ASH Clinical News June 2017 NEW #2 | Page 21

CLINICAL NEWS

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 ( ≥0.5x10 9 / L ) and platelet ( ≥25x10 9 / 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 2 ).

“ 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 .

REFERENCE

Ding W , LaPlant BR , Call TG , et al . Pembrolizumab in patients with chronic lymphocytic leukemia with Richter ’ s transformation and relapsed CLL . Blood . 2017 April 19 . [ Epub ahead of print ]

TABLE 2 . Clinical Outcomes Associated With Pembrolizumab Response

Richter ’ s Transformation ( n = 9 )

CLL ( n = 16 )

Total ( n = 25 )

ORR 44 % ( 95 % CI 14-79 )

Median PFS ( in months ) 5.4 ( 95 % CI 2.8-12.2 )

Median OS ( in months ) 10.7 ( 95 % CI 4.4-NR )

0 16 % ( 95 % CI 5-36 )

2.4 ( 95 % CI 1.2-3.3 )

11.2 ( 95 % CI 2.8-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

3.0 ( 95 % CI 2.1-5.4 )

10.7 ( 95 % CI 4.4-NR )

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