ORLANDO, Florida — Rituximab (Rituxan, Genentech/Roche) has shown efficacy in another form of acute lymphocytic leukemia (ALL).
The product is already a mainstay of therapy in lymphoma and has also shown activity in mature B-cell ALL.
The new data show that adding rituximab to chemotherapy significantly improved event-free survival in patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL).
At a median follow up of 30 months, patients who received rituximab had a lower incidence of relapse compared with those who did not (18% in the rituximab arm vs 30.5% in the control arm).
In addition, 65% of the patients receiving rituximab arm achieved 2-year event-free survival, as compared with 52% of controls.
"Adding rituximab to standard therapy should thus become a standard of care for these patients," said lead author Sébastien Maury, MD, from Hôpital Henri Mondor, Créteil, France, who presented the findings during the plenary scientific session here at the American Society of Hematology (ASH) 57th Annual Meeting
The results were welcomed by David Steensma, MD, senior physician at the adult leukemia program in the hematological malignancies division at the Dana Farber Cancer Institute, in Boston, Massachusetts, and education cochair for the meeting, "This is a very curable malignancy in children, but it has poor outcomes in adults," Dr Steensma commented in a premeeting press cast. These new results will "immediately change clinical practice," he predicted, especially because the drug is already on the market.
Rituximab is a chimeric monoclonal antibody directed against CD20.
"CD20 is expressed in 30% to 50% of adult BCP-ALL patients," Dr Maury explained, "and it has been shown to be a poor risk factor."
Some single-arm studies have suggested that adding rituximab to chemotherapy could improve the outcome of these patients, but so far there have not been any randomized clinical trial data.
Robert Hromas, MD, chair of the department of medicine at the University of Florida College of Medicine, Gainesville, commented that the new results showing a benefit from adding on rituximab "resolves a long-standing controversy in this disease.
These results are exciting for those of us who treat acute leukemia," said Dr Hromas, who moderated a press briefing where highlights of the study were presented.
Improved Event-Free Survival
Dr Maury and colleagues conducted a multicenter randomized trial that compared the pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol with the same regimen but with the addition of rituximab.
The cohort included 220 patients aged 18 to 59 years old with newly diagnosed CD20-positive Ph-negative BCP-ALL who were enrolled in the GRAALL 2005 trial. CD20 positivity was defined as expression of CD20 in more than 20% of leukemia blasts.
Patients received rituximab (375 mg/m2) during induction (day 1 and 7), salvage reinduction when needed (day 1 and 7), consolidation blocks (six infusions), late intensification (day 1 and 7), and first year of maintenance (six infusions), for a total of 16 to 18 infusions.
For patients with one or more conventional high-risk criteria and an available donor, allogeneic stem-cell transplantation (SCT) was offered when they were in first complete remission.
The primary end point of the study was event-free survival.
Following induction and salvage reinduction, the complete remission rate was 92% for patients who received rituximab and 91% for controls. Among those who achieved a complete response after first induction and who were evaluated for Ig/T-cell receptor (TCR) minimal residual disease level (MRD), the rates of patients with MRD < 10-4 in the rituximab vs control arm were 65% vs 61% (P = .82) and 91% vs 82% (P = .31), after induction and first three consolidation blocks respectively.
A higher proportion of patients in the rituximab arm received allogeneic SCT in their first complete remission (34% vs 20%; P = .029). At a median follow-up of 30 months, patients in the rituximab arm also had a lower cumulative incidence of relapse (CIR) (2-year CIR, 18% vs 30.5%; P = .02), but there was no significant difference in the 2-year nonrelapse mortality between the 2 study groups (12% vs 12%; P = .80).
This translated into a longer event-free survival, Dr Maury noted, for those treated with rituximab (65% vs 52%; hazard ratio [HR], 0.66; P = .038).
"On multivariate analysis, rituximab still impacted event-free survival, along with other factors such as age, CNS involvement, and WBC at diagnosis," said Dr Maury.
However, it did not translate into longer overall survival, which was similar in both groups (71% vs 64%; HR, 0.70; P = .095).
Overall Survival Benefit for Select Patients
When patients who received allogeneic SCT in first complete remission were censored, both event-free survival and overall survival were longer in the rituximab arm: 2-year event-free survival 66% vs 53%, and 2-year overall survival 74% vs 63%; (HR, 0.59 and 0.55, respectively; P = .021 and .018, respectively).
There were 71 infection-related serious adverse events in nontransplanted patients in the rituximab arm and 55 in the control arm, without any significantly higher incidence in the rituximab group during any treatment phase.
"In these patients, the addition of the rituximab to standard intensive chemotherapy is well-tolerated and significantly improves event-free survival," Dr Maury concluded. "The optimal dose schedule of rituximab administration remains to be determined."
In an introduction to the paper, Adele Fielding, MD, from University College London, United Kingdom, noted that "despite the promise and excitement of novel immunotherapy approaches that are being introduced in relapsed and refractory ALL, there have been no novel agents introduced into routine use for up-front treatment of Ph-negative ALL."
She pointed out that there are several good reasons to use rituximab, one being that it is already being added to chemotherapy in other settings.
There are also many questions that remain regarding the use of rituximab in this setting. One is early and late toxicities, as well as which subset of patients are most likely to achieved the best response and how and when to evaluate responses.
"The relationship of response to CD20 is important," said Dr Fielding. "The correlation between minimal residual disease assessment and response is also key."
Dr Maury reports no relevant financial relationships. Coauthor Yves Chalandon has received honoraria from Roche and has membership on an entity's board of directors or advisory committees.
American Society of Hematology 57th Annual Meeting; Orlando, Florida. Abstract 1, presented December 6, 2015.