Consensus recommendations from the 2024 Lymphoma Research Foundation workshop on treatment selection and sequencing in CLL or SLL

Abstract

Over the past decade, treatment recommendations for patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have shifted from traditional chemoimmunotherapy to targeted therapies. Multiple new therapies are commercially available, and, in many cases, a lack of randomized clinical trial data makes selection of the optimal treatment for each patient challenging. Additionally, many patients continue to receive chemoimmunotherapy in the United States, suggesting a gap between guidelines and real-world practice. The Lymphoma Research Foundation convened a workshop comprising a panel of CLL/SLL experts in the United States to develop consensus recommendations for selection and sequencing of therapies for patients with CLL/SLL in the United States. Herein, the recommendations are compiled for use as a practical clinical guide for treating providers caring for patients with CLL/SLL, which complement existing guidelines by providing a nuanced discussion relating how our panel of CLL/SLL experts in the United States care for patients in a real-world environment.

Graphical abstract

Figure 1.

When to use a cBTKi vs Ven-O in CLL or SLL. We individualize treatment recommendations for each patient after considering relevant pretreatment factors. (A) Patient preference is a very important factor when selecting between a cBTKi and Ven-O as initial therapy. Key differences affecting patient preference include: (1) therapy until progression or intolerance vs time-limited therapy, (2) oral therapy alone vs addition of intravenous obinutuzumab, and (3) limited vs frequent visits/laboratory testing over the first 8 weeks on therapy (refer to Section 4.2). (B) For patients with concomitant warfarin or dual antiplatelet therapy, or a history of major bleeding with ongoing bleeding risk, or a history of ventricular arrhythmias with ongoing ventricular arrhythmia risk, we strongly recommend Ven-O over a cBTKi. Although concomitant use of a nonwarfarin anticoagulation or single antiplatelet therapy, or a history of AF, influences treatment selection toward Ven-O, a second-generation cBTKi (acalabrutinib or zanubrutinib) remains a reasonable option (refer to Section 4.3). (C) When considering these molecular risk factors, the most impactful for treatment selection is 17p deletion or TP53 mutation (del(17p)/TP53M), which influences treatment selection toward a second-generation cBTKi (acalabrutinib or zanubrutinib). Given the lack of direct comparison of a cBTKi and Ven-O in this population, and taking other factors including patient preference into account, Ven-O remains a reasonable option for patients with CLL/SLL with del(17p)/TP53M (refer to Section 4.4). DAPT, dual antiplatelet therapy.

Figure 2.

Treatment algorithms for CLL or SLL. (1) Our approach adheres to the iwCLL guidelines 2018 for the initiation of therapy for CLL/SLL (refer to Section 1; supplemental Table 1); (2) for patients with CLL/SLL who discontinue therapy for intolerance, a treatment holiday can be considered (refer to Table 3); (3) when initial treatment of CLL/SLL is advised, we recommend targeted agents such as Ven with obinutuzumab, acalabrutinib w/wo obinutuzumab, or zanubrutinib (refer to Section 2); (4) for patients who are previously treated with Ven and an anti-CD20 mAb and later progress and require therapy, retreatment with Ven w/wo anti-CD20 mAb can be considered in patients who tolerated Ven well and whose disease did not progress within 1 year of stopping Ven (refer to Section 6.2); (5) for patients who require second-line treatment after frontline Ven and obinutuzumab, when retreatment with Ven w/wo an anti-CD20 mAb is not preferred, we recommend a second-generation cBTKi (acalabrutinib or zanubrutinib; refer to Section 6.1); (6) for patients who discontinue a cBTKi because of intolerance and require further CLL/SLL treatment, an alternative second-generation cBTKi (acalabrutinib or zanubrutinib) can be considered unless the reason for intolerance was a life- or organ-threatening condition (refer to Section 5.2); (7) for patients with CLL/SLL and 2 prior therapies including a cBTKi and Ven, when retreatment with Ven w/wo an anti-CD20 mAb or transitioning to an alternate cBTKi is not preferred, we recommend pirtobrutinib in most cases. In patients who are deemed good candidates, liso-cel should also be considered for this line or subsequent lines of therapy (refer to Section 8.1). See also Special Situations regarding use of pirtobrutinib for patients who require treatment after prior cBTKi with medical contraindication to Ven-based therapy (refer to Table 3). (8) For patients with CLL/SLL that is refractory to 3 prior therapies including Ven, a cBTKi, and pirtobrutinib, when treatment with liso-cel or participation in a clinical trial is not feasible or preferred, a PI3Kδ inhibitor should be considered (refer to Section 8.2); (9) referral to a CLL expert to discuss whether to pursue allogeneic stem cell transplant may be considered for patients with CLL/SLL who are refractory to at least 2 prior therapies including Ven and a cBTKi and obtained a remission to a subsequent therapy (refer to Section 8.3). (10) Clinical trials should be considered for all patients with CLL/SLL, when clinical trial participation is feasible and when the study objectives are well suited to the patient’s priorities (refer to Section 9). (11) Although the addition of obinutuzumab to acalabrutinib for frontline treatment of CLL/SLL may be associated with a longer PFS than acalabrutinib alone, the majority of the panel does not routinely add obinutuzumab because of potential added toxicity and the requirement for patients to receive intravenous infusion therapy; currently, the most common reason our panel adds obinutuzumab to acalabrutinib is the presence of uncontrolled autoimmune cytopenias (refer to Section 3). (12) Although rituximab with Ven is approved for patients with R/R CLL/SLL, the majority of the panel recommends obinutuzumab with Ven in this setting (refer to Section 5.1). ∗For patients previously treated with ibrutinib in place of acalabrutinib or zanubrutinib, follow guidance as if they received a second-generation cBTKi.