Blinatumomab holds promise for relapsed B-ALL in children/AYAs

The bi-specific T-cell engaging antibody blinatumomab bested chemotherapy as a post-reinduction consolidation prior to transplant in children and adolescents and young adults (AYAs) with first-relapse B-cell acute lymphoblastic leukaemia (B-ALL), according to phase III data presented at ASH 2019, highlighting the potential of blinatumomab as a new standard of care in this setting.

Despite dramatic improvements in cure rates over the years, survival remains poor for first relapse of B-ALL in this patient subgroup especially for early relapses, said study author Dr Patrick Brown from the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University in Baltimore, Maryland, US. “[We thus sought] to determine if substituting chemotherapy with blinatumomab as intensive consolidation after initial induction chemotherapy would improve survival in [this setting].”

Following risk assignment of participants with first-relapse B-ALL after receiving 1 month of induction chemotherapy (median age 9 years, 16 percent AYAs), 208 with HR/IR* were randomized 1:1 to receive either two blocks of consolidation chemotherapy (4 weeks each block) or two continuous infusions of blinatumomab 15 µg/m²/day (28 days each infusion, then 7 days off). [ASH 2019, abstract LBA1]

After a median follow-up of 1.4 years, blinatumomab demonstrated superior efficacy over chemotherapy as reflected by the improvements in disease-free survival (59 percent vs 41 percent; p=0.05) and overall survival (79 percent vs 59 percent; p=0.005).

Blinatumomab was well tolerated, with fully reversible adverse events (AEs) and no AE-related deaths. The rates of grade 3/4 febrile neutropenia, infection, sepsis, and mucositis were strikingly higher with chemotherapy during the first post-randomization block (p<0.001 for all). “These differences were even more striking during the second post-randomization block … with the exception of mucositis,” said Brown.

Of note were the four toxic deaths with chemotherapy, noted Brown. “[These were] all infections … three of [which] were AYAs, suggesting the enhanced chemotoxicity in this subset ... [This] is something that can be seen in prior studies of ALL … The improvement in survival with immunotherapy in the relapse setting may be particularly important in the AYA population since the burden seems to be greatest [in this cohort].”

In terms of MRD** response, induction chemotherapy did not appear to generate benefit, given the similar fraction of participants achieving an MRD-negative status in the chemotherapy and the blinatumomab arms (22 percent vs 18 percent). This, according to Brown, underscores the limited efficacy of chemotherapy in early relapse.

However, a striking difference in MRD negativity was observed between the two arms following the post-randomization regimens. At the first post-randomization cycle, 29 percent of chemotherapy recipients achieved MRD negativity whereas in the blinatumomab arm, the rate was much higher at 76 percent. This effect persisted until the second post-randomization cycle (33 percent vs 66 percent for chemotherapy and blinatumomab, respectively).

Nonetheless, the more pronounced MRD response with blinatumomab during the first post-randomization cycle raises the question of whether a second cycle is warranted for patients who have already achieved MRD clearance in the first cycle, Brown pointed out.

With regard to transplant bridging, only 45 percent of chemotherapy recipients were able to proceed to transplant as opposed to 73 percent in the blinatumomab arm.

The triple advantage

Brown attributed the survival improvements with blinatumomab to three factors: the higher rates of MRD response, fewer and less severe toxicities, and greater likelihood of proceeding to transplant.

“Blinatumomab recipients were more likely to have residual disease in their bone marrow cleared than patients receiving chemotherapy. [Moreover,] serious AE rates were much lower in the blinatumomab vs chemotherapy arm,” explained Brown. “The primary AEs observed with chemotherapy included life-threatening or even fatal infections. This was not seen with blinatumomab,” he continued.

“Lastly, blinatumomab recipients were far more likely to successfully proceed to therapy to receive a bone marrow transplant,” added Brown. “Since transplant is deemed as the … best chance of cure for these patients, we believe a significant contributor to the improved survival for blinatumomab is the ability to successfully bridge to transplant … This factor is particularly important.”

Future investigation will explore optimization of immunotherapy in this setting through strategies such as combining blinatumomab with checkpoint inhibitors, attempting to use immunotherapy to replace/augment reinduction chemotherapy, and investigating the ability of CAR*** T-cells to replace/augment transplant, said Brown.