© ASCO/Matt Herp
CHICAGO—The first interim analysis of rituximab plus chemotherapy in children and adolescents with high-risk B-cell non-Hodgkin lymphoma (B-NHL) and acute leukemia has yielded results that “will change our clinical practice,” according to Veronique Minard-Colin, MD, PhD, one of the study investigators.
Patients who received rituximab had 13% better event-free survival (EFS) than those who did not. “The new standard of care will be rituximab plus chemotherapy,” she said, for these high-risk patients.
“And it is very unlikely that this outcome will change if the study continues,” she added.
Dr Minard-Colin, of Institut Gustave Roussy in Villejuif, France, presented the interim analysis of the phase 3 Intergroup trial Inter-B-NHL Ritux 2010 at the 2016 ASCO Annual Meeting as abstract 10507.
She explained that when the study was started in 2010, there was a clear need to demonstrate the effectiveness of rituximab in childhood B-NHL.
So the investigators conducted the trial, which took place in 292 sites in 12 countries.
The investigators enrolled 310 patients under the age of 18 years who had mature B-NHL, including Burkitt lymphoma, diffuse large B-cell lymphoma (DLBCL), high-grade B-NHL not otherwise specified, and B-cell acute leukemia (B-AL). The investigators excluded patients with primary mediastinal B-cell lymphoma.
They defined advanced stages as stage III with LDH levels more than twice normal, any stage IV disease, or B-AL.
They randomized patients to receive the French LMB chemotherapy regimen either with or without rituximab—6 doses at 375 mg/m2.
The randomization was stratified based on national group, histology, and therapeutic group. Group B patients were in stage III or IV, with no central nervous system symptoms; group C1 patients were stage IV/B-AL with cerebrospinal fluid (CSF) negative; and group C3 patients were CSF positive.
One hundred fifty-five patients were randomized to receive rituximab, and 155 were randomized to the control arm.
The primary endpoint was improvement in EFS. Secondary endpoints included complete remission (CR) rate, overall survival (OS), safety, immunity status, and long-term risks.
Investigators performed the first interim analysis after 27 events occurred.
Patient characteristics
Patients were a median age of 8.2 years, 45% were stage III with high LDH, and 85% had Burkitt lymphoma.
About half (51%) the patients were in group B, 39% in C1, and 10% in C3.
Toxicity
There were 6 deaths due to toxicity, 3 in each arm.
Dr Minard-Colin indicated that this number reflects the high toxicity of the LMB regimen and is “similar” to the previous rate of toxic deaths observed in the international LMB 96 study.
She added, “Importantly, 5 out of 6 toxic deaths occurred in group C. The only patient who died in group B died of surgical complications after extensive inappropriate surgery at diagnosis.”
Toxicity was similar between the 2 arms except for the high rate of febrile neutropenia after the third course of cytarabine and etoposide in the rituximab arm (50% vs 34%, P=0.012).
Of the 27 events, 20 occurred in the control arm and 7 in the rituximab arm.
The control arm had 17 lymphoma events, while the rituximab arm had 3.
Only 1 patient relapsed in the rituximab arm compared to 12 who relapsed in the control arm. And no patient died of lymphoma in the rituximab arm, while 2 died of lymphoma in the control arm.
One second malignancy, melanoma, occurred in the rituximab arm.
Dr Minard-Colin noted that all events occurred in the first year after randomization
Efficacy
Event-free survival at 1 year was 94.2% in the rituximab arm and 81.5% in the control arm.
However, the investigators could not definitely conclude superiority for the rituximab arm because the P value was higher than the significance level of 0.0014 required for this first interim analysis. The hazard ratio was 0.33 (90%CI: 0.16-0.69), P = 0.006.
The investigators performed additional analyses and found the probability of getting a positive study at final analysis was very high, from 99% – 100%.
This past November, following the recommendation of the independent monitoring committee, sponsors decided to halt the randomization and continue follow-up of all patients so as to have mature data.
And in March of this year, they reopened the study with single-arm rituximab for 120 additional patients to answer the secondary objectives.
Dr Minard-Colin emphasized that the results are consistent with the recently performed LMBA02 trial in adult Burkitt lymphoma, with a gain of 13% in EFS for the rituximab arm. The 3-year EFS was 62% in the control arm compared with 75% in the rituximab arm (HR 0.59).
So while rituximab in high-risk patients appears to be practice changing, “in the standard- risk patients,” she added, “the use of rituximab is questionable.”
Sponsors of the trial are Gustave Roussy Cancer, Children’s Oncology Group, and Roche.
Data analyses will be conducted annually hereafter.
