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Supplements The Emerging Role of Targeted Therapies for the Treatment of Chronic Lymphocytic Leukemia

Evolving Approaches to the Treatment of Chronic Lymphocytic Leukemia With Targeted Therapies

The current recommendations regarding venetoclax include a ramp-up dosing schedule in which patients begin with 20-mg oral doses once daily for 7 days; doses increase weekly until the recommended daily dose of 400 mg is reached. The most common AEs (≥20%) include neutropenia, diarrhea, nausea, upper respiratory tract infection, anemia, fatigue, thrombocytopenia, musculoskeletal pain, edema, and cough.33

Anti-CD20 Antibodies

Ofatumumab is a fully humanized anti-CD20 antibody that differs from rituximab in its binding site.36 Ofatumumab has been shown to be active as a monotherapy in patients with CLL who were refractory to fludarabine and alemtuzumab, and it is currently approved for the use as monotherapy in this setting.13,37 However, ofatumumab monotherapy has been found to have inferior response rates in patients with R/R CLL when compared with ibrutinib and duvelisib in head-to-head studies.11,18 The COMPLEMENT 1 study included treatment-naïve patients with CLL who were unable to tolerate a fludarabine-based regimen. In the study, treatment with ofatumumab plus chlorambucil resulted in a median PFS of 22.4 months compared with 13.1 months in patients treated with chlorambucil alone (P <.0001).12 Ofatumumab is given as an intravenous infusion with indication-specific dosing schedules. The most common AEs reported in ≥10% of patients for any CLL indication include infusion reactions, neutropenia, leukopenia, febrile neutropenia, upper respiratory tract infection, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infection.37

Another anti-CD20 antibody, obinutuzumab, is a glycoengineered antibody.38 In a phase 1/2 study that included patients with R/R CLL, those treated with obinutuzumab monotherapy had an ORR of 62% in the phase 1 segment and 15% in the phase 2 segment.39 A phase 3 study evaluated chlorambucil plus an anti-CD20 antibody (either rituximab or obinutuzumab) in patients with CLL. Treatment with chlorambucil plus obinutuzumab resulted in prolonged median PFS (26.7 months) when compared with chlorambucil monotherapy (11.1 months) and chlorambucil plus rituximab (16.3 months; P <.001 for both).14 Obinutuzumab is currently approved for use in combination with chlorambucil for patients with treatment-naïve CLL. In this population, the most common AEs include infusion reactions, neutropenia, thrombocytopenia, and diarrhea.38

Practical Considerations

Elderly Patients

The development of new therapies for the treatment of CLL has encouraged an individualized approach to treatment that will be based on patient-specific risk factors.5 Because elderly patients can differ dramatically in physical health and comorbidities, the availability of varying treatment options that can be customized for patient-related and disease-related risk factors is important.40 Decreased level of hematopoietic reserve is an important factor to consider when treating older patients with CLL. It can put them at a high risk of myelotoxicity.41 When looking at safety data from studies specific to elderly patients, neutropenia grade 3 or higher occurred in 33% to 35% of patients who received chlorambucil plus obinutuzumab (CLL11),

26% of patients who received chlorambucil plus ofatumumab (COMPLEMENT 1), and 10% of patients who received ibrutinib (RESONATE II).7,12,14 Although ibrutinib appears to be associated with a low incidence of neutropenia, 2 other ibrutinib-associated AEs should be considered in elderly patients: fatal hemorrhage and atrial fibrillation.17,42 Elderly patients are at high risk for atrial fibrillation, and the use of anticoagulants for thrombosis prevention in atrial fibrillation is complicated further by the risk of hemorrhage associated with ibrutinib.42,43

High-Risk Groups

Several biological markers have been associated with poor clinical outcome in CLL, including del(17p), del(11q), unmutated IGHV genes, and TP53 mutations.1 Many newer agents have shown improved efficacy in difficult-to-manage groups of patients. The majority of these newer agents have demonstrated efficacy in patients with del(17p); however, ibrutinib demonstrates efficacy in the first-line setting and in patients with R/R disease.44,45 Ibrutinib plus venetoclax, as well as rituximab, idelalisib, rituximab, and duvelisib, has shown efficacy in patients with mutated TP53 genes.11,34,44-48 Patients with unmutated IGHV have experienced clinical benefit from idelalisib and rituximab.48

Resistance to Prior Therapy

Consideration should be given to the development of acquired resistance to certain agents. In particular, recent evidence suggests that resistance to ibrutinib is associated with mutations in BTK and in phospholipase Cγ2 genes.49,50 In an interim analysis of a phase 2 study, venetoclax demonstrated an ORR of 65% among patients who were resistant to prior therapy with ibrutinib.51 Further studies regarding the efficacy of agents in the setting of BTK inhibitor resistance are warranted.

Patient Convenience

Many of the new kinase inhibitors indicated for use in CLL are oral therapies that can be self-administered at home. However, some agents (eg, venetoclax and idelalisib) are often recommended for use in combination with anti-CD20 antibodies. They are intravenous infusions that require healthcare facility visits.4 Oral agents that are recommended and approved for use as a monotherapy in CLL include ibrutinib and duvelisib.4,17,29

Consideration should also be given to the complexity of the self-administered oral agents. Venetoclax has a ramp-up schedule to minimize the incidence of tumor lysis syndrome, which can potentially be difficult for patients to execute properly. To facilitate the ramp-up schedule, venetoclax is available as 10-mg, 50-mg, and 100-mg tablets. The recommended final dose is 400 mg daily, requiring 4 tablets per dose, making pill burden another potential concern.33


Recent advances in the treatment landscape for CLL have brought forth many new options. In particular, new agents have provided more effective options with manageable safety profiles for elderly patients or those with significant comorbidities who cannot tolerate conventional chemoimmunotherapy. Patients with certain biological markers have also gained several new options that are effective in high-risk populations. In addition, many new therapies are orally self-administered, providing simpler and potentially more convenient options for patients. Guidance regarding the sequencing of these options would be invaluable, especially when acquired resistance is observed. Further studies regarding effective options in the setting of acquired resistance are needed.

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