scholarly journals Phase I/II Trial of AEG35156 X-Linked Inhibitor of Apoptosis Protein Antisense Oligonucleotide Combined With Idarubicin and Cytarabine in Patients With Relapsed or Primary Refractory Acute Myeloid Leukemia

2009 ◽  
Vol 27 (28) ◽  
pp. 4741-4746 ◽  
Author(s):  
Aaron D. Schimmer ◽  
Elihu H. Estey ◽  
Gautam Borthakur ◽  
Bing Z. Carter ◽  
Gary J. Schiller ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Antisense Oligonucleotide ◽  
Myeloid Leukemia ◽  
Complete Response ◽  
Inhibitor Of Apoptosis ◽  
High Dose ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Acute Myeloid

Purpose X-linked inhibitor of apoptosis protein (XIAP) is an inhibitor of caspases 3 and 9 which are overexpressed in acute myeloid leukemia (AML) and may contribute to chemoresistance. We report on a phase I/II trial of the XIAP antisense oligonucleotide AEG35156 in combination with reinduction chemotherapy. Patients and Methods Twenty-four patients with rapidly relapsed or refractory AML were treated with escalating doses of AEG35156 (12 to 250 mg/m2) as an intravenous solution over 2 hours and 32 patients were treated with the highest planned dose of 350 mg/m2 in combination with idarubicin and high-dose cytarabine reinduction chemotherapy. Correlative studies were conducted to determine the effects of AEG35156 on levels of XIAP mRNA. Results Knockdown of XIAP mRNA during treatment increased with the dose of the antisense. All patients who received 350 mg/m2 of AEG35156 had higher than 30% target knockdown with a median maximal knockdown of 90% (range, 48% to 100%). The overall response rate was higher among the patients receiving the highest dose of AEG35156. In this group, 15 (47%) of 32 patients achieved complete response (CR)/CR with incomplete platelet count recovery (CRp) compared with only one (4%) of 24 receiving 12 to 250 mg/m2 AEG35156. Among the patients receiving 350 mg/m2 of AEG35156 in combination with chemotherapy, 10 (91%) of 11 who were refractory to a single induction chemotherapy regimen achieved CR/CRp after reinduction with AEG35156 and chemotherapy. AEG35156 was well tolerated save for two cases of peripheral neuropathy in patients receiving multiple doses of AEG35156. Conclusion At the highest dose tested, AEG35156 knocks down its target and appears very effective when combined with chemotherapy in patients with AML refractory to a single induction regimen.

Prognostic value of inhibitor of apoptosis protein family expression in patients with acute myeloid leukemia

2015 ◽  
Vol 56 (9) ◽  
pp. 2529-2535 ◽  
Author(s):  
Agnieszka Pluta ◽  
Agnieszka Wierzbowska ◽  
Barbara Cebula-Obrzut ◽  
Piotr Pluta ◽  
Konrad Stępka ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Protein Family ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Acute Myeloid

Study of Survivin and X-Linked Inhibitor of Apoptosis Protein (XIAP) Genes in Acute Myeloid Leukemia (AML)

2012 ◽  
Vol 18 (1) ◽  
pp. 1-10 ◽  
Author(s):  
Azza Mostafa Ibrahim ◽  
Iman Maher Mansour ◽  
Manal Michel Wilson ◽  
Doha Abdel-Hamid Mokhtar ◽  
Amani Mohamed Helal ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Inhibitor Of Apoptosis ◽  
Inhibitor Of Apoptosis Protein ◽  
Apoptosis Protein ◽  
Acute Myeloid

Limited Phase I Trial of Sequential High Dose Cytarabine and Clofarabine (HiDAC→CLOF) in Relapsed or Refractory Acute Myeloid Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4565-4565
Author(s):  
Bayard L. Powell ◽  
James Lovato ◽  
Claire Kimbrough ◽  
Susan Lyerly ◽  
Sonya Galloway-Daniels ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Myeloid Leukemia ◽  
Phase I Trial ◽  
Phase Ii Trial ◽  
Skin Toxicity ◽  
High Dose ◽  
High Dose Cytarabine ◽  
Grade 3 ◽  
Acute Myeloid

Abstract High dose cytarabine (HiDAC) is the most effective single agent for the treatment of acute myeloid leukemia (AML); clofarabine (CLOF) is also an active agent in AML. Preclinical data suggest synergy between cytarabine and clofarabine. We conducted a two step limited phase I trial of sequential HiDAC (2g/m2 over 3 hours) followed by CLOF (30 or 40 mg/m2 infused over 2 hours), each given daily for 5 days, in adults with AML in first or second relapse or refractory to initial induction chemotherapy. Patients with persistent leukemia on day 12–14 received a second course of HiDAC→CLOF; phase I toxicity evaluation was based on cycle 1 data only. Nine patients (6 men and 3 women) were treated. The median age was 55.5 years (range 29.2 – 68.1). All had relapsed AML; two had prior autologous stem cell transplant. The initial cohort of 3 patients received clofarabine 30 mg/m2 with one dose limiting toxicity (DLT); an additional 3 patients were treated in cohort 1. The second cohort was treated with CLOF 40 mg/m2, the target dose for a planned phase II trial of HiDAC→CLOF. Hematologic toxicities and infections were not considered DLT. In the first cohort (30 mg/m2; n = 6) there was 1 DLT - grade 4 skin rash in a patient who subsequently died on day 17 with sepsis-related multi-organ failure; 3 patients had reversible grade 3 elevations in AST/ALT, 1 had grade 3 skin toxicity. In cohort 2 (40 mg/m2 ; n = 3) there was no DLT; 1 patient had grade 3 AST/ALT; 2 had grade 3 skin. Three of nine patients received a second course of induction HiDACCLOF. Two of six patients in cohort 1 achieved complete remission (CR), 1/3 patients in cohort 2 achieved CRi(CRp). Two of three CR/CRi patients received one course and one received two courses of HiDAC→CLOF induction. Conclusion: HiDAC→CLOF was associated with transient elevation in AST/ALT (4/9) and skin rash (3/9; primarily extensive palmar/plantar); skin toxicity appeared especially prominent in patients with palmar/plantar toxicity during prior therapy with HiDAC. Toxicities (other than skin) were comparable to other salvage regimens for relapsed and refractory AML. This combination is active in relapsed AML with 3/9 CR/CRp. A phase II trial of HiDAC→CLOF is underway; prophylactic intravenous hydrocortisone has been incorporated in an attempt to decrease skin toxicity.

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