ORLANDO – Adding rituximab to standard intensive chemotherapy significantly improved event-free survival in adults with Philadelphia-negative, CD20-positive B-cell precursor acute lymphoblastic leukemia in the phase III GRAALL-R 2005 study.

Rituximab (Rituxan) is already being used to improve outcomes in patients with lymphoma, and non-randomized data support addition of the anti-CD20 monoclonal antibody to chemotherapy in B-cell precursor (BCP) ALL, where the CD20 antigen is expressed in 30% to 40% of patients at diagnosis.

In the randomized GRAALL-R 2005, 2-year event-free survival (EFS) was 65% in the rituximab arm vs. 52% in the control arm (hazard ratio, 0.66; P = .038).

This difference is not explained by the early response rates, which were very close in both arms after one or two induction courses (92% vs. 90%; P = .63), Dr. Sébastien Maury, Hôpital Henri Mondor in Créteil, France, said during the plenary session at the annual meeting of the American Society of Hematology (Ab. 1).

The beneficial effect of rituximab, however, was clearly related to the cumulative incidence of relapse at 18% with vs. 32% without rituximab (HR, 0.52; P = .017).

Despite this advantage, overall survival was similar between patients given chemotherapy with and without rituximab (71% vs. 64%; HR, 0.70; P = .095), he said.

After censoring for patients not receiving allogeneic stem cell transplant in first complete remission, however, rituximab significantly prolonged 2-year EFS (HR, 0.59; P = .021) as well as overall survival (HR, 0.55; P = .018), Dr. Maury said.

“We thus recommend that the addition of rituximab become a new standard of care for these patients, although some aspects including the definition of the optimal dose needs to be determined in further studies,” he concluded.

Dr. Adele Fielding of University College London, who introduced the study at the meeting, said, “For me, the prior knowledge that the drug can be safely already added to chemotherapy in other settings provides profound comfort in a disease in which so many people are already damaged by the current therapies we offer.”

Also, of importance is the potential relevance of rituximab in patients in whom CD20 is present on fewer than 20% of blasts at diagnosis.

Key questions that remain in rituximab therapy of ALL beyond overall benefit include early and late toxicities and how best to judge response and when, she said. Synergies with other agents and the mechanism of action will also require clarification, especially which effector cells are relevant to ensure that agents are not used with rituximab that destroy the optimal chance for response.

“Finally, the cost of introducing novel agents cannot be ignored, even in well-developed economies, and I am hopeful that the cost of this drug will be variable for many countries and many patients.” Dr. Fielding said.

Study details

A total of 220 patients, aged 18-59 years, with newly diagnosed CD20-positive Ph-negative BCP-ALL were randomized to the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) chemotherapy protocol with or without rituximab 375 mg/m² given during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (6 infusions), late intensification (day 1 and 7, and the first year of maintenance [6 infusions], for a total of 16-18 infusions. Allogeneic stem cell transplant (SCT) was offered after consolidation blocks 1 or 2 to patients with one or more high-risk criteria and an available donor. CD20-positivity was defined as expression of CD20 in more than 20% of leukemia blasts.

Eleven patients were excluded from the analysis because of non–ineligibility criteria, leaving 209 patients in the modified intent-to-treat analysis. Their median age was 40.2 years and 67% had high-risk ALL.

Rates of postinduction minimal residual disease less than 10^–4were 65% and 61% in the rituximab and control arms among 85 evaluable patients(P = .82), and rates of postconsolidation minimal residual disease less than 10^–4 were 91% and 82% among 80 evaluable patients (P = .31), Dr. Maury reported.

Notably, more patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs. 20%; P = .029).

The cumulative incidence of death in first complete remission was 12% in both arms.

In multivariate analysis, rituximab impacted EFS, together with age, central nervous system involvement, white blood cells, or CD20 expression at diagnosis. A preferential effect with rituximab was seen in patients with high CD20 levels that deserves further evaluation, he observed.

There was no difference in the incidence of adverse events between the rituximab and control arms, although there was a trend for more infectious events with rituximab (71 events vs. 55 events), Dr. Maury said.

Allergic events – all but one from aspergillosis – were significantly more common in the control arm (2 events vs. 14 events; P = .002).

The Group for Research in Adult Acute Lymphoblastic Leukemia sponsored the study. Dr. Maury reported having no disclosures.

pwendling@frontlinemedcom.com

ASH: Rituximab add-on therapy ‘new standard’ in BCP-ALL