The million-dollar question in the treatment of chronic lymphocytic leukemia (CLL) is what to do after a patient relapses following treatment with venetoclax. Anthony Mato, MD, and Lindsey Roeker, MD, both of Memorial Sloan Kettering in New York, join podcast host David H. Henry, MD, of Pennsylvania Hospital, Philadelphia, to explore the evidence about this question and to review the initial patient work-up and treatment strategies. In Clinical Correlation, Ilana Yurkiewicz, MD, of Stanford (Calif.) University, discusses patients compliance and how clinician biases can influence compliance. Practice points: For patients with CLL with unmutated immunoglobulin variable heavy chain gene (IgVH), novel agents are the first therapy. Evidence is limited about the best treatment approach after relapse on venetoclax.  * * *  Initial work-up in patients with CLL The initial work-up for patients with CLL is often fluorescent in situ hybridization (FISH), looking for trisomy 12, as well as deletion of 13q, 17p, and 11q. Next-generation sequencing is used to look for mutations in TP53 and IgVH mutational analysis is done to recognize whether a patient is mutated. IgVH-mutated patients tend to respond better to therapy. When to treat Henry recommends the “if it bothers you, it bothers me” approach, noting that indications for treatment include fever, chills, night sweats, lumps and bumps in the neck, large liver and spleen, and high creatine. Progression If a patient is IgVH unmutated, that takes chemoimmunotherapy combinations off the table, regardless of whether the patient is young or fit. Instead, they are on a pathway to receive a novel agent as first therapy. The choices for novel agents keep expanding. Some standards include ibrutinib plus or minus obinutuzumab, venetoclax plus obinutuzumab, and acalabrutinib plus or minus obinutuzumab. Each of these combinations has different adverse event profiles and dose schedules. Patient preferences and comorbidities should drive decision making on novel combinations. Relapse The million-dollar question: What is the best treatment following relapse on venetoclax? The answer is unclear but there are generally two choices: Re-treat with the same regimen or switch to a Bruton’s tyrosine kinase (BTK) inhibitor. There are limited data on re-treatment and emerging data on BTK inhibitors after venetoclax that points to success. Disclosures Dr. Anthony Mato reported research funding from DTRM Biopharma and Gilead; consultancy and research funding from Genentech, Pharmacyclics, TG Therapeutics, Adaptive, Sunesis, AstraZeneca, Abbvie, LOXO, and Johnson & Johnson; and consultancy with Verastem, Acerta, Janssen, and Celgene. Dr. Lindsey Roeker reported minority ownership interest in Abbvie and Abbott Laboratories, ASH grant funding. Dr. Henry and Dr. Yurkiewicz reported no relevant financial conflicts. * * * For more MDedge Podcasts, go to mdedge.com/podcasts Email the show: podcasts@mdedge.com Interact with us on Twitter: @MDedgehemonc David Henry on Twitter: @davidhenrymd Ilana Yurkiewicz on Twitter: @ilanayurkiewicz