Chisom Anosike, LECOM School of Pharmacy
It has be suggested that signaling from the B-cell antigen receptor (BCR) regulates multiple cellular processes, including proliferation, differentiation, apoptosis, and cell migration, and is essential for normal B-cell development and survival. The BCR pathway is implicated in the pathogenesis of several B-cell malignancies, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, and B-cell chronic lymphocytic leukemia (CLL).  Research shows that the treatment of CLL has recently changed with the introduction of agents that inhibit intracellular B-cell receptor signaling. 
|Title: Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia|
|Design||Open-label, multicenter, dose-escalation trial; N = 116|
|Objective||To determine the safety profile, pharmacokinetic profile, and maximum tolerated dose, along with developing a potential dose and treatment schedule for a phase two trial|
|Study Groups||Dose- escalation cohort (n = 56); expansion cohort (n = 60)|
|Methods||In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In the expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day.|
|Duration||June 2011 through May 2014|
|Primary Outcome Measure||To measure tumor lysis syndrome and immunoglobulin heavy-chain variable (IGHV)|
|Baseline characteristic||Characteristic||Dose-escalation cohort (n= 56)||Expansion cohort (n = 60)||All patients (n = 116)|
median (range) — year
|67 (36–86)||66 (42–84)||66 (36–86)|
|Sex — no. (%):|
|Male||41 (73)||48 (80)||89 (77)|
|Female||15 (27)||12 (20)||27 (23)|
|Diagnosis — no. (%):|
|Chronic lymphocytic leukemia||49 (88)||53 (88)||102 (88)|
|Small lymphocytic lymphoma||7 (12)||7 (12)||14 (12)|
|Rai stage III or IV — no. (%)||28 (50)||39 (65)||67 (58)|
|IGHV mutation status- no./total no. with CLL (%)|
|Unmutated||26/49 (53)||20/53 (38)||46/102 (45)|
|Mutated||6/49 (12)||11/53 (21)||17/102 (17)|
|Data missing||17/49 (35)||22/53 (42)||39/102 (38)|
|Bulky nodes – no. (%)|
|> 5 cm||29 (52)||38 (63)||67 (58)|
|> 10 cm||10 (18)||12 (20)||22 (19)|
|Results||Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in three of fifty-six patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Among the 116 patients who received venetoclax, 92 (79%) had a response.
Response rates ranged from 71% to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with un-mutated IGHV.
|Adverse Events||Common Adverse Events: diarrhea (52%), upper respiratory tract infection (URTI) (48%), nausea (47%), neutropenia (45%), fatigue (40%), cough (30%), pyrexia (26%), anemia (25%), headache (24%), constipation (21%), thrombocytopenia (21%), arthralgia (18%), vomiting (18%), peripheral edema (16%), hyperglycemia (15%)|
|Serious Adverse Events: febrile neutropenia (6%), pneumonia (4%), URTI (3%), immune thrombocytopenia (3%), tumor lysis syndrome (3%), diarrhea (2%), fluid overload (2%), hyperglycemia (2%), prostate cancer (2%), pyrexia (2%)|
|Percentage that Discontinued due to Adverse Events: progressive disease (35%), toxicity (11%), eligibility for allogeneic stem-cell transplantation (6%)|
|Study Author Conclusions||Venetoclax was shown to have substantial antitumor activity in patients with relapsed CLL, including those with poor prognostic features. Responses appeared to be more durable among those who had a complete response than among those with a partial response. Gradual dose escalation appeared to minimize the risk of the tumor lysis syndrome, the major toxicity associated with venetoclax.|
The survival of patients with relapsed CLL has improved since the development of targeted therapies that inhibit signaling from the B-cell receptor. This study was limited to adult patients with CLL relapse or refractory disease only.
- Advani RH, Buggy JJ, Sharman JP, et al. Bruton tyrosine kinase inhibitor ibrutinib (PCI-32765) has significant activity in patients with relapsed/refractory B-cell malignancies. J Clin Oncol. 2013;31(1):88-94.
- Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374(4):311-22.