Sotiris Pagageorgiou Panagiotis Tsirigiotis
e80
Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics / Leukemia Research 36 (2012) e78–e80
Haematology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University General Hospital, University of Athens, Athens, Greece Kiki Karvounis Evangelia Stathopoulou Medical Department of Hematology, GENESIS Pharma SA, Athens, Greece Theofanis Economopoulos George Dimitriadis Ioannis Dervenoulas
Haematology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University General Hospital, University of Athens, Athens, Greece ∗ Corresponding
author. Tel.: +30 210 5832305. E-mail address: vas [email protected] (V. Pappa) 7 November 2011 Available online 26 December 2011
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics: Outcomes of prolonged therapy
1. Introduction Acute myeloid leukemia (AML) is predominantly a disease of the elderly, with over half of patients aged >60 years at diagnosis [1]. Prognosis in this age group is typically poor, and use of intensive therapies is limited by factors such as comorbidities and poor performance status, often resulting in inferior response to treatment and pronounced toxicities compared with younger patients [2]. Azacitidine (Vidaza® ; Celgene) has recently been approved in the European Union for the treatment of patients with AML with 20–30% bone marrow (BM) blasts and multi-lineage dysplasia, according to World Health Organization (WHO) criteria. In a recent phase III study (AZA-001), azacitidine significantly prolonged overall survival (OS) compared with conventional care regimens (CCR) in patients with higher-risk myelodysplastic syndromes (MDS) (p = 0.001) [3]. In this trial, patients had intermediate-2- or high-risk MDS according to French–American–British (FAB) classification, including 113 patients with refractory anemia with excess blasts in transformation (RAEB-t; 20–30% BM blasts), who would now be considered as having AML according to revised WHO criteria [4]. A subsequent analysis demonstrated a median OS of 24.5 months with azacitidine versus 16.0 months with CCR (p = 0.005) in these patients [4]. Here we report the case of an elderly patient with WHO AML, initially randomized to receive azacitidine in the AZA-001 trial in July 2006, and who has continued to receive azacitidine therapy to present day.
2. Case report A 78-year-old female Caucasian patient with newly diagnosed AML was referred to our hospital in June 2006 for treatment. Physical examination showed the patient was pale with bruising and petechiae over her trunk and extremities. She had no significant comorbidities. Laboratory analysis of peripheral blood showed hemoglobin (Hb) level of 9 g/dL, a platelet count of 12 × 109 L−1 , an absolute neutrophil count (ANC) of 0.15 × 109 cells/L and a white blood cell (WBC) count of 1 × 109 cells/L (Fig. 1). A BM aspirate was hypocellular with dysplastic features in the granulocytic and erythroid lineages. The number of megakaryocytes was severely reduced and there were 24% myeloblasts present. Karyotype analysis revealed complex cytogenetic aberrations (Table 1). Virology, coagulation tests and blood biochemistry were normal. A diagnosis of MDS, RAEB-t (equivalent to WHO AML) was made, and an International Prognostic Scoring System (IPSS) classification of high-risk (score: 3.5) was assigned. The patient declined chemotherapy and was enrolled in the AZA-001 trial following informed consent. The 0145-2126/$ – see front matter © 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.leukres.2011.11.022
patient was randomized to receive azacitidine 75 mg/m2 administered subcutaneously (s.c.) from days 1 to 7 of a 28-day cycle. During the first azacitidine cycle, the patient experienced an injection site reaction, which was resolved without treatment. The patient received three units of red blood cells (RBC), and 30 multiple-donor and 5 single-donor platelet units. During this cycle, no granulocyte colony-stimulating factor (G-CSF) was administered, as per the AZA-001 trial protocol. Blood counts on day 14 of cycle 1 showed WBC 0.48 × 109 cells/L, ANC 0.2 × 109 cells/L, platelets 24 × 109 L−1 and Hb 9.5 g/dL. The kinetics of WBC, ANC and platelet counts is described in Fig. 1. At cycles 2 and 3 the patient again received azacitidine 75 mg/m2 s.c., days 1–7 of a 28-day cycle. No hematological toxicities were observed and no transfusions or additional medications were required. Follow-up blood counts for cycle 2, in August 2006, showed WBC 1.54 × 109 cells/L, ANC 0.6 × 109 cells/L, platelets 131 × 109 L−1 and Hb 8.7 g/dL (Fig. 1). Blood counts at the start of cycle 3 in September 2006 showed WBC 2.1 × 109 cells/L, ANC 1 × 109 cells/L, platelets 184 × 109 L−1 and Hb 11.6 g/dL (Fig. 1). By November 2006 the patient had achieved complete remission (CR) confirmed by BM smear, BM biopsy and cytogenetics. Subsequently the patient received monthly azacitidine dosing for 15 months and thereafter has received a reduced dose of azacitidine 75 mg/m2 s.c. 5 days every 2 months, following the patient’s request. She became RBC transfusion independent in July 2006. Karyotype analysis showed a change in karyotype from 46, XX[20] in November 2006 (at time of CR) to an abnormal karyotype after 8 months’ azacitidine treatment in April 2007, which persisted to the most recent analysis in December 2009 (41 months; Table 1). In November 2009, blood counts showed WBC 3.55 × 109 cells/L, ANC 1.85 × 109 cells/L, platelets 227 × 109 L−1 and Hb 11.1 g/dL (Fig. 1). The most recent BM aspirate (April 2010) revealed recurrent disease with a 12% blast count. She became RBC and platelet transfusion dependent in June 2010. At the time of writing (June 2011) she is alive with stable disease and is continuing azacitidine treatment.
3. Discussion In this elderly patient with AML and 24% BM blasts, azacitidine was well tolerated, adverse events were predictable and transient, and a durable response to therapy was obtained. Our patient experienced a sustained CR following initiation of azacitidine therapy, and remains alive more than 4 years later. This reflects the median OS of 24.5 months and 2-year OS rate of 50% obtained with azacitidine in elderly patients (median age, 70 years) with WHO AML in study AZA-001 [4]. In contrast, a median OS of 5 months has been reported for patients with RAEB-t treated with best supportive care [5]. In a meta-analysis of 36 trials in elderly AML patients, treatment with intensive chemotherapy resulted in an averaged median OS of approximately 7 months [6].
Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics / Leukemia Research 36 (2012) e78–e80
e79
Table 1 Karyotype analysis from initiation of azacitidine treatment to December 2009. Date
Time after azacitidine treatment initiation
Karyotype
08 June 2006
0 months
12 November 2006 12 April 2007
4 months 9 months
16 December 2008
29 months
16 December 2009
41 months
46, XX[3] 46, XX, −5, +mar 1 [16] 46, XX, t(3;3) (q21;q26), −5, +mar 1 [1] 46, XX [20] 46, XX [12] 46, XX, −5, +mar 1 [8] 46, XX [9] 46, XX, −5, +mar 1 [10] 47, XX, +8 [1] 46, XX [2] 46, XX, –5, +mar 1 [18]
study, which was supported by funding from Celgene International. Contributions. VP and KG, with ID, TE, GD, conceived, designed and carried out the case study; KG, SP, and PT were in day to day clinical charge of the case study; VP, with KG and SP, analyzed the data; CS performed cytogenetic analysis. All authors reviewed the article critically and approved the final manuscript for submission. References
Fig. 1. Blood counts from initiation of azacitidine treatment to November 2009.
Cytogenetic analysis showed normalization of an initially complex karyotype concurrent with achievement of CR 4 months post-azacitidine therapy. It is notable that, despite the reemergence of an abnormal karyotype in April 2007, the patient continued to achieve clinical benefit from azacitidine and remained transfusion independent more than 3 years later. Our patient tolerated azacitidine well, and experienced only mild toxicities. The patient has shown a long-term hematological improvement, and has remained transfusion independent from July 2006 until June 2010 and has reported an improvement in quality of life (QoL). The favorable toxicity profile and apparent improvement in QoL obtained in this 78-year-old patient is of particular relevance given the need for well-tolerated treatment options for AML in the elderly. Several ongoing studies are further investigating the potential of azacitidine in AML, including higher blast-count disease, especially as first-line therapy, and promising preliminary efficacy findings have been reported [7,8]. The good tolerability observed in our patient over a period of >4 years adds to the rationale for assessment of azacitidine as maintenance therapy, which has been investigated in a number of recent and ongoing studies in various settings [9,10]. Further studies are needed to provide valuable data on the potential utility of azacitidine across the whole spectrum of patients with AML, but particularly for elderly patients with poor prognosis, for whom current treatment options are limited. Conflict of interest No potential conflicts of interest were declared by any author. Acknowledgments The authors would like to acknowledge writing assistance of Lynn Pritchard of FireKite during the development of this case
[1] Ferrara F, Annunziata M, Copia C, Magrin S, Mele G, Mirto S. Therapeutic options and treatment results for patients over 75 years of age with acute myeloid leukemia. Haematologica 1998;83:126–31. [2] National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology. Acute myeloid leukemia. V. 2.2010. http://www.nccn.org/professionals/physician gls/f guidelines.asp; accessed 01.06.10. [3] Fenaux P, Mufti GJ, Hellstrom-Lindberg E, Santini V, Finelli C, Giagounidis A, et al. Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study. Lancet Oncol 2009;10:223–32. [4] Fenaux P, Mufti GJ, Hellström-Lindberg E, Santini V, Gattermann N, Germing U, et al. Azacitidine prolongs overall survival compared with conventional care regimens in elderly patients with low bone marrow blast count acute myeloid leukemia. J Clin Oncol 2010;28:562–9. [5] Germing U, Gattermann N, Strupp C, Aivado M, Aul C. Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: a retrospective analysis of 1600 patients. Leuk Res 2000;24:983–92. [6] Deschler B, de Witte T, Mertelsmann R, Lübbert M. Treatment decision-making for older patients with high-risk myelodysplastic syndrome or acute myeloid leukemia: problems and approaches. Haematologica 2006;91:1513–22. [7] Thépot S, Itzykson R, Seegers V, Recher C, Quesnel B, Delaunay J, et al. Azacytidine (AZA) as first line therapy in AML: results of the French ATU program. Blood 2009;114:347 [abstract 843]. [8] Cross M, Jaekel N, Krahl R, Junghanss C, Maschmeyer G, Tran T, et al. Low levels of global (LINE) and CDH13 methylation at diagnosis and rapid clearance of marrow blasts correlate with a better haematological response to azacitidine in patients with newly diagnosed and refractory/relapsed AML not eligible for or resistant to chemotherapy: a multi-centre phase I/II-study of the East German Haematology and Oncology Study Group (OSHO). Blood 2009;114:1036 [abstract 2642]. [9] Gardin C, Prébet T, Bouabdallah K, Caillot D, Guerci A, Raffoux E, et al. A phase II study of post-remission therapy with azacitidine (AZA) in patients with AML post-MDS and high-risk MDS: a GFM group study. Blood 2009;114:348 [abstract 344]. [10] Jabbour E, Giralt S, Kantarjian H, Garcia-Manero G, Jagasia M, Kebriaei P, et al. Low-dose azacitidine after allogeneic stem cell transplantation for acute leukemia. Cancer 2009;115:1899–905.
Vasiliki Pappa ∗ Konstantinos Girkas Haematology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University General Hospital, University of Athens, Athens, Greece Constantina Sambani Laboratory of Cytogenetics, NCSR “Demokritos”, Athens, Greece Sotiris Pagageorgiou Panagiotis Tsirigiotis
e80
Azacitidine in a patient with newly diagnosed acute myeloid leukemia and poor risk cytogenetics / Leukemia Research 36 (2012) e78–e80
Haematology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University General Hospital, University of Athens, Athens, Greece Kiki Karvounis Evangelia Stathopoulou Medical Department of Hematology, GENESIS Pharma SA, Athens, Greece Theofanis Economopoulos George Dimitriadis Ioannis Dervenoulas
Haematology Unit, Second Department of Internal Medicine-Propaedeutic, Attikon University General Hospital, University of Athens, Athens, Greece ∗ Corresponding
author. Tel.: +30 210 5832305. E-mail address: vas [email protected] (V. Pappa) 7 November 2011 Available online 26 December 2011