Lancet Haematol: Hyper-CVAD sequential berintoolomab for Ph-B-ALL, with a 3-year survival rate of over 80%

Blinatumomab is a CD19/CD3 bispecific T cell adaptor with excellent efficacy in monotherapy for relapsed or refractory B-cell acute lymphoblastic leukemia (ALL), and its early experience as the first-line treatment for older (age> 65 years) Philadelphia chromosome (Ph)-positive and Ph-negative ALL (a population with poor outcomes due to poor biology and poor tolerance to chemotherapy)
is also encouraging.

In the recent issue of the journal Lancet Haematology, Elias Jabbour et al.
added belintoumab to hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) regimens, alternating high-dose methotrexate and cytarabine as first-line treatment
for Ph-negative B-ALL adult patients.

A total of 38 patients were included in the study, with a median age of 37 years (IQR 29-45); Twenty-two (58%) patients were adolescents or young adults, and 26 patients (68%) were male
.

The results of the study were impressive, with a median follow-up of 37 months, and even after excluding 4 to 6 cycles of intensive chemotherapy, belintosumab consolidation and maintenance therapy achieved a high MRD-negative rate (97% achieving MRD-negative remission at any time of treatment), a sustained response rate (73% relapse-free survival at 3 years), and an estimated 3-year overall survival rate of 81%, providing a new option
for initial treatment of the disease.

After 1 cycle, 4 (100%) of 4 MRD-positive patients before belintoolomab treatment were MRD-negative
by multiparametric flow cytometry.
Of the 10 patients who were MRD-negative prior to next-generation sequencing of belintoumab, 8 (80%) were MRD-negative
after belintoumab.
The 3-year recurrence-free survival rate of 21 high-risk patients was 66%, and the overall survival rate was 76%; All patients with relapse had high-risk features, suggesting that adverse cytogenetic changes remain a considerable barrier to
improving outcomes.

The most common non-hematology grade 3 to 4 adverse event was infection, which occurred in 14 (37%) of 38 patients during induction and 27 (71%) of 38 patients during a consolidation chemotherapy cycle
.
Five (15%) patients developed any grade of cytokine release syndrome (1 ≥grade 3 and resolved within 24 hours), and 16 (47%) patients had any grade of berintoumab-related neurological events (4 grade 3 but no identifiable associated risk factors).

However, as with other single-arm, phase 2 studies, this study had a small sample size (n=38), thus limiting within-group comparisons, even though patients aged 18 to 29 years (n= 12) had the highest 3-year recurrence-free survival (83%) and overall survival (100%)
.

Although the above phase II study results are good, it is not possible to recommend belintoumab for all patients with Ph-negative acute lymphoblastic leukemia, and randomized trials are needed, after all, this study is small in sample size and is a single-center, single-arm, phase 2 trial, which may be accidental and overestimate the effect
of the drug 。 Beyond that, new research always raises more questions than answers: What is the optimal number of cycles for chemotherapy and berintoumab? Is there an increase in benefit or harm for a subset of patients? Do immune checkpoint inhibitors improve the efficacy of belintoumab? What is the role of consolidation allogeneic transplantation? Does early use of belintoumab reduce the efficacy of CD19 CAR T-cell therapy?

Although some questions remain, an exciting new era has begun
for first-line treatment of B-cell acute lymphoblastic leukemia.
Harnessing the power of the immune system can reduce the number of chemotherapy cycles with promising
results.
It is hoped that this regimen will improve cure rates and ultimately bridge the gap between adult and pediatric outcomes with acute lymphoblastic leukaemia worldwide
.

References

1.
Elias Jabbour,et al.
Hyper-CVAD and sequential blinatumomab for newly diagnosed Philadelphia chromosome-negative B-cell acute lymphocytic leukaemia: a single-arm, single-centre, phase 2 trial.
Lancet Haematol .
2022 Oct 21; S2352-3026(22)00285-X.
doi: 10.
1016/S2352-3026(22)00285-X.

2.
León AG,Mejía-Aranguré JM.
Blinatumomab plus hyper-CVAD: the prelude to a new era in acute lymphocytic leukaemia.
Lancet Haematol .
2022 Oct 21; S2352-3026(22)00294-0