Treatment of Elderly and Unfit AML Patients with Prolonged Administration of Low Dose Cytarabine and Thioguanine Achieves High Complete Remission Rates in an Outpatient Setting
Authors: Arthur Christopher K , Jeffrey Anthony , Forbes Molly , Yip Eva , Katsioulas Vicki , Stevenson William S. 
Published: October 2019

Abstract
Background: The treatment of elderly or unfit patients with AML is disappointing with little improvement in the past 30 years. Studies in the 1960s (Clarkson, Cancer 1972) explored the use of prolonged low dose cytarabine (Ara-C) with frequent bone marrow monitoring until marrow hypoplasia. Treatment was given as long as needed with up to 6 weeks continuous therapy with some studies combining with synergistic thioguanine (TG). We developed a modification of the prolonged therapy concept using a 21 day course of low dose subcutaneous Ara-C with TG. Maintenance therapy with the same drugs was given for 2 yrs.
Aim: To assess the safety and efficacy of low-dose sc cytarabine in combination with TG in patients with AML.
Methods: Patients included (i) de novo AML, aged > 65, or unfit for intensive chemotherapy or (ii) patients >18 yrs with relapsed/refractory (R/R) AML. Patients received repeated administration of cycles of Ara-C 20mg/m2 s/c once daily with TG 40 mg/m2 PO once daily for 21 days. Bone marrow biopsy was performed within 4-7 days of completing the 21-day cycle and if blasts > 5% the next cycle was started immediately.There was no specified limit to the induction cycles which was at the investigators discretion considering patient tolerability. Once remission was achieved cycles were reduced to 14 days every 4-6 weeks for 2 years. Supportive care mandated posaconazole, ciprofloxacin, amoxycillin and pegfilgrastim 6 mg every 14 days continued until remission. Treatment was administered in an outpatient setting and Ara-C was given in the home by community nurses or local medical practitioners. The study was approved by the local hospital Human Ethics Committee and registered on the ANZ Clinical Trials Registry (ACTRN12617000231347).
Results: Sixty patients were treated, Median age was 75 (range 72-94), 42 (70%) had de-novo AML and 18 (30%) R/R AML. Presenting WCC ranged from 0.8 to 185. Adverse cytogenetics were present in 40 (66%). In de-novo patients, 17 (40%) had prior haematologic disorders and 4 (10%) were treatment related. Response rates were: complete remission 40% or CR with incomplete count recovery (CRi) 28.5% in the entire cohort giving a response rate of CR+CRi of 68.5%. In the newly diagnosed group CR/CRi was 74%. Responses were also seen in the relapsed/refractory group with 5 of 18 (30%) achieving CR/CRi. The median number of cycles to achieve remission was 2 but some patients required up to 4 cycles. There were 9 (15%) deaths during induction. The median overall survival is 15 months in the de-novo group and 5 months in the relapsed/refractory group. A proportion of patients, 20-25% remain alive and in remission at 3 years post treatment. The main toxicity was as expected in this group of patients with infections predominating. No cases of severe liver toxicity were seen despite the prolonged use of thioguanine.
Conclusion: Prolonged therapy with low dose Ara-C and TG can be given as an outpatient in elderly AML patients. Complete remission rates appear equal to or better than other commonly used protocols. Anthracyclines are not used. Toxicity was manageable and mainly neutropenia related but some patients never developed serious infections or required hospitalisation. We suggest that this concept of prolonged low dose cytotoxics with individual patient adjusted therapy based on bone marrow response has been overlooked since it was first proposed 40-50 years ago. Further studies are required to independently confirm these results.

Disclosures
No relevant conflicts of interest to declare.