ABSTRACT
The 5-year overall survival (OS) in patients ≥ 60 years old with acute myeloid leukemia (AML) remains < 10%. Clofarabine-based induction (CLO) provides an alternative to low-intensity therapy (LIT) and palliative care for this population, but supporting data are conflicted. Recently, our institution adopted the FLAG regimen (fludarabine, cytarabine, and granulocyte colony-stimulating factor) based on data reporting similar outcomes to CLO in elderly patients with AML unable to tolerate anthracycline-based induction. We retrospectively analyzed the efficacy and safety of patients ≥ 60 years old with AML treated with FLAG or CLO over the past 10 years. We performed a propensity score match that provided 32 patients in each group. Patients treated with FLAG had a higher CR/CRi rate (65.6 vs. 37.5%, P = 0.045) and OS (7.9 vs. 2.8 months, P = 0.085) compared to CLO. Furthermore, FLAG was better tolerated with significantly less grade 3/4 toxicities and a shorter duration of neutropenia (18.5 vs. 30 days, P = 0.002). Finally, we performed a cost analysis that estimated savings to be $30,000-45,000 per induction with FLAG. Our study supports the use of FLAG both financially and as an effective, well-tolerated high-dose treatment regimen for elderly patients with AML. No cases of cerebellar neurotoxicity occurred.
Subject(s)
Adenine Nucleotides/therapeutic use , Aging , Antimetabolites, Antineoplastic/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Arabinonucleosides/therapeutic use , Induction Chemotherapy , Leukemia, Myeloid, Acute/drug therapy , Vidarabine/analogs & derivatives , Adenine Nucleotides/adverse effects , Adenine Nucleotides/economics , Aged , Aged, 80 and over , Antimetabolites, Antineoplastic/adverse effects , Antimetabolites, Antineoplastic/economics , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/economics , Arabinonucleosides/adverse effects , Arabinonucleosides/economics , Case-Control Studies , Chemical and Drug Induced Liver Injury/economics , Chemical and Drug Induced Liver Injury/epidemiology , Chemical and Drug Induced Liver Injury/mortality , Chemical and Drug Induced Liver Injury/therapy , Clofarabine , Cohort Studies , Combined Modality Therapy/economics , Cost Savings , Costs and Cost Analysis , Cytarabine/adverse effects , Cytarabine/economics , Cytarabine/therapeutic use , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/economics , Granulocyte Colony-Stimulating Factor/therapeutic use , Hospital Costs , Humans , Incidence , Induction Chemotherapy/adverse effects , Induction Chemotherapy/economics , Length of Stay , Leukemia, Myeloid, Acute/economics , Leukemia, Myeloid, Acute/mortality , Michigan/epidemiology , Middle Aged , Neutropenia/chemically induced , Neutropenia/economics , Neutropenia/mortality , Neutropenia/therapy , Propensity Score , Retrospective Studies , Survival Analysis , Tertiary Care Centers , Vidarabine/adverse effects , Vidarabine/economics , Vidarabine/therapeutic useABSTRACT
Composite nucleic acids, known as 2-5A antisense chimeras, cause the 2-5A-dependent ribonuclease (RNase L) to catalyze the specific cleavage of RNA in cell free systems and in intact cells. Such 2-5A antisense chimeras are 5'-monophosphorylated, 2,'5'-linked oligoadenylates covalently attached to antisense 3',5'-oligodeoxyribonucleotides by means of a linker containing two residues of 1,4-butanediol phosphate. Here we report a fully automated synthesis of 2-5A antisense chimeras on a solid support using phosphoramidite methodology with specific coupling time modifications and their subsequent purification by reverse-phase ion-pair and anion exchange HPLC. Purified 2-5A antisense chimeras were characterized by [1H]NMR and [31P]NMR, MALDIMS, and capillary gel electrophoresis. The synthetic 2',5'-linked oligoadenylate showed no phosphodiester isomerization to 3',5' during or after synthesis. In addition, we have developed facile methodologies to characterize the chimeras using digestion with various hydrolytic enzymes including snake venom phosphodiesterase I and nuclease P1. Finally, Maxam-Gilbert chemical sequencing protocols have been developed to confirm the entire sequence of these chimeric oligonucleotides.
