Blinatumomab overcomes the poor prognostic impact of measurable residual disease in pediatric high-risk first relapse B-cell precursor acute lymphoblastic leukemia

As previously reported on the ALL Hub, the CD3/CD19 bispecific T-cell engager blinatumomab is superior to high-risk third-course consolidation chemotherapy (HC3), prolonging event-free survival (EFS) in children with high-risk first relapse B-cell precursor acute lymphoblastic leukemia (B-ALL). However, the initial results indicated that blinatumomab could have further clinical benefits than those detected in the study; patients treated with blinatumomab had a significantly lower incidence of EFS compared with those who received intensive multidrug chemotherapy. Here, we summarize recently reported results from a post hoc measurable residual disease (MRD) analysis of this phase III study (NCT02393859) by Locatelli, et al., in Pediatric Blood Cancer. The analysis aimed to assess the impact of blinatumomab versus HC3 on MRD, EFS, and overall survival (OS) across different MRD levels and reveal the underlying mechanism behind these observations.¹

MRD is an independent prognostic indicator in B-ALL and is important for risk stratification and treatment planning. Notably, persistence of MRD after induction chemotherapy and prior to allogeneic hematopoietic stem cell transplantation can be predictive of disease recurrence. MRD assays can detect small quantities of malignant cells that may be missed by other detection methods.

Methods

Children >28 days and <18 years of age with high-risk first relapse B-ALL in cytomorphological complete remission (M1 marrow, <5% blasts), or with M2 marrow (blasts ≥5% and <25%), were eligible for enrollment. In addition, patients who completed induction and the first two cycles of high-risk consolidation therapy (HC1 and HC2) were also included, while those who were refractory to induction or relapsed during HC1/HC2 were excluded.

Enrolled patients were randomized to receive a third course of consolidation chemotherapy, involving either one cycle of blinatumomab (15 μg/m²/day, 4 weeks, continuous intravenous infusion; N = 54) or a third cycle of intensive multidrug chemotherapy (HC3; N = 54).

In the post hoc analysis, patients with MRD of <10⁻⁴ by polymerase chain reaction (PCR) were grouped as either having positive but not quantifiable (pbnq) or undetectable disease. Multiparametric flow cytometry data were used if MRD was not evaluable by PCR. The primary endpoint was EFS, and key secondary endpoints included OS and MRD remission. MRD was assessed by real-time quantitative PCR of clonal T-cell receptor or immunoglobulin gene rearrangements and by multiparametric flow cytometry, with molecular remission being defined as MRD <10⁻⁴ cells. Subgroup analyses were performed to determine EFS and OS by end of induction (EOI) and end of second consolidation (baseline) MRD status.

To determine the point at which patients with MRD ≥10⁻⁴ at EOI responded to blinatumomab, MRD remission data on Day 15 and Day 29 were also compared.

Key findings

EFS and OS by EOI and end of second consolidation MRD status

• Patients who received blinatumomab had improved EFS and OS compared with those who received HC3, irrespective of EOI or end of second consolidation (baseline) MRD status.
• Within the subgroup of patients with end-of-second consolidation MRD levels <10⁻⁴ pbnq, fewer EFS events were reported for those treated with blinatumomab compared with those treated with HC3 (38% vs 86%, respectively). In addition, no deaths occurred in patients treated with blinatumomab, while 3 out of 8 patients died in the HC3 group.

MRD following HC3 or blinatumomab treatment

• MRD remission (MRD level, <10⁻⁴) was observed in 81% of patients in the blinatumomab group compared with 48% in the HC3 group.
• Of the 27 patients with MRD ≥10⁻⁴ at end of induction who were treated with blinatumomab and had achieved remission, 96% achieved remission by Day 15.
• Similarly, of the 22 patients with MRD ≥10⁻⁴ at baseline who achieved MRD remission after treatment with blinatumomab, 91% achieved remission by Day 15.
• Among all patients with MRD <10⁻⁴ at the end of treatment, a greater proportion of those who received blinatumomab had undetectable versus pbnq disease by PCR than those who received HC3.
• Change in MRD following treatment was characterized by comparing patients with baseline MRD <10⁻⁴, baseline MRD <10⁻⁴ pbnq, and baseline MRD <10⁻⁴ undetectable disease:
  • Overall, 86% of patients treated with blinatumomab and 73% of patients treated with HC3 with baseline MRD <10⁻⁴ remained at MRD <10⁻⁴ on Day 29.
  • Similarly, 77% of patients treated with blinatumomab and 81% of patients treated with HC3 with baseline MRD <10⁻⁴ undetectable, remained at MRD <10⁻⁴ on Day 29.
  • Among those with baseline MRD <10⁻⁴ pbnq, 88% of patients treated with blinatumomab achieved MRD <10⁻⁴ undetectable by Day 29, compared with only 14% of those treated with HC3.

Conclusion

As previously reported, blinatumomab induces high rates of MRD remission in adults and children with B-ALL. This subgroup analysis has revealed that MRD remission following blinatumomab is deeper than that achieved with HC3, explaining why patients with MRD <10⁻⁴ remission at baseline experienced improved rates of EFS and OS following treatment with blinatumomab. This also elucidates why patients with persistent MRD following HC1 and HC2 received little benefit from HC3, while treatment with blinatumomab was able to drive MRD remission. In addition, blinatumomab was able to eliminate the poor prognostic impact of persistent MRD after induction and at baseline. It was also observed that a large majority of patients with MRD at baseline were able to achieve MRD remission by Day 15 when treated with blinatumomab and maintain it through to Day 29.

These findings support the use of blinatumomab in the treatment of pediatric patients with high-risk first relapse B-ALL, including those with MRD levels <10⁻⁴ prior to beginning treatment. A longer follow-up period combined with deeper analysis afforded by next-generation sequencing technologies may provide even further insights.