Blinatumomab was superior to high-risk consolidation (HC) 3 chemotherapy in a phase 3 clinical trial among children with high-risk first-relapse acute lymphoblastic leukemia (ALL), according to Franco Locatelli, MD, PhD, Ospedale Pediatrico Bambino Gesú and Sapienza, Rome.
Blinatumomab constitutes a new standard of care because of superior event-free survival (EFS) and other comparative benefits, including fewer and less severe toxicities, he said in a presentation at theannual meeting of the American Society of Hematology, which was held virtually.
About 15% of children with B-cell precursor (BCP) ALL relapse after standard treatment. Prognosis depends largely on time from diagnosis to relapse and the site of relapse. After relapse, when a second morphological complete remission (M1 marrow) is achieved, most are candidates for allogeneic hematopoietic stem cell transplant (alloHSCT), Dr. Locatelli noted. Immuno-oncotherapy with blinatumomab, a bispecific T-cell–engager molecule, has been shown to be efficacious in children with relapsed/refractory BCP-ALL.
In the open-label, controlled trial, investigators randomized children with M1 (<5% blasts) or M2 (<25% and 5% or greater blasts) marrow 1:1 after induction therapy and cycles of HC1 and HC2 chemotherapy to a third consolidation course with blinatumomab (15 µg/m2/day for 4 weeks) or HC3 (dexamethasone, vincristine, daunorubicin, methotrexate, ifosfamide, PEG-asparaginase); intrathecal chemotherapy (methotrexate/cytarabine/prednisolone) was administered before treatment. Patients achieving a second complete morphological remission (M1 marrow) after blinatumomab or HC3 proceeded to alloHSCT. EFS was the primary endpoint (from randomization until relapse date or M2 marrow after a complete response [CR], failure to achieve CR at end of treatment, second malignancy, or death from any cause).
Investigators had enrolled 108 (54 received HC3; 54 received blinatumomab) out of a target of about 202 patients when the data-monitoring committee recommended termination because of blinatumomab benefit observed at the first interim analysis. Median age was around 5.5 years (1-17), with the mean time from first diagnosis to relapse at approximately 22 months.
Dr. Locatelli reported events for 18/54 (33.3%) in the blinatumomab arm and 31/54 (57.4%) in the HC3 arm, with a median EFS of “not reached” and 7.4 months, respectively. The risk of relapse with blinatumomab was reduced by 64% versus HC3 (hazard ratio, 0.36; 95% confidence interval, 0.19-0.66, P < .001). Overall survival (OS) favored blinatumomab over HC3, as well, with a hazard ratio of 0.43 (95% CI, 0.18-1.01). Minimal residual disease (MRD) remission (MRD < 10-4) was seen in 43/46 (93.5%) blinatumomab-randomized and 25/46 (54.3%) HC3-randomized patients.
Relapses occurred more often in the HC3 group (blinatumomab 13, 24%; HC3 29, 54%) overall, and at each of the assessments at 6 months, 12 months, and 24 months. Also, MRD remissions by PCR (polymerase chain reaction) were superior in the blinatumomab arm overall (90% versus 54%) and according to baseline MRD status with strikingly divergent rates in those with MRD greater than or equal to 104 at baseline (93% blinatumomab/24% HC3). Rates were relatively similar in patients with MRD less than 104 at baseline (85% blinatumomab/87% HC3).
Grade 3 or greater treatment-emergent adverse events were reported by 30/53 (57%) and 41/51 (80%) patients in the blinatumomab and HC3 groups, respectively, with several markedly lower in the blinatumomab group (neutropenia/neutrophil count decrease 17 versus 31; anemia 15 versus 41; febrile neutropenia 4 versus 26). As expected, grade 3 or greater neurologic events occurred more frequently with blinatumomab than with HC3 (48% versus 29%); no grade 3 or greater cytokine release syndrome events were reported.
Tallying the blinatumomab benefits (superior EFS and MRD negativity prior to alloHSCT, improved OS, fewer relapses, fewer and less severe toxicities), Dr. Locatelli concluded, “Blinatumomab constitutes a new standard of care in children with high-risk first-relapse ALL.”
In the postpresentation discussion, Dr. Locatelli underscored the blinatumomab benefit versus a third course of chemotherapy: “Monotherapy with blinatumomab was able to present a higher proportion of patients in CR2 who could proceed to transplant.”
Dr. Locatelli disclosed relationships with multiple companies.
SOURCE: Locatelli F et al. ASH 2020, Abstract 268.