Rituximab in B-ALL: How Much and for Whom?

Rituximab is a chimeric monoclonal antibody targeting the cell surface differentiation antigen, CD20, that was licensed by the U.S. Food and Drug Administration in 1997 as the first anticancer monoclonal antibody for the treatment of relapsed non-Hodgkin lymphoma (NHL).¹  Its incorporation into standard chemotherapy regimens for NHL has led to considerable improvements in survival. In B-lineage acute lymphoblastic leukemia (B-ALL), CD20 is present on approximately 30 to 50 percent of B-ALL blasts.^2,3  Several investigations have observed that higher CD20 cell surface expression is associated with inferior survival in adults with B-cell ALL.^3,4  Thus, the addition of rituximab into multiagent chemotherapy frontline ALL regimens was a logical strategy to improve the outcome for patients with CD20-positive B-ALL.

Investigators at the University of Texas MD Anderson Cancer Center were the first to incorporate rituximab into their hyperfractionated cyclophosphamide, doxorubicin, vincristine, and dexamethasone (hyper-CVAD) regimen in a single-arm study for patients with de novo CD20-positive, Philadelphia chromosome (Ph) –negative B-ALL and demonstrate an overall survival benefit compared to historical controls (75% vs. 47%; p=0.003).⁵  Subsequently, the 2016 randomized phase III study from the French Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) examined the efficacy of rituximab when added to induction, consolidation, late intensification, and maintenance in CD20-positive (defined as ≥ 20% expression at baseline assessment) Ph-negative B-cell precursor ALL (GRAALL-2005-R).⁶  The addition of rituximab to the chemotherapy backbone demonstrated a significant improvement in event-free survival (EFS) compared to chemotherapy alone (hazard ratio [HR], 0.66; 95% CI, 0.45-0.98; p=0.04). The survival benefit was explained primarily by a reduction in the cumulative incidence of relapse (18% vs. 32% at 2 years) and thus led to a change in the standard-of-care chemotherapy regimen for patients with CD20-positve Ph-negative B-ALL. One meaningful question remained, however: Would the addition of rituximab to chemotherapy be beneficial in patients with B-ALL regardless of CD20 expression level at the diagnostic assessment?

Data to support such a treatment strategy emerged from an international study on flow cytometric minimal residual disease (MRD) assessment in childhood ALL that observed that CD20 cell surface expression is sometimes upregulated on leukemia blasts that persist during induction treatment.^7,8  Further analysis of this phenomenon was performed in a large cohort of pediatric patients with B-ALL who had significant MRD (≥ 0.1%) at the end of induction therapy and revealed that CD20 expression significantly increased from the baseline assessment to the end of induction.⁹  This immunophenotypic change was frequently found in patients with high-risk clinical features, including those with high MRD at end-induction and in patients who experienced relapse. It was less frequently observed in patients with favorable-risk features, such as in patients with the TEL/AML1 gene rearrangement. Interestingly, in vitro assays showed that CD20 expression could be induced with glucocorticoid, and that CD20 upregulation enhanced rituximab cytotoxicity. Based on these collective data, there appeared to be a rationale for testing the efficacy of rituximab in B-ALL regardless of CD20 baseline expression.

In the current article, Dr. David Marks and colleagues on behalf of the UK NCRI Adult ALL group report the results of the prospective, multicenter, randomized phase III UKALL14 trial to determine if the addition of rituximab to standard induction chemotherapy improves EFS in adult patients with precursor B-lineage ALL. The trial enrolled 586 patients aged 25 to 65 years, in 65 trial sites throughout the United Kingdom between 2012 and 2017. Patients were eligible for enrollment regardless of baseline CD20 expression level or BCR-ABL1 status. Patients were randomly assigned in a 1:1 ratio to standard-of-care chemotherapy or standard of care with rituximab at a dose of 375 mg/m² administered on days 3, 10, 17, and 24 of induction therapy only. The primary end point of the trial was three-year EFS, and the trial was designed to show a 12 percent improvement in EFS from 40 percent to 52 percent in the historical control standard-of-care group with the addition of four total doses of rituximab during induction therapy. Important secondary end points were complete remission rates at the end of induction phase 2, overall survival, cumulative incidence of relapse, nonrelapse mortality, measurement of MRD at the end of induction 1 and 2, and antiasparaginase antibody formation (data not yet available). Additional information about CD20 expression levels was collected from excess bone marrow samples for a correlative analysis to determine the association between CD20 cell surface expression on ALL blasts and response to rituximab therapy.

The addition of four doses of rituximab to a standard induction therapy was safe, with no increase in short-term or long-term adverse events, but did not result in improved EFS. The three-year EFS rate for standard-of-care treatment versus standard of care plus rituximab was 43.7 percent and 51.4 percent, respectively (HR, 0.85; 95% CI, 0.69-1.06; p=0.14). There was no significant difference in overall survival between the groups (HR, 0.88; 95% CI, 0.70-1.11; p=0.29). The three-year cumulative incidence of relapse was 31.1 percent for standard of care versus 26.3 percent for standard of care and rituximab. The complete remission rates (93% vs. 95%) and the undetectable MRD rates (36% and 35%) were similar between cohorts.

The investigators examined a subset of cryopreserved patient samples to analyze treatment effects by CD20 expression levels. CD20 expression levels were quantified by proportion of blasts expressing CD20 as assessed by central flow cytometry, and by calculating the CD20 molecules per cell. In the subset analysis, CD20 expression remained significantly associated with inferior EFS, and there was no evidence that greater CD20 expression improved the efficacy of rituximab.