Blinatumomab is changing the standard of care paradigms of newly diagnosed and relapsed pediatric B-cell acute lymphoblastic leukemia

While acute lymphoblastic leukemia (ALL) is the most common malignant disease of childhood and adolescence, accounting for 25–30% of all cancers, the first relapse of ALL represents the sixth most common pediatric cancer and remains the leading cause of pediatric cancer-related mortality. Newly diagnosed ALL is curable with frontline therapy in 80–85% of children and adolescence, and the first relapse of ALL can be cured with salvage therapy in 50–60% of patients [1, 2]. However, it must be taken into account that the results achieved to date with intensive chemotherapy are associated with severe acute toxicities, long treatment duration, and also late effects. Further intensification of conventional chemotherapies (and allogeneic hematopoietic stem cell transplantation [allo-HSCT]) is not feasible and, in particular, not justifiable [3]. The success of allo-HSCT has already impressively demonstrated the efficacy of immunotherapy for childhood ALL (graft-vs.-leukemia effect; [4]).

It is thus expected that new antibody-based or cellular immunotherapies will significantly change the treatment spectrum of children and adolescents with ALL in the coming years, aiming not only to enhance outcomes, but also to mitigate treatment toxicity [5]. CD19 and CD22 are highly expressed on B‑ALL blasts and CD38 and CD7 on T‑ALL blasts, and these antigens are currently of great interest for targeted immunotherapeutic interventions. The successful use of monoclonal antibodies (mABs), unconjugated (i.e., daratumumab, anti-CD38), conjugated to toxins (i.e., inotuzumab ozogamicin, anti-CD22 + calicheamicin), or as bi-specific antibodies (i.e., blinatumomab, anti-CD19/CD3), has already been impressively shown in the relapsed and refractory (r/r) setting of pediatric ALL [5‐10]. “Off-the-shelf” mABs and antibody–drug conjugates have the advantage of being tumor-specific rather than patient-specific and can, therefore, be produced industrially, stocked easily, and used immediately in patients without waiting times. However, they are generally not curative as monotherapies, but “only” induce and/or maintain complete morphological/molecular remission, which needs to be consolidated by allo-HSCT (or chimeric antigen receptor [CAR] T cells) in the r/r setting of ALL [11]. By contrast, adding mAB to a multiphase chemotherapy protocol in the context of the frontline ALL setting usually aims at improving disease-free survival (DFS) and/or reducing acute toxicities for all risk groups without the need for allo-HSCT. The concept of combining the MHC-independent antigen recognition of mAB and the effector function of T cells was a breakthrough in the field of immunotherapy of malignant diseases and led to the development and broad clinical testing of blinatumomab but also, of course, of CAR T cells (i.e., tisagenlecleucel).

Blinatumomab is currently administered in children with B‑ALL via continuous intravenous (IV) infusion for 28 days per cycle and targets CD19 on B cells and CD3 on T cells, thereby allowing T cells to recognize and destroy CD19-positive leukemia cells [12]. The first phase I/II trial (NCT01471782) and the successive phase II trial (RIALTO, NCT02187354) tested single-agent blinatumomab for r/r pediatric B‑ALL (refractory disease, ≥  2nd relapsed B‑ALL, any relapse after allo-HSCT; [13‐15]). Together they demonstrated (1) its anti-leukemic efficacy in morphologically visible disease (≥ 25% blasts), with 52% of the responders (39%) achieving minimal residual disease (MRD) negativity; (2) its enhanced anti-leukemic activity in minimal residual bone marrow (BM) disease (52% achieved remission with MRD response); (3) its favorable toxicity profile; and (4) its anti-leukemic activity across all age and risk groups. Neurological toxicities and cytokine release syndrome were the most relevant but well manageable toxicities reported. The successive NEUF study, involving a real-world pediatric cohort of r/r B‑ALL and providing blinatumomab in an expanded access program, also showed that blinatumomab is effective, with > 50% of patients with relapse achieving remission and those treated in an MRD-positive setting also doing extremely well [16].

In addition to the RIALTO trial, three randomized phase III trials of the International Relapsed B‑ALL (high-risk relapse, NCT02393859) consortium and the Children’s Oncology Group AALL1331 (COG, low-, intermediate-, and high-risk relapse; NCT02101853, NCT02101853) for a first relapse of B‑ALL were conducted [17‐19]. The improved outcome measures (event- and disease-free survival, overall survival, MRD response, toxicity, and realization of allo-HSCT) obtained with blinatumomab in the context of multiphase therapy protocols established blinatumomab as a new standard of care for post-reinduction consolidation in pediatric patients with a high- and intermediate-risk first relapse of B‑ALL and with a standard-risk first relapse of B‑ALL with BM involvement [17‐19]. Notably, similarly dismal outcomes for isolated extramedullary relapses were reported with both standard of care chemotherapy and blinatumomab-based therapy in AALL1731 [17], leading to the pursuit of alternative approaches in this relapse setting.

A recent pilot trial also added one cycle of blinatumomab to post-induction Interfant-06 consolidation therapy for infants with newly diagnosed KMT2A-rearranged B‑ALL (EudraCT number 2016-004674-17; [20]). The addition of blinatumomab to this chemotherapy regimen was feasible, it markedly increased the rate of MRD-negative remission, and, most importantly, it led to significantly improved clinical outcomes with 2‑year DFS of 81.6% and overall survival (OS) of 93.3% compared to historic Interfant-06 chemotherapy-only outcomes of 49.4% and 65.8%, respectively [21]. Consequently, this major breakthrough established blinatumomab as a new standard of care in the context of a multiphase therapy of newly diagnosed infant KMT2A-rearranged B‑ALL. The addition of two cycles of post-induction blinatumomab with some chemotherapy reduction is now under prospective evaluation in a larger cohort of infants with newly diagnosed KMT2A-rearranged B‑ALL in the current international Interfant-21 trial (NCT05327894) with the goal of validating the superior outcomes observed in the Interfant-06/blinatumomab pilot trial and reducing chemotherapy-associated toxicity.

The AIEOP-BFM ALL 2017 trial (NCT03643276) was the first randomized phase III trial to evaluate a multi-agent chemotherapy regimen without or with the addition of blinatumomab in children with newly diagnosed intermediate-risk B‑ALL patients. This study also randomized patients with high-risk B‑ALL to two cycles of blinatumomab versus two intensive consolidation blocks with the goal of understanding the potential for improved DFS and OS and for decreased infectious and other acute toxicity [22]. Although outcome data are still pending, the toxicity profile appeared to be significantly in favor of blinatumomab with no life-threatening events recorded and the majority of adverse events of special interest in the blinatumomab arm to be neurological disorders (mainly grade 2 or 3 seizures; [22]). If upcoming analyses of outcome data show at least non-inferiority in terms of anti-leukemia efficacy, replacement of the intensive chemotherapy blocks by blinatumomab will become the new standard of care for consolidation treatment of newly diagnosed non-infant patients with high-risk B‑ALL.

The COG also performed a recent phase III trial (NCT03914625) of children with newly diagnosed standard-risk B‑ALL who had an average or higher risk of relapse [23]. Patients were randomized to receive standard-of-care chemotherapy alone or chemotherapy with the addition of two non-sequential cycles of blinatumomab. The randomization was permanently stopped following an interim analysis demonstrating clearly superior results for the blinatumomab arm compared to the chemotherapy-only arm, with 3‑year DFS for those with standard average-risk B‑ALL of 97.5 ± 1.3% vs. 90.2 ± 2.3% and for those with standard high-risk B‑ALL of 94.1 ± 2.5% vs. 84.8 ± 3.8% [24]. Notably, the incidence of non-fatal sepsis/catheter-related infections increased in children with standard average-risk B‑ALL treated in the blinatumomab arm, not just during blinatumomab cycles with continuous IV access, but well into maintenance therapy for reasons not yet fully understood [24]. Nevertheless, the addition of blinatumomab to therapy was established as the new standard of care for consolidation treatment of newly diagnosed non-infant patients with standard-risk B‑ALL.

Blinatumomab has also been documented as an effective consolidation approach for pediatric and adolescent patients with B‑ALL with chemotherapy intolerance during frontline treatment due to severe acute toxicities (e.g., infections, typhlitis, or L‑asparaginase-associated acute pancreatitis). The United Kingdom ALL group studied a cohort of 105 pediatric patients who received one to two cycles of blinatumomab as replacement for post-remission consolidation chemotherapy, 82% of whom were treated due to chemotherapy intolerance and 18% due to persistent leukemia/MRD positivity after induction therapy [25]. Blinatumomab was well tolerated and very effective, with 97% of patients achieving MRD-negative complete remission (CR). Event-free survival rates were similar to a matched chemotherapy patient cohort [25]. In line with the preliminary results of the AIEOP-BFM ALL 2017 trial, this study suggested that blinatumomab could replace intensive chemotherapy blocks in a high-risk B‑ALL population.

Collectively, according to recent data clearly demonstrating the superiority of blinatumomab-based therapy in infants with KMT2A-rearranged B‑ALL and children with SR B‑ALL and the similarly impressive rates of MRD-negative CR of adult patients with Philadelphia-negative B‑ALL treated with post-induction blinatumomab, the US Food and Drug Administration approved blinatumomab as consolidation therapy for patients \(\geq\)28 days of age with newly diagnosed B‑ALL. It is anticipated the European Medicines Agency will similarly update approved indications for blinatumomab in the near future. As a consequence of this success story, blinatumomab will be further investigated in soon-to-open and planned frontline pediatric B‑ALL trials, including for patients with Philadelphia-positive and ABL class Ph-like B‑ALL in combination with tyrosine kinase inhibitors via the EsPhALL2022/COG AALL2131 pilot study (NCT06124157), and in those with first relapsed B‑ALL treated at early time points of protocol therapy (now also replacing very early consolidation chemotherapy elements; [27‐29]). Although generally less toxic than intensive cytotoxic chemotherapy and amenable to outpatient administration, blinatumomab has potential for specific immunologic and neurologic adverse events (e.g., cytokine release syndrome, seizure, encephalopathy), and its current need for continuous infusion and IV access may be logistically challenging [30]. A recent subcutaneous formulation of blinatumomab has been tested in adults with r/r B‑ALL and demonstrated high CR rates and impressive rates of MRD clearance, representing an emerging viable alternative to continuous IV delivery and meriting pediatric-specific investigation [31].

In conclusion, the use of blinatumomab now gives children and adolescents with resistant or multiple relapsed B‑ALL the chance of achieving molecular remissions and definitive cures through therapy with successive allo-HSCT or CAR T cells. However, as blinatumomab also improved outcomes in the frontline and first-relapse setting of pediatric B‑ALL, but mostly when “only” given on top of a multiphase chemotherapy protocol, its use at earlier time points of our study protocols seems warranted in order to replace conventional chemotherapy. Thereby, acute toxicities could be further reduced and with improved early response to therapy, high-risk group allocations and allo-HSCT rates could be decreased.