Treatment Landscape Is Quickly Evolving for CLL/SLL

Health-System Edition, September 2021, Volume 10, Issue 5

Patients now have multiple options, including continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens.

Chronic lymphocytic leukemia (CLL) is an indolent B-cell malignancy. Approximately 195,000 people in the United States are living with CLL, and an estimated 21,250 new cases and 4320 deaths are predicted for 2021.1,2

“Small lymphocytic lymphoma (SLL)” is used to describe patients with CLL with limited circulating CLL cells.3,4 The median age of diagnosis is 72 years, and it’s more common in men.3

CLL has a heterogeneous presentation and clinical course.5 Treatment options have evolved from chemoimmunotherapy to the use of targeted small molecules that inhibit Bruton tyrosine kinase (BTK), PI3K, and BCL2.4,5 National Comprehensive Cancer Network guidelines recommend acalabrutinib (Calquence) plus or minus obinutuzumab (Gazyva), ibrutinib (Imbruvica), or venetoclax (Venclexta) plus obinutuzumab as preferred treatment regimens in the first-line setting and acalabrutinib, ibrutinib, or venetoclax plus rituximab (Rituxan) in the second-line or subsequent therapy setting.1

BTK inhibitor therapy (acalabrutinib and ibrutinib) provides high response rates and durable remissions but requires continuous therapy.6-9 These drugs are generally tolerable, but toxicities developing with continuous therapy include bleeding, cardiac arrhythmias, diarrhea, hypertension, and infection.10 Adherence, cost, drug interactions, and resistance can also pose issues.5,10

Venetoclax inhibits the antiapoptotic molecule BCL2, which is highly expressed in CLL cells. Because venetoclax is highly effective, it can cause tumor lysis syndrome. Venetoclax can also cause neutropenia and thrombocytopenia. Recently, 2 clinical trials investigated fixed-duration therapy with venetoclax and a CD20 monoclonal antibody.

The phase 3 MURANO trial randomized 389 patients with relapsed or refractory (R/R) CLL/SLL after at least 1 prior treatment to either bendamustine-rituximab (BR) for 6 months or venetoclax-rituximab for 2 years. The median age of patients was 65 years. After a median follow-up of 23.8 months, the primary end point of progression-free survival (PFS) was not reached in the venetoclax-rituximab arm and was 17 months in the BR arm.11 Grade 3/4 neutropenia and tumor lysis syndrome occurred in 57.7% and 3.1% of patients treated with venetoclax-rituximab, respectively. A longer follow-up showed continued durability of a fixed-duration regimen with a 4-year PFS of 4.6% in the BR arm and 57.3% in the venetoclax-rituximab arm.12

The phase 3 CLL14 trial randomized 432 treatment-naive patients with CLL/SLL for 1 year to either chlorambucil (Leukeran)-obinutuzumab or venetoclax-obinutuzumab. The median age was 72 years. After a median follow-up of 28.1 months, the results favored venetoclax-obinutuzumab (HR, 0.35; P < .001 for PFS).13 Grade 3/4 neutropenia occurred in 52.8% of patients, with no cases of tumor lysis syndrome. At a median of 39.6 months, PFS continued to favor venetoclax-obinutuzumab (HR, 0.31; P < .0001).14

The findings of the MURANO trial in R/R and the CLL14 trial in patients who are treatment naive for CLL/SLL showed that fixed-duration venetoclax with a CD20 monoclonal antibody is superior to chemoimmunotherapy (BR or chlorambucil-obinutuzumab) and offers a viable treatment option for patients that allows for treatment-free intervals.

Conclusion

The treatment landscape in CLL/SLL is quickly evolving and offers patients multiple options, including but not limited to continuous therapy with BTK inhibitors and fixed-duration therapy with venetoclax-based regimens. Fixed-duration, venetoclax-based combination therapy may be an option for patients who are resistant or do not tolerate BTK inhibitors or prefer fixed-duration therapy. In addition, fixed-duration venetoclax may limit treatment-related adverse effects, cost, and therapy resistance.12

Jeremiah Moore, PharmD, BCOP, is a hematology/oncology clinical pharmacy specialist at the University of Rochester Medical Center in New York.

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