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In this article, we attempt to define the \u201cdouble refractory\u201d patient as resistant to both Bruton's tyrosine kinase inhibitors (BTKi) and venetoclax for which prognosis is poor and there remains no standard of care. We further examine the mechanism of resistance to these targeted agents and discuss the current landscape for managing this patient population. Finally, we explore data supporting promising new agents, including non\u2010covalent BTKi, chimeric antigen receptor T cells, and additional classes of agents currently in development.<\/jats:p>","DOI":"10.1002\/ajh.26682","type":"journal-article","created":{"date-parts":[[2022,9,20]],"date-time":"2022-09-20T10:54:50Z","timestamp":1663671290000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Approach to a patient with \u201cdouble refractory\u201d chronic lymphocytic leukemia: \u201cDouble, double toil and trouble\u201d (Shakespeare)"],"prefix":"10.1002","volume":"97","author":[{"given":"Julia H.","family":"Aronson","sequence":"first","affiliation":[{"name":"CLL Program, Division of Hematological Oncology Memorial Sloan Kettering Cancer Center  New York New York USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid S.","family":"Sk\u00e5nland","sequence":"additional","affiliation":[{"name":"Department of Cancer Immunology, Institute for Cancer Research Oslo University Hospital  Oslo Norway"},{"name":"The K. 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