Blood cancers

‘CLL flares’ reported after stopping ibrutinib

Patients with ibrutinib-resistant CLL should remain on the BTK inhibitor until immediately before starting their next therapy, Australian haematologists have advised.

In a Commentary article in Leukemia & Lymphoma, Dr Chloe Tang and Associate Professor Constantine Tam wrote that ‘CLL flares’ – accelerated CLL progression after ceasing ibrutinib – can be difficult to distinguish from the natural course of disease progression after drug withdrawal.

However the evidence was growing that true CLL flares were seen in patients between ibrutinib withdrawal and initiation of salvage treatment.

“In light of this, to ensure a seamless transition between ibrutinib treatment and salvage therapy, it is advisable to continue treatment with ibrutinib until immediately before the initiation of the next therapy,” they wrote.

Dr Tang and Associate Professor Tam, from St Vincent’s Hospital Melbourne, were responding to a US study of 200 patients with CLL who received ibrutinib at the Mayo Clinic between 2013 and 2017.

The study found the 2-year risk of ibrutinib discontinuation was 28%. Most patients stopped due to toxicity (56%), disease progression (17%) or Richter’s transformation (15%).

Most patients (37/52) received a subsequent therapy with a median time to next therapy of 2.7 months (range 0.3-6.5 months).

The study found rapid disease progression in nine patients (25%) within four weeks of discontinuing ibrutinib. Progression was defined as worsening of disease-related symptoms and clinical, laboratory or radiographic changes consistent with progressive disease.

These included increasing lymphocyte counts and worsening adenopathy.

“The development of rapid progression after stopping ibrutinib was not associated with age, sex, FISH, IGHV mutation status, TP53 disruption, duration of ibrutinib therapy, or reason for discontinuation on univariate analyses,” the study said.

“In our series, approximately one in four patients developed rapid progression of disease after discontinuing ibrutinib. While we were unable to identify consistent predictors of this phenomenon occurring in our cohort due to the small number of patients, awareness of the possibility is useful to practicing hematology-oncologists to avoid potential morbidity and mortality.”

The study authors said further research is needed to identify which population of CLL cells – the ibrutinib-resistant clones or the remaining drug-sensitive cells – were driving the accelerated progression.

Other factors such as altered cytokine profiles or immunoregulatory cells may also be implicated.

“One plausible mechanism of this ‘CLL flare’ phenomenon may be that during CLL progression, mutations in BTK and PLCδ conferring resistance to ibrutinib not only alter the responsiveness of CLL cells to ibrutinib therapy by converting to reversible binding (in the case of BTK C481S), they also increase the aggressiveness of the underlying tumour biology by autonomous B cell receptor (BCR) signalling and enhanced downstream cMyc and pErk expression,” the commentary authors postulated.

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