Blinatumomab as Post-Reinduction Therapy Improves Survival in Pediatric and AYA B-ALL

Patrick A. Brown, MD

Blinatumomab (Blincyto) as post-reinduction consolidation therapy before hematopoietic stem cell transplantation (HSCT) improved disease-free survival (DFS) and overall survival (OS) by approximately 20% compared with intensive chemotherapy in pediatric and adolescent and young adult (AYA) patients with high- or intermediate-risk of first relapse of B-cell acute lymphoblastic leukemia (B-ALL), according to results presented at the 2019 ASH Annual Meeting.¹

In the randomized, phase III AALL1331 trial (NCT02101853), which was conducted by the Children’s Oncology Group, results showed that the 2-year disease-free survival (DFS) was 59.3+5.4% with blinatumomab compared with 41.0+6.2% with those who received intensive chemotherapy (P = .050) at a median follow-up of 1.4 years.

Additionally, the OS at 2 years was 79.4+4.5% and 59.2+6.0% with blinatumomab and chemotherapy, respectively (P = .005).

“For children, adolescents, and young adults who have a first relapse of B-lineage ALL that is either early or [minimal residual disease (MRD)]—positive after the first month [of chemotherapy], blinatumomab is superior to chemotherapy as post-reinduction consolidation prior to transplant,” Patrick A. Brown, MD, director of the Pediatric Leukemia Program, and associate professor of oncology at Johns Hopkins Medicine, said in a press conference during the meeting.

“This is due to fewer and less severe toxicities, higher rates of MRD response, greater likelihood of proceeding to transplant, and improved DFS and OS. Thus, blinatumomab constitutes a new standard of care in this setting.,” he explained.

Cure rates for pediatric and AYA ALL are high; however, relapse occurs in approximately 15% of patients. This leads to poor survival outcomes, especially in those that occur within 3 years of diagnosis or when the patient’s relapse is still MRD-positive after the first month of chemotherapy. Standard options for this specific population include intensive chemotherapy followed by transplant.

Blinatumomab is an anti-CD19 bispecific T-cell engager that is currently approved by the FDA for the treatment of adult and pediatric patients with relapsed/refractory B-cell precursor ALL, as well as adult and pediatric patients with B-cell precursor ALL in first or second complete remission with MRD ≥0.1%.

In the AALL1331 trial, investigators sought to determine whether substitution blinatumomab for intensive consolidation chemotherapy improves survival in first relapse of pediatric and AYA B-ALL. A total 208 patients who were between the ages 1 and 30, received 1 month of induction chemotherapy, and had early or late relapse with high levels of MRD were randomized to either a control arm of 2 blocks of intensive chemotherapy (n = 103) or 2 cycles of blinatumomab (n = 105) and then went onto HSCT.

Investigators initially planned to enroll 222 patients. However, randomization was halted at 208 patients; in September 2019, a Data Safety Monitoring Committee determined that the blinatumomab arm was superior based on better survival and MRD clearance as well as less toxicity.²

To be eligible for enrollment, patients must have had an ECOG performance score of 0 to 2 and had no prior stem cell transplant or rescue or prior treatment with blinatumomab. Patients with Philadelphia chromosome—positive disease were excluded from enrollment.

The primary endpoint was DFS of high- and intermediate-risk patients with B-ALL at first relapse; secondary endpoints include MRD clearance, adverse events (AEs), and bridge to transplant.

Additional data showed that MRD clearance was improved with blinatumomab compared with the end of chemotherapy block 1 (P = .65) and end of chemotherapy block 2/blinatumomab cycle 1 (P <.0001) and end of chemotherapy block 3/blinatumomab cycle 2 (P <.0001).

Grade ≥3 AEs, including febrile neutropenia, infection, sepsis, and mucositis, were significantly higher with chemotherapy than blinatumomab (P <.001).

Moreover, more patients on blinatumomab had a greater ability to successfully bridge to transplant than those on intensive chemotherapy at each treatment point: those who started chemotherapy block 2/were on cycle 1 of blinatumomab (94% vs 97%; P = .5), on chemotherapy block 3/cycle 2 of blinatumomab (56% vs 79%; P = .0008), and went on to transplant (45% vs 73%; P <.0001).

"The improved survival with blinatumomab was likely related to 3 major factors: the first was that patients treated with blinatumomab were much more likely to have the residual disease in their bone marrow cleared than those treated with chemotherapy,” Brown explained. “The second is the rate of AEs was much lower in the patients receiving blinatumomab compared with chemotherapy, and the primary AEs seen with chemotherapy included life-threatening or even fatal infections—this was not seen with blinatumomab. Finally, patients treated with blinatumomab were far more likely to successfully proceed through therapy to receive bone marrow transplant.”

The phase III AALL1331 trial also compares the DFS of patients with low-risk relapse B-ALL patients who are randomized following chemotherapy block 1 to receive either chemotherapy alone or chemotherapy plus blinatumomab.

Future research efforts in this space will focus on optimizing immunotherapy in relapsed ALL, Brown added, such as combining blinatumomab with checkpoint inhibitors, using immunotherapy to replace or augment reinduction chemotherapy, and using CAR T-cell therapy to replace or augment HSCT.

Robert Brodsky, MD, professor of medicine and director of the Division of Hematology, Johns Hopkins School of Medicine, who moderated the press conference, commented on the phase III findings.

“This is a new standard of care, the big problem with pediatric ALL […] is when they relapse it’s very hard to get them back into remission,” said Brodsky. “When they relapse, the only way we really have a chance to cure these patients is to get them to transplant, and what [investigators] clearly showed is that with blinatumomab, they have a much better chance at getting the transplant and being cured of their disease.”

References

1. Brown PA, Lingyun Ji, Xu X, et al. A randomized phase 3 trial of blinatumomab vs. chemotherapy as post-reinduction therapy in high and intermediate risk (HR/IR) first relapse of B-ALL in children and AYAs demonstrates superior efficacy and tolerability of blinatumomab: a report from Children’s Oncology Group Study AALL1331. Presented at: 2019 ASH Annual Meeting; December 7-10, 2019; Orlando, FL. LBA_1. bit.ly/2LDMr7U.
2. Amgen announces positive results from two phase 3 BLINCYTO (blinatumomab) studies in pediatric patients with relapsed acute lymphoblastic leukemia. Amgen. Published September 25, 2019. bit.ly/2l4RcNU. Accessed December 9, 2019.

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