Extended follow-up and impact of high-risk prognostic factors from the phase 3 RESONATE study in patients with previously treated CLL/SLL

Abstract

In the phase 3 RESONATE study, ibrutinib demonstrated superior progression-free survival (PFS), overall survival (OS) and overall response rate (ORR) compared with ofatumumab in relapsed/refractory CLL patients with high-risk prognostic factors. We report updated results from RESONATE in these traditionally chemotherapy resistant high-risk genomic subgroups at a median follow-up of 19 months. Mutations were detected by Foundation One Heme Panel. Baseline mutations in the ibrutinib arm included TP53 (51%), SF3B1 (31%), NOTCH1 (28%), ATM (19%) and BIRC3 (14%). Median PFS was not reached, with 74% of patients randomized to ibrutinib alive and progression-free at 24 months. The improved efficacy of ibrutinib vs ofatumumab continues in all prognostic subgroups including del17p and del11q. No significant difference within the ibrutinib arm was observed for PFS across most genomic subtypes, although a subset carrying both TP53 mutation and del17p had reduced PFS compared with patients with neither abnormality. Reduced PFS or OS was not evident in patients with only del17p. PFS was significantly better for ibrutinib-treated patients in second-line vs later lines of therapy. The robust clinical activity of ibrutinib continues to show ongoing efficacy and acceptable safety consistent with prior reports, independent of various known high-risk mutations.

A krónikus lymphocytás leukaemia korszerű molekuláris diagnosztikája és kezelése az új célzott terápiák korszakában

“…Ezen eltérések prognosztikailag egyenrangúak, így a nemzetközi irodalomban együtt, TP53-defektus néven szerepelnek, amely a legrosszabb prognózisú, nagy rizikójú betegcsoportot definiáló genetikai eltérés [19][20][21]. A TP53-deficiens betegek kemoimmuno-terápiára nem vagy alig reagálnak, így ennek a betegcsoportnak az azonosítása kiemelt jelentőségű, mivel az újonnan megjelenő célzott terápiáknak (ibrutinib, idelalisib, venetoclax) köszönhetően több, ebben a csoportban is hatékony kezelési lehetőség áll rendelkezésre [22][23][24]. A két laesio előfordulhat külön-külön vagy együtt is, utóbbi esetben az egyik allélon mutáció, a má-sikon deletio jelentkezik.…”

How I treat CLL patients with ibrutinib

“…The infection rate has been reported to decline by more than half after six months of therapy, although what happens after many years is unknown 1,6,40 . Ibrutinib has been reported to allow for partial reconstitution of normal B cells 40 , and IgG levels remain stable for the first 6 months of therapy 5,40 , before declining thereafter 40 .…”

“…Our group recently reported on rare cases of ventricular arrhythmias and sudden death associated with ibrutinib, and concern remains that risk of this serious outcome would be higher with significant cardiac disease 31 . Prior to initiation, even difficult to control hypertension should be managed, as patients very commonly develop worsened hypertension on ibrutinib 1,6 .…”

“…Its use has rapidly become standard of care for relapsed CLL patients, as well as for many frontline high-risk or older patients. In the most recent update of the RESONATE registration trial, with four year follow-up, only 12% of relapsed CLL patients had discontinued for AEs that included atrial fibrillation (AF), bleeding, and infection 1,2,4,5 . Diarrhea, arthralgia and skin toxicity can also be significant, and hypertension emerges over time 6,7 .…”

“…Ibrutinib has demonstrated marked efficacy in CLL in clinical trials [1][2][3] and is approved by the US FDA for the therapy of any CLL patient in any line of therapy. Its use has rapidly become standard of care for relapsed CLL patients, as well as for many frontline high-risk or older patients.…”