Currently Viewing:
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

Conclusions

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.

  1. Scarfò L, Ferreri AJ, Ghia P. Chronic lymphocytic leukaemia. Crit Rev Oncol Hematol. 2016;104:169-182. doi: 10.1016/j.critrevonc.2016.06.003.
  2. Managing cancer as a chronic condition. National Comprehensive Cancer Network website. nccn.org/patients/resources/life_after_cancer/managing.aspx. Accessed October 11, 2018.
  3. Managing cancer as a chronic illness. American Cancer Society website.
    cancer.org/treatment/survivorship-during-and-after-treatment/when-cancer-doesnt-go-away.html. Updated February 12, 2016. Accessed October 11, 2018.
  4. NCCN Clinical Practice Guidelines in Oncology. Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, version 2.2019. National Comprehensive Cancer Network website. nccn.org/professionals/physician_gls/pdf/cll.pdf. Updated October 5, 2018. Accessed October 18, 2018.
  5. Burger JA, O’Brien S. Evolution of CLL treatment – from chemoimmunotherapy to targeted and individualized therapy. Nat Rev Clin Oncol. 2018;15(8):510-527. doi: 10.1038/s41571-018-0037-8.
  6. About chronic lymphocytic leukemia. American Cancer Society website.cancer.org/content/dam/CRC/PDF/Public/8679.00.pdf. Updated May 10, 2018. Accessed July 18, 2018.
  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. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med. 2013;369(1):32-42. doi: 10.1056/NEJMoa1215637.
  9. Furman RR, Sharman JP, Coutre SE, et al. Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med. 2014;370(11):997-1007. doi: 10.1056/NEJMoa1315226.
  10. Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):311-322. doi: 10.1056/NEJMoa1513257.
  11. Flinn IW, Hillmen P, Montillo M, et al. The phase 3 DUO trial: duvelisib versus ofatumumab in relapsed and refractory CLL/SLL [published online October 4, 2018]. Blood. doi: 10.1182/blood-2018-05-850461.
  12. Hillmen P, Robak T, Janssens A, et al; COMPLEMENT 1 Study Investigators. Chlorambucil plus ofatumumab versus chlorambucil alone in previously untreated patients with chronic lymphocytic leukaemia (COMPLEMENT 1): a randomised, multicentre, open-label phase 3 trial. Lancet. 2015;385(9980):1873-1883. doi: 10.1016/S0140-6736(15)60027-7.
  13. Wierda WG, Kipps TJ, Mayer J, et al; Hx-CD20-406 Study Investigators. Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol. 2010;28(10):1749-1755. doi: 10.1200/JCO.2009.25.3187.
  14. Goede V, Fischer K, Busch R, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions. N Engl J Med. 2014;370(12):1101-1110. doi: 10.1056/NEJMoa1313984.
  15. Furman RR, Allan JN, Howes AJ, Mahler M, Wildgust MA. Comparing overall survival (OS) outcomes in patients with newly diagnosed chronic lymphocytic leukemia (CLL) with normal life expectancy. J Clin Oncol. 2016;34(3 suppl):7. doi: 10.1200/jco.2016.34.3_suppl.7.
  16. Goede V, Fischer K, Engelke A, et al. Obinutuzumab as frontline treatment of chronic lymphocytic leukemia: updated results of the CLL11 study. Leukemia. 2015;29(7):1602-1604. doi: 10.1038/leu.2015.14.
  17. Imbruvica [prescribing information]. Sunnyvale, CA: Pharmacyclics LLC; 2018. imbruvica.com/docs/librariesprovider7/default-document-library/prescribing-information.pdf. Accessed November 7, 2018.
  18. 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.
  19. O’Brien S, Furman RR, Coutre SE, et al. Ibrutinib as initial therapy for elderly patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma: an open-label, multicentre, phase 1b/2 trial. Lancet Oncol. 2014;15(1):48-58. doi: 10.1016/S1470-2045(13)70513-8.
  20. O’Brien S, Furman RR, Coutre S, et al. Single-agent ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia: a 5-year experience. Blood. 2018;131(17):1910-1919. doi: 10.1182/blood-2017-10-810044.
  21. Calquence [prescribing information]. Wilmington, DE: AstraZenenca Pharmaceuticals LP; 2017. accessdata.fda.gov/drugsatfda_docs/label/2017/210259s000lbl.pdf. Accessed November 7, 2018.
  22. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323-332. doi: 10.1056/NEJMoa1509981.
  23. Byrd JC, Wierda WG, Schuh A, et al. Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated results from the phase 1/2 ACE-CL-001 study. Blood. 2017;130(suppl 1):498.
  24. Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with ibrutinib intolerance: results from the phase 1/2 ACE-CL-001 clinical study. Blood. 2016;128(22):638.
  25. Acalabrutinib With or Without Obinutuzumab in Treating Participants With Early-Stage Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma. ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT03516617. Updated September 27, 2018. Accessed November 7, 2018.
  26. Acalabrutinib in Combination With Obinutuzumab in Relapsed/Refractory or Untreated CLL/SLL/PLL. CinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02296918. Updated February 7, 2018. Accessed December 3, 2018.
  27. Acalabrutinib in Patients With Relapsed/Refractory and Treatment naïve Deletion 17p CLL/SLL. ClinicalTrials.gov website. clinicaltrials.gov/ct2/show/NCT02337829. Updated December 5, 2016. Accessed December 3, 2018.
  28. Zydelig [prescribing information]. Foster City, CA: Gilead Sciences Inc; 2018. gilead.com/~/media/CF1E73FFB80B42E2A39F9F5758DB3001.ashx. Accessed November 7, 2018.
  29. Copkitra [prescribing information]. Needham, MA: Verastem Inc; 2018. accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf. Accessed November 7, 2018.
  30. Faia K, White K, Proctor J, et al. High throughput in vitro combination sensitivity screen in hematologic malignancies with the phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib. J Clin Oncol. 2015;33(suppl 15):8559. doi: 10.1200/jco.2015.33.15_suppl.8559.
  31. O’Brien S, Patel M, Kahl BS, et al. Duvelisib, an oral dual PI3K-δ,γ inhibitor, shows clinical and pharmacodynamic activity in chronic lymphocytic leukemia and small lymphocytic lymphoma in a phase 1 study. Am J Hematol. 2018;93(11):1318-1326. doi: 10.1002/ajh.25243.
  32. Faia K, White K, Murphy E, et al. The phosphoinositide-3 kinase (PI3K)-δ,γ inhibitor, duvelisib shows preclinical synergy with multiple targeted therapies in hematologic malignancies. PLoS One. 2018;13(8):e0200725. doi: 10.1371/journal .pone.0200725.
  33. Venclexta [prescribing information]. North Chicago, IL: AbbVie Inc; 2018. accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf. Accessed November 7, 2018.
  34. Stilgenbauer S, Eichhorst B, Schetelig J, et al. Venetoclax in relapsed or refractory chronic lymphocytic leukaemia with 17p deletion: a multicentre, open-label, phase 2 study. Lancet Oncol. 2016;17(6):768-778. doi: 10.1016/S1470-2045(16)30019-5.
  35. 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.
  36. Pawluczkowycz AW, Beurskens FJ, Beum PV, et al. Binding of submaximal C1q promotes complement-dependent cytotoxicity (CDC) of B cells opsonized with anti-CD20 mAbs ofatumumab (OFA) or rituximab (RTX): considerably higher levels of CDC are induced by OFA than by RTX. J Immunol. 2009;183(1):749-758. doi: 10.4049/jimmunol.0900632.
  37. Arzerra [prescribing information]. Needham, MA: Novartis Pharmaceuticals Corporation; 2016. pharma.us.novartis.com/sites/www.pharma.us.novartis.com/files/arzerra.pdf. Accessed November 7, 2018.
  38. Gazyva [prescribing information]. South San Francisco, CA: Genentech Inc; 2017. gene.com/download/pdf/gazyva_prescribing.pdf. Accessed November 7, 2018.
  39. Cartron G, de Guibert S, Dilhuydy MS, et al. Obinutuzumab (GA101) in relapsed/refractory chronic lymphocytic leukemia: final data from the phase 1/2 GAUGUIN study. Blood. 2014;124(14):2196-2202. doi: 10.1182/blood-2014-07-586610.
  40. O’Reilly A, Murphy J, Rawe S, Garvey M. Chronic lymphocytic leukemia: a review of front-line treatment options, with a focus on elderly CLL patients. Clin Lymphoma Myeloma Leuk. 2018;18(4):249-256. doi: 10.1016/j.clml.2018.02.003.
  41. Zinzani PL. Complications of cytotoxic chemotherapy in older patients: focus on myelotoxicity in lymphomas. Crit Rev Oncol Hematol. 2003;48(suppl):S27-S31.
  42. Jain N, Thompson P, Ferrajoli A, Nabhan C, Mato AR, O’Brien S. Approaches to chronic lymphocytic leukemia therapy in the era of new agents: the conundrum of many options. Am Soc Clin Oncol Educ Book. 2018;(38):580-591. doi: 10.1200/EDBK_200691.
  43. Wasmer K, Eckardt L, Breithardt G. Predisposing factors for atrial fibrillation in the elderly. J Geriatr Cardiol. 2017;14(3):179-184. doi: 10.11909/j.issn.1671-5411.2017.03.010.
  44. O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol. 2016;17(10):1409-1418. doi: 10.1016/S1470-2045(16)30212-1.
  45. Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol. 2015;16(2):169-176. doi: 10.1016/S1470-2045(14)71182-9.
  46. Brown JR, Hillmen P, O’Brien S, et al. Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL. Leukemia. 2018;32(1):83-91. doi: 10.1038/leu.2017.175.
  47. Seymour JF, Kipps TJ, Eichhorst BF, et al. Venetoclax plus rituximab is superior to bendamustine plus rituximab in patients with relapsed/refractory chronic lymphocytic leukemia - results from preplanned interim analysis of the randomized phase 3 Murano study. Blood. 2017;130(suppl 1):LBA-2.
  48. Sharman JP, Coutre SE, Furman RR, et al. Second interim analysis of a phase 3 study of idelalisib (ZYDELIG) plus rituximab (R) for relapsed chronic lymphocytic leukemia (CLL): efficacy analysis in patient subpopulations with del(17p) and other adverse prognostic factors. Blood. 2014;124(21):330.
  49. Ahn IE, Underbayev C, Albitar A, et al. Clonal evolution leading to ibrutinib resistance in chronic lymphocytic leukemia. Blood. 2017;129(11):1469-1479. doi: 10.1182/blood-2016-06-719294.
  50. Woyach JA, Ruppert AS, Guinn D, et al. BTK C4815-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol. 2017;35(13):1437-1443. doi: 10.1200/JCO.2016.70.2282.
  51. Jones JA, Mato AR, Wierda WG, et al. Venetoclax for chronic lymphocytic leukaemia progressing after ibrutinib: an interim analysis of a multicentre, open-label, phase 2 trial. Lancet Oncol. 2018;19(1):65-75. doi: 10.1016/S1470-2045(17)30909-9.
PDF
 
Copyright AJMC 2006-2019 Clinical Care Targeted Communications Group, LLC. All Rights Reserved.
x
Welcome the the new and improved AJMC.com, the premier managed market network. Tell us about yourself so that we can serve you better.
Sign Up