Venetoclax, inotuzumab ozogamicin promising in older leukemia patients
medwireNews: Two trials reported in The Lancet Oncology point to novel, first-line treatment options for older patients with acute myeloid leukemia (AML) and those with acute lymphoblastic leukemia (ALL).
One study investigated the addition of the BCL-2 inhibitor venetoclax to hypomethylating agents in AML patients aged 65 years and older, while the other evaluated the combination of inotuzumab ozogamicin – an anti-CD22 antibody bound to the cytotoxic agent calicheamicin – and low-intensity chemotherapy in ALL patients aged at least 60 years.
Because the global population is aging, with an accompanying expected increase in the incidence of acute leukemia, there is an urgent need to improve outcomes in the older population.
In the first trial, Daniel Pollyea (University of Colorado School of Medicine, Aurora, USA) and co-workers enrolled 57 treatment-naïve AML patients who were ineligible for standard induction therapy into one of three groups for the dose-escalation phase of the study. Patients in all groups received venetoclax initiated on the second day of each 28-day cycle at doses of 20–100 mg, with daily administration until the target dose for the cohort was reached, at 400–1200 mg. In addition, groups A and C received decitabine 20 mg/m2 on days 1–5, group B was given azacitidine 75 mg/m2 on days 1–7, and group C participants also received the CYP3A inhibitor posaconazole, an anti-fungal agent.
During a median follow-up of 12.4 months, the most frequent grade 3–4 treatment-emergent side effects were thrombocytopenia, febrile neutropenia, and neutropenia, occurring in 47%, 42%, and 40% of the overall trial population. Febrile neutropenia was the most common serious adverse event in groups A (30% of 23 patients) and B (32% of 22), while it was lung infection in group C (33% of 12).
Four study participants died within 30 days of initiating venetoclax, with one case each of sepsis, bacteremia, lung infection, and respiratory failure.
There was no incidence of laboratory or clinical tumor lysis syndrome, no dose-limiting toxicities, and the maximum tolerated dose was not reached in this phase Ib trial. However, due to an increased incidence of gastrointestinal toxicities with the 1200 mg dose of venetoclax, the recommended phase II dose is 400 mg/day or 800 mg on an interrupted dosing schedule.
Sixty-one percent of all participants achieved either complete remission or complete remission with incomplete marrow recovery, with respective rates of 61%, 59%, and 67%, in groups A, B, and C. And the responses were “rapid and durable,” reached at a median of 1.0, 1.2, and 0.9 months, and maintained for a median of 8.4, 12.3, and 4.3 months, say Pollyea et al.
They conclude: “Venetoclax plus hypomethylating agent therapy seems to be a novel, well-tolerated regimen with promising activity in this underserved patient population.”
The second study – a single-center phase II trial – included 52 patients with Philadelphia chromosome-negative ALL, the majority (92%) of whom had not received prior treatment. They received low-intensity induction chemotherapy with mini-hyper-CVD, comprising cyclophosphamide, dexamethasone, vincristine, methotrexate, and cytarabine, with administration of inotuzumab ozogamicin on the third day of the first four cycles, at 1.3–1.8 mg/m2 in cycle 1 and 1.0–1.3 mg/m2 in subsequent cycles. Patients also received maintenance treatment with dose-reduced POMP (purinethol, oncovin, methotrexate, and prednisone) for 3 years.
The primary endpoint of progression-free survival (PFS) at 2 years was achieved by 59% of patients, with a median PFS duration of 35 months. The overall survival rate at 2 years was 66% and the median was unreached after a median follow-up of 29 months.
Ninety-eight percent of participants achieved an overall response, defined as a complete response or a complete response without platelet or complete hematologic recovery.
Prolonged thrombocytopenia was the most common adverse event of grade 3 or worse, at a rate of 81%, followed by infections during consolidation (69%) and induction chemotherapy (52%), hyperglycemia (54%), and hypokalemia (31%).
Hepatic events and veno-occlusive disease are a known side effect of inotuzumab ozogamicin, the study authors explain, adding that 33% of participants had a grade 3–5 liver toxicity, while four patients experienced veno-occlusive disease.
There were no early deaths, that is, during the initial 4 weeks of the trial, but six deaths over the course of the study were judged to be treatment-related, five due to sepsis and one due to veno-occlusive disease.
Lead author Hagop Kantarjian (The University of Texas MD Anderson Cancer Center, Houston, USA) and team conclude: “The regimen is highly effective and prospective confirmation of these findings in a randomized phase 3 setting comparing this regimen with standard intensive induction regimens for this older population is warranted.”
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