Novel agents may transform the outcomes of lymphocytic leukemias. In acute lymphocytic leukemia (ALL), encouraging data were presented for two monoclonal antibodies, and in chronic lymphocytic leukemia (CLL), a completely novel class of agents produced surprisingly robust results, said Attaya Suvannasankha, MD, of Indiana University School of Medicine, Indianapolis, at the Best of ASCO Boston meeting.
The anti-CD19 bi-specific T-cell engager (BiTE) antibody blinatumomab produced responses (complete remission or complete remission with partial hematologic recovery) in 72% of patients with relapsed/refractory B-precursor ALL in a phase II study of 36 patients.1 All but two responders achieved a molecular response. Median overall survival in this heavily pretreated population was 9.0 months, and the median duration of hematologic complete remission was 8.9 months.
BiTE antibodies are designed to direct the body’s cell-destroying T cells against tumor cells, enabling T cells to recognize and attack tumor cells in much the same manner as naturally occurring T cells. Blinatumomab targets CD19, which is expressed by 100% of leukemia cells.
Fully reversible central nervous system events leading to treatment interruptions were observed in six patients, including three with seizures and three with encephalopathy; all six patients continued treatment at a lower dose. A global phase II trial has been initiated.
Other investigators reported encouraging results with inotuzumab ozogamicin, an anti-CD22 monoclonal antibody conjugated to calecheamicin. In relapsed/refractory ALL, inotuzumab was associated with a 52% overall response rate, including 11% complete responses, “which is very high for single-agent therapy,” Dr. Suvannasankha noted.2 Median progression-free survival is currently 5 months.
A pivotal trial of weekly inotuzumab vs standard of care in relapsed/refractory ALL is planned, and the drug is currently being evaluated in combination with low-intensity chemotherapy in patients < 60 years of age.
“These agents have impressive single-agent activity in relapsed/refractory ALL,” she said, “but the duration of response remains short. It’s possible these drugs could be used as a bridge to allogeneic stem cell transplant. Because of their limited side effects, patients can go on to tolerate transplant quite nicely.”
Novel Oral Agent for CLL
In chronic lymphocytic leukemia (CLL), the Bruton’s tyrosine kinase inhibitor ibrutinib holds promise. The oral agent is the first drug designed to target Bruton’s tyrosine kinase, a protein that is critical for B-cell receptor signaling in B lymphocytes and essential for CLL cell survival and proliferation. Other such agents are in development.
In a phase II study of 31 previously untreated patients, the overall response rate was 75%, including 10% complete and 65% partial responses with daily dosing. The progression-free survival rate at 15 months was 96%, and all subgroups responded equally well. Response to the single agent included complete remissions with no morphologic evidence of CLL.
“[Bruton’s tyrosine kinase] is a promising new target for CLL, and so far with the [Bruton’s tyrosine kinase] inhibitors, a lack of resistance has been seen across all subgroups, including patients with the 17p deletion. This means that conventional prognostic factors may not be as relevant with these drugs,” Dr. Suvannasankha said.
“Continuing daily dosing is well tolerated, allowing for extended treatment,” she added. “With the caveat that the follow-up is short and the long-term toxicity unknown, it is conceivable that for older or sicker patients this could be a nonchemotherapy treatment that gives long-term disease suppression, and for younger patients, we might be able to combine this with chemotherapy for curative potential.” ■
Disclosure: Dr. Suvannasankha reported no potential conflicts of interest.
1. Topp M, Goekbuget N, Zugmaier G, et al: Effect of anti-CD19 BiTE blinatumomab on complete remission rate and overall survival in adult patients with relapsed/refractory B-precursor ALL. 2012 ASCO Annual Meeting. Abstract 6500. Presented June 4, 2012.
2. Jabbour E, O’Brien SM, Thomas DA, et al: Inotuzumab ozogamycin, a CD22 monoclonal antibody conjugated to calcecheamicin, given weekly, for refractory-relapse acute lymphocytic leukemia. 2012 ASCO Annual Meeting. Abstract 6501. Presented June 4, 2012.