Daratumumab improves response among younger patients with acute lymphoblastic leukemia
Click Here to Manage Email Alerts
CHICAGO — The addition of daratumumab to chemotherapy improved outcomes among younger patients with relapsed or refractory T-cell acute lymphoblastic leukemia, study results showed.
Data from the phase 2 DELPHINUS trial presented at ASCO Annual Meeting suggest the addition of daratumumab (Darzalex, Janssen) — a CD38-directed monoclonal antibody — to a standard chemotherapy regimen is safe and increases complete response rates compared with chemotherapy alone as reinduction therapy.
Background
The rationale for employing daratumumab as part of the regimen derives from its use as an FDA-approved therapy for multiple myeloma.
The marker of CD38 is present on T-ALL cells, and the intensity of the marker is similar to that of CD19, for which blinatumomab (Blincyto, Amgen) is approved by the FDA for B-cell ALL, according to Teena Bhatla, MD, director of pediatric hematology/oncology at Children’s Hospital of New Jersey at Newark Beth Israel Medical Center, an RWJBarnabas Health facility.
“The thought was that if the intensity of the marker is similar, then daratumumab should work similarly for T-cell ALL as it does in multiple myeloma,” Bhatla told Healio.
“Historically patients with T-cell ALL who experience disease relapse have a poor prognosis,” she added. “Up until about 5 years ago, their 5-year event-free survival rate was in the range of 6% to 20%.”
Bhatla and colleagues aimed to improve complete remission rates after the first cycle of therapy by adding daratumumab to the chemotherapy backbone. Chemotherapy alone as induction therapy typically has produced minimal residual disease (MRD)-negative complete response rates in the range of 30% to 40% among these patients.
The strategy was to increase the proportion of patients who achieved MRD-negative complete responses before moving onto consolidation therapy with hematopoietic stem cell transplantation.
“The theory is that if these patients are able to make it to transplant, then it would improve their overall prognosis and outcomes,” she said.
Methodology
The multicenter DELPHINUS trial included 29 patients with T-cell ALL and 10 patients (median age, 14.5 years; range, 5-22) with lymphoblastic lymphoma who experienced disease relapse or were refractory to at least one previous treatment regimen.
The investigators divided those with T-cell ALL into pediatric (median age, 10 years; range, 1-17; n = 24) and young adult (median age, 23 years; range, 18-25; n = 5) groups.
Study participants received two cycles of therapy. The first cycle included daratumumab in combination with vincristine, prednisone, doxorubicin and peg-asparaginase. The second cycle included daratumumab plus cyclophosphamide, cytarabine, 6-mercaptopurine and methotrexate.
Complete response rates among patients with T-cell ALL after the first treatment cycle served as the study’s primary endpoint.
Key findings
Ten patients (41.7%; 90% CI, 24.6-60.3) in the pediatric ALL group achieved complete response to therapy after the first treatment cycle.
The investigators reported an 83.3% (90% CI, 65.8-94.1) objective response rate in the pediatric ALL group. Thirteen patients (54.2%) achieved complete response and seven patients (29.2%) achieved complete response with incomplete hematologic recovery.
Sixty percent (90% CI, 18.9-92.4) of patients in the young adult ALL group had an objective response after one cycle of therapy, whereas 50% (90% CI, 22.2-77.8) of patients with lymphoblastic leukemia had an objective response to the treatment regimen.
All patients in the pediatric T-cell ALL group experienced grade 3 or grade 4 treatment-related adverse events; however, none of these patients discontinued treatment due to the use of daratumumab. One patient in the pediatric T-cell ALL group died of brain edema and hepatic failure related to the regimen but not attributed to the use of daratumumab, the investigators noted.
Clinical implications
The addition of daratumumab to chemotherapy produced a clinically meaningful increase in the overall response rate, which is typically in the 50% to 60% range for younger patients with T-cell ALL, Bhatla said.
Likewise, the addition of daratumumab increased the rate of MRD-negative complete responses compared with the historical performance of chemotherapy alone.
“Daratumumab can be safely combined with a chemotherapy backbone and, based on its tolerability, should be tested in the upfront setting,” Bhatla said.
Perspective
Back to Top
Bijal D. Shah, MD
These are outstanding results. Combining daratumumab with chemotherapy appears to be a powerful tool for relapsed T-cell ALL and lymphoblastic lymphoma.
Nelarabine (Arranon, GlaxoSmithKline) is currently the only FDA-approved agent for the treatment of relapsed or refractory T-cell ALL. However, single-agent nelarabine is not a very potent drug, with overall response rates of approximately 20%. At best, this therapy serves as a bridge to transplant, but only for a select few patients.
Adding daratumumab to a chemotherapy backbone generated complete responses among 54% of younger patients after one cycle of therapy, which is more than double the complete responses seen with nelarabine.
This trial has treated a small number of patients, and we won't know if this is a worthwhile strategy until a larger study is completed. However, these results do establish daratumumab as a potentially important factor in the treatment of T-cell ALL. This has been reflected in the National Comprehensive Cancer Network guidelines, where daratumumab has existed as an option even before results from this trial were presented.
Moving forward, we will need to deal with the toxicities associated with the use of daratumumab for patients with relapsed or refractory disease, especially older patients.
We need new options for both adults and children with T-cell ALL. It will be interesting to see if we can effectively combine daratumumab with immunotherapies to generate meaningful responses.
Collapse
Hogan LE, et al. Abstract 10001. Presented at: ASCO Annual Meeting; June 3-7, 2022; Chicago.
Read more about
Click Here to Manage Email Alerts