T cells in the bone marrow of patients with acute myeloid leukemia (AML) over-express PD-1 leading to anti-tumor activity,1but checkpoint inhibitors have been shown to overcome this in mouse models.2 Cytarabine is known to suppress the expression of PD-1 allowing cytotoxic T lymphocytes (CTLs) to attack AML cells more efficiently, while idarubicin causes the release of antigens which prime CTLs to further promote anti-tumor activity. The combination of both idarubicin and cytarabine has resulted in remission rates of 80%, but despite this high initial response, only 3050% of patients with AML are disease-free long-term2. Alterations of dosing and treatment schedules of this standard induction method have had a limited effect on this outcome.

Professor Farhad Ravandi, The University of Texas MD Anderson Cancer Center, Houston, TX, US, and colleagues conducted a phase II trial to assess nivolumab in combination with idarubicin and cytarabine as a frontline treatment for patients with newly diagnosed AML. They hypothesised that the addition of a further anti-PD-1 agent may improve remission duration by enhancing the anti-tumor activity of CTLs2. Professor Ravandi previously presented this data at the 59th American Society of Hematology (ASH) Annual Meeting and Exposition in 2017 in Atlanta (our interview with him can be found here).

In this single-arm phase II part of the phase I/II study (NCT02464657), 44 patients aged 1860 years (>60 years if eligible for intensive chemotherapy) with newly diagnosed AML (n=42) or high-risk myelodysplastic syndrome (n=2) who had an Eastern Cooperative Oncology Group Performance (ECOG) status of 02 were eligible for inclusion induction treatment.

Induction treatment included a 1.5g/m2, 24-hour infusion of cytarabine daily on Days 14 (three days only for patients >60 years), alongside 12mg/m2 daily on days 13 of idarubicin. Nivolumab was then given on Day 24 at a dose of 3mg/kg which was repeated every two weeks for a year in responders. Initially, a run-in phase was performed with patients with relapsed AML (n=3) who received 1mg/kg nivolumab with idarubicin and cytarabine and no toxicity was observed.

Responders were given consolidation cycles of attenuated doses of idarubicin and cytarabine (up to five) or allogeneic hematopoietic stem cell transplantation (allo-HSCT). The primary endpoint was event-free survival (EFS), with relapse-free survival (RFS) and overall survival (OS) as secondary outcomes. The trial would have stopped if the median EFS was less than seven months or if there was significant toxicity associated with nivolumab use (>10%) at one year.

Grade 12

n (%)

Grade 3

n (%)

Grade 4

n (%)

Nausea

1 (2)

1 (2)

0

Diarrhea

3 (7)

7 (16)

0

Mucositis or stomatitis

1 (2)

0

0

Muscle weakness

0

1 (2)

0

Syncope

0

1 (2)

0

Elevated transaminases

3 (5)

1 (2)

0

Elevated bilirubin

0

1 (2)

0

Febrile Neutropenia

1 (2)

13 (30)

1 (2)

Rash

1 (2)

2 (5)

0

Pneumonitis

1 (2)

0

0

Colitis

1 (2)

1 (2)

1 (2)

Pancreatitis

1 (2)

1 (2)

0

Cholecystitis

0

1 (2)

0

Small bowel obstruction

0

1 (2)

0

Thrombosis or embolism

1 (2)

0

0

Despite a small sample size, short follow-up and a lack of comparator population, the study demonstrates that the use of nivolumab alongside idarubicin and cytarabine as an intensified induction therapy in patients with AML (including those over 60 years old) is safe and feasible. Patients undergoing subsequent allo-HSCT showed promising responses and no increase in complications such as severe GvHD. Whether this combination produces similar outcomes compared to standard induction therapy with or without allo-HSCT needs to be confirmed in larger, randomized trials.

Link:
Nivolumab as an addition to frontline therapy of AML in younger patients - AML Global Portal

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