Treatment Landscape Is Quickly Evolving for CLL/SLL

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.

REFERENCES

1. Chronic lymphocytic leukemia. National Comprehensive Cancer Network. 2021. Accessed August 19, 2021. https://www.nccn.org/patients/guidelines/content/PDF/cll-patient.pdf

2. Cancer stat facts: leukemia — chronic lymphocytic leukemia (CLL). National Cancer Institute. Accessed August 17, 2021. https://seer.cancer.gov/statfacts/html/clyl.html

3. Hallek M. Chronic lymphocytic leukemia: 2020 update on diagnosi s, risk stratifi cation and treatment. Am J Hematol. 2019;94(11):1266-1287. doi:10.1002/ajh.2559

4. Hallek M, Cheson BD, Catovsky D, et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131(25):2745-2760. doi:10.1182/blood-2017-09-806398

5. Burger JA. Treatment of chronic lymphocytic leukemia. N Engl J Med. 2020;383(5):460-473. doi:10.1056/NEJMra1908213

6. Byrd JC, Brown JR, O’Brien S, et al; RESONATE Investigators Ibrutinib versus ofatumumab in previously treated chronic lymphoid leukemia. N Engl J Med. 2014;371(3):213-223. doi:10.1056/NEJMoa1400376

7. Burger JA, Tedeschi A, Barr PM, et al; RESONATE-2 Investigators. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373(25):2425-2437. doi:10.1056/NEJMoa1509388

8. Sharman JP, Egyed M, Jurczak W, et al. Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzumab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial. Lancet. 2020;395(10232):1278-1291. doi:10.1016/S0140-6736(20)30262-2

9. Ghia P, Pluta A, Wach M, et al. ASCEND: phase III, randomized trial of acalabrutinib versus idelalisib plus rituximab or bendamustine plus rituximab in relapsed or refractory chronic lymphocytic leukemia. J Clin Oncol. 2020;38(25):2849-2861. doi:10.1200/JCO.19.03355

10. Lipsky A, Lamanna N. Managing toxicities of Bruton tyrosine kinase inhibitors. Hematology Am Soc Hematol Educ Program. 2020;2020(1):336-345. doi:10.1182/hematology.2020000118

11. Seymour JF, Kipps TJ, Eichhorst B, et al. Venetoclax-rituximab in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2018;378(12):1107-1120. doi:10.1056/NEJMoa1713976

12. Kater AP, Wu JQ, Kipps T, et al. Venetoclax plus rituximab in relapsed chronic lymphocytic leukemia: 4-year results and evaluation of impact of genomic complexity and gene mutations from the MURANO phase III study. J Clin Oncol. 2020;38(34):4042-4054. doi:10.1200/JCO.20.00948

13. Fischer K, Al-Sawaf O, Bahlo J, et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380(23):2225-2236. doi:10.1056/NEJMoa1815281

14. Al-Sawaf O, Zhang C, Tandon M, et al. Venetoclax plus obinutuzumab versus chlorambucil plus obinutuzumab for previously untreated chronic lymphocytic leukaemia (CLL14): follow-up results from a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2020;21(9):1188-1200. doi:10.1016/S1470-2045(20)30443-5