No 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.

polynomial (FP) models using survivalNMA package in R (v3.6.2) and parameters were estimated accordingly. A deviance information criterion (DIC) was used to compare the goodness-of-fit. Results: Among the parametric and FP models, loglogistic showed the best fit (DIC=431.65; 248.18), followed by FP1 and Weibull for both PFS and OS outcomes. The predicted survival of lanreotide LAR, octreotide LAR, and placebo was 44%, 40% and 6% in terms of PFS at 5 years, and 54%, 57% and 54% in terms of OS at 10 years. Lanreotide LAR showed highest PFS, followed by octreotide LAR and Placebo. Regarding OS, octreotide LAR showed the highest survival, while lanreotide LAR and placebo showed near-identical survival prospects. The findings were not sensitive to different distributions, although the survival probabilities varied substantially. The ordering of treatments was also consistent across distributions. Conclusions: Octreotide LAR and lanreotide LAR significantly delayed the time to progression compared to placebo. The results of our multi-dimensional evidence synthesis approach are consistent with previously published HR based metaanalyses. The use of this approach may be more informative for any subsequent costeffectiveness modelling over constant HRs.

To detect, report, assess and document the ADRs associated with chemotherapy in geriatric patients. METHODS: A hospital based prospective observational study was carried out among 153 inpatients in the department of medical oncology for a period of 6 months. Patients above 60 years of age with confirmed history of malignancy were included in the study. The potential risk factors for ADR were defined in relation to patient and chemotherapeutic regimen. The relationship between those risk factors and ADRs was assessed by univariate and multi variate logistic-regression analysis. RESULTS: A total of 136 ADRs were observed in 94 patients, the mean age of the study population was 64.75±4.97 years among which females accounted for majority of the ADRs (60.64%). The organ systems mostly affected were found to be Gastrointestinal system (44.85%) (OR= 1.358; 95% CI 0.69-2.64 p< 0.001) followed by dermatologicals (30.15%) (OR= 1.50; 95% CI 0.63-3.56 p< 0.001) and immune system (17.65%) (OR= 2.27; 95% CI 0.9-5.7 p< 0.001). The most commonly reported ADR was found to be alopecia (30.15%) followed by diarrhoea (28.68%), vomiting (14.8%), neutropenia (7.35%), myelosupression (3.68%) and nephrotoxicity (2.94%). Cyclophosphamide (OR= 2.98 95%CI 1.26-7.07 p< 0.001), Carboplatin (OR= 13.359; 95%CI 3.056-58.406 p< 0.001) 5 Fluoro Uracil (OR= 1.938 95%CI 1.266-2.935 p< 0.001) and Adriamycin (OR= 16.45; 95% CI 2.41-112.22 p< 0.001) were found to be the most significant drugs causing ADRs. Assessment of causality by WHO causality assessment scale indicated that 97% of the reactions were 'probable' and 1% was 'possible'. In one patient with cisplatin induced hypersensitivity reaction, rechallenge was attempted and the causality was made as 'certain'. CONCLUSIONS: Individualizing drug therapy, implementation of preventive measures will lead to reduction in the severity of ADRs and thereby reduce the economic burden to the patient and helps to improve the treatment outcome. Knowing the commonly occurring ADRs will aid the practitioner in early detection of ADRs.

This study presents a limitation regarding the subjectivity inherent to costs determination based on answers given by the HP. Moreover values may be underestimated due to lack of information regarding fixed costs.