Systematic Review of Non-Conventional Dosing of Oral Anticancer Therapies in Malignant Haematology
Authors: Djebbari Faouzi , Stoner Nicola , Lavender Verna 
Published: October 2019

Abstract
Introduction
Survival outcomes for patients with lymphoid, myeloid and plasma cell malignancies, have improved with the use of oral small molecule inhibitory agents. Oral anti-cancer therapies are often administered continuously and can have significant side-effects, which can adversely impact adherence, quality of life (QoL) and survival outcomes. In order to improve tolerability, non-standard dosing strategies are increasingly adopted in clinical practice; although, with limited guidance. A systematic review was conducted to identify evidence of, and outcomes from, non-conventional dosing of oral anti-cancer therapy in malignant haematology.
Methods
A comprehensive search of all oral anti-cancer therapy listed in the British National Formulary for use to treat haematological malignancies was undertaken using the following databases: MEDLINE®, EMBASE®, and Cochrane Library©, and Cumulative Index to Nursing and Allied Health Literature (CINAHL©). The search was expanded using prospective citation chaining in the Web of Science and retrospective snowballing of reference lists of included studies to ensure a sensitive, comprehensive search. Studies were selected based on predefined inclusion/exclusion criteria, and were critically appraised. Extracted data were tabulated to summarise key findings, which were analysed by type of non-dosing strategy: dose interruption; dose reduction; and other dosing strategies.
Results
Eleven studies were included and reviewed: two late phase clinical trials, four cohort studies, and five case reports. Findings from each included study (aim, design, treatment schdeule, reported efficacy/toxicty/QoL outcomes) are presented in the accompanying Table 1. These studies evaluated non-standard dosing of dasatinib, imatinib, lenalidomide and thalidomide. Four studies were conducted in Italy, four in the US, and one in Brazil, South Korea and UK. Dose reductions were the most commonly reported strategy (five studies). Two studies reported dose interruptions and four reported other dosing strategies. The quality of the studies ranged from moderate to high (e.g. clinical trials) to moderate to low (e.g. case reports).
Russo et al (2015) conducted a single arm, open-label trial, in which the use of one month on/one month off schedule of imatinib was investigated in 96 CML patients aged ≥65 years. Although this trial did not report toxicity or QoL outcomes, there were no transformations (progressions) of CML to an accelerated or blast phase of disease using this alternative schedule. Therefore, results do not draw definitive conclusions that intermittent treatment can be offered to optimal and stable responders. However, they indicate a role for alternative treatment schedules tailored to individual patients, particularly those experiencing significant toxicities.
Mangiacavalli et al (2012) investigated efficacy and adverse effects of a one-week interruption of thalidomide following daily administration for three weeks, compared to continuous therapy. Limited patient numbers (13 vs. 10) prevented this trial from obtaining definitive data regarding efficacy, but there was a trend for worse overall survival (OS, p< 0.001) and progression free survival (PFS, p=0.02) in the intermittent arm compared to the continuous one, with no difference in peripheral neuropathy.
Dose reduction was reported in two imatinib retrospective cohort studies and three case reports (2 dasatinib, 1 imatinib). Results were inconclusive, primarily due to limitations in the design of the studies, small sample sizes and lack of detail in reporting toxicities and QoL outcomes. Lenalidomide was investigated in two small prospective cohort studies using alternate-day dosing in myelodysplastic syndrome and multiple myeloma. Toxicity outcomes were only reported in the myeloma study and QoL outcomes were reported in neither study.
Conclusions
This review identified limited evidence to support non-standard dosing strategies in malignant haematology. Imatinib dose interruption in optimally responsive CML patients warrants further investigation in large-scale, prospective, ideally blinded trials.
Table 1. Table 1.

Disclosures
Djebbari: Pfizer: Other: conference registration; Takeda: Honoraria, Other: travel support; Celgene: Honoraria, Other: travel support, Research Funding.