ASH Clinical News ACN_4.13_full issue_Web | Page 51

TRAINING and EDUCATION How I Treat In Brief Jennifer A. Woyach, MD, associate professor at the Ohio State University Comprehensive Cancer Center, wrote about her strategy for the management of patients with chronic lymphocytic leukemia whose disease is refractory to ibrutinib. Below, we summarize her approach. This material was repurposed from “How I manage ibrutinib-refractory chronic lymphocytic leukemia,” published in Blood on January 17, 2017. Managing Ibrutinib-Refractory Chronic Lymphocytic Leukemia The introduction of the oral Bruton tyrosine kinase (BTK) inhibitor ibrutinib for the treat- ment of patients with chronic lymphocytic leukemia (CLL) dramatically changed the management of this disease. In clinical trials, ibrutinib improved both progression-free survival (PFS) and overall survival for patients with relapsed and treatment-naive CLL, includ- ing those with high-risk disease, compared with prior standard of care. While the remarkable data make it tempt- ing to think that patients could be treated with ibrutinib for the rest of their natural lives, relapse does indeed occur, and ibrutinib- refractoriness is becoming an increasingly common clinical problem. Defining Relapse on Ibrutinib Relapse on ibrutinib occurs in two forms: • progressive CLL, which typically occurs after at least 1 year of therapy and increases in frequency with time on therapy • histologic transformation, or Richter transformation, which generally occurs within the first 2 years of treatment, more frequently with large cell lymphoma or prolymphocytic leukemia Because most patients who are on continuous ibrutinib therapy will not attain a complete response and many will have circulating leuke- mia cells for long periods of time, determining which patients are indeed relapsing can be a challenge. Case #1: Ruling out Ibrutinib Resistance A 53-year-old man with relapsed CLL started ibrutinib seven months ago and had a partial response with lymphocytosis (PRL), along with a steadily decreasing absolute lymphocyte count (ALC; last recorded value was 20,000/μL 1 month prior). He was feeling well until about four days ago, when he began to have a low- grade fever, myalgia, cough, and new cervical adenopathy. On exam, he has bilateral cervical nodes 2×2 cm and no other adenopathy. His white blood cell count (WBC) is 36×10 9 /L, with an ALC of 30/μL. Comments: This patient’s scenario is common for an upper respiratory infection leading to cervical adenopathy and increased WBC. Infections are frequently accompanied by a rise in lymphocyte count, especially in patients with residual lymphocytosis on ASHClinicalNews.org ibrutinib. The PRL status is a newer designa- tion in which patients may meet criteria for a partial response (PR) by node resolution and blood count improvement long before lymphocytosis resolves; however, it has not been shown to result in an inferior remission duration compared with patients who achieve a standard PR. For this patient, ibrutinib should be con- tinued but, because constitutional symptoms can occasionally herald the development of Richter transformation in these patients, I would have the patient return if symptoms persist longer than one week and consider rechecking blood counts in one month. Patients must show progression on repeated evaluations to avoid abandoning an effective therapy. If a relapse is confirmed, ibruti- nib should not be discontinued until a new treatment plan is in place. Case #2: Identifying Ibrutinib Relapse A 50-year-old woman with CLL has been receiving ibrutinib for three years as her third-line therapy and has been feeling well. On routine exam, she has no palpable lymphadenopathy, but ALC has increased from 3,000/μL to 6,000/μL. Two months later, her ALC has further risen to 8,000/μL, and, although she remains asymptomatic, she has a new 1.5 cm lymph node in her neck. Comments: This patient is relapsing on ibrutinib with an increasing WBC count and the presence of new palpable adeno- pathy. It is important to closely monitor patients who show any signs of disease progression, so that relapse can be caught early. The tempo of relapse tends to escalate when ibrutinib is discontinued, so ibrutinib should be continued until the next therapy is started. If a wash-out period is necessary Fast Facts ✓ ✓ Ibrutinib-refractoriness is determined by progression on repeated evaluations so that an effective therapy is not abandoned. ✓ ✓ There are two forms of ibrutinib relapse: progressive CLL and histologic transformation. ✓ ✓ Ibrutinib should not be discontinued in a relapsing patient without a new treatment plan in place. ✓ ✓ Karyotypic complexity at baseline and the development of BTK and PLCG2 mutations can help clinicians identify which patients will relapse on ibrutinib. ✓ ✓ Short-term disease management options include venetoclax or idelalisib plus rituximab in certain patients. ✓ ✓ Long-term disease control can include transplant for eligible patients or enrollment in a clinical trial of CAR T-cell therapies or a checkpoint inhibitor for transplant-ineligible patients. ASH Clinical News 49