The Brilliant Success of Blinatumomab for Babies With Acute Lymphoblastic Leukemia

Although survival outcomes for children with acute lymphoblastic leukemia (ALL) have improved markedly over the past two decades,¹  outcomes for infants diagnosed at less than one year of age remain grim with six-year event-free-survival (EFS) and overall survival (OS) rates of 46.1% and 58.2%, respectively.²  Moreover, the long-term survival rate among the 75% of infants with ALL harboring KMT2A (histone lysine N-methyltransferase 2A) rearrangements is less than 40%,^2-4  which contrasts sharply with the much more favorable EFS and OS rates among infants (and older children) with KMT2A wild-type ALL.^5-8 

In a recent international phase II clinical trial (EudraCT 2016-004674-17),⁹  Inge van der Sluis, MD, PhD, and colleagues examined the addition of post-induction blinatumomab, a bispecific antibody that directs CD3⁺ host T cells against CD19⁺ B-lineage ALL (B-ALL) cells, to the standard-of-care chemotherapy regimen for infants with newly diagnosed CD19⁺KMT2A-rearranged ALL, all of whom had under 25% leukemic blasts in the bone marrow at the end of induction chemotherapy. The primary study endpoint was toxicity attributed to blinatumomab resulting in permanent drug discontinuation or death. Secondary endpoints included other therapy-associated toxicities, drug tolerability, measurable residual disease (MRD) responses, and survival outcomes. Following induction therapy as per the Interfant-06 protocol,²  infants enrolled in the study received one cycle of blinatumomab (15 mg/m²) administered as a continuous intravenous infusion for 28 days. Upon completion of the first cycle, patients with medium-risk disease (defined as negative or low MRD [<5x10^-4] based on the results of an immunoglobulin or T-cell receptor rearrangement polymerase chain reaction analysis)¹⁰  received three additional intensive Interfant-06 blocks of chemotherapy followed by a maintenance phase consisting of oral mercaptopurine and methotrexate, resulting in a total therapy duration of two years. All patients with high-risk disease (defined based on an age less than 6 months at ALL diagnosis, presenting white blood cell count >300x10⁹/L, and/or poor response to prednisone) and those with persistent MRD (>5x10^-4) after two post-blinatumomab chemotherapy cycles were allocated to undergo allogeneic hematopoietic stem cell transplantation (HSCT) at first complete remission (CR1).

All 30 infants with KMT2A-rearranged B-ALL received the complete four-week cycle of blinatumomab with a single two-day disruption for one patient with hypertensive crisis, who successfully resumed treatment without complication. Blinatumomab was very well tolerated, and no toxic effects leading to drug discontinuation or drug-attributed deaths were reported. Among the nine infants with high-risk disease, eight underwent HSCT in CR1. The remaining patient died following an unrelated mechanical bleeding event prior to planned HSCT. Although not statistically significant, there were notable differences in MRD responses relative to historical control data: Following blinatumomab infusion, 93% of patients (n=28/30) had no or low-level MRD versus 83% at the pre-cycle 3 chemotherapy timepoint of the Interfant-06 protocol.²  Furthermore, the survival outcomes observed were extremely promising: Dr. Van der Sluis and colleagues reported two-year disease-free survival and OS rates of 81.6% (95% CI 60.8-92.0) and 93.3% (95% CI 75.9-98.3),⁹  respectively, while the respective EFS and OS rates for historical controls in the Interfant-06 trial were 42.4% (95% CI 37.9-46.8) and 54.5% (95% CI 49.9-58.9).²  Despite the relatively short follow-up period, these results are nonetheless paradigm-changing given that nearly all relapses in infants with KMT2A-rearranged ALL occur within two years of initial diagnosis.