Photo courtesy of ASH
ORLANDO, FL—Investigators from the Group for Research on Adult Lymphoblastic Leukemia (GRAALL) recommend integrating rituximab into the treatment of adult patients with acute lymphoblastic leukemia (ALL) based on results of the GRAALL-R 2005 study.
Patients who received rituximab as part of their therapy had a median event-free survival (EFS) at 2 years of 65%, compared to 52% for patients who did not receive rituximab. After censoring for stem cell transplant in first complete remission, the benefit was even greater.
Sébastien Maury, MD, PhD, of Hȏpital Hénri Mondor in Creteil, France, presented the results during the plenary session of the 2015 ASH Annual Meeting as abstract 1.
Dr Maury said GRAALL-R 2005 is the first phase 3, randomized study to evaluate the role of rituximab in the treatment of B-cell precursor (BCP) ALL.
Only one previous study, he said, suggested a potential benefit of adding rituximab compared to historic controls of chemotherapy alone.
He explained that, because the CD20 antigen is expressed at diagnosis in 30% to 40% of patients with BCP-ALL, investigators undertook to evaluate whether adding the anti-CD20 monoclonal antibody rituximab to the ALL treatment regimen could be beneficial for newly diagnosed Ph-negative BCP-ALL patients.
Study design & population
Investigators randomized 105 patients to receive the pediatric-inspired GRAALL protocol plus rituximab and 104 patients to the same regimen without rituximab.
Patients had to have 20% or more CD20-positive leukemic blasts.
Patients in the rituximab arm received 375 mg/m2 during induction on days 1 and 7, during salvage reinduction (if needed) on days 1 and 7, during consolidation blocks (6 infusions), during late intensification on days 1 and 7, and during the first year of maintenance (6 infusions), for a total of 16 to 18 infusions.
“In this trial, allogeneic transplantation was offered in first remission to high-risk patients who were those patients with at least one of these baseline or response-related criteria,” Dr Maury said.
Investigators defined high-risk at baseline as having a white blood cell count of 30 x 109/L or higher, CNS involvement, CD10-negative disease, or unfavorable cytogenetics.
And response-related criteria for high-risk disease included poor peripheral blast clearance after the 1-week steroid pre-phase, poor bone marrow blast clearance after the first week of chemotherapy, or no hematologic complete response after the first induction course.
Patient characteristics were well balanced between the arms, with a median age for the entire group of 40.2 years. Rituximab-treated patients had 61% CD20-positive blasts, and the no-rituximab arm had 69%.
More patients in the rituximab arm had a better ECOG performance status, although the difference was not significant. Thirteen percent were assessed as being grade 2 or higher in the rituximab arm, compared with 18% in the no-rituximab arm (P=0.06).
“The proportion of high-risk patients was comparable in both arms,” Dr Maury said, “representing around two-thirds of the study population.”
In the rituximab arm, 70% were considered high-risk, compared with 64% in the no-rituximab arm (P=0.46).
“However, despite this,” he said, “a significantly higher proportion of patients received allo transplant at first remission in the rituximab arm, 34% versus 20%. And since this was not explained by a different proportion of high-risk patients, this was probably due to differences in donor availability.”
Dr Maury noted that compliance to treatment was “quite good.”
Efficacy
The median follow-up was 30 months, and the primary endpoint was EFS.
The EFS rate for rituximab-treated patients at 2 years was 65%, compared with 52% for the non-rituximab patients (hazard ratio=0.66, P=0.038).
EFS was also significantly better with rituximab when patients were censored at allogeneic transplant, with a hazard ratio of 0.59 and a significance of 0.021.
However, there were no significant differences in early complete response rates, minimal residual disease (MRD) after induction, and MRD after consolidation.
“[O]nly 40% of patients could be centrally analyzed [for MRD],” Dr Maury explained, “which may be the reason why we could not detect any impact of rituximab on MRD.”
The cumulative incidence of relapse at 2 years was 18% in the rituximab arm and 32% in the no-rituximab arm (hazard ratio=0.52, P=0.017). And after censoring for stem cell transplant in first complete remission, the hazard ratio was 0.49 in favor of rituximab (P=0.018).
Overall survival (OS) was not significantly different between the arms. Rituximab-treated patients had an OS rate of 71%, compared with 64% in the no-rituximab arm (P=0.095).
“However, this difference became significant when censoring patients at time of allo-transplant,” Dr Maury said.
There was a 12% cumulative incidence of death in first complete remission at 2 years in each arm.
Investigators performed multivariate analysis and found that treatment with rituximab (P=0.020), age (P=0.022), white blood cell count of 30 x 109/L or higher (P=0.005), and CNS involvement all significantly impacted EFS.
When they introduced stem cell transplant in first remission as a covariable, the same factors remained significant. Allogeneic stem cell transplant in first remission did not make a significant difference on EFS (P=0.62).
Safety
One hundred twenty-four patients reported 246 severe adverse events, the most frequent of which was infection—71 in the rituximab arm and 55 in the no-rituximab arm, a difference that was not significant (P=0.16).
Severe allergic events were significantly different between the arms, with 2 severe allergic events reported in the rituximab arm and 14 in the no-rituximab arm (P=0.002). Of these 16 events, all but one were due to asparaginase.
“We believe that this may reflect the protective effect of rituximab that might inhibit B-cell protection of antibodies against asparaginase,” Dr Maury said, although the investigators did not actually measure the antibodies.
Severe lab abnormalities, neurologic and pulmonary events, coagulopathy, cardiologic and gastrointestinal events were not significantly different between the arms.
Dr Maury emphasized that the addition of rituximab to standard intensive chemotherapy is well tolerated, significantly improves EFS, and prolongs OS in patients not receiving allogeneic transplant in first remission.
While the optimal dose schedule of rituximab still remains to be determined, the GRAALL investigators believe that “the addition of rituximab should be the new standard of care for these patients,” Dr Maury declared.
