Salvage therapy with endostatin, low‐dose homoharringtonine, and cytarabine in combination with granulocyte‐colony stimulating factor for elderly patients with primary refractory acute myeloid leukemia
Authors: Baijun Fang, Yuzhang Liu, Jian Zhou, Yanan Li, Yongping Song
Journal: American Journal of Hematology (2011)

Outcome of relapsed or refractory acute myeloid leukemia (AML) in elderly patients remains poor. Two-year survival in this subgroup is rare. The aim of this study was to evaluate the efficacy of recombinant human endostatin (rhEndostatin), low-dose homoharringtonine, and cytarabine in combination with granulocyte-colony stimulating factor (G-CSF) (HAG-rhEndostatin) protocol in elderly patients with primary refractory AML. Six patients were enrolled. The HAG-rhEndostatin regimen consisted of rhEndostatin (7.5 mg/m2 i.v. daily on days 1–14), homoharringtonine (1 mg/m2 i.v. daily for 14 days every 28 days), cytarabine (7.5 mg/m2 s.c. twice daily for 14 days every 28 days), and G-CSF (5 μg/kg s.c. daily), which was administered 1 day before chemotherapy. Patients who failed to obtain at least a partial remission (PR) after two courses were taken off study. Of five evaluable patients, all achieved complete remission (CR), indicating that the HAG-rhEndostatin regimen is beneficial to the treatment of refractory AML. In addition, performance status (PS) after chemotherapy in patients who achieved CR was generally favorable. These findings suggest that HAG-rhEndostatin therapy is efficacious and well tolerated in the elderly patients with primary refractory AML. The clinical characteristics of patients entered into our study are summarized in Table I. One patient (Patient 4) died of an acute myocardial infarction on Day 2 of the first course of induction. The other five patients achieved CR after 1–2 courses of HAG-rhEndostatin regimen. Table I shows the features of the five evaluable patients' responses to the HAG-rhEndostatin regimen. The patients who achieved CR received two courses of HAG followed by maintenance therapy of HAG-rhEndostatin regimen once every 4 months over 2 years. At the time of the last follow-up, two of the five patients who achieved CR relapsed and died. The other three patients remained in CR for 33.2, 16.8, and 12.2 months, respectively. The median DFS was 12.2 months (range: 8.2–33.2 months) and the median OS was 16.2 months (range: 2.9–35.4 months). Two-year OS rate was 45% (Fig. 1). PS after chemotherapy in most patients who achieved a CR did not deteriorate, and their quality of life was maintained despite of a prolonged duration of chemotherapy. Overall survival in six elderly patients with primary refractory acute myeloid leukemia treated with a HAG-rhEndostatin regime. Grade 3–4 anemia, neutropenia, and thrombocytopenia were recorded in all patients. The most frequent grade 1–2 nonhematologic toxicities experienced in the study were fatigue (n = 5), edema (n = 2), and diarrhea (n= 1). Grade 3 infections occurred in two (33.3%) patients. No patient discontinued therapy because of toxicity and there were no treatment-related deaths. The prognosis is very poor for patients with refractory AML, especially for elderly patients. The effect of the intensive chemotherapy in elderly patients with AML is not as well as younger patients due to the biologic characteristics and poor tolerance to chemotherapy. The CR rate of elderly patients was about 40–55% [1-3]; however, median survival is usually only 3–8 months. Therefore, low-dose therapies have been sought as less toxic alternatives. One therapeutic trial with low-dose cytarabine and homoharringtonine combined with human G-CSF have shown relatively high CR rates in elderly patients with refractory and relapsed AML [4]. Angiogenesis is an absolute requirement for the viability and growth of solid tumors [5]. Therapies targeting this process are showing promising results in clinical trials [6]. Recent developments focused on the role of angiogenesis in hematological malignancies. Several studies have demonstrated that there was a increased angiogenesis in the bone marrow of AML patients [7-9]; while, when the patients achieved a CR after induction chemotherapy, histological analysis revealed a decreased microvessel density in the bone marrow [10, 11]. Recently, Schuch et al. [12] reported that endostatin had inhibitory effects on neo-angiogenesis in the bone marrow and on progression of leukemia in vivo. Their experiments suggest a possible therapeutic role of anti-angiogenic therapy with endostatin in AML. Therefore, anti-angiogenic therapy might be a valuable adjunct to cytotoxic therapy. In this study, we treated the patients with HAG-rhEndostatin regimen. Our patients were at very high risk for resistance to chemotherapy and for death based upon their diagnoses, prior therapy, and advanced age. The majority were >56-year old with refractory AML. Despite their unfavorable clinical characteristics, of five evaluable patients, all achieved clinically significant responses and prolonged survival after treatment. Furthermore, PS after chemotherapy in patients who achieved CR was generally favorable. In summary, HAG-rhEndostatin regimen as the induction therapy seemed to be promising in the elderly patients with primary refractory AML. More work should be done to accumulate more patients and evaluate therapeutic efficacy in the future. A total of six consecutive patients aged 68 or older with primary refractory AML were enrolled in this study between September 2007 and March 2010 (Table I). The study was approved by the Institutional Review Board and all patients signed an informed consent. Primary refractory AML was defined as a failure to achieve a CR after two cycles of induction chemotherapy or the persistence of >40% bone marrow blasts after one cycle of chemotherapy induction. Other eligibility criteria included a PS of 0–2 according to the Eastern Cooperative Oncology Group (ECOG), bilirubin < 1.5 × upper limit of normal value, serum creatinine < 2.0 mg/dl, aspartate aminotransferase < 3.0 × upper limit of normal value, left ventricular ejection fraction > 40%, and pulmonary function forced expiratory volume at 1 s > 50% is predicted. Exclusion criteria included blast crisis of chronic myeloid leukemia and AML after other myeloproliferative diseases, other progressive malignant diseases. The HAG-rhEndostatin regimen consisted of rhEndostatin (Simcere Pharmaceutical Group, Nanjing, China; 7.5 mg/m2/day, intravenously, on days 1–14), cytarabine (7.5 mg/m2/12 hr, subcutaneously, on days 1–14), homoharringtonine (1 mg/m2/day, intravenously, on days 1–14), and G-CSF (5 μg/kg/day, subcutaneously), which was administered 1 day before chemotherapy. The administration of G-CSF was postponed or interrupted in the event of leukocytosis (leukocytes ≥ 30 × 109/l) until the white-cell count fell < 20 × 109/l. A second cycle was administered if the patient did not go into CR after the first course. Patients who achieved CR after one or two courses of HAG-rhEndostatin, received post-remission chemotherapy that included two additional courses of HAG, followed by maintenance therapy of HAG-rhEndostatin regimen once every 3 months over 2 years. Patients who did not achieve CR or relapsed received a salvage regimen consisted in a unique induction course where arsenic trioxide was administered intravenously at a dose of 0.25 mg/kg on days 1–5 and on days 8–12, together with low-dose cytarabine ((10 mg/m2 s.c. twice daily for 14 days). CR required morphologically normal marrow with <5% blasts, normal karyotype, neutrophil count >1 × 109/L, platelet count >100 × 109/L, and normal physical findings for >4 weeks. Partial remission (PR) was defined as having <15% but >5% blasts or as having <5% blasts but not reaching the CR criteria for blood cell count or clinical manifestation. The duration of overall survival (OS) was calculated from the beginning of induction chemotherapy to the date of the last follow-up or death, whatever the cause was. Disease-free survival (DFS) was calculated from date of CR to relapse, death in remission, or the last contact. Probability of OS rate was estimated according to the Kaplan and Meier method. The authors thank all patients for their cooperation. Baijun Fang*, Yuzhang Liu* , Jian Zhou*, Yanan Li* , Yongping Song*, * Henan Key Laboratory of Experimental Hematology, Henan Institute of Hematology, Henan Tumor Hospital, Zhengzhou University, Zhengzhou, China, Department of Hematology, Henan Medical School, Henan University, Zhengzhou, China.