Leukemia & Lymphoma, 2014; Early Online: 1–2 © 2014 Informa UK, Ltd. ISSN: 1042-8194 print / 1029-2403 online DOI: 10.3109/10428194.2014.904512
CORRESPONDENCE
A 5-day outpatient regimen of azacitidine is effective and well tolerated in patients with acute myeloid leukemia unsuitable for intensive chemotherapy
Leuk Lymphoma Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/06/14 For personal use only.
Maeve A. O’Reilly1, Cathy McHale2, Ahmed Almazmi1, Abdul Hameed3, Dalia Benjamin3, Niamh O’Connell2, Philip Murphy1, John Quinn1, Patrick Thornton1, Peter O’Gorman3, Hana Frankova4, Jeremy Sargent1, Estelle Verburgh3, John McHugh2, Pamela Evans2 & Helen Enright2 1Department of Haematology, Beaumont Hospital, Dublin, Ireland, 2Department of Haematology, Adelaide and Meath
Hospital Incorporating the National Children’s Hospital, Dublin, Ireland, 3Department of Haematology, Mater Misericordiae Hospital, Dublin, Ireland, and 4Department of Haematology, Letterkenny General Hospital, Letterkenny, Ireland
We read with great interest the recently published phase II trial of Passweg et al. [1] on a 5-day regimen of azacitidine (100 mg/m2/day) in elderly or frail patients with newly diagnosed acute myeloid leukemia (AML). AML in younger patients is frequently treated successfully by intensive chemotherapy (IC) with or without stem cell transplant. However, the median age at presentation of AML is 70 years. Elderly patients with AML often have a poor prognosis due to underlying myelodysplasia, adverse cytogenetics, resistant disease and medical comorbidities, with high rates of treatment-related toxicity. It is estimated that only 30% receive IC [2]. Azacitidine, with a recommended 7-day regimen (75 mg/m2/day), is approved for patients with AML with 20–30% bone marrow blasts [3]. There is evidence to support its use in elderly patients unsuitable for or refractory to IC, including those with a blast count ⬎ 30% [4–9]. However, there are barriers to the successful implementation of this 7-day regimen. Limited access to weekend services combined with the challenge of providing a convenient and cost-effective service has led to the use of 5-day treatment cycles (75 mg or 100 mg/m2/day) in many institutions. We retrospectively evaluated the outcome of all patients with AML (n ⫽ 47) treated with a 5-day outpatient regimen of azacitidine in four Irish institutions from 2006 to 2012. Azacitidine was selected in all cases due to poor performance status, unsuitability for IC and/or failure of prior therapy. Azacitidine was given in 5-day cycles in a day ward setting, at doses of 75 mg/m2/day (n ⫽ 28) or 100 mg/m2/day (n ⫽ 19) every 28 days as frontline therapy (n ⫽ 21) and in the relapsed/refractory (n ⫽ 21) and consolidation setting (n ⫽ 5). Median age was 70 years (range 29–89 years) with a male predominance (55%). Twenty-eight (60%) had secondary AML. Forty-two (89%) were transfusion dependent at commencement of treatment. Thirty percent had a
poor karyotype. Twenty patients (43%) had a marrow blast count ⬎ 30% (median 58%, range 30–95%) at initiation of treatment. The dosing regimen was dependent on the preference of each center. A median of 5 cycles was administered (range 1–27). Treatment was continued until loss of response. Fourteen patients received one cycle of azacitidine only. Two patients proceeded to allogeneic stem cell transplant (HSCT) after a single cycle. The remainder were deemed unfit for further cycles and died shortly thereafter. The modified International Working Group criteria (IWG 2006) were used to determine response to treatment [10]. Survival curves were estimated using the Kaplan–Meier method. A Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals (CIs). All patients were considered evaluable for response. The overall response rate (ORR) was 32%. Complete remission (CR, defined as ⬍ 5% marrow blasts with normalization of peripheral blood counts) was achieved in three patients (6%). Hematological improvement (HI) was seen in an additional 12 patients (26%), and 11 (23%) had stable disease on treatment. Best response was achieved after a mean of 4 cycles (range 1–10) for a median duration of 4.5 months. Fourteen (33%) became independent of red cell or platelet transfusions after a mean of 4 cycles (range 1–11). The duration of transfusion independence ranged from 2 to 16 months with a mean of 5 months. The ORR in the frontline setting was 29% (CR n ⫽ 2, HI n ⫽ 4) with a median survival of 8 months. In patients with relapsed and refractory disease the ORR was 24% (CR n ⫽ 1, HI n ⫽ 4) with a median survival of 5 months. Sixty percent of those consolidated with azacitidine responded (HI n ⫽ 3), with a median survival of 9 months. Median overall survival was 7 months (range 1–27 months). Twelve patients (26%) died within 6 weeks of receiving their first cycle of azacitidine. Excluding these, median survival in
Correspondence: Maeve A. O’Reilly, Department of Haematology, Beaumont University Hospital, Beaumont Road, Dublin 9, Ireland. Tel: ⫹ 35318093000. E-mail: [email protected] Received 9 February 2014; accepted 26 February 2014
1
Leuk Lymphoma Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/06/14 For personal use only.
2
M. A. O’Reilly et al.
the other 35 patients with AML was 10 months (range 2–27 months). Ten patients (21%) received ⱖ 10 cycles. Median survival in this subset was 23 months (range 10–27 months). With regard to responses in this specific patient population, two achieved CR (20%), six a HI (60%) and two stable disease (20%). There was no significant correlation between survival and the type of AML (p ⫽ 0.2), previous IC (p ⫽ 0.29) or blast count at diagnosis (p ⫽ 0.75). High-risk cytogenetics increased the risk of death, but this did not reach significance (p ⫽ 0.13). A dose-intensified regimen (100 mg/m2/day) reduced the hazard ratio and trended toward significance (p ⫽ 0.09). Azacitidine was quite well tolerated. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0 (NCI-CTC v3). Hematological toxicity was the most common adverse event, not necessarily always attributable to drug toxicity, often confounded by ongoing marrow failure due to underlying disease. Ten (24%) developed grade 3–4 neutropenia from a normal pretreatment neutrophil count or grade 1 neutropenia. Twelve (29%) developed grade 3–4 thrombocytopenia from normal/grade 1 thrombocytopenia (n ⫽ 9) or progressed from grade 2 to grade 4 (n ⫽ 3). Thirty-four (81%) required admission during therapy, with a median of 2 admissions per patient (range 1–5). Nineteen (45%) were admitted with ⱖ 1 episode of neutropenic sepsis. The dose of azacitidine was attenuated by 25% temporarily in two patients due to slow count recovery. This was a retrospective study of 5-day regimens of azacitidine in a very heterogeneous population of elderly AML including patients with newly diagnosed, relapsed and refractory disease with no control group. No inclusion or exclusion criteria were applied. Dosing regimens were at the discretion of each center, with a proportion of patients receiving close to the recommended total monthly dose, rendering interpretation of response rates based on dosing difficult. Despite the limitations of this study, we have demonstrated that a more conveniently administered 5-day regimen of azacitidine has activity in a spectrum of elderly patients with high-risk AML outside of a clinical trial setting, including those with a blast
count ⱖ 30% at diagnosis. The ORR and survival in the frontline setting were comparable to those reported by Passweg et al., albeit with a lower CR rate. These results should be validated in larger prospective randomized studies. Quality of life is paramount in elderly AML patients with medical comorbidities and/or resistant disease. Five-day treatment cycles of azacitidine can offer a well-tolerated outpatient therapy with the potential to decrease transfusion dependence, improve quality of life and prolong survival in some instances. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Passweg JR, Pabst T, Blum S, et al. Azacitidine for acute myeloid leukemia in elderly or frail patients. Leuk Lymphoma 2014;55:87–91. [2] Rowe JM. Closer to the truth in AML. Blood 2009;113:4129–4130. [3] Kaminskas E, Farrell A , Abraham S, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 2005;11:3604–3608. [4] Al-Ali HK, Jaekel N, Junghanss C, et al. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 2012;51:110–117. [5] Sudan N, Rosseti JM, Shadduck RK, et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer 2006;107: 1839–1843. [6] Maurillo L, Venditti A , Spagnoli A , et al. Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer 2012;118:1014–1022. [7] Quintas-Cardama A , Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012;120:4840–4845. [8] Van der Helm LH, Veeger NJGM, Van Marwijk Kooy M, et al. Azacitidine results in comparable outcome in newly diagnosed AML patients with more or less than 30% bone marrow blasts. Leuk Res 2013;37:877–882. [9] Tawfik B, Sliesoraitis S, Lyerly S, et al. Efficacy of the hypomethylating agents as frontline, salvage or consolidation therapy in adults with acute myeloid leukemia. Ann Hematol 2013;93:47–55. [10] Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419–425.
CORRESPONDENCE
A 5-day outpatient regimen of azacitidine is effective and well tolerated in patients with acute myeloid leukemia unsuitable for intensive chemotherapy
Leuk Lymphoma Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/06/14 For personal use only.
Maeve A. O’Reilly1, Cathy McHale2, Ahmed Almazmi1, Abdul Hameed3, Dalia Benjamin3, Niamh O’Connell2, Philip Murphy1, John Quinn1, Patrick Thornton1, Peter O’Gorman3, Hana Frankova4, Jeremy Sargent1, Estelle Verburgh3, John McHugh2, Pamela Evans2 & Helen Enright2 1Department of Haematology, Beaumont Hospital, Dublin, Ireland, 2Department of Haematology, Adelaide and Meath
Hospital Incorporating the National Children’s Hospital, Dublin, Ireland, 3Department of Haematology, Mater Misericordiae Hospital, Dublin, Ireland, and 4Department of Haematology, Letterkenny General Hospital, Letterkenny, Ireland
We read with great interest the recently published phase II trial of Passweg et al. [1] on a 5-day regimen of azacitidine (100 mg/m2/day) in elderly or frail patients with newly diagnosed acute myeloid leukemia (AML). AML in younger patients is frequently treated successfully by intensive chemotherapy (IC) with or without stem cell transplant. However, the median age at presentation of AML is 70 years. Elderly patients with AML often have a poor prognosis due to underlying myelodysplasia, adverse cytogenetics, resistant disease and medical comorbidities, with high rates of treatment-related toxicity. It is estimated that only 30% receive IC [2]. Azacitidine, with a recommended 7-day regimen (75 mg/m2/day), is approved for patients with AML with 20–30% bone marrow blasts [3]. There is evidence to support its use in elderly patients unsuitable for or refractory to IC, including those with a blast count ⬎ 30% [4–9]. However, there are barriers to the successful implementation of this 7-day regimen. Limited access to weekend services combined with the challenge of providing a convenient and cost-effective service has led to the use of 5-day treatment cycles (75 mg or 100 mg/m2/day) in many institutions. We retrospectively evaluated the outcome of all patients with AML (n ⫽ 47) treated with a 5-day outpatient regimen of azacitidine in four Irish institutions from 2006 to 2012. Azacitidine was selected in all cases due to poor performance status, unsuitability for IC and/or failure of prior therapy. Azacitidine was given in 5-day cycles in a day ward setting, at doses of 75 mg/m2/day (n ⫽ 28) or 100 mg/m2/day (n ⫽ 19) every 28 days as frontline therapy (n ⫽ 21) and in the relapsed/refractory (n ⫽ 21) and consolidation setting (n ⫽ 5). Median age was 70 years (range 29–89 years) with a male predominance (55%). Twenty-eight (60%) had secondary AML. Forty-two (89%) were transfusion dependent at commencement of treatment. Thirty percent had a
poor karyotype. Twenty patients (43%) had a marrow blast count ⬎ 30% (median 58%, range 30–95%) at initiation of treatment. The dosing regimen was dependent on the preference of each center. A median of 5 cycles was administered (range 1–27). Treatment was continued until loss of response. Fourteen patients received one cycle of azacitidine only. Two patients proceeded to allogeneic stem cell transplant (HSCT) after a single cycle. The remainder were deemed unfit for further cycles and died shortly thereafter. The modified International Working Group criteria (IWG 2006) were used to determine response to treatment [10]. Survival curves were estimated using the Kaplan–Meier method. A Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals (CIs). All patients were considered evaluable for response. The overall response rate (ORR) was 32%. Complete remission (CR, defined as ⬍ 5% marrow blasts with normalization of peripheral blood counts) was achieved in three patients (6%). Hematological improvement (HI) was seen in an additional 12 patients (26%), and 11 (23%) had stable disease on treatment. Best response was achieved after a mean of 4 cycles (range 1–10) for a median duration of 4.5 months. Fourteen (33%) became independent of red cell or platelet transfusions after a mean of 4 cycles (range 1–11). The duration of transfusion independence ranged from 2 to 16 months with a mean of 5 months. The ORR in the frontline setting was 29% (CR n ⫽ 2, HI n ⫽ 4) with a median survival of 8 months. In patients with relapsed and refractory disease the ORR was 24% (CR n ⫽ 1, HI n ⫽ 4) with a median survival of 5 months. Sixty percent of those consolidated with azacitidine responded (HI n ⫽ 3), with a median survival of 9 months. Median overall survival was 7 months (range 1–27 months). Twelve patients (26%) died within 6 weeks of receiving their first cycle of azacitidine. Excluding these, median survival in
Correspondence: Maeve A. O’Reilly, Department of Haematology, Beaumont University Hospital, Beaumont Road, Dublin 9, Ireland. Tel: ⫹ 35318093000. E-mail: [email protected] Received 9 February 2014; accepted 26 February 2014
1
Leuk Lymphoma Downloaded from informahealthcare.com by Ondokuz Mayis Univ. on 11/06/14 For personal use only.
2
M. A. O’Reilly et al.
the other 35 patients with AML was 10 months (range 2–27 months). Ten patients (21%) received ⱖ 10 cycles. Median survival in this subset was 23 months (range 10–27 months). With regard to responses in this specific patient population, two achieved CR (20%), six a HI (60%) and two stable disease (20%). There was no significant correlation between survival and the type of AML (p ⫽ 0.2), previous IC (p ⫽ 0.29) or blast count at diagnosis (p ⫽ 0.75). High-risk cytogenetics increased the risk of death, but this did not reach significance (p ⫽ 0.13). A dose-intensified regimen (100 mg/m2/day) reduced the hazard ratio and trended toward significance (p ⫽ 0.09). Azacitidine was quite well tolerated. Adverse events were graded according to the National Cancer Institute Common Toxicity Criteria version 3.0 (NCI-CTC v3). Hematological toxicity was the most common adverse event, not necessarily always attributable to drug toxicity, often confounded by ongoing marrow failure due to underlying disease. Ten (24%) developed grade 3–4 neutropenia from a normal pretreatment neutrophil count or grade 1 neutropenia. Twelve (29%) developed grade 3–4 thrombocytopenia from normal/grade 1 thrombocytopenia (n ⫽ 9) or progressed from grade 2 to grade 4 (n ⫽ 3). Thirty-four (81%) required admission during therapy, with a median of 2 admissions per patient (range 1–5). Nineteen (45%) were admitted with ⱖ 1 episode of neutropenic sepsis. The dose of azacitidine was attenuated by 25% temporarily in two patients due to slow count recovery. This was a retrospective study of 5-day regimens of azacitidine in a very heterogeneous population of elderly AML including patients with newly diagnosed, relapsed and refractory disease with no control group. No inclusion or exclusion criteria were applied. Dosing regimens were at the discretion of each center, with a proportion of patients receiving close to the recommended total monthly dose, rendering interpretation of response rates based on dosing difficult. Despite the limitations of this study, we have demonstrated that a more conveniently administered 5-day regimen of azacitidine has activity in a spectrum of elderly patients with high-risk AML outside of a clinical trial setting, including those with a blast
count ⱖ 30% at diagnosis. The ORR and survival in the frontline setting were comparable to those reported by Passweg et al., albeit with a lower CR rate. These results should be validated in larger prospective randomized studies. Quality of life is paramount in elderly AML patients with medical comorbidities and/or resistant disease. Five-day treatment cycles of azacitidine can offer a well-tolerated outpatient therapy with the potential to decrease transfusion dependence, improve quality of life and prolong survival in some instances. Potential conflict of interest: Disclosure forms provided by the authors are available with the full text of this article at www.informahealthcare.com/lal.
References [1] Passweg JR, Pabst T, Blum S, et al. Azacitidine for acute myeloid leukemia in elderly or frail patients. Leuk Lymphoma 2014;55:87–91. [2] Rowe JM. Closer to the truth in AML. Blood 2009;113:4129–4130. [3] Kaminskas E, Farrell A , Abraham S, et al. Approval summary: azacitidine for treatment of myelodysplastic syndrome subtypes. Clin Cancer Res 2005;11:3604–3608. [4] Al-Ali HK, Jaekel N, Junghanss C, et al. Azacitidine in patients with acute myeloid leukemia medically unfit for or resistant to chemotherapy: a multicenter phase I/II study. Leuk Lymphoma 2012;51:110–117. [5] Sudan N, Rosseti JM, Shadduck RK, et al. Treatment of acute myelogenous leukemia with outpatient azacitidine. Cancer 2006;107: 1839–1843. [6] Maurillo L, Venditti A , Spagnoli A , et al. Azacitidine for the treatment of patients with acute myeloid leukemia: report of 82 patients enrolled in an Italian Compassionate Program. Cancer 2012;118:1014–1022. [7] Quintas-Cardama A , Ravandi F, Liu-Dumlao T, et al. Epigenetic therapy is associated with similar survival compared with intensive chemotherapy in older patients with newly diagnosed acute myeloid leukemia. Blood 2012;120:4840–4845. [8] Van der Helm LH, Veeger NJGM, Van Marwijk Kooy M, et al. Azacitidine results in comparable outcome in newly diagnosed AML patients with more or less than 30% bone marrow blasts. Leuk Res 2013;37:877–882. [9] Tawfik B, Sliesoraitis S, Lyerly S, et al. Efficacy of the hypomethylating agents as frontline, salvage or consolidation therapy in adults with acute myeloid leukemia. Ann Hematol 2013;93:47–55. [10] Cheson BD, Greenberg PL, Bennett JM, et al. Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia. Blood 2006;108:419–425.
