Venetoclax plus low-dose chemotherapy appears highly effective at treating early relapse in patients with acute myeloid leukaemia, an Australian study suggests.

The researchers say their findings, published in the Journal of Clinical Oncology [link here], demonstrate the clinical benefits of Measurable Residual Disease (MRD) molecular technology to monitor patients with acute myeloid leukaemia (AML).

Some 48 patients (median age 67) with AML and either MRD (≥1 log10 rise) or oligoblastic relapse (5%-15% bone marrow blasts) received venetoclax 600 mg once daily (D1-28) plus low-dose cytarabine once daily (D1-10) in 28-day cycles.

The phase II study was conducted at five centres with enrolment from December 2019 until April 2022. Most patients (94%) had intensive chemotherapy previously.

Led by Peter MacCallum Cancer Centre and the Alfred Hospital, the researchers said their findings indicated that response to treatment was rapid.

In the MRD relapse cohort, a log10 reduction in MRD was observed in 69% of patients by cycle two. Just under half (46%) achieved MRD negative remission.

Some 27% of patients had no MRD response and one patient was nonevaluable.

In the oligoblastic relapse cohort, 73% achieved haematologic response (CR/CRh/CRi) by cycle 2, with an additional 9% achieving morphologic leukaemia-free state.

The researchers noted 14% had no response and one patient died early.

With a median follow-up of 25 months and 22 months, respectively, the median overall survival in the MRD and the oligoblastic relapse cohorts were not reached. But the estimated two-year overall survival rates were 67% and 53%, respectively.

Successful transition to haematopoietic cell transplantation was achieved in 44% of patients with the median overall survival not reached in either cohort.

The two-year overall survival rates were 83% and 62%, respectively.

During therapy, 36 episodes of unplanned hospital admissions occurred in 35% and 59% of patients in the MRD and oligoblastic relapse cohorts, respectively.

The median durations of hospitalisation were 6 and 7.5 days per episode.

The majority of all hospital admissions occurred within the first two cycles of therapy, predominantly related to infection (41%), febrile neutropenia (18%), or non-neutropenic fever (9%).

Uncertainty

Dr Ing-Soo Tiong, a haematologist and researcher at Peter Mac, said the median survival after first relapse with the previous approach was only 6-8 months.

Results of the trial showed 50-70% of patients were still alive after two years.

“Prior to this discovery, patients and clinicians face the uncertainty of disease relapse, and the only treatment option then was an even stronger dose of salvage chemotherapy requiring at least a month of stay in hospital associated with a very high risk of infection,” he said.

“In this new study we measured a patient’s MRD as soon as they finished chemotherapy with the aim of the data telling us which patients were most likely to relapse.”

Professor Andrew Wei, co-lead of the AML program at Peter Mac and Royal Melbourne Hospital, said patients could be treated as an outpatient or by hospital in the home with results comparable to intensive chemotherapy.

“This is a paradigm-changing clinical trial that utilises molecular technologies to enable patients to receive their interventional therapy much earlier than normal and with less toxicity,” he said.

“The response to treatment was fast and durable, enabling patients to receive a subsequent stem cell transplant with much lower levels of disease burden and enhanced fitness.

“This is the first ever prospective trial using a pre-emptive MRD targeted approach. It has led to the development of a new national trial called INTERCEPT, coordinated by the Australasian Leukaemia and Lymphoma Group.”

The INTERCEPT trial is currently recruiting patients at multiple sites nationwide.

The study was partly funded by AbbVie.