The Past, Present, and Future Front-Line Treatment Strategies for Chronic Lymphocytic Leukemia

Anthony J. Perissinotti, PharmD, BCOP
Clinical Pharmacist Specialist - Hematology
Michigan Medicine: University of Michigan
Ann Arbor, MI

Chronic lymphocytic leukemia (CLL) is the most prevalent type of leukemia in the United States. With a median age at diagnosis of 72, CLL primarily affects older adults; many of whom have several comorbidities.^{1, 2} As a result, treatment selection necessitates caution. As our understanding of the underlying biology improves, there has been a trend away from the use of cytotoxic chemotherapy and toward oral targeted therapies. This paradigm shift brings new challenges, which pharmacists must be aware of to stay ahead of the curve and lead change.

The Past
Chemotherapy was once the most common treatment modality for patients with CLL. Fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) were prescribed to young, fit patients, whereas BR or chlorambucil with obinutuzumab (O-Clb) were given to older patients with comorbidities.^3-6 Unfortunately, these treatments did not result in disease cure, and the prognosis for patients with high-risk cytogenetics were dismal.⁴ In fact, the only chance for cure was for patients to receive an allogeneic cell transplantation.⁷ One caveat is that FCR has shown durable remissions for patients with mutated IGHV.^{6, 8, 9} It can, however, only be recommended to a small set of CLL patients who are young, fit, and have mutated immunoglobulin heavy chain variable region gene (IGHV), as acute toxicities prohibit its use in older patients.¹⁰ Furthermore, even in young individuals, the risk of secondary malignancy makes this an unappealing alternative.³ In summation, new therapies were desperately needed.

The Present
A number of front-line therapy trials demonstrated the safety and efficacy of Bruton Tyrosine Kinase (BTK) inhibitors (ibrutinib and acalabrutinib) and venetoclax with obinutuzumab for first-line CLL compared to chemotherapy.^11-16 These included the front-line ECOG 1912 (FCR versus ibrutinib with rituximab), Alliance A041702 (BR versus ibrutinib versus ibrutinib with rituximab), RESONATE-2 (chlorambucil versus ibrutinib), iLLUMINATE (O-Clb versus ibrutinib with obinutuzumab), ELEVATE-TN (O-Clb versus acalabrutinib versus acalabrutinib with obinutuzumab), and CLL14 (O-Clb versus venetoclax with obinutuzumab) trials.^11-16 In the relapsed/refractory (R/R) setting, the RESONATE (ofatumumab versus ibrutinib), ASCEND (BR or idelalisib with rituximab versus acalabrutinib) and MURANO (BR versus venetoclax with rituximab) studies also paved the transition away from chemotherapy toward targeted therapies.^17-21 Two major questions remain: first, which BTK inhibitor should be chosen, and second, should BTK inhibitors be selected instead of a venetoclax-based regimen?

With the success of targeted therapies such as ibrutinib came new challenges, including unique toxicity profiles. Despite being a BTK inhibitor, ibrutinib inhibits several kinases including TEC, EGFR, ITK, BMX, ERBB4, among others.²² This may lead to “off-target” side effects such as atrial fibrillation, hypertension, bleeding, diarrhea, dermatitis, and myalgias.²³ Randomized controlled trials presented at this year’s American Society of Clinical Oncology Annual Meeting (ASCO 2021) and European Hematology Association Congress (EHA 2021) sought to determine whether second generation BTK inhibitors acalabrutinib or zanubrutinib are better tolerated than ibrutinib.^{16, 24} For patients with R/R CLL, ALPINE compared zanubrutinib to ibrutinib, whereas ELEVATE-RR evaluated acalabrutinib versus ibrutinib. Collectively, these data imply patients may tolerate second generation BTK inhibitors better than ibrutinib, but the “off-target” toxicities are not completely abrogated with the more selective second generation BTK inhibitors. For example, in ELEVATE-RR ibrutinib increased the rate of any grade atrial fibrillation (16% versus 9.4%; p=0.02), minor bleeding (51.3% versus 38%; p < 0.05), hypertension (23.2% versus 9.4%; p < 0.001), and interstitial lung disease or pneumonitis (6.5% versus 2.5%; p = 0.0241) compared to acalabrutinib. Additionally, diarrhea, arthralgia, back pain, muscle spasms, and dyspepsia occurred more frequently with ibrutinib, whereas headache and cough occurred more frequently with acalabrutinib.¹⁶ Similar results were found in ALPINE which demonstrated a lower rate of any grade atrial fibrillation/flutter with zanubrutinib compared to ibrutinib (10.1% vs 2.5%; p = not reported) while neutropenia was higher with zanubrutinib (28.4% versus 21.7%) but the increased risk for neutropenia did not appear to increase the risk for infections. There was no difference in hypertension or major hemorrhage but longer follow-up and/or larger studies are necessary to determine whether these and other adverse effects are truly different.²⁴

One practical consideration clinicians should keep in mind when choosing a BTK inhibitor is that acalabrutinib and zanubrutinib were both evaluated on a twice-daily schedule, which may affect adherence rates. Nonadherence to BTK inhibitors has been associated with poor outcomes. Regardless of which BTK inhibitor is chosen, the therapy will be indefinite and will necessitate years of continuous follow-up, managing adverse events, navigating financial assistance, and assessing adherence by pharmacists and other members of the care team.

The question of whether a BTK inhibitor should be used instead of a venetoclax-based regimen will most likely not be answered until the results of the CLL-17 study (comparing ibrutinib vs. venetoclax/obinutuzumab vs. ibrutinib/venetoclax, in frontline CLL) are reported. In the absence of data demonstrating superior efficacy of BTK inhibitors over venetoclax, cost should be a major consideration. In the CLL-14 trial, patients received venetoclax for only one year, rather than the alternative approach of an indefinite BTK inhibitor.¹⁴ There is an initial expense and time commitment when  treating patients with venetoclax, due to tumor lysis syndrome monitoring and simultaneous use of an intravenous anti-CD20 monoclonal antibody; however, data have shown overall costs are significantly reduced over time because patients can remain off therapy.²⁵ In fact, long-term follow-up data from the CLL-14 trial have shown the majority of patients can remain off therapy for several years when treated with venetoclax/obinutuzumab despite only a year of therapy.^{14, 26} At four years, 81% of patients have still not required additional CLL therapy. Not only were remissions durable, they were also deep. Venetoclax/obinutuzumab led to high rates of undetectable measurable residual disease (uMRD) in peripheral blood in 42% of patients via Clonoseq Assay/next generation sequencing (<10-6) and 76% of patients via an allele-specific oligonucleotide PCR assay (<10-4) at the end of treatment.¹⁴ Patients who are unlikely to remain progression-free and off therapy for an extended period of time (e.g., patients with TP53 mutated CLL) may not benefit from this cost savings, thus the therapy choice may shift back to BTK inhibitors given the durable outcomes that have been reported in this population.^{27, 28} Furthermore, with the ongoing COVID-19 pandemic, BTK inhibitors are an appealing choice because they do not require frequent exposure to the healthcare system and do not necessitate the use of a B-cell directed monoclonal antibody, which has important implications for the efficacy of COVID-19 vaccines.²⁹ Ultimately, both BTK inhibitors and venetoclax/obinutuzumab are exceptional new standards of care for CLL. Shared decision making with patients outlining the pros and cons of each treatment approach should drive therapy decisions.

The Future
Combining a BTK inhibitor with venetoclax is a promising future strategy. Deep remissions can be achieved, and like venetoclax/obinutuzumab, patients can come off therapy after a specified period of treatment. Several approaches are being used to investigate a variety of combinations.^30-36 Double and triple combinations (incorporating anti-CD20 monoclonal antibody), MRD-directed therapy (using uMRD to indicate when to stop therapy or detectable MRD to guide when to continue therapy), and combinations with a finite duration irrespective of MRD are among these approaches. It is unlikely these combinations will improve overall survival for most patients with CLL over sequential therapy, and even if they do, it will take a decade to reveal this benefit. In the short term, our goal should focus on keeping patients off therapy for as long as feasible while also lowering the overall economic burden on patients and the healthcare system. Attaining deep remissions does not guarantee this. Time off therapy and overall costs need to be a prioritized outcome. In current trials, rates of MRD- are a major focus, however, not discontinuing therapy until MRD- and/or treating MRD relapse may inadvertently lead to additional time on therapy and healthcare costs without improvements in quality of life or overall survival. Since venetoclax/obinutuzumab is the current finite standard of care, it should be used as a benchmark for establishing if a BTK inhibitor in combination with venetoclax +/- obinutuzumab genuinely improves the aforementioned clinical endpoints. Combination therapy will be utilized in practice soon but whether these combinations improve quality of life, decrease the cost of care, decrease patients’ time off therapy, or improve overall survival will not be known for years to come.

REFERENCES

1. National Cancer Institute. Accessed October 8, 2021. seer.cancer.gov/statfacts/html/clyl.html.
2. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. Jan 2021;71(1):7-33. doi:10.3322/caac.21654
3. Kutsch N, Bahlo J, Robrecht S, et al. Long Term Follow-up Data and Health-Related Quality of Life in Frontline Therapy of Fit Patients Treated With FCR Versus BR (CLL10 Trial of the GCLLSG). Hemasphere. Feb 2020;4(1):e336. doi:10.1097/hs9.0000000000000336
4. Döhner H, Stilgenbauer S, Benner A, et al. Genomic aberrations and survival in chronic lymphocytic leukemia. N Engl J Med. Dec 28 2000;343(26):1910-6. doi:10.1056/nejm200012283432602
5. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. Mar 20 2014;370(12):1101-10. doi:10.1056/NEJMoa1313984
6. Fischer K, Bahlo J, Fink AM, et al. Long-term remissions after FCR chemoimmunotherapy in previously untreated patients with CLL: updated results of the CLL8 trial. Blood. Jan 14 2016;127(2):208-15. doi:10.1182/ blood-2015-06-651125
7. van Gelder M, de Wreede LC, Bornhäuser M, et al. Long-term survival of patients with CLL after allogeneic transplantation: a report from the European Society for Blood and Marrow Transplantation. Bone Marrow Transplant. Mar 2017;52(3):372-380. doi:10.1038/bmt.2016.282
8. Thompson PA, Tam CS, O’Brien SM, et al. Fludarabine, cyclophosphamide, and rituximab treatment achieves long-term disease-free survival in IGHV-mutated chronic lymphocytic leukemia. Blood. Jan 21 2016;127(3):303-9. doi:10.1182/blood-2015-09-667675
9. Rossi D, Terzi-di-Bergamo L, De Paoli L, et al. Molecular prediction of durable remission after first-line fludarabine-cyclophosphamide-rituximab in chronic lymphocytic leukemia. Blood. Oct 15 2015;126(16):1921-4. doi:10.1182/ blood-2015-05-647925
10. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, v1.2022.
11. Woyach JA, Ruppert AS, Heerema NA, et al. Ibrutinib Regimens versus Chemoimmunotherapy in Older Patients with Untreated CLL. N Engl J Med. Dec 27 2018;379(26):2517-2528. doi:10.1056/NEJMoa1812836
12. Moreno C, Greil R, Demirkan F, et al. Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial. Lancet Oncol. Jan 2019;20(1):43-56. doi:10.1016/s1470- 2045(18)30788-5