By: Nishanth Viswanath, PharmD Candidate c/o 2022
Chronic lymphocytic leukemia (CLL) is a hematological malignancy of mature CD5 positive B-lymphocytes that primarily affects elderly patients.1 With the average age of diagnosis being 71, the incidence of CLL is relatively rare in younger populations, though cases have occurred in those under the age of 50.1 CLL is much more prevalent in those of Caucasian descent than those of Asian or African descent. This distinction adds evidence to the genetic morphology of CLL, yet the true reasoning for it remains elusive.2 CLL is the most common form of leukemia in the United States. In 2020 it is estimated that approximately 21,040 new cases will be diagnosed and about 4,060 patients will succumb to the disease.3 Due to advancements in therapies and diagnostic measures, the 5-year overall survival rate has increased from sixty-nine percent in 1980 to eighty-eight percent in 2007, and has likely become even higher today.1 While CLL generally remains an incurable illness, contemporary therapies have rendered it a manageable and tolerable condition for most patients, especially through the latter stages of their lives.
Chemotherapy and Chemoimmunotherapy
Monotherapy with chlorambucil (Leukeran®) has been used the longest of all the available effective CLL regimens due to its low cost, and low toxicity profile.4 Other alkylating agents such as fludarabine (Fludara®), cyclophosphamide (Cytoxan®), and bendamustine (Bendeka®) have displayed longer progression-free survival (PFS) and higher response rates, but have made no significant impact on overall survival (OS) and are accompanied by more toxicities than chlorambucil.4 Anti-CD20 antibodies such as ofatumumab (Arzerra®) and obinutuzumab (Gazyva®) have been studied alongside chlorambucil for more elderly and frail patients, but have shown only median PFS rates of 22.4 months and 26.7 months respectively.5 Side effects such as neutropenia, thrombocytopenia and infusion-related reactions are common with ofatumumab and obinutuzumab as well.5,6
The chemoimmunotherapy regimen of fludarabine, cyclophosphamide and rituximab (Rituxan®) (FCR) has been established as the gold standard for younger patients requiring initial pharmacologic treatment, but is not suitable for older patients due to its high rate of treatment related adverse events.5 Additionally, though the average PFS in patients treated with first line FCR is fifty-two percent, the same benefit is not seen in patients older than 65 or those who have unfavorable cytogenetic aberrations associated with CLL such as a chromosomal 11q deletion, 17p deletion, or unmutated immunoglobulin heavy chain variable (IGHV) region.1
Novel Intracellular Oncogenic Pathways
Only recently did studies elucidate the role of B cell receptor (BCR) signaling in the molecular pathogenesis of CLL, and its ability to drive the proliferation of neoplastic B-lymphocytes.5 BCR signaling involves both “tonic” and antigen-activated stimulation, which both lead to downstream phosphorylation by kinases to provide for activation of transcription factors such as NF-kB and NFAT.7 As BCR signaling is an essential function of normal B-lymphocyte survival, its activity in CLL promotes extensive malignancy and over proliferation of B-lymphocytes.7 Novel agents that target BCR signaling mechanisms have displaced the use of cytotoxic chemotherapy regimens, and have greatly increased PFS rates in the majority of patients. Bruton’s Tyrosine Kinase (BTK) and isoforms of Phosphoinositide 3-Kinase (PI3K) are evidently targetable biomarkers for CLL therapy, while others are currently being evaluated in ongoing research.7
Ibrutinib (Imbruvica®) is a first in class, irreversible, relatively selective inhibitor of BTK.1 BTK is essential in leukemic B-cells for the downstream release of calcium and NF-kB, and for cell survival and proliferation.7 Initially approved for patients with relapsed or refractory CLL, ibrutinib has evolved into a reliable option for the first-line treatment of CLL in all age groups and for those exhibiting 17p deletion.1,5 When studied against chlorambucil in previously treated patients, seventy percent of patients on ibrutinib therapy experienced PFS as opposed to twelve percent with chlorambucil at 5 years of treatment.8 Additionally, when ibrutinib monotherapy was compared to ofatumumab in treatment naive patients for 63 months, the median length of PFS was 44.1 months (95% CI [38.5, 56.9]) and 8.1 months (95% CI [7.8, 8.3]) in the ibrutinib and ofatumumab arms, respectively.8 Most notably, when the combination of ibrutinib and rituximab was studied in comparison to FCR, patients on ibrutinib and rituximab displayed a median PFS at 3 years of eighty-nine percent (95% CI [85, 92]), as opposed to seventy percent of patients for FCR (95% CI [61, 78]).8
Acalabrutinib (Calquence®), a second generation BTK inhibitor, binds more tightly to the C481 residue of BTK than ibrutinib.9 This pharmacological profile leads to the rationale that second generation BTK inhibitors such as acalabrutinib may diminish the off-target kinase inhibiting properties of ibrutinib, which may lead to arthralgias, atrial fibrillation, rash, hypertension, bleeding and diarrhea.9 In clinical studies, the efficacy of acalabrutinib monotherapy has been compared to therapy with acalabrutinib + obinutuzumab and chlorambucil + obinutuzumab, with PFS being the primary endpoint.10 At a median follow-up time of 28.3 months, the chlorambucil + obinutuzumab arm displayed a median PFS of 22.6 months [95% CI (20, 28)], while the acalabrutinib + obinutuzumab and acalabrutinib monotherapy arms did not possess average PFS rates as not enough patients displayed progressive disease.10 Compared to ibrutinib, acalabrutinib offers a lesser risk of cardiovascular comorbidities such as thrombotic risk and atrial fibrillation, but is unsuitable for patients using proton-pump inhibitors (PPI) or medications that are strong CYP-3A4 inducers or inhibitors.10 Zanubrutinib (Brukinsa®), another second generation BTK inhibitor is currently in phase-3 evaluation against ibrutinib for its safety and efficacy in patients with CLL, and may further abridge the risk of BTK inhibitor use in patients with cardiac dysfunctions .11
Idelalisib (Zydelig®) is a first in class, highly selective inhibitor of PI3Kδ that is approved in combination with rituximab for patients with relapsed or refractory CLL.7, 12 PI3K is a multifarious kinase that is expressed as many ubiquitous isoforms such as PI3Kα and PI3Kβ, whereas PI3Kδ is found solely in B-lymphocytes.7 The activity of PI3Kδ allows for the phosphorylation of phosphatidylinositol-bisphosphate (PIP2) creating PIP3, which assists in anchoring BTK to the cell membrane of B-lymphocytes.7 The efficacy of idelalisib was displayed in studies assessing it in combination with rituximab versus placebo in combination with rituximab, with PFS being the primary endpoint. Patients enrolled experienced relapsed disease or were refractory to conventional chemoimmunotherapy.12 At a median follow-up time of 8.3 months, the median PFS for the idelalisib + rituximab arm was 19.4 months (95% CI [12.3, Not Estimable]) versus 6.5 months (95% CI [4.0, 7.3]) in the placebo + rituximab arm.12
Duvelisib (Copiktra®) is an inhibitor of PI3K with activity against both PI3Kδ and PI3Kγ, with additional inhibitory function of T cell migration.13 This pharmacological activity sanctions duvelisib as an effective monotherapy for relapsed or refractory patients, as opposed to idelalisib which is only approved in combination with rituximab.12,13 Evidently, this efficacy was proven in studies assessing duvelisib monotherapy in comparison to ofatumumab monotherapy, where patients were highly treatment experienced (2 prior therapies or more).13 With PFS being the primary endpoint, at a median follow-up time of 22.4 months the median PFS in the duvelisib arm was 17.6 months (95% CI [15, 22]) and 9.7 months (95% CI [9, 11]).13
Common toxicities in both idelalisib and duvelisib such as neutropenia, anemia, diarrhea, musculoskeletal pain and respiratory infections are synonymous with those of BTK inhibitor therapy.12,13 Advantageously however, both idelalisib and duvelisib are plausible options for patients with cardiac comorbidities or hypertension as opposed to ibrutinib and acalabrutinib.12,13
B-cell lymphoma 2 (BCL-2) is a regulatory protein exhibited in malignant B-cells that regulates the anti-apoptotic mechanisms of B-lymphocytes.5 In CLL this protein, in combination with the TP53 gene, is overexpressed and provides for the prolonged survival and resistance to certain chemotherapeutics against B-lymphocytes.5 Venetoclax (Venclexta®) is a selective inhibitor of BCL-2 which assists in regulating the natural apoptosis of leukemic cells and has shown remarkable clinical efficacy in relapsed and refractory CLL as monotherapy, and in combination with obinutuzumab and ibrutinib.5, 14 In combination with other agents venetoclax demonstrates high rates of undetectable minimal residual disease (uMRD) potentiating the possibility of fixed-duration therapies, as opposed to indefinite therapy with other novel agents.5 When venetoclax in combination with obinutuzumab was compared against chlorambucil with obinutuzumab with 2-year PFS being the primary endpoint, eighty-eight percent versus sixty-four percent of patients were progression free in each arm respectively (HR = 0.35, 95% CI [0.23, 0.53]).5,14 Additionally, the uMRD incidence in the venetoclax + obinutuzumab group was substantial, as fifty-seven percent (95% CI [59, 78]) and seventy-six percent (95% CI [69, 81]) of patients in the venetoclax + obinutuzumab group did not have detectable amounts of leukemic cells in bone marrow and peripheral blood respectively.14
Two-year studies utilizing fixed-duration regimens of ibrutinib as a lead in therapy and venetoclax for the remaining duration have also elucidated considerable uMRD rates.5 The synergistic action of BTK inhibitors and venetoclax offers an explorable treatment mechanism with acalabrutinib and zanubrutinib, and moreover a potential cure for CLL.5
The action of BCR signalling antagonists and venetoclax have offered a multitude of novel treatment options that have revolutionized the therapeutic landscape of CLL. Conventional chemotherapy regimens have been widely superseded by immunotherapies, offering patients more effective and less toxic treatment options. More research is required, however, to determine the most effective combination regimens of venetoclax, BRC signalling antagonists and CD20 antagonists. The introduction of an anti-apoptotic agent with venetoclax has resulted in the most substantial rates of uMRD in patients, especially in combination with obinutuzumab and rituximab which are approved for 1 year and 2 year fixed-duration regimens, respectivley.14 Further studies must be conducted to identify the most suitable BTK or PI3K agent to be used in combination with venetoclax for a non-invasive, simplified regimen. Additionally, as ibrutinib has gained mass acceptance as the most reliable and definitive BTK inhibitor, toxicities such as neutropenia, diarrhea, arrhythmias and hypertension are common and frequently lead to discontinuation of therapy.5 Acalabrutinib diminishes such adverse effects to some extent, but is unsuitable for those receiving PPIs or strong inducers or inhibitors of CYP-3A4. The PI3K inhibitors available to date present with less toxicities but have not demonstrated the clinical efficacy of ibrutinib and acalabrutinib. Investigational BCR signalling antagonists such as zanubrutinib, vecabrutinib, ARQ-531 and umbralisib may offer even stronger clinical efficacy than currently available agents and reinforce the use of venetoclax as a fixed-duration regimen.15
The treatment landscape of CLL has evolved over the last decade, shifting from chemotherapy to chemoimmunotherapy and immunotherapy. Due to existing combination regimens of BTK inhibitors, PI3K inhibitors, CD20 antagonists, and venetoclax, patients have experienced remarkable lengths of PFS and OS and now commonly present with uMRD. Traditionally, the onset of CLL results in a permanent and enduring malignancy with therapy focused on prolonging PFS. Today, studies of new BCR signalling antagonists may elucidate a curative regimen for CLL.
- Woyach JA, Byrd JC. Chronic Lymphocytic Leukemia. In: Jameson J, Fauci AS, Kasper DL, Hauser SL, Longo DL, Loscalzo J. eds. Harrison’s Principles of Internal Medicine, 20e. McGraw-Hill; Accessed 07/05/2020.
- Fabbri G, Dalla-Favera R. The molecular pathogenesis of chronic lymphocytic leukaemia. Nat Rev Cancer. 2016;16(3):145-62. doi: 10.1038/nrc.2016.8.
- American Cancer Society. Key Statistics for Chronic Lymphocytic Leukemia. https://www.cancer.org/cancer/chronic-lymphocytic-leukemia/about/key-statistics.html. Accessed 07/5/2020.
- Burger JA, Tedeschi A, Barr PM, et al. Ibrutinib as Initial Therapy for Patients with Chronic Lymphocytic Leukemia. N Engl J Med. 2015;373(25):2425-37. doi: 10.1056/NEJMoa1509388
- Sengar M, Jain H, Rajendra A, Rengaraj K, Thorat J. Frontline Therapy of Chronic Lymphocytic Leukemia: Changing Treatment Paradigm. Curr Hematol Malig Rep. 2020;15(3):168-176. doi: 10.1007/s11899-020-00580-7.