An older BCL-2 inhibitor has been pulled off the shelf and tested in combination with venetoclax for patients with relapsed/refractory ALL.

Navitoclax, which is also a BCL-XL and BCL-W inhibitor, was shelved in the past due its primary toxicity of severe thrombocytopenia.

However the advent of the highly selective BCL-2 inhibitor venetoclax provided an opportunity to dust off and reduce the dose of navitoclax and take advantage of the efficacy of the combination. 

Paediatric haematologist and oncologist Associate Professor Norman Lacayo told delegates at ASH 2019 that a small, phase 1, open label, dose escalation study involved 45 heavily pre-treated patients from age 4 years through to older adults.

Half the patients had received blinatumomab, 30% had received a stem cell transplant, 29% had prior inotuzumab and 29% had previous  CAR T-cell therapy.

Associate Professor Lacayo, from Stanford University, said a synergistic effect from the combination was evident in a 49% complete response (CR) rate.

Adverse events related to either drug included febrile neutropenia, hypokalaemia and increased ALT levels, however only 9% of patients discontinued the drugs because of treatment-related adverse effects. 

There was one death from intestinal ischaemia which was considered to be related to the drug combination and seven other patients died from adverse effects not thought to be treatment related. 

One manageable episode of tumour lysis syndrome occurred on day 1 after treatment with venetoclax.

Associate Professor Lacayo told the limbic there was a lot of interest from paediatrics, adolescents and young adults and adults, and in particular how to sequence the combination into clinical protocols. 

Patients at the highest risk and those requiring a bridge to transplant or new therapies like CAR T-cell therapy were the most likely targets.

“These drugs can be made into a suspension to deliver adequate pharmacokinetics so hopefully one day we will have those drugs available and we can try them in even younger kids,” he said. 

He added that dose expansion studies were underway although it appeared the higher doses came with more toxicity but without more efficacy.