Small Molecule Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) is characterized by excess lymphocyte production, which leads to abnormal amounts of immature lymphocytes.¹ This hematologic malignancy mainly affects the older adult population, and its prognosis varies depending on cytogenetics, staging, and pattern of progression. Treatment of CLL involves targeting key pathways involved in the pathogenesis of B-cell proliferation. Bruton tyrosine kinase (BTK), phosphoinositide-3-kinase (PI3K), and the B cell lymphoma 2 receptor (BCL-2) are 3 major molecular targets of oral small molecule inhibitors that treat CLL.² Importantly, when considering the use of small molecule inhibitors, potential drug interactions must be evaluated; these medications interact with cytochrome P450 (CYP) 3A4 inhibitors and inducers.

Ibrutinib (Imbruvica; AbbVie), first manufactured in August 2013, was the initial small molecule inhibitor brought to market to treat CLL.³ It has since been approved for numerous indications in a variety of lymphomas and hematologic malignancies. An irreversible BTK inhibitor, ibrutinib is considered as first-line treatment in CLL. However, increasing resistance limits its use, necessitating the development of subsequent small molecule inhibitors. A 28-day supply of ibrutinib is priced at $517.40 per 140-mg capsule.⁴ The recommended dose for ibrutinib is 420 mg by mouth daily (Table).⁴ Common adverse effects (AEs) of ibrutinib include peripheral edema, fatigue, skin rash, gastroin-testinal upset, and hematologic dyscrasias. Serious but less common AEs to consider include hemorrhage and secondary malignancies, as well as cardiotoxicity with concomitant atrial fibrillation. Additionally, new studies have linked ibrutinib administration to cardiovascular toxicity in patients with preexisting hypertension.⁵

In response to increasing resistance to ibrutinib, acalabrutinib (Calquence; AstraZeneca), was first approved for treatment of mantle cell lymphoma in October 2017.6 As of November 2019, acalabrutinib has gained new indications for the treatment of CLL and small lymphocytic leukemia.⁷ Acalabrutinib is also an irreversible BTK inhibitor, but unlike ibrutinib, it has greater selectivity for the BTK inhibitor, which accounts for its more favorable safety profile.8Acalabrutinib is priced at $281.28 per 100-mg capsule, pending insurance coverage, and must be taken orally twice daily (Table).⁹ Special attention must be paid to concomitant administration with gastric acid—altering agents, and proton-pump inhibitors must be avoided with acalabrutinib therapy.⁶ Important AEs of acalabrutinib to consider are similar to those of ibrutinib.

Idelalisib (Zydelig; Gilead Sciences) is the first oral agent in the new class of isoform-specific inhibitors of PI3K-δ.¹⁰ It was approved in July 2014 for the treatment of relapsed CLL in combination with rituximab.10 Idelal-isib is a potent selective inhibitor of the kinase activity of PI3Kδ.¹¹ Resistance to idelalisib is hypothesized to be associated with amplification of PI3K and Myc, loss of phosphatase and tensin homologue protein expression, and upregulation of PI3Kg.^11,12 The cost of idelalisib is $214.34 per 150-mg tablet and it should be taken twice daily (Table).¹³ All patients administered idelalisib should receive prophylaxis for Pneumocystis jirovecii with trimethoprim—sulfamethoxazole once daily.¹⁰

Important AEs include transient lymphocytosis, diar-rhea/colitis, hepatotoxicity, pneumonitis, neutropenia, and thrombocytopenia.¹⁰

Duvelisib (Copiktra; Verastem Oncology) was approved by the FDA in September 2018.¹⁴ Unlike idelalisib, duvelisib is a dual inhibitor of PI3K, targeting both the PI3K and PI3K receptor subtypes.¹⁵ Resistance to duvelisib is low; however, cytokine array studies revealed an upregulation of interleukin-6 in resistant cells, in addi-tion to increased phosphorylation of the signal transducer and activator of transcription 3 pathway involved in tumor cell survival.¹⁵ The cost of duvelisib is $252.86 per 25-mg capsule and it should be taken twice daily (Table).¹⁶ Similar to idelalisib, prophylaxis for Pneumocystis jirovecii with trimethoprim—sulfamethoxazole once daily is indicated for patients receiving duvelisib.¹⁴

Significant AEs associated with duvelisib include serious diarrhea/colitis, pneumonitis, and hepatotoxicity.¹⁴

Venetoclax (Venclexta; AbbVie), the first approved BCL-2 inhibitor for CLL, was approved by the FDA in April 2016.¹⁷ Venetoclax is a selective small molecule inhibitor for BCL-2, an antiapoptotic protein.¹⁸ Resistance to venetoclax is speculated to be due to upregula-tion or mutation within the BCL-2 family.¹² The cost of venetoclax is $11.71 for a 10-mg tablet, $58.54 for 50-mg tablet, and $117.08 for a 100-mg tablet.18 The initial dosing is 20 mg per day (Table).^17,18 Important AEs include diarrhea, nausea, neutropenia, thrombocytopenia, and tumor lysis syndrome (TLS).¹⁷ Although TLS can occur with all small molecule inhibitors, its severity in association with venetoclax use is distinct.¹⁷ It is important that patients who receive venetoclax are risk-stratified appropriately and that they receive the proper treatment prior to and during therapy for TLS.¹⁹ This includes adequate hydration and the use of antihyperuricemics, such as allopurinol, febuxostat, or rasburicase; however, rasburicase is indicated only in patients who are at particularly high risk for TLS due to elevated uric acid levels at baseline.¹⁹

Small molecule inhibitors are reshaping the treat-ment of CLL. The discovery of these medications helped to overcome resistance and are associated with positive outcomes in therapy. Given the proven importance of the different pathways and the preva-lence of resistance, future research should be directed at discovering new agents that target the BTK, PI3K, and/or BCL-2 pathways and can be used in the treat-ment of CLL.

Cedric White is a UConn 2020 PharmD candidate who will be a PGY1 resident at Massachusetts General Hospital in 2020-2021.Mallory Norma is a UConn 2020 PharmD candidate who will be a PGY1 resident at New York Presbyterian Hospital in 2020-2021.Lisa Holle is an Associate Clinical Professor at UConn School of Pharmacy and UConn Health Neag Cancer Center.

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