Refractory or relapsed chronic lymphocytic leukemia is still a hematologic malignancy with an unfavorable evolution after several lines of chemotherapy, even when associated with immunotherapy.
The additional presence of adverse prognostic factors such as17p deletion, 11 q deletion, unmutated IgVH genes, CD 38 and ZAP 70 expression further limits therapeutic possibilities.
Over the past two years numerous studies have focused on finding new therapeutic options useful in cases of relapsed or refractory chronic lymphocytic leukemia.
Ibrutinib is a new agent that has shown efficacy in treating these cases, the benefits of response and survival rate having been obtained using Ibrutinib as monotherapy, as well as in combination with immunotherapy or chemotherapy.
Ibrutinib irreversibly inhibits Bruton's tyrosine kinase, which is an important enzyme in the B cell receptor activation pathway for both normal and malignant B lymphocytes. Ibrutinib, administrated orally is involved in the inhibition of cytokines of the signaling pathways which mediate chemotaxis, of chemokines, also reduces the population of Ki67+cells and initiates apoptosis (1-3).
During the 10-15 months follow up period, a phase Ib/II trial concluded that treatment with ibrutinib leads to a lasting complete remission and increases survival without disease progression even in cases of Richter transformation or bulky disease (4-7).
Results are even more encouraging regarding previously untreated patients. In a group of 26 patients older than 65 years, disease progression free survival at 15 months was 96% (5,7).
Ibrutinib treatment was generally well tolerated, the major side effects related to administration were nausea, fatigue, diarrhea, rash and bruising. Grade 3-4 adverse reactions such as diarrhea, infections and hematological toxicity (anemia and / or thrombocytopenia), were reported with an average incidence of 10-13%. There was also an initial but transitory increase in absolute lymphocyte count, more pronounced in previously treated patients (4-6,8).
The partial results of the ongoing study indicate that the association of ibrutinib with bendamustine or ofatumumab tends to limit or prevent the appearance of lymphocytosis (8). Also Ibrutinib administration in combination with rituximab or bendamustine resulted in obtaining good quality remissions and a better quality of life (9,10).
Favorable results obtained with ibrutinib as monotherapy especially in previously untreated elderly patients, support the evaluation in phase III trials. Further Phase I studies related to the use of BTK class II (AVL-292) and specific inhibitors of the delta isoform of phosphatidylinositol-3 kinase (GS-1101), may bring hope and new perspectives in the therapy of chronic lymphocytic leukemia (8).
CONFLICT OF INTEREST
none declared.
FINANCIAL SUPPORT
none declared.
References
- 1.Wu M, Akinleye A, Zhu X. Novel agents for chronic lymphocytic leukemia. J Hematol Oncol. 2013;6:36–36. doi: 10.1186/1756-8722-6-36. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Farooqui M, Aue G, Valdez J, et al. Single agent ibrutinib (PCI-32765) achieves equally good and durable responses in chronic lymphocytic leukemia (CLL) patients with and without deletion 17p.. Abstract 673.ASH 55th Annual Meeting; 2013; [Google Scholar]
- 3.Wang YL, Cheng S, Ma J, et al. BTK Inhibition Targets in Vivo CLL Proliferation Through Its Effects On B-Cell Receptor Signaling Activity.. ASH Annual Meeting Abstract; 2012; pp. 2903–2903. [DOI] [PubMed] [Google Scholar]
- 4.Byrd JC, Blum KA, Burger JA, et al. Activity and tolerability of the Bruton's tyrosine kinase (Btk) inhibitor PCI-32765 in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): Interim results of a phase Ib/II study. J Clin Oncol. 2011;29(suppl):abstr6508–abstr6508. [Google Scholar]
- 5.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. The Lancet Oncology. 2014;15:48–58. doi: 10.1016/S1470-2045(13)70513-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Byrd JC, Furman RR, Coutre S, et al. The Bruton's Tyrosine Kinase (BTK) Inhibitor Ibrutinib (PCI-32765) Promotes High Response Rate, Durable Remissions, and Is Tolerable in Treatment Naive (TN) and Relapsed or Refractory (RR) Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL) Patients Including Patients with High-Risk (HR) Disease: New and Updated Results of 116 Patients in a Phase Ib/II Study.. Blood; ASH Annual Meeting Abstracts; 2012; pp. 189–189. [Google Scholar]
- 7.O'Brien S, Kristie JA, Blum A, et al. The Bruton's Tyrosine Kinase (BTK) Inhibitor PCI-32765 Induces Durable Responses in Relapsed or Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Follow-up of a Phase Ib/II Study.. Blood; ASH Annual Meeting Abstracts; 2011; pp. 983–983. [Google Scholar]
- 8.Brown JR. Update on Novel and Standard Therapies for CLL - Medscape Education 2012. http://www.medscape.org/viewarticle/768046 [Google Scholar]
- 9.Brown JR, Barrientos JC, Barr PM, et al. Ibrutinib in combination with bendamustine and rituximab is active and tolerable in patients with relapsed/refractory CLL/SLL: final results of a phase 1b study.. Abstract 525; ASH 55th Annual Meeting; 2013. [Google Scholar]
- 10.Burger JA, Keating MJ, Wierda WG, et al. Ibrutinib in combination with rituximab (iR) is well tolerated and induces a high rate of durable remissions in patients with high-risk chronic lymphocytic leukemia (CLL): new, updated results of a phase II trial in 40 patients.. Abstract 675; ASH 55th Annual Meeting; 2013. [Google Scholar]