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According to a randomized , placebocontrolled , phase III study published in the Lancet Oncology , adding idelalisib to the combination of bendamustine and rituximab ( BR ) nearly doubled the length of progression-free survival ( PFS ), compared with placebo and BR : 20.8 months versus 11.1 months ( hazard ratio [ HR ] = 0.33 ; 95 % CI 0.25-0.44 ; p < 0.0001 ).

BR is the standard of care for the management of relapsed / refractory chronic lymphocytic leukemia ( CLL ), but relapse remains high in this patient population , particularly among those with high-risk features , including unmutated IGHV , TP53 mutation , or del17p . “ The results of our study are clear that both PFS and overall survival ( OS ) are significantly enhanced when idelalisib is added to BR ,” lead author Andrew D . Zelenetz , MD , PhD , of Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York , told ASH Clinical News .

Dr . Zelenetz and co-authors evaluated the efficacy and safety of idelalisib plus BR in 416 adult patients who were enrolled from 110 sites in 19 countries in North America , Europe , and Asia between June 26 , 2012 , and August 21 , 2014 .

Patients were included if they had :

• a diagnosis of B-cell CLL requiring treatment ( per International Workshop on CLL criteria )

• measurable lymphadenopathy ( ≥1 nodal lesion that measured ≥2.0 cm in the longest diameter and ≥1.0 cm in the longest perpendicular diameter )

• prior therapy , including a purine analogue or bendamustine and an anti-CD20 monoclonal antibody

• documented disease progression of < 36 months since completion of previous therapy

• discontinuation of all therapy at least 3 weeks prior to randomization

Patients were excluded if they had known histologic transformation to an aggressive lymphoma , the presence of intermediate- or high-grade myelodysplastic syndromes , or disease that was refractory to bendamustine , or if they had received previous therapy with inhibitors of AKT , BTK , JAK , mTOR , PI3K , or SYK .

All patients received bendamustine 70 mg / m 2 administered intravenously on days 1 and 2 of six 28-day cycles , plus rituximab 375 mg / m 2 administered on day 1 of cycle 1 and 500 mg / m 2 on day 1 of cycles 2-6 . Patients were randomized 1:1 to receive placebo ( n = 209 ) or idelalisib 150 mg administered orally twice daily ( n = 207 ). Treatment was continued until unacceptable toxicity , death , disease progression , pregnancy , substantial non-compliance with study procedures , study discontinuation , or withdrawal of consent .

At data cutoff ( October 7 , 2015 ), 34 percent of patients ( n = 141 ) remained in the study : 46 percent in the idelalisib cohort ( n = 95 ) and 22 percent in the placebo cohort ( n = 46 ). At a median of 14 months of followup ( range = 7-18 months ), 20 percent of idelalisib-treated patients ( n = 42 ) and 51 percent of placebo-treated patients ( n = 107 ) experienced progressive disease .

The PFS benefit with idelalisib treatment was consistent across most risk subgroups , the authors noted . For patients with neither del17p nor TP53 mutation , median PFS was longer in the idelalisib group than in the placebo group ( 24.5 months [ 95 % CI 19.5-30.3 ] vs . 11.2 months [ 95 % CI 11.1- 13.6 ]; HR = 0.27 ; p < 0.0001 ). The same was true for patients with either del17p or TP53 mutation ( 11.3 months [ 95 % CI 8.8-16.6 ] vs . 8.3 months [ 95 % CI 5.9-8.5 ]; HR = 0.47 ; p < 0.0001 ).

Median OS was also longer in the idelalisib group ( not reached [ NR ] vs . 31.6 months [ range = 21.3 to NR ]; HR = 0.62 ; p = 0.031 ), and there was a trend toward improvement in OS across risk subgroups , but the association was not significant .

The proportion of patients achieving an overall response was significantly higher in the idelalisib group ( p < 0.0001 ; see TABLE ). A greater proportion of patients with del17p mutations had progressive disease as best overall response in the placebo cohort than in the idelalisib group ( HR = 0.62 ; 95 % CI 0.37-1.04 ).

The most common grade ≥3 adverse events ( AEs ) were neutropenia ( 60 %; n = 124 ) and febrile neutropenia ( n = 48 ; 33 %) in the idelalisib group and neutropenia ( n = 99 ; 47 %) and thrombocytopenia ( n = 27 ; 13 %) in the placebo group .

A total of 97 patients ( 54 in the idelalisib group and 43 in the placebo group ) discontinued treatment . At data cutoff , more patients continued to receive idelalisib ( n = 90 ; 43 %) than placebo ( n = 45 ; 22 %). However ,

AEs leading to treatment discontinuation occurred more frequently in the idelalisib group ( n = 120 ; 58 %) than in the placebo group ( n = 50 ; 24 %). The most common of these AEs were pneumonia ( 4 % in the idelalisib group vs . 2 % in the placebo group ), diarrhea ( 2 % vs . 0 %), and pyrexia ( 2 % vs . < 1 %).

Patients receiving idelalisib had a greater frequency of infections ( 69 %; n = 143 ) than the placebo cohort ( 59 %; n = 124 ; p values not reported ), most of which were bacterial . These infections led to six deaths in the idelalisib cohort and three in the placebo cohort . “ The increased infectious risk requires careful monitoring of the patients ,” Dr . Zelenetz told ASH Clinical News .

Forty-three patients in the idelalisib group ( 21 %) and 59 patients in the placebo group ( 28 %) died during study followup . Treatment-emergent AEs leading to death occurred in 11 percent of the idelalisib cohort ( n = 23 ) and 7 percent of the placebo cohort ( n = 15 ).

Patients who received BR plus idelalisib had a median duration of exposure of 14.8 months ( range = 5.9-18.9 ) while patients who received BR plus placebo had a median duration of exposure of 11.1 months ( range = 5.8-15.3 ). “ The higher number of deaths in the idelalisib group was possibly a result of a longer median exposure to study treatment ,” the authors noted .

“ The major limitation of this study is that it did not include a third arm in which bendamustine was eliminated ,” Dr . Zelenetz said . “ Thus , it does not address the question of whether there was additional benefit of having both bendamustine and idelalisib .” The study ’ s results were also limited by the short duration of follow-up . The study was designed and sponsored by Gilead Sciences , the manufacturer of idelalisib .

REFERENCE

Zelenetz AD , Barrientos JC , Brown JR , et al . Idelalisib or placebo in combination with bendamustine and rituximab in patients with relapsed or refractory chronic lymphocytic leukaemia : interim results from a phase 3 , randomised , double-blind , placebo-controlled trial . Lancet Oncol . 2017 ; 18:297-311 .

Patients with venous thromboembolism ( VTE ) require anticoagulation , but concerns about bleeding have complicated decisions about using higher- or lowerintensity anticoagulation or aspirin

TABLE . Treatment Responses for Idelalisib Versus Placebo

Idelalisib + BR ( n = 207 )

Overall response 70 % ( n = 145 ) ( 95 % CI 63-76 )

Placebo + BR ( n = 209 )

45 % ( n = 94 ) ( 95 % CI 38-52 )

≥50 % reduction in lymph nodes

Duration of response

Organomegaly response

97 % ( n = 186 / 192 ) ( 95 % CI 93-99 )

22.8 months ( 95 % CI 19.1-27.2 )

Spleen 85 % ( n = 125 / 148 ) ( 95 % CI 78-90 )

Liver 58 % ( n = 57 / 99 ) ( 95 % CI 47-68 )

Hematologic response

Hemoglobin 88 % ( n = 58 / 66 ) ( 95 % CI 78-95 )

Neutrophils 86 % ( n = 24 / 28 ) ( 95 % CI 67-96 )

Platelets 89 % ( n = 71 / 80 ) ( 95 % CI 80-95 )

61 % ( n = 120 / 197 ) ( 95 % CI 54-68 )

11.2 months ( 95 % CI 8.5-13.7 )

57 % ( n = 80 / 141 ) ( 95 % CI 48-65 )

43 % ( n = 47 / 109 ) ( 95 % CI 34-53 )

70 % ( n = 50 / 71 ) ( 95 % CI 58-81 )

81 % ( n = 26 / 32 ) ( 95 % CI 64-93 )

78 % ( n = 49 / 63 ) ( 95 % CI 66-87 )

BR = brentuximab plus rituximab ; CR = complete response ; CRi = complete response with incomplete marrow recovery ; PR = partial response

for subsequent long-term preventive treatment . The randomized , double-blind , phase III EINSTEIN CHOICE ( Reduceddosed Rivaroxaban in the Long-term Prevention of Recurrent Symptomatic

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