Combination of Ibrutinib and As2O3 in the Treatment of CLL
Combination of Ibrutinib and As2O3 in the Treatment of CLL
The purpose of this study is to determine whether the combination of As2O3 and ibrutinib is
 synergistic in chronic lymphocytic leukemia
Chronic lymphocytic leukemia (CLL) is a common adult leukemia characterized by the extensive
 accumulation of monoclonal, relatively mature , positives of cluster of differentiation
 antigen 5 and cluster of differentiation antigen 23 B lymphocytes in lymphoid organs, bone
 marrow, and peripheral blood. CLL cells accumulate because of defective apoptosis, which
 extends survival. CLL is a heterogeneous disease. Chemoimmunotherapy is the standard
 front-line approach for patients younger than 65 years with CLL, with the combination of
 fludarabine, cyclophosphamide, and rituximab used most commonly. Some CLL patients do not
 respond well to routine chemoimmunotherapy. Despite recent advances in the treatment of CLL
 by use of modern chemoimmunotherapy, the disease remains incurable for most patients with the
 exception of those who have the option of an allogeneic transplantation. However, treatments
 with chemoimmunotherapy are associated with significant toxicities and sustained
 immunosuppression, and the rates of myelosuppression and infection are high. Such
 complications are more frequent and more severe in patients older than 65 years because of
 reduced marrow reserve, and presence of comorbidities. Because CLL is a disease of the
 elderly, identifying effective therapies with better toxicity profiles is thus a high
 priority, and targeted therapies may allow attainment of this goal.

 Ibrutinib is an irreversible inhibitor of Bruton tyrosine kinase (BTK) that binds covalently
 to the cysteine residue (C481) in the kinase domain. This inhibition has been shown in vitro
 to induce modest CLL cell apoptosis and to abolish proliferation and B-cell receptor (BCR)
 signaling. Clinical trial results with this agent have been outstanding, including an
 estimated 26-month progression-free survival (PFS) of 75% for patients with relapsed and
 refractory disease. Although PFS with ibrutinib is excellent, the overall response rate for
 this group of relapsed patients is only 71%, lagging behind the clinical benefit seen in 88%
 of patients because of lymphocytosis induced by this agent and all agents targeting the BCR
 pathway.

 Nevertheless, the long-term safety for ibrutinib has not been established. Caution must be
 exercised for the development of resistant clones due to the persistence of the disease,
 because most patients treated with ibrutinib often have prolonged partial remissions.
 Moreover, about 2-5% of CLL patients will develop Richter's syndrome or transformation during
 the disease course and treatment. The rate of serious adverse events in patients who
 continued treatment for 1 year or longer was 43% in the first year of treatment and 32% after
 the first year. Within the first year of treatment, 8% patients discontinued therapy, while
 6% discontinued therapy after the first year. Besides, considering that genetic mutations
 cause resistance to ibrutinib in CLL patients and altered signaling pathways are common
 mechanisms of resistance to single agents. It's expected to combine other agent with
 ibrutinib to obtain higher response in those CLL patients who have not obtained perfect
 effect and to relieve the toxicity from treatment of ibrutinib.

 However, arsenic trioxide (As2O3) has attracted worldwide interest in the field of oncology
 because of its substantial anticancer activity in patients with acute promyelocytic leukemia
 (APL). Interestingly, a number of studies have revealed that As2O3 can induce apoptosis, not
 only in APL, but also in a wide variety of hematologic malignancies, including CLL, either as
 monotherapy or combined therapy. Investigators previous study has also suggested that As2O3
 could induce CLL cells apoptosis, and could be an efficient therapeutic agent for CLL.
Inclusion Criteria:

 -  patients fulfilling clinical and immune-phenotypic criteria for CLL

 Exclusion Criteria:

 -  none