A Pilot Study of Decitabine Maintenance in Elderly Acute Myeloid Leukemia Patients Who Can Tolerate Aggressive Therapy
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 3
- 试验地点
- 1
- 主要终点
- Primary: Safety and tolerability of the decitabine regimen in the post remission state.
研究概览
简要总结
The study aims at determining the feasibility of using maintenance Decitabine therapy following remission induction and consolidation in elderly Acute Myeloid Leukemia patients who are fit for aggressive therapy.
Primary: Safety and tolerability of the decitabine regimen in the post remission state.
Secondary:
- Disease-free survival - To determine the one-year disease-free survival in elderly patients with acute myeloid leukemia (AML) in complete remission treated with Decitabine as post-consolidation maintenance therapy.
- Overall survival
详细描述
The median age of patients with AML at presentation is between 65 to 70 years (Peterson 1977, Brincker 1985, Baudard 1994) and the incidence of AML increases with advancing age (Wingo 1995). Given this, increased attention should be focused on adult patients 60 years or older with this disease. Treatment strategies in younger patients are well established however therapy in the elderly deserves particular thought (Foon 1981, Sebban 1998, Lowenberg 1998). Also progress in the treatment of AML in the elderly population is not near progress that has been made in the treatment of the younger population (Stone 2002, Kantarjian 2006). Poor tolerability and questionable treatment benefit have left older adult patients with AML often without effective treatment options or with best supportive care. According to Medicare records, only 30% of a cohort of 2657 AML patients older than 65 years were provided chemotherapy treatment (44% in patients 65 to 74 years, 24% in patients 75 to 84, and 6% in patients 85 and above). The mortality was 86% at 1 year and 94% at 2 years following the diagnosis. The overall survival in this cohort was only 2 months (Menzin 2002). The study could not distinguish between intensive induction chemotherapy and palliative therapy.
Despite modest improvements in outcomes for younger patients with AML, adults over 55 years of age (the majority of patients with AML) continue to do poorly (Tallman 2005).
In patients over 60 years response rates have ranged from 40% to 55% and in patients over 70 years have ranged from 24% to 33% (Buchner 2009, Estey 2007, Lowenberg 1998, Rowe 2004). Patient and leukemia related factors could explain the poor result of older patients with AML (Harry 2007, Gupta 2005). Also in patients over 60, with adverse cytogenetics the response rates range from 26% to 34%; with antecedent hematologic disorder they range between 28% and 46%; and with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 it is around 26%. (Grimwade 2001, Rowe 2004, Appelbaum 2006).
For the past several decades, standard induction chemotherapy for acute myeloid leukemia (AML) has consisted of the "7+3" regimen of cytarabine plus an anthracycline. Standard consolidation chemotherapy has consisted of high dose cytarabine for 3-4 cycles. Few trials have randomized older patients with AML to receive standard remission induction (i.e., anthracycline-containing) chemotherapy versus either palliative therapy or less intensive chemotherapy. The median survival of older adults with AML treated with cytarabine plus an anthracycline on the "7+3" schedule is 8 to 12 months (Estey 2007, Rowe 2004). Less than 10% of patients remain in remission for more than 3 years. (Lowenberg 1998, Godwin 2003, Roboz 2007).
The European Organization for the Research and Treatment of Cancer (EORTC) conducted a trial on 60 patients and randomized them to intensive chemotherapy (daunorubicin 30 mg/m2/day intravenously [IV] for 3 days, vincristine 1 mg/m2/day IV on Day 2, cytarabine 100 mg/m2/day IV for 7 days with 50 mg/m2/day IV bolus every 12 hours for 7 days) or a "watch and wait" approach (supportive care alone with hydroxyurea 3 g PO on Days 1 and 4 and LDAC (subcutaneous cytarabine) 100 mg/m2 every 12 hours SC on Days 2, 3, 5, and 6 administered only when leukemia-related symptoms occurred). All patients were more than 65 years old, but had to have preserved organ function and performance status. The patients who received induction chemotherapy had a higher complete remission (CR) rate (58% vs. 0%), lower incidence of early mortality (3/31 vs. 18/29 patients), longer median survival (21 weeks vs. 11 weeks) and greater chance of survival at 2.5 years (17% vs. 0%). The median duration of hospitalization did not statistically differ between the two groups.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 60 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients with AML (excluding Acute Promyelocytic Leukemia) according to the WHO classification, including de novo and secondary AML. Patient must be in complete remission after 1 cycle of induction therapy consisting of cytarabine (100 mg/m2 as a 24 hour infusion for 7 consecutive days) and idarubicin (12 mg/m2 as a slow intravenous push daily for 3 days), and 2 cycles of consolidation therapy (each consisting of cytarabine at a dose of 1 g/m2 given intravenously over 3 hours every 12 hours on days 1,3,and 5).
- •Patients who maintain morphologic complete remission as documented by a bone marrow aspirate/biopsy after consolidation therapy will be eligible to receive Decitabine maintenance therapy. Maintenance therapy should be started as soon as feasible after recovery from the last consolidation cycle but no sooner than 29 days after start of the last consolidation cycle and no later than 60 days after recovery from the last cycle of consolidation therapy.
- •Age ≥ 60 years
- •Eastern Cooperative Oncology Group (ECOG) performance status 0-1
- •Informed consent, personally signed and dated to participate in the study
- •Be able to comply with study procedures and follow-up examinations
- •Be non-fertile or agree to use birth control during the study through the end of last treatment visit
- •Adequate renal and hepatic function as indicated by all of the following: Total bilirubin ≤ 1.5 institutional Upper Limit of Normal (ULN); and Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 ULN; and Serum creatinine ≤ 1.5 mg/dL
- •Adequate cardiac function as measured by at least 1 of the following: Left ventricular ejection fraction (LVEF) ≥ 50% on multigated acquisition (MUGA) scan, similar radionuclide angiographic scan, or echocardiogram
排除标准
- •Diagnosis of acute promyelocytic leukemia (APL, WHO classification of APL with t(15;17)(q22;q12)
- •Prior diagnosis and treatment for AML, including hematopoietic stem cell transplant (HSCT)
- •Previous therapy with a hypomethylating agent including decitabine or azacitidine (i.e. for an antecedent myelodysplastic syndrome)
- •Any prior therapy for AML except for hydroxyurea for the control of blood counts
- •Psychiatric disorders that would interfere with consent, study participation, or follow-up
- •Cardiac Disease: Heart failure NYHA class 3 or 4; unstable coronary artery disease (MI more than 6 months prior to study entry is permitted); serious cardiac ventricular arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)
- •Chronically impaired renal function (creatinine clearance < 30 ml / min)
- •Inadequate liver function (ALT and AST ≥ 2.5 x ULN) if not caused by leukemic infiltration
- •Total bilirubin ≥ 1.5 x ULN if not caused by leukemic infiltration
- •Known HIV and/or hepatitis C infection
- •Evidence or history of severe non-leukemia associated bleeding diathesis or coagulopathy
- •Evidence or recent history of CNS disease, including primary or metastatic brain tumors, seizure disorders
- •Clinical evidence suggestive of central nervous system (CNS) involvement with leukemia unless a lumbar puncture confirms the absence of leukemic blasts in the cerebrospinal fluid (CSF)
- •Any other severe concurrent disease, or have a history of serious organ dysfunction or disease involving the heart, kidney, liver, or other organ system that may place the patient at undue risk to undergo therapy on this protocol
- •Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment)
- •Diagnosis of another malignancy, unless the patient has been disease-free for at least 5 years following the completion of curative intent therapy with the following exceptions: Patients with treated non-melanoma skin cancer, in situ carcinoma, or cervical intraepithelial neoplasia, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Patients with organ-confined prostate cancer with no evidence of recurrent or progressive disease based on prostate-specific antigen (PSA) values are also eligible for this study if hormonal therapy has been initiated or a radical prostatectomy has been performed
- •History of organ allograft
- •Any severe concomitant condition, which makes it undesirable for the patient to participate in the study or which could jeopardize compliance with the protocol
- •Patients who have an indication for and can undergo a non-myeloablative transplant procedure
研究组 & 干预措施
All patients
All participants enrolled.
干预措施: Decitabine (Dacogen) (Drug)
结局指标
主要结局
Primary: Safety and tolerability of the decitabine regimen in the post remission state.
时间窗: 18 mos on treatment and one year followup thereafter
Patient will come to the infusion center for a one-hour infusion on three (3) consecutive days during a 28-day cycle. The 28-day cycle will be repeated for up to 18 months if tolerated or there is no evidence of loss of remission. Patient will receive maintenance therapy with the study drug Decitabine. The Long-Term Follow-Up Schedule begins from the end of treatment. All patients who receive at least one dose of study drug will be followed for a minimum of one year. The maximum follow-up for all patients will be 5 years from the date of last enrolled patient.
次要结局
- 1- Disease-free survival -(One Year)