Acute lymphoblastic leukemia (ALL) is a highly curable disease in children (80%-90%), while the cure rate in adults ranges between 35% and 50% [1]. Relapse or resistance (occurring in 10%-15% of children and in 50%-60% of adults) is the most important cause of therapeutic failure and represents an important problem in ALL management. Salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) in responding patients is the standard therapy for children with early relapses and for all adults with relapsed/refractory (R/R) ALL. However, only 50-60% of children and 30-40% of adults achieve a second complete remission (CR), and only half of these patients can be transplanted. In all, only 20% of children with early relapse and 10% of adults with relapsed/refractory ALL can be cured with standard therapies [2]. Consequently, the development of effective and relatively non-toxic rescue therapies for R/R ALL patients is clearly needed

Immunotherapy is a promising modality of treatment of neoplastic diseases. Among the several strategies used, the engagement of cytotoxic T cells irrespective of their T-cell receptor (TCR) specificity to the neoplastic cells has shown the highest therapeutic potential. Two therapeutic modalities have been especially useful for the treatment of B-cell precursor ALL [3,4]. One uses the ectopic expression of a CD19^-specific chimeric antigen receptor construct in transfected autologous T-cells of patients (CART). The other approach uses a CD19/CD3^-bispecific T cell–engager (BiTE®) monoclonal antibody (MoAb) blinatumomab, which can transiently engage any cytotoxic T cell to CD19⁺ target B cells [5-10]

The clinical development program of blinatumomab in ALL was initially focused on adult patients with R/R ALL and in ALL patients with high levels of minimal residual disease (MRD), a situation associated with a high risk of relapse [11]. The first two trials were conducted by the German Multicenter Adult Acute Lymphoblastic Leukemia (GMALL) Group, with complete responses (CR) of 42% (69% if CR with incomplete hematological recovery –CRh- was considered) in R/R patients [12] and of 80% in patients with MRD-positive ALL [13,14]. A global phase II study in R/R adult ALL patients was activated and of the 189 patients treated, 81 (43%) achieved CR/CRh within the first two cycles [15]. AlloHSCT was performed in 32 (40%) of the 81 patients with CR/CRh. At a median follow-up of 8.9 months the median RFS was 5.9 months. The median OS was 6.1 months (median follow-up 9.8 months), without differences after censoring the follow-up at alloHSCT. The OS was significantly better for patients achieving CR/CRh after two treatment cycles (median of 9.9 months vs. 2.7 months). In turn, the preliminary results of a confirmatory multicenter phase II study in adult patients with MRD-positive B-cell precursor ALL has shown that 89 out of 106 patients (80%) had complete MRD response after 2 cycles (88 [78%] after 1 cycle) [16]. The results of a phase II study of blinatumomab in pediatric patients with R/R B-precursor ALL have shown similar results than those of the adult trials [17]. Based on these results blinatumomab was approved by the US Food and Drug Administration (FDA) on December 3, 2014 following an accelerated review process, for patients with R/R, Philadelphia chromosome-negative B-cell precursor ALL

A phase II single-arm, multicenter trial aimed to evaluate the efficacy of blinatumomab in adults with R/R ALL and Philadelphia chromosome is currently being conducted, and the accrual of the 41 patients has been completed. In addition, a phase III, randomized, multicenter, open-label study investigating the efficacy of blinatumomab vs. standard of care (SOC) chemotherapy in adults with R/R, Philadelphia chromosome-negative, B-cell precursor ALL is now underway, and several trials in children with R/R ALL in both the US and Europe are in the activation process. The next logical step is to evaluate the activity of blinatumomab in early phases of ALL. An ongoing phase III study of combination chemotherapy with or without blinatumomab in patients with newly diagnosed Ph-, B-lineage ALL is being conducted in the US by the Eastern Cooperative Oncology Group (ECOG)

Blinatumomab has a specific safety profile. The most significant toxicities reported in the studies performed in R/R ALL and in MRD-positive ALL using the dose of 15 ug/m²/day CIV during 4 weeks with 2 weeks off between cycles were central nervous system (CNS) events and the cytokine release syndrome (CRS). The adverse CNS events consisted of encephalopathy, aphasia, tremor, and disorientation, and were reversible in most cases but led to early discontinuation of the drug in others [18]. Neurological events are managed with temporary interruption of blinatumomab and dexamethasone treatment. The CRS is thought to occur due to rapid lysis of tumor cells by T- lymphocytes during the first infusion, being more pronounced during the beginning of the first cycle of treatment [19]. Baseline disease burden is associated with risk of CRS and pre-phase dexamethasone is required for patients with more than 50% blasts or a peripheral blast count over 15 × 10⁹/L. The reduction in the dose of blinatumomab to 5 µg/m²/day (or 9 µg/day) in the first week of the first cycle also prevents the development of CRS

Despite the promising results of treatment with blinatumomab and the high rate of HSCT in responding patients, a significant number of patients do not respond or experience relapse. In a significant proportion of relapsed patients the leukemic blasts are CD19 negative, suggesting a selection of CD19-negative sub clones that are present at low levels at relapse. On the other hand, some of the relapses after blinatumomab are extra medullary, especially in CNS, suggesting an insufficient activity of blinatumomab in sanctuary sites.

Together with other immunotherapeutic approaches, blinatumomab provides a window of hope for patients with R/R B-precursor ALL, allowing a significant proportion of responses with an acceptable safety profile and increasing the proportion of patients that could be successfully rescued by alloHSCT. These results can hopefully be translated to early phases of the treatment of ALL.

Funding Supported in part by grants from the Red Temática de Investigación Cooperativa en Cáncer (RTICC, FEDER) (RD12/0036/0029); 2014 SGR225 (GRE) Generalitat de Catalunya; and PI14/01971 from Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, and Obra Social ”La Caixa”, Spain.