GRAALL-R 2005 Study: Improved Survival With Rituximab Suggests New Standard of Care in ALL Subgroup

di Mary Mosley

Rituximab has now been shown to improve event-free survival (EFS) in patients with untreated CD20-positive, Ph-negative, B-cell precursor acute lymphoblastic leukemia (BCP-ALL) when added to standard intensive chemotherapy, in results from the GRAAL-R 2005 study presented by Sébastien Maury, MD, Hôpital Henri Mondor, Créteil, France. This regimen should become standard of care in these patients, who represent about a third of the population with BCP-ALL, stated Prof. Maury, although the optimal dose schedule for rituximab must be determined.

From 2006 to 2014, 220 patients between the ages of 18 to 59 years from 56 centers were randomized to standard intensive chemotherapy with or without rituximab (375 mg/m2). A total of 16 to 18 infusions of rituximab was administered: on days 1 and 7 during induction therapy, on days 1 and 7 during salvage reinduction when needed, 6 infusions during consolidation block, days 1 and 7 of late intensification, and 6 infusions during year one of maintenance. Allogenic stem cell transplantation (SCT) was offered in first complete remission (CR) to patients with one or more conventional high-risk criteria and a donor. The modified intention-to-treat analysis included 105 patients in the rituximab group and 104 patients in the chemotherapy only group.

The median age was 40 years. More patients treated with rituximab group, compared with chemotherapy only, had high-risk ALL (70% vs. 64%; p = 0.46) and allogenic SCT (34% vs. 20%; p = 0.029). The median CD20 positivity was 61% and 69%, respectively (p = 0.24).

The median age of the study patients was 66 years, most were men (58%) and white (86%), and most (>90%) had an ECOG performance status of 0 or 1, and 87% had an ISS stage of I or II. Seven percent of the IRd and 6% of the placebo-Rd patients had primary refractory disease. Prior treatment included a PI in 70% of patients and stem cell transplantation in >50%.

The rituximab-treated patients had a significantly higher probability of EFS, the primary study endpoint, over the median 30-month follow-up, compared with chemotherapy only (65% vs. 52%; HR, 0.66; 95% CI, 0.45-0.988; p = 0.038). This improvement remained significant after censoring for SCT (HR, 0.59; 95% CI, 0.37-0.93; p = 0.021). Rituximab was more beneficial than no rituximab in each of the prespecified subgroups of age ≥40 years, central nervous system involvement, white blood cell count ≥30 g/L, and CD20 expression ≥66%.

The response to treatment is shown in Table 1. No significant difference was found between groups in the rate of early response to treatment (about 90%). Fewer patients treated with rituximab had a relapse, with a cumulative incidence of 18% compared against 32% with chemotherapy only (cause-specific HR, 0.52; 95% CI, 0.31-0.89; p = 0.017). Again, the significant improvement remained after censoring for SCT (HR, 0.49; 95% CI, 0.27-0.89; p = 0.018). Nonrelapse mortality was similar at 12% in both groups, even after adjusting for SCT.

Overall survival (OS) was significantly improved by 45% with rituximab compared with chemotherapy alone in patients who did not receive SCT (HR, 0.55; 95% CI, 0.34-0.91; p = 0.018). However, in the overall population, the difference in the probability of OS did not reach statistical significance, at 71% for rituximab and 64% for chemotherapy (HR, 0.70; 95% CI, 0.46-1.07; p = 0.095).

Treatment with rituximab was a significant predictor of EFS, even after adjusting for SCT, in the multivariate analysis. The results of this analysis are detailed in Table 2.

The safety profile was similar in both arms, with a similar incidence of adverse events. Slightly more rituximab-treated patients had infection (71 vs. 55 patients; p = 0.16), while fewer had an allergic response (2 vs. 14 patients; p = 0.002). The substantial benefits with rituximab over chemotherapy alone of a significant improvement in EFS and longer OS, along with a positive safety profile, achieved in the GRAAL-R 2005 trial suggest its use as part of standard of care for patients CD20-positive ALL.


Source: ASH 2015,
abs 1


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