Venetoclax for chronic lymphocytic leukaemia patients who progress after more than one B-cell receptor pathway inhibitor.

B‐cell receptor signalling pathway inhibitors (BCRi) have changed the treatment paradigm for chronic lymphocytic leukaemia (CLL), with durable responses achieved with ibrutinib monotherapy (Bruton tyrosine kinase inhibitor [BTKi]) (https://www.accessdata.fda.gov/drugsatfda_docs/label/2015/205552s002lbl.pdf, Burger et al, 2015) and idelalisib (phosphatidylinositol‐3‐kinase inhibitor [PI3Ki]) with rituximab or ofatumumab (https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf, Byrd et al, 2014; Furman et al, 2014). For patients with progressive disease (PD) who have exhausted all available BCRi, treatments have only recently been characterized in prospective studies (Coutre et al, 2018; Jones et al, 2018).

The oral BCL2 inhibitor venetoclax has shown promising efficacy across clinical studies in relapsed/refractory (R/R) CLL and, based on the critical need for therapies following BCRi discontinuation, we report on a post‐hoc subgroup analysis of high‐risk patients who previously received BTKi and PI3Ki (>1 prior BCRi) from a phase 2 study of venetoclax in patients with CLL R/R to ibrutinib and/or idelalisib (Coutre et al, 2018; Jones et al, 2018).

This phase 2, open‐label trial (NCT02141282) enrolled patients with R/R CLL to ibrutinib and/or idelalisib, although prior investigational BTKi or PI3Ki were also allowed (Coutre et al, 2018; Jones et al, 2018). Patients in this post‐hoc analysis received >1 prior BCRi, including 16 who received BTKi then PI3Ki, nine who received PI3Ki then BTKi, two who received two BTKi, and one who received PI3Ki, then BTKi, then another PI3Ki (Table 1). Efficacy is also reported for 99 patients who only received one prior BCRi. The institutional review board of each study site approved the study protocol and amendments. Study activities were conducted in accordance with ethical principles of the Declaration of Helsinki and International Conference on Harmonization Guideline for Good Clinical Practice. All patients provided written informed consent.

Table 1

Patient demographics and baseline characteristics

	Patients who received >1 prior BCRi n = 28
Age, years: median (range)	65 (53–80)
ECOG performance status, n (%)
0	6 (21)
1	16 (57)
2	6 (21)
Number of prior therapies, median (range)	6·5 (2–15)
Prior BCRi therapies, n (%)
Ibrutinib*	27 (96)
Idelalisib†	25 (89)
Ibrutinib and idelalisib	24 (86)
Investigational agents	11 (39)
Acalabrutinib (ACP‐196)‡ (BTKi)	6 (21)
AVL292 (BTKi)	2 (7)
INCB040093 (PI3Ki)	2 (7)
Duvelisib (PI3Ki)	1 (4)
Laboratory values,§ median (range)
Beta‐2 microglobulin, mg/l	2·9 (2–5·7)
Creatinine clearance, ml/min	72 (44–140)
Lymphocyte count, ×109/l	13·5 (·5–407)
25 × 109/l or more, n (%)	11 (39)
Haemoglobin, g/l	119 (82–152)
Platelet count, ×109/l	123 (12–452)
Neutrophil count, ×109/l	3·9 (1·1–8·4)
Bulky nodal disease, n (%)
5 cm or more	15 (54)
10 cm or more	5 (18)
Tumour lysis syndrome risk category,¶ n (%)
High	10 (36)
Medium	11 (39)
Low	7 (25)
Prognostic factors,** n/N (%)
Unmutated IGHV	16/23 (70)
17p deletion	10/26 (36)
11q deletion	15/27 (54)
13q deletion	13/28 (46)
12q trisomy	4/25 (14)
TP53 mutation	6/27 (22)
CD38 positive	14/27 (52)
ZAP70 positive	4/23 (17)
17p deletion and/or TP53 mutation	12/28 (43)

BCRi, B‐cell receptor signalling pathway inhibitor; ECOG, Eastern Cooperative Oncology Group (performance status ranges from 0 to 5, where higher numbers indicate greater disability).

Patients had received prior ibrutinib for a median of 17 months (range: 2–53). Best response on ibrutinib for 22 patients with available data: 1 complete remission, 11 partial remission and 10 did not respond to treatment. Of 16 patients who received ibrutinib as their most recent BCRi, one discontinued due to adverse events (AEs) and progressed off therapy and 15 discontinued with progressive disease (PD).

Patients had received prior idelalisib for a median of 4 months (range: 1–33). Of 20 patients with available data, eight had a best response of partial remission (PR) and 12 did not respond to idelalisib. Of 12 patients who received idelalisib as their most recent BCRi, five discontinued due to AEs and progressed off therapy, six with PD, and one had refractory disease.

Six patients had received the investigational agent acalabrutinib (ACP‐196) for a median of 9.4 months (range: 1–23). Two patients had a best response of PR and 4 did not respond to therapy. Patients discontinued acalabrutinib due to PD (n = 4), AEs (n = 1), or stopped the clinical trial due to Bruton tyrosine kinase (BTK) resistance (n = 1).

Values were assessed after screening but before the first venetoclax dose.

Low – all lymph nodes ≤5 cm with an absolute lymphocyte count (ALC) <25 × 109/l); Medium – any lymph node ≥5 cm to <10 cm or an ALC ≥25 × 109/l; High – any lymph node ≥10 cm or lymph node ≥5 cm and ALC ≥25 × 109/l.

Site‐reported data. Data are presented for all patients with available data.

Patients received venetoclax with weekly ramp‐up to 400 mg/day dose to mitigate the risk of tumour lysis syndrome (TLS) (https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/208573s000lbl.pdf).

Responses were assessed by investigators based on 2008 International Workshop on Chronic Lymphocytic Leukaemia criteria (Hallek et al, 2008) and confirmed with an assessment ≥2 months later. Confirmatory bone marrow aspiration and biopsy were performed at screening and ≤2 months after meeting other criteria for complete remission (CR). Safety was assessed up to 30 days post‐treatment. Minimal residual disease (MRD) was evaluated by flow cytometry in central laboratory. Data cut‐off for this analysis was 30 June 2017. Analyses were 2‐sided with P ≤ 0·05 being considered significant.

Of 127 patients enrolled (Coutre et al, 2018; Jones et al, 2018), 28 received >1 prior BCRi (Table 1), with a median follow‐up on venetoclax of 11·8 months (range: 0·1–30·6) for 28 patients who received >1 prior BCRi; this was 13·9 months (0·2–30·5) for 99 patients who received 1 prior BCRi. Investigator‐assessed objective response rate (ORR) for patients who received >1 vs. 1 prior BCRi was 43% (12/28: 1 CR, 11 partial remission [PR]) vs. 75% (74/99: 10 CR/CRi, 64 PR; Fig 1A). Median time to first response was 2·5 months, regardless of number of prior BCRi received. There was no difference in number/types of prior therapies received or disease burden for responders versus non‐responders. Median progression‐free survival (PFS) for patients who received >1 prior BCRi was 16·4 months (95% confidence interval [CI]: 8, ‐) and was not reached for patients who had received 1 prior BCRi; 12‐month Kaplan–Meier estimates for these subgroups were 58% (95% CI: 37%, 75%) and 82% (95% CI: 72%, 88%), respectively (Fig 1B). Median overall survival was not reached for all patients, and 12‐month estimates for patients who received >1 vs. 1 prior BCRi were 89% (95% CI: 70%, 96%) and 93% (95% CI: 86%, 97%), respectively (Fig 1C). Median duration of response for patients who received >1 prior BCRi was 16·6 months (95% CI: 14·5, ‐) and was not reached for patients who received 1 prior BCRi; 12‐month estimates for these patient subgroups were 92% (95% CI: 54%, 99%) and 88% (95% CI: 77%, 94%), respectively (Fig 1D).

Figure 1

Response and outcomes on venetoclax. Shown are the (A) investigator‐assessed response on venetoclax, and Kaplan–Meier curves for (B) PFS, (C) OS and (D) duration of response for patients who received >1 vs. 1 prior BCRi. The number of patients at risk for the event at each time point are shown below the curve in panels (B–D). Tick marks represent patients censored for each outcome measure. *6 patients discontinued venetoclax prior to disease assessment. BCRi, B‐cell receptor signalling pathway inhibitor; CR/CRi, complete remission/with incomplete bone marrow recovery; NA, disease assessment not available; ORR, overall response rate; OS, overall survival; PD, progressive disease; PFS, progression‐free survival; PR, partial remission; SD, stable disease.

Based on sequence of treatment, ORR on venetoclax was 50% (8/16) for patients who received BTKi then PI3Ki and 30% (3/9) for those who received PI3Ki then BTKi. Two patients received two prior BTKi, one achieved PR and one had stable disease on venetoclax. One patient received a PI3Ki, then BTKi, then another PI3Ki and progressed on venetoclax. When assessed by discontinuation of last BCRi for adverse events (AEs) versus PD, ORR on venetoclax was 50% (3/6) and 38% (8/21), respectively. Though based on these small numbers, venetoclax was active in patients who discontinued the most recent BCRi for either AEs or PD, with higher response rates for those who stopped therapy due to AEs on prior BCRi.

Six of 14 patients who had received >1 prior BCRi assessed for MRD had undetectable MRD in blood (<10−4 CLL cells), and one of two patients assessed had confirmed MRD‐negativity in bone marrow. All achieved PR and continue on study.

Eighteen of 28 patients who received >1 prior BCRi discontinued venetoclax: 11 due to CLL progression [median time to PD, 8·1 months (0·1–22·5)], two had Richter transformation at 4·4 and 16·3 months, two due to AEs, one per investigator request, one for non‐compliance, and one proceeded to stem cell transplant (SCT) in PR. The median time to next CLL therapy from venetoclax discontinuation was 19·5 days (0–175); including commercially‐available venetoclax (n = 2), ibrutinib (n = 2), idelalisib + rituximab (n = 1), allogeneic SCT (n = 2), and chimeric antigen receptor T cell (CAR‐T) therapy (n = 3).

All 28 patients experienced at least one AE, and safety profile was consistent with prior reports of venetoclax monotherapy in R/R CLL (Coutre et al, 2018; Jones et al, 2018). Common AEs included grade 1/2 gastrointestinal toxicities and grade 3/4 cytopenias. Two patients died, one due to PD and one due to Corynebacterium sepsis. No patients had TLS per Howard criteria (Howard et al, 2011).

This represents the first retrospective analysis of this high‐risk patient population, who were uniformly evaluated as part of a prospective trial with an effective therapy. With higher ORR and longer PFS for patients who only received 1 vs. >1 prior BCRi, these data support the earlier use of venetoclax in the treatment paradigm to optimize response, though venetoclax was still active in this poor‐risk group of patients who had received >1 prior BCRi. Given the relatively small number of patients treated with venetoclax after discontinuing multiple BCRi who had lower responses and remission durations than those treated earlier in their disease, consideration of transitioning such patients after disease control is obtained to either CAR‐T therapy trials or allogeneic SCT could be pursued if patients are eligible.

Conflict‐of‐interest disclosures

W Wierda: Research funding from AbbVie, Genentech. J Byrd: Clinical trial support from Pharmacyclics and Acerta; Unpaid consultant for Genentech, AbbVie, Acerta, Pharmacyclics, Leukemia and Lymphoma Society LLC. M Davids: Advisory board member for Genentech, Pharmacyclics, TG Therapeutics, Gilead, Incyte; Institutional research funding from Genentech, Pharmacyclics, TG Therapeutics, BMS, MEI Pharma, Surface Oncology; Consultant for Genentech, AbbVie, Pharmacyclics, Janssen, Merck, Celgene, Astra‐Zeneca. R Furman: Consultant for AbbVie, Pharmacyclics, Janssen, Gilead, Genentech, Sunesis, Verastem, TG Therapeutics. B Cheson: Paid consultancy for AbbVie, Roche‐Genentech, Pharmacyclics, Acerta; Institution receives research support from Acerta, Pharmacyclics, Roche, AbbVie, TG Therapeutics. P Barr: Consultancy for AbbVie, Gilead, Verastem, Celgene. H Eradat: Consultant for AbbVie, Gilead, Genentech; Advisory board member for AbbVie, Gilead, Genentech; Speaker for AbbVie, Gilead, Genentech. L Heffner: Institutional Research funding from Abbvie and Pharmacyclics. L Zhou, M Verdugo, J Potluri: AbbVie employees and own stock. M Choi: Advisory board/consultancy for AbbVie and PCYC; Institutional research funding from Pharmacyclics and AbbVie; Speakers bureau for Gilead, Genentech, Abbvie, and Pharmacyclics.

Author contributions

WW, JB, MD, RF, BC, PB, HE, LH, MC: collected data, analysed and interpreted data, wrote the manuscript. LZ, MV: analysed and interpreted data, wrote the manuscript. JP: designed study, analysed and interpreted data, wrote the manuscript.