Relapsed CLL Hope With Acalabrutinib, Venetoclax Early Trial Findings

Acalabrutinib and venetoclax both show promise in preliminary trials for relapsed chronic lymphocytic leukaemia

medwireNews: Early trial results suggest that patients with relapsed chronic lymphocytic leukaemia (CLL) may benefit from treatment with the second-generation Bruton’s tyrosine kinase (BTK) inhibitor acalabrutinib or the BCL2 inhibitor venetoclax.

The findings of both studies have been published in The New England Journal of Medicine and presented at the 2015 American Society of Hematology Annual Meeting in Orlando, Florida, USA.

The phase I dose-escalation study for the oral selective, irreversible BTK inhibitor used a dose of 100–400 mg/day and identified 100 mg twice daily as the optimal dose in the phase II expansion study, report John Byrd, from Ohio State University in Columbus, USA, and co-authors.

In all, 61 patients, aged a median of 62 years, were treated with acalabrutinib for relapsed CLL after a median of three prior treatments. Most adverse events were grade 1 or 2, mostly commonly headache (43%), diarrhoea (39%) and weight gain (26%).

The overall response rate (ORR), after a median of 14.3 months, was 95%, with 85% of patients achieving a partial response and 10% a partial response with lymphocytosis, while 5% had stable disease. And the ORR was 100% for the 31% of patients who had a chromosome 17p13.1 deletion.

None of the patients experienced Richter’s transformation and there was just one case of CLL progression, the researchers add, concluding that their results “provide strong justification for further clinical investigation of the efficacy and safety of this drug as compared with those of ibrutinib and other CLL therapies”.

Andrew Roberts, from Royal Melbourne Hospital in Victoria, Australia, and co-authors report the phase I dose-escalation results for oral venetoclax at a dose of 150–1200 mg/day in 56 patients with relapsed or refractory CLL or small lymphocytic lymphoma.

They report that clinical tumour lysis syndrome occurred in three of the 56 patients in the dose-escalation group, resulting in one death. But no further episodes were reported in the expansion group of 60 patients after the dose was adjusted to a maximum of 400 mg/day.

Mild diarrhoea (52%), upper respiratory tract infection (48%) and nausea (47%) were common and 41% of patients experienced grade 3 or 4 neutropenia.

The ORR to venetoclax was 79% for all 116 patients and 20% of patients achieved a complete response, including those with complete remission but incomplete count recovery.

And the ORR ranged from 71% for the patients with a chromosome 17p deletion to 94% for the patients with a mutated immunoglobulin heavy-chain variable region. The lowest and highest complete response rates were found in patients with and without bulky nodes greater than 5 cm, at 8% versus 38%.

At 15 months, progression-free survival was estimated to be 69% for the patients treated with venetoclax 400 mg/day, the researchers say. Sixteen percent of patients experienced Richter’s transformation and this was more common in patients with chromosome 17p deletion.

“[V]enetoclax was shown to have substantialantitumor activity in patients with relapsed CLL, including those with poor prognostic features”, say Andrew Roberts et al, observing that responses appeared “more durable” after a complete response than a partial response.

“Gradual dose escalation appeared to minimize the risk of the tumor lysis syndrome, the major toxicity associated with venetoclax”, they add.


Byrd JC, Harrington B, O’Brien S,et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med 2015; Advance online publication 7 December. DOI: 10.1056/NEJMoa1509981

Roberts AW, Davids MS, Pagel JM, et al. Targeting BCL2 with venetoclax in relapsed chronic lymphocytic leukemia. N Engl J Med 2015; Advance online publication 6 December. DOI:10.1056/NEJMoa1513257

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