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Rituximab extends EFS in B-cell precursor ALL
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ORLANDO, Fla. — The addition of rituximab to the pediatric-inspired GRAALL protocol prolonged EFS among adult patients with CD20-positive, Philadelphia chromosome-negative acute lymphoblastic leukemia, according to randomized trial results presented at the ASH Annual Meeting and Exposition.
Further, rituximab (Rituxan; Genentech, Biogen Idec) appeared to prolong OS when ignoring outcome after transplantation in first complete remission, according to the researchers.
Rituximab has led to significant improvement in the treatment of B-cell non-Hodgkin’s lymphoma and mature B-cell ALL, according to study background. CD20 is expressed in 30% to 50% of adult patients with B-cell precursor ALL (BCP-ALL), and although data from some single-arm studies have suggested that adding rituximab to chemotherapy could improve outcomes in these patients, a randomized study had not been reported so far.
“One single-arm study from The University of Texas MD Anderson Cancer Center suggested the potential benefit of adding rituximab vs. historical controls,” Sébastien Maury, MD, PhD, of the department of hematology at Henri Mondor Hospital in Créteil, France, said during a press conference. “This is notably on the basis of these data that we attempted to randomize, for the first time, rituximab in addition to chemotherapy in these patients.”
Maury and colleagues conducted a multicenter randomized trial comparing the pediatric-inspired GRAALL protocol to the same regimen plus rituximab in 209 adult patients (aged 18-59 years; median age, 40.2 years) with newly diagnosed CD20-positive, Philadelphia (Ph)-negative BCP-ALL.
Researchers assigned patients to the rituximab (n = 105) or control arms (n = 104).
The experimental arm included rituximab (375 mg/m2) during induction (days 1 and 7), salvage reinduction when needed (days 1 and 7), consolidation blocks (6 infusions), late intensification (days 1 and 7) and during the first year of maintenance (6 infusions), for a total of 16 to 18 infusions.
Patients with one or more conventional high-risk criteria and a donor underwent allogeneic stem cell transplantation in first complete remission.
EFS served as the primary endpoint.
Following induction and salvage reinduction, 92% of patients assigned rituximab and 91% in the control arm achieved complete remission.
A significantly higher proportion of patients assigned rituximab underwent allogeneic stem cell transplantation in first complete remission (34% vs. 20%; P = .029).
The median follow-up was 30 months.
Patients assigned rituximab had a lower 2-year cumulative incidence of relapse (18% [95% CI, 10-26] vs. 30.5% [95% CI, 21-40]). Thus, more patients in the rituximab arm also achieved 2-year EFS (65% vs. 52%; HR = 0.64; 95% CI, 0.43-0.96).
Rates of 2-year nonrelapse mortality appeared comparable in the rituximab and control arms (both, 12%; 95% CI, 5-18). Further, a comparable proportion of patients in each arm achieved 2-year OS (71% vs. 64%; HR = 0.7; 95% CI, 0.46-1.07).
Age, central nervous system involvement and white blood cell count at diagnosis appeared associated with EFS impact. Along with the randomization arm, these factors remained significantly associated with EFS in multivariate analyses, even after adjustment for allogeneic stem cell transplantation in first complete remission.
When censoring patients who received allogeneic stem cell transplantation in first complete remission at time of transplant, the researchers observed improved EFS (2-year EFS, 66% vs. 53%; HR = 0.59; 95% CI, 0.37-0.93) and OS (2-year OS, 74% vs. 63%; HR = 0.55; 95% CI, 0.34-0.91) in the rituximab arm.
Seventy-one patients assigned rituximab and 55 patients in the control arm reported severe adverse events during their exposure to chemotherapy with or without rituximab.
“Adding rituximab to standard therapy should thus become a standard of care for patients with Ph-negative BCP-ALL,” Maury said. “However, some specific concerns — such as the definition of the best dose — needs to be addressed in future studies.” – by Cameron Kelsall
Reference:
Maury S, et al. Abstract 1. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: The researchers report that rituximab is not currently approved for the indication studied in this trial. One study researcher reports honoraria from and an advisory board role with Roche. Maury and the other researchers report no relevant financial disclosures.Perspective
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Timothy Graubert, MD
Roughly a third of patients with Philadelphia (Ph)-negative acute lymphoblastic leukemia express CD20, which is the target of rituximab (Rituxan; Genentech, Biogen Idec). This drug has been employed frequently in the care of patients — retrospective data have suggested it might have a benefit, but there has never been a prospective randomized trial that formally addressed whether the addition of rituximab benefits these patients. This was the first important study in that respect, and the investigators are to be congratulated for conducting a multi-institutional study across several countries in Europe, enrolling a large number of patients in this relatively rare subtype of acute leukemia.Researchers enrolled approximately 100 newly diagnosed patients with Ph-negative, CD20-positive ALL in each of the two arms. All patients received standard induction, intensification and consolidation therapy with or without the addition of rituximab in each of those blocks of therapy.
The addition of rituximab did not change some endpoints, but did change others. In particular, the induction of complete remission, or the achievement of negativity for residual disease, was identical in the two arms, but the risk for relapse appeared improved in the arm that received rituximab. Thus, patients who received rituximab had a meaningful clinical benefit in PFS.
This was tempered somewhat by an unexpectedly high frequency of patients who went on to receive allogeneic stem cell transplant. In fact, there were more patients in the rituximab arm who went on to receive transplant, and the researchers speculated that accounted for the fact there was no OS benefit with the addition.
Researchers also observed a significantly lower rate of allergic reaction among the patients receiving rituximab. Asparaginase is commonly employed in the treatment of ALL and was part of this chemotherapy regimen. Because it is a bacterially derived protein, it is associated with allergic reactions. Rituximab depletes normal B cells, as well as the tumor cells expressing CD20. Therefore, it was speculated that the clearance of normal cells and the depletion of antibodies accounted for this reduced incidence of allergic reactions.
In a nutshell, the question this raises is whether the benefit of rituximab does not entirely stem from improving the treatment of leukemia and having a direct antitumor effect, but rather may also reduce the frequency of allergic reactions, allowing for better tolerability of asparaginase and the receipt of more intensive therapy. This is an important observation to follow up on.
Overall, these data are an important addition to a rapidly changing field, with many new therapies coming into play for patients with ALL.
Perspective
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Robert A. Hromas, MD, FACP
Whether or not to add rituximab to the standard treatment regimen has been a longstanding controversy in acute lymphoblastic leukemia. Rituximab has been around for decades, and recent advances in ALL are about a decade old — this includes taking pediatric protocols and using them to treat younger, healthier adults. This study by Maury and colleagues resolves the controversy of whether or not rituximab improves OS. It is a very well done study: it had a large number of patients, it was carefully planned and well-randomized, and it shows that rituximab conferred a survival advantage.
ALL cells do not have a lot of CD20 on their surface. Because CD20 is the target of rituximab, some thought it was not effective. Maury and colleagues puts that question to rest. If you just express CD20 on the surface, then rituximab should be added to your treatment regimen.
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