RESONATE-17 Findings Support Ibrutinib For del17p CLL

Study findings confirm a high rate of efficacy for ibrutinib in patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma characterised by a 17p deletion

medwireNews: RESONATE-17 results published in The Lancet Oncology confirm that the BTK inhibitor ibrutinib is effective for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma with a chromosome 17p deletion (del17p).

The author of an accompanying comment notes that ibrutinib was incorporated into practice for high-risk CLL patients in the absence of strong trial evidence as a “leap of faith” and says the “robust data” from the study provide “reassurance about the durability of the responses”.

“[D]ata from the RESONATE-17 study will be beneficial also in the future since, with a longer follow-up in such a large cohort of high-risk patients, it will help to elucidate whether del17p remains a marker of poor prognosis also with the novel inhibitors”, writes Paolo Ghia, from IRCCS Ospedale San Raffaele in Milan, Italy.

After a median of 11.5 months, the prespecified primary endpoint of an independently assessed overall response to oral ibrutinib 420 mg/day was achieved by 64% of the 137 patients with del17p CLL and seven patients with small lymphocytic lymphoma, all of whom had undergone at least two prior lines of treatment. All responses were partial.

Investigator-assessed overall response at this time was reported for 83% of the patients, including a partial response in 63%, a partial response with lymphocytosis in 17%, a complete response in 1% and a complete response with incomplete bone marrow recovery in 1%.

And the rate of overall response remained at 83% at the extended analysis, performed after a median of 27.6 months, say Susan O’Brien, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

Median duration of response was not reached in the study cohort, with estimated rates of continuous remission at 12 and 24 months for patients with a partial response or better of 88% and 70%, respectively.

Two-year rates of progression-free survival and overall survival were 63% and 75%, respectively, and median overall survival was not reached.

The researchers observe that 79% of 91 patients with any baseline cytopenia experienced a “sustained haematological improvement”, including 88%, 59% and 76% of those with a baseline neutrophil count ≤1500 cells/μL, haemoglobin ≤110 g/L or a platelet count ≤100,000 cells/μl, respectively.

None of the patients experienced clinically relevant alterations in the first 6 months or 2 years of treatment with regard to levels of immunoglobulin (Ig)A, IgG or IgM.

In all, 24% of patients discontinued ibrutinib therapy because of progressive disease and 17% because of adverse events, unacceptable toxicity or death.

The most common grade 3 events were hypertension (13%), pneumonia (11%), neutropenia (9%), thrombocytopenia (8%) and anaemia (8%), with grade 4 events including neutropenia (13%), thrombocytopenia (3%) and atrial fibrillation (2%). Grade 5 pneumonia occurred in 3%.

At the time of extended analysis, 38 patients had died including 18 fatalities from pneumonia (n=4), CLL (n=3), Richter’s syndrome (n=2) and sepsis (n=2). Single fatalities were also attributed to acute myocardial infarction, septic shock, encephalopathy, general deterioration in health, liver dysfunction, myocardial infarction and renal infarction.

“A high proportion of patients had an overall response to ibrutinib and the risk:benefit profile was favourable, providing further evidence for use of ibrutinib in the most difficult subset of patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma”, write Susan O’Brien and team.

They add: “Alongside data from other emerging treatments, ibrutinib might contribute to a reassessment of the role and timing of stem cell transplantation by changing the choice and sequence of treatments used for management of high-risk chronic lymphocytic leukaemia.

“These data mark an era of targeted therapeutics that is changing historical treatment algorithms for patients with del17p chronic lymphocytic leukaemia or small lymphocytic lymphoma, the most difficult subset of patients to treat.”

References

O’Brien S, Jones JA, Coutre SE, et al. Ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia with 17p deletion (RESONATE-17): a phase 2, open-label, multicentre study. Lancet Oncol 2016; Advance online publication 13 September. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30212-1

Ghia P. Ibrutinib holds promise for patients with 17p deletion CLL. Lancet Oncol 2016; Advance online publication 13 September. DOI: http://dx.doi.org/10.1016/S1470-2045(16)30442-9

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