CLL Trial Results Support First-, Second-line Ibrutinib Use

Ibrutinib shows efficacy for patients with treatment-naive and relapsed or refractory chronic lymphocytic leukaemia

medwireNews: Phase II trial results add support for the use of the Tyrosine kinase inhibitor ibrutinib as a first- or second-line treatment for patients with chronic lymphocytic leukaemia (CLL) with TP53 aberrations.

“With the advent of active targeted agents such as ibrutinib, chemoimmunotherapy for patients with CLL with TP53 aberrations should be avoided”, recommend Adrian Wiestner, from the National Heart, Lung, and Blood Institute in Bethesda, Maryland, USA, and co-authors in The Lancet Oncology.

“The role of allogeneic stem-cell transplantation in such patients is being re-assessed.”

In all, 47 CLL patients with deletion 17p13.1 and four patients with a TP53 mutation alone were given ibrutinib 420 mg/day in 28-day cycles. The treatment group included 35 patients with treatment-naive CLL and 16 patients with relapsed or refractory disease.

Radiology assessment results at 24 weeks were available for 33 patients with previously untreated CLL, 32 (97%) of whom had an objective response. Over half (55%) of these patients had a partial response, and 42% a partial response with lymphocytosis, while one patient had progressive disease.

Radiological assessments at 24 weeks were also available for 15 patients with refractory or relapsed CLL, 80% of whom had an objective response, 40% a partial response and 40% a partial response with lymphocytosis. Three (20%) patients had stable disease.

The researchers report that “rapid disease control” occurred in all tissue compartments, with an average tumour burden decrease of at least 50% achieved within 8 weeks in the bone marrow, lymph node and spleen of 44%, 70% and 79%, respectively, of the 38 patients with a complete set of results.

Overall survival after 24 months was estimated to be 84% for previously untreated patients and 74% for those with relapsed or refractory CLL. Progression occurred in 9% and 20% of these patient groups, respectively.

Disease progression on treatment was reported for just five (10%) patients after a median of 7.5 months, manifesting as Richter’s syndrome in three and prolymphocytic Transformation in two. The researchers believe this rate compares well with a reported 12-month Richter’s syndrome rate of 23% for patients with deletion 17p13.1 treated with first-line chemotherapy.

Analysis of data from 43 patients showed that the proportion of CLL cells with 17p13.1 deletion fell in 47% after 24 weeks, increased in 47% and was unchanged in 6%. None of those with an increased proportion experienced progression after 24 weeks, 90% had a clinical response and 10% had stable disease.

“Subclones with deletion 17p13.1 were equally sensitive to ibrutinib as were those not carrying the deletion, which is consistent with a p53-independent mechanism of action of the drug”, the researchers comment.

Adrian Wiestner and team suggest that CLL response to ibrutinib might be improved in quality and duration if used in combination with other treatments.

“Longer follow-up will be needed to assess the effect of this targeted agent on long-term survival, which will clarify whether or not ibrutinib could eventually replace allogeneic stem-cell transplantation for these high-risk patients”, they conclude.

Reference

Farooqui MZ, Valdez J, Martyr S, et al. Ibrutinib for previously untreated and relapsed or refractory chronic lymphocytic leukaemia with TP53 aberrations: a phase 2, single-arm trial. Lancet Oncol 2014; Published online 30 December. DOI: dx.doi.org/10.1016/S1470-2045(14)71182-9

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