Blitzing ALL with blinatumomab Free

In this issue of Blood, Bassan et al¹ report the results of the phase 2 Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) LAL2317 trial following the addition of blinatumomab to multiagent chemotherapy in 149 adult patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). They found that after 1 cycle of consolidation therapy with blinatumomab, the measurable residual disease (MRD) complete remission rate increased from 72% to 93% (P < .001), thus fulfilling the primary end point of the study.

The immunotherapeutic revolution in the treatment of B-cell hematologic malignancies has been a remarkable achievement in the annals of modern medicine. Monoclonal antibodies, antibody-drug conjugates, bispecific T-cell engager (BiTE) molecules, and chimeric antigen receptor T cells have led to dramatic improvements in outcomes of patients with multiple myeloma, non-Hodgkin lymphoma, and ALL. Blinatumomab was the first BiTE molecule approved by the US Food and Drug Administration (FDA) with breakthrough therapy designation in July 2014 for relapsed and refractory ALL followed by full approval for adults and children for this indication in July 2017. This was largely based on the seminal results of the TOWER study which compared blinatumomab to multiagent chemotherapy.² In March 2018 the FDA expanded the approval to include patients with MRD positive ALL as an accelerated approval following the results of the BLAST trial with full approval for this indication following in June 2023.³ In June 2024, the FDA expanded the approval again for the therapy of children and adults in the consolidation phase of multiagent chemotherapy, largely based on the results of the E1910 clinical trial which showed a significant survival advantage for the addition of blinatumomab to consolidation chemotherapy in patients aged 30 to 70 years who were MRD negative after induction chemotherapy. In these patients overall survival improved from 68% with chemotherapy to 85% with blinatumomab plus chemotherapy at 3 years.⁴ Blinatumomab has also been found to significantly improve survival compared to historical controls in infants with KMT2A rearranged ALL.⁵ Most recently the Children’s Oncology Group study, AALL1731, showed improved disease-free survival of 96% with the addition of 2 cycles of blinatumomab to chemotherapy compared to 88% with chemotherapy only, in standard risk ALL pediatric patients aged 1 to 10 years.⁶ Thus, pivotal trials, largely phase 3, have demonstrated significant benefit for the addition of blinatumomab to multiagent chemotherapy in virtually all ages of patients from infancy to adults (see figure ^2-9).

The GIMEMA LAL2317 study gave multiagent chemotherapy as per their previous LAL1913 study and added 2 cycles of blinatumomab after cycles 3 and 6 of chemotherapy. A Philadelphia (Ph)-like signature was found in 31 out of 111 (28%) evaluable patients. Forty two percent were considered to be high risk or very high risk by an integrated risk classification. Complete remission was achieved in 89% of patients with an induction death rate of 4% in patients under the age of 55, but a high rate of induction death at 25% in patients over 55 years of age. Not surprisingly, patients who were MRD negative prior and after cycle 1 of blinatumomab had better survival than patients who were MRD positive prior to cycle 1 of blinatumomab even if they converted to MRD negativity post blinatumomab. Many of these latter patients had high-risk genetic features including KMT2A rearrangements, Ph-like disease, IKZF1 deletions, and adverse karyotypes. Results were very favorable in patients aged 18 to 40 years who were MRD negative prior to blinatumomab and had a non–Ph-like genotype with a disease-free survival of 92%. The regimen had a relatively low rate of high-grade adverse events but was associated with a higher rate of neurotoxicity related to blinatumomab.

What can we learn from the LAL2317 trial? First, it confirms the benefit of blinatumomab in treating MRD positive disease and as was seen in the E1910 trial appeared to bring the greatest benefit to younger patients. With this regimen allogeneic hematopoietic stem cell transplant (allo-HSCT) was applied to very high-risk patients and patients who were MRD positive and appeared to show a benefit to patients who were able to get to allo-HSCT compared to those who were not. Whether blinatumomab can overcome the effects of adverse genetic features, remains uncertain and an area worthy of further study. The regimen was toxic to patients over the age of 55 with an induction death rate of 25% and underscores the limits we can achieve with multiagent chemotherapy. Multiple phase 2 studies have shown encouraging results with reductions in chemotherapy and increased emphasis on the use of immunotherapy with inotuzumab ozogamicin and blinatumomab in older patients, and these findings may eventually allow us to reduce the amount of chemotherapy administered to younger patients as well.

It is remarkable that blinatumomab is effective in patients who are MRD negative, but it is important to recall that many of these patients may still have undetectable leukemic cells that immunotherapies can attack. Moreover, why blinatumomab remains effective in patients who have received multiple cycles of chemotherapy is unclear, but small studies have shown that patients who respond to blinatumomab are able to expand their T-cell pool, thus suggesting that chemotherapy does not entirely inhibit T-cell responsiveness.¹⁰ Intrinsic immune surveillance mechanisms may also play a role in preventing relapse in patients who remain in remission after completion of therapy.

The past 10 years have been a remarkable journey of benefit for our BCP-ALL patients as exemplified by the remarkable success that blinatumomab has wrought in children and adults in multiple phases of ALL and bodes well for continued success as we exploit the benefits of immunotherapy to improve survival and lessen the toxic effects of chemotherapy.

Conflict-of-interest disclosure: M.R.L. receives research funding from and serves on a speaker’s bureau at Amgen.