Patients with chronic lymphocytic leukemia (CLL) who progress early during ibrutinib treatment often develop Richter’s transformation (RT), which is associated with an average survival of approximately 4 months. Prompted by recent data from a mouse model in which blocking the programmed death 1 (PD-1) pathway prevented CLL disease progression, researchers from the Mayo Clinic in Rochester, Minnesota assessed the safety and clinical activity of pembrolizumab monotherapy in this group of patients.
Their findings, published in Blood, suggest that pembrolizumab has selective efficacy in patients with CLL who have developed RT. “These results could change the landscape of therapy for RT patients if further validated,” Wei Ding, MD, PhD, and co-authors wrote.
This phase II study enrolled 25 patients (16 with CLL [64%] and 9 with RT [36%]) between February 2015 and June 30, 2016 (the data cutoff).
Patients were included if they had progressive symptoms requiring therapy (based on the International Workshop on CLL 2008 criteria), at least one measurable lesion (>1.5 cm), and minimal neutrophil (≥0.5×109/L) and platelet (≥25×109/L) levels. Patients were excluded if they had active autoimmune disease, a concomitant active secondary cancer, a history of cancer involving the central nervous system, or had received allogeneic hematopoietic cell transplantation.
The median patient age was 69 years (range = 46-81 years), most were male (n=17; 68%), and all were white. Patients had received a median of four prior therapies (range = 1-10 therapies), with most (n=15; 60%) having received ibrutinib.
Patients received pembrolizumab 200 mg administered intravenously every 3 weeks for up to 2 years until disease progression, excessive toxicities, or consent withdrawal.
They also received a median of three cycles of pembrolizumab (range = 1-20 cycles) for a median treatment duration of 11 weeks (range = 1-56 weeks). The median treatment duration was longer for those with RT (13 weeks) than for those with CLL (7.5 weeks; ranges not provided).
After a median follow-up of 10.4 months (range = 2.7-16.1 months), pembrolizumab demonstrated clinical activity in CLL patients with RT, but no clear activity was observed for patients with relapsed CLL. “In heavily pretreated RT patients, the majority of whom had received prior anthracycline-containing chemotherapy and/or ibrutinib, pembrolizumab was associated with an overall response rate of 44 percent (n=4/9),” the authors noted, “while no CLL patient had a confirmed response to pembrolizumab.”
All patients with CLL discontinued therapy because of a lack of response, while three patients with RT continued to receive pembrolizumab at data cutoff.
The median overall survival (OS) and progression-free survival were longer for those with RT (TABLE).
“The etiology for the differential responses of CLL versus RT disease to pembrolizumab is unclear and needs to be further investigated,” Dr. Ding and co-authors noted. “One potential explanation may be the tumor-specific antigens in RT versus CLL are different and tumor reactive T cells are only capable of recognizing RT derived antigens to trigger cytotoxicity.” For patients with RT and co-existing CLL, they added, combination therapy with PD-1 blockade and CLL-directed therapy is likely needed to control both diseases.
For the 15 patients who received prior ibrutinib therapy, the median OS was 4.3 months (95% CI 0.6-not reached [NR]) for those with CLL, and NR (95% CI 4.4-NR) for those with RT (p=0.13). “In patients developing RT after receiving prior ibrutinib, four out of six (66%) had a confirmed clinical response, and the median OS has not been reached,” Dr. Ding and researchers reported. “These results compare extremely favorably to patients with ibrutinib-treated CLL with RT, in whom the median survival was 4 months after treatment using standard chemotherapy.”
Treatment-related grade ≥3 AEs were reported in 60 percent of patients (n=15). Serious AEs included grade 3 lung infection (n=3; 12%), grade 3 hepatic toxicity (n=2; 8%), and grade 2 pneumonitis (n=2; 8%). Two early deaths (8%) were reported, and, during the entire study, 11 patients (3 with RT and 8 with CLL) experienced disease progression and 12 patients (4 with RT and 8 with CLL) died.
Dr. Ding and researchers conducted a biomarker assessment in a subgroup of 10 patients (6 with RT and 4 with CLL) who had tissue samples available at baseline. Patients with confirmed responses (either complete or partial response) had increased expression of PD-L1 and an increased trend of expression of PD-1, compared with non-responders (progressive or stable disease; p=0.03 for PD-L1 and p=0.1 for PD-1), suggesting that PD-1 and PD-L1 expression in tumor microenvironment are promising biomarkers to select patients with RT for PD-1 blockade.
The study is limited by its single-center design, small patient population, and limited follow-up.
|TABLE. Clinical Outcomes Associated With Pembrolizumab|
|Complete response||1 (11%)||0||1 (4%)|
|Partial response||2 (22%)||0||2 (8%)|
|Partial metabolic response||1 (11%)||0||1 (4%)|
|Stable disease||4 (44%)||5 (31%)||9 (36%)|
|Progressive disease||1 (11%)||8 (50%)||9 (36%)|
|Not evaluable*||0||3 (19%)||3 (12%)|
(95% CI 14-79)
(95% CI 5-36)
|Median PFS (in months)||5.4
(95% CI 2.8-12.2)
(95% CI 1.2-3.3)
(95% CI 2.1-5.4)
|Median OS (in months)||10.7
(95% CI 4.4-NR)
(95% CI 2.8-NR)
(95% CI 4.4-NR)
|*Three patients were not evaluable because of death and loss to follow-up.
CLL = chronic lymphocytic leukemia; ORR = overall response rate; PFS = progression-free survival; OS = overall survival; NR = not reached