Acute myeloblastic leukemia

Adv Ther (2011) 28(Suppl.3):10-16. DOI 10.1007/s12325-010-0109-3 CLINICAL CASES Acute Myeloblastic Leukemia IB IT ED Carmen Avellaneda Molina ∙ Maria José Requena Rodríguez ∙ Nieves Somolinos de Marcos ∙ Patricia Font O H Received: September 9, 2010 / Published online: March 9, 2011 © Springer Healthcare 2011 SE INTRODUCTION Myelodysplastic syndromes (MDS) are a group of clonal cell disorders characterized by maturation defects, resulting in ineffective hematopoiesis and an increased risk of developing acute myeloblastic leukemia (AML). Azacitidine is a hypomethylating agent approved for the treatment of patients with MDS.1 The recommended dose of azacitidine is 75 mg/m 2/day during 7 days administered subcutaneously, in a cycle of 28 days, for a minimum of six cycles. Treatment should be continued until disease progression or unacceptable toxicity occurs. Azacitidine was authorized in the European Union in 2008 for the treatment of adult patients who are not eligible for hematopoietic stem cell transplantation with: 1) intermediate-2 and highrisk MDS according to the International Prognostic Scoring System (IPSS); 2) chronic myelomonocytic leukemia with 10% to 29% marrow blasts without myeloproliferative disorder; and 3) AML with 20% to 30% blasts and multi-lineage dysplasia, according to World Health Organization (WHO) classification.2 N AU TH O R IZ ED U U N SE AU PR TH O O H R IB IZ ED U Myelodysplastic syndromes (MDS) are a group of clonal cell disorders characterized by maturation defects, resulting in ineffective hematopoiesis. They often transform to acute myeloblastic leukemia (AML), which is difficult to treat and carries a dismal prognosis. Azacitidine is a hypomethylating agent approved for the treatment of patients with MDS, including AML with 20% to 30% bone marrow blasts, according to World Health Organization classification. The three patient cases presented in this paper exemplify the spectrum of antitumor activity and toxicity of azactidine in patients where MDS transformed to AML. U Carmen Avellaneda Molina Department of Hematology, Hospital Universitario San Agustín, Linares, Jaén, Spain Maria José Requena Rodríguez Department of Hematology, Hospital Severo Ochoa, Madrid, Spain Nieves Somolinos de Marcos Department of Hematology, Hospital Universitario de Getafe, Madrid, Spain Patricia Font () Department of Hematology, Hospital General Universitario Gregorio Marañón, Madrid, Spain. Email: pfontlopez@yahoo.es IT ED Keywords: acute myeloblastic leukemia; azacitidine; myelodysplastic syndromes PR ABSTRACT Adv Ther (2011) 28(Suppl.3):10-16. 11 H IB IT ED 8421, 8921, and 9221, including complete and partial responses and hematological improvement, were 48 % , 35% , and 36% , respectively.4,7,8 The AZA-001 study was a randomized international phase III study that enrolled 358 patients with high-risk MDS, including 113 patients with AML less than 30% blasts and trilineage dysplasia.9 The trial compared azacitidine at the recommended dose and combined with one of the following conventional treatment options: supportive care; low-dose cytarabine; and intensive chemotherapy. Conventional treatments were selected by the treating physician prior to randomization. With a median follow-up of 21 months, the median survival of patients treated with azacitidine was 24.5 months, compared to 15 months for patients treated with conventional treatments (P=0.0001). The 2-year overall survival was 50.8% for patients treated with azacitidine, versus 26.2% for patients treated in the control treatment group (P<0.0001). Azacitidine was effective in all IPSS cytogenetics groups. Recently, a sub-analysis of this trial that focused on patients with AML was published.10 This report analyzed 106 patients, 53 of whom received treatment with azacitidine. The median survival of patients treated with azacitidine was 24.5 months, versus 16 months for patients treated with conventional treatments (P=0.004). The 2-year overall survival was 50% in the azacitidine group, versus 16% in patients treated with conventional treatments. The data from this study also indicate that the improvement in survival is not necessarily a result of achieving a complete response, and that the response rate increases with the number of cycles administered, with 90% of responses achieved after nine cycles of treatment. Thus, the current recommendation is to maintain treatment until maximal response or unacceptable toxicity occurs. U N AU IT ED IB H O PR SE U ED IZ R TH O U N AU TH O R IZ ED U SE PR O There are currently 23 clinical trials enrolling patients with AML, and the activity of azacitidine has been explored in clinical trials conducted in adult as well as pediatric populations.3 The role of azacitidine in MDS in general, and AML with 20% to 30% bone marrow blasts in particular, has been elucidated in recent phase III clinical trials. Hence, the Cancer and Leukemia Group B (CALGB) 9221 study trial randomized patients with intermediate or high risk MDS, according to the IPSS index, to single-agent azacitidine versus best supportive care.4 Crossover was allowed for patients allocated in the best supportive care arm. This study included 27 patients with AML in the azacitidine treatment group and 25 in the control treatment group (13 of these patients received the agent in the crossover phase of the study). No significant differences were observed in the median survival between patients treated with azacitidine and patients treated with best supportive care alone (19.3 vs. 12.9 months). Sixty percent of the patients responded to the drug in the first randomization and 47% in the crossover phase and, most likely, that was the reason why no differences in survival were observed. The complete response rate was lower than expected with conventional chemotherapy; however, the median survival was rather long, suggesting that this agent is able to impact the natural history of AML, regardless of the achievement of a complete response. In addition, an improvement in quality of life (QoL) was reported in patients treated with azacitidine.5 In 2006, CALGB reanalyzed several of their clinical trials based on the WHO classification and the International Working Group (IWG) response data. A total of 103 patients were classified as having AML, and 90 of them received azacitidine. 6 The global response rates repor ted i n t he C A LGB protocols 12 Adv Ther (2011) 28(Suppl.3):10-16. ED ED IT ED U CLINICAL CASES U N AU TH O R IZ ED U U N SE AU PR TH The first case was a 56-year-old male with a 7-year history of splenomegaly (16 cm) without hepatitis C virus infection. Four years prior to diagnosis, the patient presented thrombocytopenia (69,000 platelets/mm3) and leukopenia (3100-3750 cells/mm3), with normal differential counts. One year prior to diagnosis, there was progression of the splenomegaly. A bone marrow aspiration at that time showed normocellularity and marked autolysis that limited evaluation of progenitors maturation. One year later, and because of persistent cytopenias, a second bone marrow aspiration was performed that was consistent with MDS (refractory anemia with excess blasts type 2 with 20q12 deletion). The patient’s past medical history was only significant for a history of gastrointestinal bleeding secondary to a duodenal ulcer. His father died of lung cancer, as did several maternal uncles. A physical examination was O O H R IB IZ Case 1 only remarkable for hepatomegaly of 4 cm, and splenomegaly of 8 cm. Blood work showed pancytopenia with hemoglobin of 7.1 g/dL; platelets of 112,000 cells/mm3; and leukocytes of 2100 cells/mm3. The bone marrow aspirate showed a severe trilineage with excess blasts of 4% to 12% dysplasia, with a 20q12 deletion. The immunophenotype showed 15% CD45+ cells consistent with blasts with negative membrane CD3, CD4, CD8, CD79alfa, MPO, CD19, CD13, CD33, CD7, CD10, CD65, CD15, CD61, glycoforin A, and CD49b, and only positive for CD34, CD117, and the human leukocyte antigen DR-1. This pattern was consistent with type 2 refractory anemia with excess blasts with intermediate IPSS-2 in progression to AML. The patient was initially treated with cytarabine and idarubicin for one cycle, followed by high-dose cytarabine and mitoxantrone on day 14. Subsequently, the patient developed acute left ventricular dysfunction and shock, that required prolonged treatment in the intensive care unit (ICU). At this point, a bone marrow assessment showed a discrete hypercellular marrow with persistent trilineage dysplasia and 3.5% of blasts. The patient remained pancytopenic with hemoglobin of 11.6 g/dL, leukocytes of 1740 cells/mm 3, neutrophils of 840 cells/mm3, and platelets of 208,000 cells/mm3. Given the serious complications with the prior treatment and the residual presence of blasts in the bone marrow, the patient initiated treatment with azacitidine 75 mg/m2/day subcutaneously for 7 days, every 28 days. After four cycles of treatment the bone marrow showed a discrete trilineage dysplasia with less than 2% blasts, and new karyotypes appeared. A physical examination demonstrated a resolution of the hepatomegaly and splenomegaly. The patient remained anemic and needed a transfusion every 7 to 10 days. Treatment was IB IT SE PR O H Azacitidine has also been tested in compassionate use in higher-risk MDS patients,11,12 as well as in combination with other treatments, with promising outcomes.13-18 Retrospective analyses have explored the role of treatment with azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. The results have shown that treatment with azacitidine may be of value in stabilizing the disease, thereby allowing time for patients to undergo transplant, and does not appear to affect transplant outcomes.19 Here, we present three cases of patients treated with azacitidine, to illustrate the spectrum of antitumor activity and toxicity of the agent. Adv Ther (2011) 28(Suppl.3):10-16. 13 ED IB IT H N AU U IB H O SE PR Case 3 IZ ED U The third case was a 73-year-old female patient with AML, with 20% to 30% blasts and multilineage dysplasia. The patient presented with asthenia and weight lost. She had a history of breast cancer at age 34, which had been treated with surgery and oral cyclophosphamide for 6 months. Upon physical examination she appeared pale, but was unremarkable otherwise. Her blood laboratory tests showed a hemoglobin of 12.4 g/dL; platelets of 64,000 cells/mm3; and leukocytes of 1670 cells/mm3. A bone marrow aspiration showed trilineage dysplasia and 20% of blasts. The bone marrow karyotype was 46,XX, del(2)(p13p21), del(5)(q31q35), 11, t (13;15)(q33;q14), +mar(20), and by fluorescent in-situ hybridization: negative monosomy 7th, 5q deletion, and 42% with a single signal in the ERG1 gene. TH O U N AU TH O R The second case was a 79-year-old female with a diagnosis of AML M6. The patient presented with a 1-month history consisting of asthenia, papillary hemorrhage, and frequent hematomas. The blood count showed hemoglobin of 8.9 g/dL; leukocytes of 3140 cells/mm3; and platelets of 24,000 cells/mm3. A bone marrow aspiration showed marked hypercellular bone marrow with essentially no megakaryocytes, increased in erythroid elements and a 27% of total blasts. The immunophenotype showed 18% myeloid blasts and 56% erythroblasts. The karyotype showed trisomy 8 and a marker chromosome derived from chromosome 9. This pattern was consistent with a diagnosis of AML M6 (myeloerythroid). The patient started treatment with azacitidine 75 mg/m 2 /day subcutaneously for 7 days, every 28 days. After the first cycle, the patient developed a generalized drug induced purpuric skin reaction, and a bilateral fungal pneumonia after the second cycle. Both of these toxicities R ED IZ Case 2 resolved with supported treatments. The patient received the third and fourth cycle with adequate tolerance. A bone marrow examination after the fourth cycle showed a complete remission (bone marrow aspirate: 3% blasts by morphology and 0% by cytometry; normal cytogenetics: 46,XX). The patient resumed treatment with a dose-reduced schedule (dose reduction during the seventh and eighth cycles: 75 mg/m2/day subcutaneously for 5 days, and then 50 mg/m2/day every day for 5 days during the ninth and tenth cycle; the patient received a full dose of 75 mg/m2/day subcutaneously for 7 days during cycle 11). The patient was admitted into hospital with febrile neutropenia, and Candida albicans and Candida glabrata pneumonia after the 11th cycle, and died of this complication. A bone marrow examination performed during the ICU stay in this last admission showed disease progression with 32% of blasts. IT ED U SE PR O continued, reducing the treatment duration to 5 days for three additional cycles, upon which the bone marrow showed persistent dysplasia but no excess of blasts. The treatment was then discontinued and the patient remained well, requiring a blood transfusion every 10 to 12 days. Treatment was reinitiated a few weeks later in an attempt to achieve a transfusion-independent status. At that point, the bone marrow again showed marked trilineage dysplasia with 2%-6% of blasts. After 12 additional cycles of treatment, the patient remained transfusion dependent every 15 to 18 days. The bone marrow showed discrete dysplasia and 3% of blasts. Currently, the patient remains on treatment (15th cycle of the second treatment round), with a survival of 31 months since azacitidine treatment initiation. 14 Adv Ther (2011) 28(Suppl.3):10-16. ED and 500 neutrophils/mm3. Although transfusion independence was not achieved, the patient shows a remarkably long survival. The second case was an elderly patient with AML and alterations consistent with MDS according to WHO associated with two chromosome alterations. This patient achieved a complete remission that lasted for 13 months. While complete remissions are rare, this case illustrates that azacitidine is able to reverse the disease, and lead to prolonged survival with an excellent QoL. This patient required a dose reduction after the seventh cycle, and is not known if the dose reduction contributed to the disease progression. In general, it is recommended to sustain the recommended dose, avoiding dose reduction whenever possible. The last case pertained a patient with AML and a complex karyotype, who received 14 cycles of the drug. While there was persistence of blasts, and no response in the bone marrow was achieved, the patient presented with improved leukocyte and platelet counts, combined with a reduction in transfusion requirements. This case is a good example that azacitidine is able to improve blood counts without necessarily affecting the response in the bone marrow. IB IT SE PR O H Wi t h t h e d i a g n o s i s o f A M L w i t h myelodysplasia-related changes, the patient started treatment with azacitidine at the standard dose and administration schedule. After two cycles, the patient developed painful skin nodules with a local inflammatory reaction that were consistent with erythema nodosum. This skin reaction was attributed to the administration of pegfilgrastim. The patient received a total of 14 cycles, with improvement in bone marrow (bone marrow aspiration performed immediately before the 15th cycle: 12% of blasts; karyotype of persistence of the same chromosomal abnormalities at diagnosis), as well as in blood counts (leukocytes: 3.5-4.0 x 103 cells/ mm 3 ; hemoglobin: 9.7-10 g/dL; platelets: AU PR TH O O H R IB IZ ED IT ED U 80,000-85,000 cells/mm3), though there was still persistence of blasts in the bone marrow and trilineage dysplasia. The patient continued to do well 18 months after treatment initiation, with no side effects and an excellent QoL. U N AU ED IZ TH O R These three cases illustrate the emerging role of azacitidine in patients with MDS and AML. The first case showed the effects of azacitidine after obtaining a complete remission with chemotherapy. This approach is supported by a phase 2 study from the Nordic group, in which 60 patients with either AML and previous MDS or high risk MDS received azacitidine after achieving a complete remission with conventional chemotherapy.14 Twenty-three patients with a complete remission after chemotherapy received azacitidine. The median duration of response was 13.5 months, and in 30% of patients the remission lasted more than 20 months. In this case, despite a clonal evolution after four cycles the patient remains with less than 5% of blasts, and maintains 100,000 platelets/mm3 U U N SE DISCUSSION CONCLUSION The three clinical cases illustrate the efficacy of azacitidine in the treatment of MDS-AML. This includes maintenance treatment once complete remission with chemotherapy is attained; induction of complete cytogenetic remission, reflecting the ability of the drug to reverse the disease; and improvement in survival despite the presence of significant blastic infiltration in the bone marrow. Overall, these cases support the use of azacitidine in patients with MDS and AML. Adv Ther (2011) 28(Suppl.3):10-16. 15 ACKNOWLEDGMENTS 9. Fenaux P, Mufti G, Hellstrom-Lindberg E, 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;10:223-232. We thank Sofia Perea, PharmD, PhD, from PIPELINE BIOMEDICAL RESOURCES, S.L., for the medical writing of this article. This supplement was supported by Celgene. 10. Fenaux P, Mufti GJ, Hellström-Lindberg E, et al. 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A phase I/II study of vorinostat, an oral histone deacetylase inhibitor, in combination with 19. Itzykson R, Thépot S, Quesnel B, et al. 5-Azacitidine for myelodysplasia before allogeneic hematopoietic cell transplantation. Bone Marrow Transplant. 2010;45:255-260. azacitidine in patients with the myelodysplastic syndrome (MDS) and acute myeloid leukemia U N AU TH O R IZ ED U U N SE AU PR TH O O H R IB IZ ED IT ED U SE PR O H IB IT ED (AML). Initial results of the phase I trial: a New York View publication stats