With the emergence of targeted therapies, the traditional maximum tolerated dosing where toxicities guide the treatment dose is no longer relevant. Especially in the case of tyrosine kinase inhibitors (TKIs), where higher doses lead to therapeutic resistance due to ligand or receptor upregulation and where off-target toxicities plague any increase of dose. In the case of TKIs, where the most effective dose is at the bottom of a U-shaped curve, therapy should be guided by biomarkers, or by minimal residual disease. We present a case of relapsed chemotherapy-refractory ALK-positive anaplastic large cell lymphoma treated with lorlatinib, where we used frequent minimal disseminated disease monitoring to guide the length of on/off therapy periods during intermitted dosing in order to prevent treatment resistance.