PRIMARY OBJECTIVE:
I. To determine whether progression free survival (PFS) is superior after therapy with
bendamustine hydrochloride (bendamustine) in combination with rituximab, ibrutinib alone, or
ibrutinib in combination with rituximab in patients age 65 or older with previously untreated
chronic lymphocytic leukemia (CLL).
SECONDARY OBJECTIVES:
I. To determine 2-year PFS in each of the three treatment arms. II. To determine which
treatment arm produces superior overall survival (OS). III. To determine the complete
response (CR) rate, complete and nodular partial response (CR/nPR) rate, and overall response
(PR+nPR+CR) rate (ORR) among the three treatment arms and compare these arms.
IV. To determine the impact of minimal residual disease (MRD)-negative disease at time of CR
documentation and at 2 years on PFS and OS in each of the treatment arms.
V. To determine duration of response after each of the three treatments and compare these
treatment arms.
VI. To determine toxicity and tolerability of the three treatment regimens. VII. To determine
response and PFS of patients initially on the bendamustine in combination with rituximab arm
who cross over to ibrutinib.
OTHER PRE-SPECIFIED OBJECTIVES:
I. To determine whether baseline cytogenetic markers, Zap-70 methylation, IgVH mutational
status, or select deoxyribonucleic acid (DNA) mutations predict outcomes or time to response
in these three arms.
II. To determine whether local fluorescence in situ hybridization (FISH) results for
del(11q22.3) and del(17p13.1) are consistent with central analysis.
III. To determine whether baseline micro ribonucleic acid (RNA) and gene expression markers
are correlated with clinical outcomes of interest (e.g. progression-free and alive at 2 years
versus not), as well as to explore changes in microRNA expression from baseline to
post-treatment time points, with a focus on those with persistent lymphocytosis and relapse.
IV. To determine whether eradication of MRD predicts longer duration of response with
standard therapy and ibrutinib-based regimens.
V. To describe the baseline functional status, comorbid medical conditions, and number of
medications of older CLL patients who meet criteria for therapy.
VI. To determine how functional status changes with therapy using baseline to 3-month
evaluation and end-of-study/2-year evaluation; to determine whether this change is different
among the treatment groups.
VII. To determine whether geriatric assessment variables known to be associated with
chemotherapy toxicity in other disease groups can also predict therapy-associated toxicity in
the CLL population.
VIII. To assess whether the FCGR3A polymorphism (rs396991) is correlated with depth of
response (MRD status) to ibrutinib plus rituximab after 6 cycles, with secondary endpoints CR
rate, rapidity of response, and progression-free survival (PFS).
IX. To assess whether C1QA polymorphism (rs172378) is correlated with MRD status, CR rate,
rapidity of response, and PFS.
OUTLINE: Patients are randomized to 1 of 3 treatment arms.
ARM I: Patients receive rituximab intravenously (IV) on day 1 (day 0 course 1) and
bendamustine hydrochloride IV over 30 minutes on days 1-2. Treatment repeats every 28 days
for 6 courses in the absence of disease progression or unacceptable toxicity. Patients
experiencing disease progression may crossover to Arm II.
ARM II: Patients receive ibrutinib orally (PO) daily on days 1-28. Courses repeat every 28
days in the absence of disease progression or unacceptable toxicity.
ARM III: Patients receive ibrutinib as in Arm II. Patients receive rituximab IV on days 1, 8,
15, and 22 of course 2 and on day 1 of courses 3-6. Courses repeat every 28 days in the
absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up every 6 months for up to 10
years.