All about blinatumomab: the bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia

ABSTRACT

Introduction:

B cell acute lymphoblastic leukemia-lymphoma (B-ALL) accounts for approximately 75% of ALL cases and is observed in children and adults. Recent advances in disease diagnosis, stratification and prognostication have led to a better characterization of different subgroups of ALL. Notwithstanding the significant improvement in the complete remission rate of B-ALL, patients with minimal residual disease (MRD) and relapsed/refractory (R/R) settings suffer from poor outcomes. Hypothesis: However, novel therapies, such as agents targeting tyrosine kinases or the CD20 molecule, combination therapies and improved supportive care, have changed the treatment landscape of B-ALL.

Method and results:

Meanwhile, blinatumomab has been FDA-approved for MRD-positive or R/R B-ALL patients. Blinatumomab is a bispecific T cell engager containing the CD3 and CD19 that recognize domains redirecting cytotoxic T cells to lyse B cells. Promising outcomes, including long-term overall survival and improved MRD-negative response rates, have been reported in patients who received this drug. Adding blinatumomab to new ALL regimens seems promising for achieving better outcomes in poor prognosis B-ALL patients. Nevertheless, the neurotoxicity and cytokine release syndrome are the two major adverse events following the blinatumomab therapy.

Conclusion:

This review summarizes the function and effectiveness of blinatumomab in R/R and MRD positive B-ALL patients. Furthermore, blinatumomab’s positive and negative aspects as a novel therapy for B-ALL patients have been briefly discussed.

Keywords:
Acute lymphoblastic leukemia; Lymphoma; Blinatumomab; Minimal residual disease; Relapsed/refractory

Introduction

Enhancing conventional chemotherapy with targeted therapies increased the complete remission (CR) rate and the long-term survival rate of newly diagnosed acute lymphoblastic leukemia (ALL) patients to 85–90% and 40–45%, respectively. However, about one-third of patients at standard risk and two-thirds of high-risk patients experience relapse.¹,² Relapsed/ Refractory (R/R) B cell ALL (B-ALL) results in worse CR and long-term survival outcomes.¹,³,⁴ Numerous studies are underway to improve R/R ALL outcomes. Applying advanced methods, such as real-time quantitative-PCR (q-PCR), multicolor flow cytometry (MFC) and next-generation sequencing (NGS) for accurate diagnosis of minimal residual disease (MRD), has a significant impact on managing patients’ recurrence and improving their survival. Evaluating the MRD is the most beneficial tool in the relapsed ALL diagnosis. The presence of more than 0.01% of the detectable blast percentage is considered positive MRD.⁵,⁶,⁷,⁸,⁹

As mentioned above, the combination of targeted therapies, such as tyrosine kinase inhibitors (TKIs) and anti-CD20-antibodies, with conventional chemotherapy significantly impacted the ALL outcome.¹⁰,¹¹,¹²,¹³,¹⁴ The CD19, a type I transmembrane (TM) glycoprotein, is exclusively expressed in the B lineage, including both normal B cells and B cell leukemia and lymphoma.¹⁵,¹⁶ Blinatumomab (Blincyto, Amgen), a newly emerged CD3-CD19 bispecific T cell engager (BiTE),¹⁷ has two recombinant single-chain variable fragments that temporarily link CD3+ T cells and CD19+ B cells, leading to the T cell-mediated lysis of neoplastic B cells.¹⁸ This article reviewed the effects of blinatumomab on B-ALL management.

Blinatumomab mediates B cell apoptosis via activated T-cells

Blinatumomab is an anti-CD3/CD19 BiTE antibody with two recombinant single-chain variable fragments that temporarily link CD3+ T cells (ε chain in CD3) and CD19+ B cells (CD19 chain), leading to T cell-mediated lysis of B cells.⁷,¹² Since the CD19 is a pan B cell antigen, the anti-CD19 variable fragment of blinatumomab targets this antigen and overcomes the B cell lineage leukemia/lymphoma. The transient engagement of tumor cells occurs by linking the drug to the CD3 of T cells. After the bridge-like linking of blinatumomab between B cells and T cells, a signaling pathway is triggered, leading to the T cell activation and release of granzymes and perforins into the immunological synapse. At the end of these interactions, tumor cell destruction occurs by the activation of caspases and apoptosis (Figure 1).¹³

Figure 1
Blinatumomab’s mechanism of action. a. Interaction between anti-CD19 and CD19 on B cells and anti-CD3 and CD3 on T cells. b. The main components of the blinatumomab (two recombinant single-chain variable fragments of anti-CD3 and anti-CD19) and its mechanism of action; 1. Transient engagement of B cells and T cells by blinatumomab; 1.1. Anti-CD3 links ε chain of CD3 on T-cells anti-CD19 connects CD19 on B cells; 2. Immunological synapse formation and releasing of serine proteases (such as perforins and granzymes) by activated T cells, and; 3. B cell apoptosis.

Blinatumomab in MRD+ patients

Eradicating MRD is one of the most critical goals in disease management and outcomes improvement in ALL patients. The MRD is incapable of detection by routine cytomorphology and is only detected by more sensitive methods, such as flow cytometry, PCR techniques and NGS.¹,²,¹⁹ Various clinical trials investigated the effect of blinatumomab on MRD+ B-ALL patients. In a study by Topp et al., blinatumomab (15 μg/day, 4 weeks on and 2 weeks off) was administered to 21 B-ALL patients with MRD ≥ 1 × 10^–4. Among the evaluated patients, sixteen (80%) achieved negative MRD after administrating the first course of blinatumomab.³ Eligible patients with suitable donors were allowed for allogeneic hematopoietic stem cell transplantation (allo-HSCT) after the first course of blinatumomab therapy. Thirty-three months of follow-up disclosed the efficacy of a 61% overall relapse-free survival (RFS) rate (65% in patients who underwent HSCT and 60% in patients who did not undergo HSCT).⁴ Moreover, 50% of the 20 mentioned patients remained in CR at the end of the analysis at 50.8 months (56% of the patients had undergone HSCT and 45% had not).⁵

Gökbuget et al. followed the earlier study with 4 courses of blinatumomab (15 μg/day, 4 weeks on and 2 weeks off) in B-ALL patients in hematologic CR and with recurrent or persistent MRD (≥ 10^–3) after ≥ 3 courses of intensive chemotherapy. Of 116 patients who received blinatumomab and were evaluated for MRD, 78% achieved negative MRD after the first course of blinatumomab and approximately 2% achieved negative MRD after the second course, but other patients did not achieve MRD negativity even after courses 3 or 4.⁶ The second study by the same group investigated the survival and HSCT in 110 ph+ B-ALL patients; they reported a median relapse-free survival (RFS) and overall survival (OS) of 18.9 months and 36.5 months, respectively.²⁰

Remarkably, patients achieving negative MRD after the first course of blinatumomab demonstrated significantly superior survival outcomes than MRD+ patients; the median RFS was 23.5 vs. 5.6 months (p = 0.002) and median OS was 38.8 us. 12.4 months (p = 0.002) in MRD-positive and MRD-negative patients, respectively. Thus, these observations revealed a privilege in altering the positive MRD to the negative one. Since this study showed a superior effect of blinatumomab on RFS and OS in the first CR, compared to the second or third ones, administering it in the first CR was suggested to eradicate the MRD. Among 110 ph-positive B-ALL patients, 67% (74/110) underwent allo-HSCT and 49% (36/74) remained in CR. Interestingly, 25% (9/36) of ph-ALL patients who did not receive chemotherapy or HSCT remained in CR after blinatumomab.²¹ Blinatumomab received FDA approval for B-ALL patients in CR with MRD ≥ 10^–3 (0.1%) in 2018.⁷

The effect of blinatumomab on the survival of Ph-positive B-ALL patients with recurrent or persistent MRD of ≥ 10^–4 was evaluated by Richard-Carpentier et al., who showed no significant difference in RFS or OS between Ph-positive and Ph-negative patients in two years of follow-up.⁸

Optimal MRD for using blinatumomab

As mentioned earlier, blinatumomab was approved by the FDA for an MRD ≥ 10^–3 according to the Gökbuget et al. study.²¹ However, the problematic feature of MRD thresholds, absence of standardization of the MRD level for clinical decisions and advent of high sensitivity methods for MRD detection led to using various MRD thresholds in different clinical trials.³,⁸ For example, the FDA-approved-clonoSEQ-NGS assays support MRD detection at 10^–6.⁷ On the other hand, more technological advances in the future are likely to increase the ability to detect very low levels of MRD. Therefore, future studies should be conducted to clarify if patients with very low levels of MRD benefit from blinatumomab or not.

Performing HSCT after MRD-negativity following blinatumomab or not?

The allo-HSCT is recommended for ALL patients who do not respond to induction therapy.⁹,¹⁰ However, it is not yet clear whether positive MRD patients who show undetectable MRD after blinatumomab therapy will benefit from the HSCT or not. For example, the BLAST study showed that 25% of non-transplanted patients and 49% of transplanted patients remained in CR. Therefore, all blinatumomab respondents did not require HSCT.⁷,²¹ However, these trials were not performed to evaluate the impact of HSCT after blinatumomab.

For those MRD patients who respond to blinatumomab, but are not suitable candidates for transplantation, it is necessary to determine the optimal number of blinatumomab cycles and evaluate the demand for combination therapy. In the case of HSCT with blinatumomab administration, the effect of blinatumomab in post-HSCT maintenance should be investigated.¹¹

Real-world data of B-ALL patients treated with blinatumomab

The advent and utilization of blinatumomab is evidence of shifting the old paradigm to the emerging plans for better B-ALL management (Table 1). A B-ALL cohort with 239 patients (relapsed refractory, n = 227, and MRD positive, n = 12) who received blinatumomab therapy evaluated the safety and efficacy of this approach in the real-world context. Before blinatumomab initiation, 26% (n = 61) patients had received ≥ 3 previous therapies and 19% (n = 46) had undergone HSCT. The CR/CRi rate (CR with incomplete hematologic recovery) was 65% in RR patients. Among MRD-positive patients who received blinatumomab, 75% achieved MRD negativity. RR patients who received blinatumomab showed median RFS and OS of 32 months and 13 months, respectively. In positive MRD patients, the median RFS and OS were not achieved. Neurotoxicity, hepatotoxicity and cytokine release syndrome (CRS) with grade ≥ 3 were reported in 7%, 10% and 3% of patients, respectively. The allo-HSCT, as consolidation therapy in patients with CR/Cri, retained its favorable prognostic effect for OS (p = 0.04).¹³,¹⁴

Table 1
Clinical trials of blinatumomab in R/R B-ALL.

Study	Results	Ref
Phase II trial	• Blinatumomab was tolerable at the dosage of 5 - 15μg/m2/d.	22
	• Of 36 patients who received blinatumomab, 25 achieved CR and MRD became negative in 88% of responders.
Phase II trial	• 36% of patients achieved CR/CRh within the first two cycles.	23
	• 88% of CR/CRh responders achieved a complete MRD response.
	• Median RFS and OS were 6.7, and 7.1 months.
	• Of the 16 responders, 44% were alive without relapse, and 50% had relapsed with a median time of 6.7 months.
Phase Ib	• The maximum tolerable blinatumomab dose was 5μg/m2/day for week 1, followed by 15μg/ m2/day for weeks 2 to 4.	24
	• Blinatumomab appeared to be safe, with preliminary evidence of efficacy in Japanese children with R/RBCP ALL.
	• All patients had at least one treatment-emergent adverse event.
	• The Ml remission rate within the first two treatment cycles was 56%, while 44% of M1 remission showed full bone marrow recovery.
	• The MRD response was detected in one patient who had M1 remission.
Phase II	• A total of 86% of the patients received dexamethasone within 30 days of blinatumomab therapy.	25
	• Of the 89 patients treated with blinatumomab, after two cycles, 81 patients had achieved a CR or CRh.
	• Median relapse-free survival was 5.9 months for the 82 patients in CR or CRh.
	• Median overall survival was 6.1 months for all 189 patients, with a median follow-up of 9.8 months.
	• The treatment-related mortality was low.
	• Of the 73 patients who achieved CR or CRh, 82% of them achieved an MRD response.
Phase II	• Of the 45 patients, 16 achieved CR/CRh within the first two cycles of blinatumomab.	26
	• After a median follow-up of 25.1 months, the median OS was 9.0 months.
	• A total of 87.5% of CR/CRh patients achieved a complete MRD response with a 9.7-month median duration.
	• Patients with R/R PhÞ ALL revealed a long-term durable response to single-agent blinatumomab.
Phase III	• The OS for blinatumomab versus chemotherapy was higher, both in first salvage and in later salvage.	27
	• Safety was similar between patients in first salvage and those in later salvage.
	• Blinatumomab was associated with greater remission or survival than chemotherapy, resulting in similar or higher transplantation rates.
	• Salvage therapy with blinatumomab, as the first salvage in adults with Ph-precursor BCP-ALL, may be particularly more beneficial than chemotherapy for overall survival; it may serve as a bridge to transplant in patients in later salvage.
Phase II	• The rate of CR or CRh was 36% for blinatumomab and 25% for SOC.	28
	• Compared to external SOC, blinatumomab improves treatment outcomes in patients with r/r Ph + ALL.
Randomized phase III	• The MRD remission in the blinatumomab vs. consolidation chemotherapy groups was 90% vs. 54%.	29
	• In the Blinatumomab vs. consolidation chemotherapy group, the death rate was 14.8% vs. 29.6%.
	• Using blinatumomab before allo-HSCT resulted in improved event-free survival, compared to standard chemotherapy.
Retrospective multicenter study	• A total of 75% of the patients became MRD negative following blinatumomab.	30
	• The OS was 12.7 months using blinatumomab.
	• Blinatumomab provides a higher response rate, compared to conventional chemotherapy in RR ALL.
	• Combination therapy with blinatumomab and tyrosine kinase inhibitor combination is safe and effectively improves the long-term outcome of RR Ph1 B-cell ALL patients.

• CR/CRh, Complete Remission/Complete Remission with Partial Hematologic Recovery; MRD, Minimal Residual Disease; RFS, Relapse-Free Survival; OS, Overall Survival; R/R B-cell precursor ALL, Relapsed/Refractory B-Cell Precursor Acute Lymphoblastic Leukemia; R/R PhÞ ALL, Relapsed/Refractory Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia; SOC, Standard Of Care; allo-HSCT, Allogeneic-Hematopoietic Stem Cell Transplantation.

Blinatumomab adverse drug reactions

Approximately 98.5% of patients receiving blinatumomab will show adverse drug reactions, including 62% presenting serious complications and 19%, fatal adverse effects, with 12.5% requiring immediate treatment cessation.¹⁵ Blinatumomab side effects and its standard of care chemotherapy (with or without anthracycline chemotherapy, high-dose methotrexate, high-dose cytarabine (HiDAC), or clofarabine regimens) are displayed in Figure 2. The most significant adverse drug reactions are neurotoxicity and cytokine release syndrome.

Figure 2
The reported adverse drug reactions for blinatumomab-treated patients compared to the standard of care chemotherapy.⁷ TR, Transfusion Related, CRS, Cytokine Release Syndrome.⁷

Unexpected neurological adverse events and their management

Neurological adverse events are one of the major causes of the blinatumomab therapy termination.¹⁷ Manifestations of neurotoxicity vary from mild symptoms, such as headache, confusion, tremor, or disorientation, to serious clinical symptoms, such as seizures, aphasia, or stupor. The major reason for blinatumomab-induced neurologic toxicity is still ambiguous.

A probable two-step model has been suggested for a comprehensive understanding of the blinatumomab-induced neurotoxicity mechanism. First, blinatumomab induces T-cell reorganization from the peripheral blood to the perivascular space in a B-cell-independent manner. Subsequently, in a B-cell-dependent manner, it induces T-cell activation and cytokine release. In sequence, the released cytokines cause neurotoxicity.¹⁸,³¹ In neurotoxicity grades 1 to 2, supportive treatments with intravenous fluids, anti-inflammatory agents and respiratory support therapies are suggested. Additionally, steroid therapy with dexamethasone 8 mg/ every 8 hours should be started as a priority to avoid progression to a higher grade. In the case of symptom progression, blinatumomab therapy discontinuation is necessary. In the case of grade 3 neurotoxicity, blinatumomab therapy must be ceased to reduce the neurotoxicity grade ≤ 1 for at least 3 days. Once the patient’s condition becomes stable, blinatumomab can be resumed at the initial dose and increased after 7 days. For patients who present continuous grade 3 neurotoxicity for more than 7 days, or reach grade 4 neurotoxicity, following the re-administration of blinatumomab, permanent drug termination is recommended.³² In these cases, dexamethasone at 8mg., every 8 hours for 3 days, and a tapering dose in 4 days is recommended. Since the seizure incidence rate is very low (< 1%), prophylaxis is only conducted in particular contexts.¹⁵ Moreover, further central nervous system (CNS) examinations are needed to rule out other probable neurological diseases.

Unexpected cytokine release syndrome and its management

Although immunotherapy adventures profoundly affect managing hematological malignancies, its related toxicity has overshadowed its valuable benefits. The CRS is one of the most crucial neurological adverse effects following T cell-based therapies, such as blinatumomab. Antigen-antibody interaction, cytotoxic T cells activation and subsequent monocytes and macrophages activation, which are all induced by blinatumomab, are the major causes of massive inflammatory cytokine release, systemic inflammatory response syndrome and CRS.³¹ In this regard, increased levels of interferon gamma (IFN-γ), interleukin 6 (IL-6) and interleukin 10 (IL-10) have been reported in ALL patients who received blinatumomab.³³ Cytokine elevation could be associated with both the toxicity and efficacy of blinatumomab. The CRS could present a broad spectrum of clinical manifestations from mild to severe symptoms, including fever, flu-like symptoms, hemodynamic instability, coagulopathy and capillary leak syndrome, resulting in multi-organ system failure.²²

A phase III clinical trial has reported a relative incidence rate of 16% and 5% in CRS with any grade and CRS with grade ≥ 3, respectively.³⁴ Treatment discontinuation and interruption due to CRS occurred in 1% and 5%, respectively.¹⁵ On the other hand, the CRS rate was lower in the MRD positive group than in the R/R patients due to the difference in tumor burden and elevated cytokines release in the two groups.²⁰ Considering the CRS incidence and severity are considerable issues in starting the blinatumomab therapy, prophylactic treatment, cytoreduction, pre-phase dexamethasone, dose modification and dose interruption are the assessments for such a purpose.³⁵

A corticosteroid is suitable supportive care to restrain blinatumomab-induced CRS. However, disrupting the T cell function and reducing the blinatumomab clinical benefit has remained a concern in the corticosteroid therapy. In light of IL-10, IL-6, and IFN-γ increase following the blinatumomab-related CRS, treatment options targeting these cytokines could address the CRS consequences.³⁶ The IL-10 and IFN- γ are undesirable cytokines for targeting therapy because the IFN-γ likely plays a role in the blinatumomab efficacy and the IL-10 is a negative regulator of the immune system.³⁷,³⁸

The IL-6 blockade using tocilizumab provides promising results in controlling CRS in patients who received blinatumomab or chimeric antigen receptor T cells (CAR T cells).³⁹,⁴⁰ Tocilizumab received FDA approval in 2010 and is prescribed to treat rheumatoid arthritis, systemic juvenile idiopathic arthritis, polyarticular juvenile idiopathic arthritis, giant cell arteritis and CRS.⁴¹,⁴² Studies suggested that tocilizumab could ameliorate CRS symptoms without affecting the effectiveness of T cell-related therapies. Tocilizumab at dosages of 12 mg/kg and 8 mg/kg is prescribed for patients weighing less than or over 30kg.⁴³ Anakinra, an IL-1 receptor antagonist, has shown remarkable effects in controlling CAR T-induced CRS and CAR-related encephalopathy syndrome.⁴⁴ Anakinra or tocilizumab have not inhibited CAR T cell effectiveness; therefore, they are suitable for the prophylactic management of CRS.⁴⁵ Since CRS pathophysiology mechanisms are similar in both blinatumomab and CAR T cell therapy, IL-1 antagonists may hinder blinatumomab-induced CRS. Further experimental and clinical studies would be essential in understanding the efficacy of tocilizumab and anakinra in CRS prevention and treatment.

Resistance to blinatumomab therapy

One of the critical issues considered in blinatumomab therapy is the risk of resistance.⁷ As Table 2 shows, one possible mechanism of blinatumomab resistance is the loss of the target antigen.⁴⁶ Treating mixed-lineage leukemia (MLL)-rear-ranged B-ALL patients with blinatumomab is another possible mechanism of blinatumomab resistance, which may switch lineage from ALL to AML.⁴⁷,⁴⁸,⁴⁹,⁵⁰

Table 2
The mechanisms of resistance to blinatumo-mab therapy.

Type of Resistance	Mechanism	Ref
Loss of T cell activity	Up-regulation of PDL-1 expression on leukemic cells and PD-1 expression on T cells contributes to T cell exhaustion.	51,53,54
	Up-regulation of Tim-3, and TIGIT expression in CD8+ T cells of non-responder patients and elevated expression of Galectin-9 (Tim-3 ligand), PD-L2 (PD-1 ligand) and CD155 (TIGIT ligand) on tumor cells.
	High regulatory T cell (Treg) frequency leads to suppression of T cell proliferation and reduction of anti-leukemic cytotoxicity.
Modification of the target antigen	Down-regulation CD19 expression Suppressive microenvironment Disruption in CD19 membrane export	55,56

• PDL-1, Programmed death ligand- 1; PD-1, programmed cell death protein 1; Tim-3, T cell immunoglobulin and mucin domain 3; TIGIT, T cell immunoreceptor with immunoglobulin and ITIM domains.

On the other hand, since the T cell activity is one of the important parameters in blinatumomab efficacy, decreasing the T cell activation could be a possible reason for the blinatumomab resistance. Evidence of this claim is the increased expression of T cell exhaustion markers PD1 and PD-L1 following blinatumomab therapy. Thus, the immune checkpoint inhibitors may influence the blinatumomab efficacy.⁵¹,⁵² The anti-leukemic response was increased in a 12-year-old patient with refractory ALL after combination therapy with blinatumomab and anti-PD-1 antibody. The blockade of the PD-1/PDL-1 pathway or CTLA-4 could enhance the T cell function and improve the blinatumomab efficacy in patients who expressed T cell exhaustion markers [51]. A multi-center phase I dose-escalation study evaluated the combination of blinatumomab plus nivolumab (anti-PD-1 monoclonal antibody) and ipilimumab (anti-CTLA-4 monoclonal antibody) in R/R CD19⁺ ALL patients. Their results revealed that the combination of blinatumomab and nivolumab/ipilimumab is feasible and tolerable. Among five patients, four achieved CR, whereas one developed extra-medullary relapse.⁵¹ Several clinical trials (such as NCT02879695, NCT04546399 and NCT03512405) were conducted to explore the effectiveness of combination therapy by blinatumomab and the immune checkpoint inhibitors in R/R ALL patients. Further studies would be required to prove the positive impacts of immune checkpoint inhibitors on overcoming blinatumomab resistance.

Conclusion

Advanced treatment strategies and novel drugs have improved the clinical outcome of B-cell ALL patients. For instance, tyrosine kinase inhibitors (target JAK/STAT and mTOR pathways), antibody drug-conjugate, bispecific antibodies and chimeric antigen receptor T cells are promising in achieving more favorable outcomes. However, the outcome in R/R ALL patients remains poor. The FDA has approved blinatumomab for R/R B-ALL and MRD+B-ALL. The poor prognosis ALL patients with some translocations, such as the TCF3/HLF-fusion and Philadelphia-positive or Philadelphia-like ALL are candidates to receive blinatumomab. single-agent blinatumomab and its combination with other therapies, such as TKIs have improved survival and long-term outcomes. Furthermore, combining checkpoint inhibitors (anti-PDL-1 and anti-CTLA-4 antibodies) with blinatumomab could enhance its effectiveness. Although blinatumomab administration is tolerable and safe, prevention and optimal management of blinatumomab-induced adverse reactions are considerable issues.

• Data availability statement
  The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
• Funding
  This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

This study was supported by the Hematopoietic Stem Cell Research Center (HSCRC), Shahid Beheshti University of Medical Sciences, Tehran, Iran.

REFERENCES

• ¹
  Beldjord K, Chevret S, Asnafi V, Huguet F, Boulland M-L, Leguay T, et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood. 2014;123(24):3739–49.
• ²
  Brüggemann M, Raff T, Flohr T, Gökbuget N, Nakao M, Droese J, et al. Clinical significance of minimal residual disease quantification in adult patients with standard-risk acute lymphoblastic leukemia. Blood. 2006;107(3):1116–23.
• ³
  Topp MS, Kufer P, Gökbuget N, oebeler M, Klinger M, Neumann S, et al. Targeted therapy with the T-cell–engaging antibody Blinatumomab of chemotherapy-refractory minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival. J Clin Oncol. 2011;29(18):2493–8.
• ⁴
  Topp MS, Gökbuget N, Zugmaier G, Degenhard E, Goebeler M-E, Klinger M, et al. Long-term follow-up of hematologic relapse-free survival in a phase 2 study of Blinatumomab in patients with MRD in B-lineage ALL. Blood. 2012;120(26):5185–7.
• ⁵
  Gökbuget N, Zugmaier G, Klinger M, Kufer P, Stelljes M, Viardot A, et al. Long-term relapse-free survival in a phase 2 study of Blinatumomab for the treatment of patients with minimal residual disease in B-lineage acute lymphoblastic leukemia. Haematologica. 2017;102(4):e132.
• ⁶
  Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522–31.
• ⁷
  Sigmund AM, Sahasrabudhe KD, Bhatnagar B. Evaluating blinatumomab for the treatment of relapsed/refractory ALL: design, development, and place in therapy. Blood Lymphat Cancer. 2020;10:7.
• ⁸
  Richard-Carpentier G, Kantarjian HM, Jorgensen JL, Wang SA, Khoury JD, Ravandi F, et al. Phase II study of Blinatumomab in patients with B-cell acute lymphoblastic leukemia (B-ALL) with positive measurable residual disease (MRD). Blood. 2019;13(134):1299.
• ⁹
  Gökbuget N, Kneba M, Raff T, Tabrizi R, Beldjord K, Asnafi V, et al. Adult patients with acute lymphoblastic leukemia and molecular failure display a poor prognosis and are candidates for stem cell transplantation and targeted therapies. Blood. 2012;120(9):1868–76.
• ¹⁰
  Dhédin N, Huynh A, Maury S, Tabrizi R, Beldjord K, Asnafi V, et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood. 2015;125(16):2486–96.
• ¹¹
  Kebriaei P, Banerjee PP, Ganesh C, Kaplan M, Nandivada VD, Cortes AKN, et al. Blinatumomab is well tolerated maintenance therapy following allogeneic hematopoietic cell transplantation for acute lymphoblastic leukemia. Biol Blood Marrow Transplant. 2020;26(3). S102–S3.
• ¹²
  Huehls AM, Coupet TA, Sentman CL. Bispecific T-cell engagers for cancer immunotherapy. Immunol Cell Biol. 2015;93(3):290–6.
• ¹³
  Badar T, Szabo A, Litzow M, Burkart M, Yurkiewicz I, Dinner S, et al. Multi-institutional study evaluating clinical outcome with allogeneic hematopoietic stem cell transplantation after Blinatumomab in patients with B-cell acute lymphoblastic leukemia: real-world data. Bone Marrow Transplant. 2021:1–7.
• ¹⁴
  Zeiser R, Blazar BR. Acute graft-versus-host disease—biologic process, prevention, and therapy. N Engl J Med. 2017;377 (22):2167–79.
• ¹⁵
  Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376(9):836–47.
• ¹⁶
  Turner JA, Schneider SM. Blinatumomab: a new treatment for adults with relapsed acute lymphocytic leukemia. Clin J Oncol Nurs. 2016;20(2).
• ¹⁷
  Jain T, Litzow MR. No free rides: management of toxicities of novel immunotherapies in ALL, including financial. Blood Adv. 2018;2(22):3393–403.
• ¹⁸
  Stein AS, Schiller G, Benjamin R, Jia C, Zhang A, Zhu M, et al. Neurologic adverse events in patients with relapsed/refractory acute lymphoblastic leukemia treated with Blinatumomab: management and mitigating factors. Ann Hematol. 2019;98(1):159–67.
• ¹⁹
  Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncol. 2017;3(7):e170580-e.
• ²⁰
  Goekbuget N, Dombret H, Zugmaier G, Bonifacio M, Graux C, Faul C, et al. Blinatumomab for minimal residual disease (MRD) in adults with B-cell precursor acute lymphoblastic leukemia (BCP-ALL): median overall survival (OS) is not reached in complete MRD responders at a median follow-up of 53.1 months. Blood. 2018 Nov 29;132:554.
• ²¹
  Gökbuget N, Zugmaier G, Dombret H, Stein A, Bonifacio M, Graux C, et al. Curative outcomes following Blinatumomab in adults with minimal residual disease B-cell precursor acute lymphoblastic leukemia. Leuk Lymp. 2020;61(11):2665–73.
• ²²
  Topp MS, Gökbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, et al. Phase II trial of the anti-CD19 bispecific T cell–engager Blinatumomab shows hematologic and molecular remissions in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia. J Clin Oncol. 2014;32(36):4134–40.
• ²³
  Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, et al., editors. Complete Hematologic and Molecular Response in Adult Patients with Relapsed/Refractory Philadelphia Chromosome-Positive B-Precursor Acute Lymphoblastic Leukemia Following Treatment with Blinatumomab: Results from a Phase II, Single-Arm, Multicenter Study. American Society of Clinical Oncology; 2017.
• ²⁴
  Horibe K, Morris JD, Tuglus CA, Dos Santos C, Kalabus J, Anderson A, et al. A phase lb study of Blinatumomab in Japanese children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. Int J Hematol. 2020;112(2):223–33.
• ²⁵
  Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of Blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 2015;16(1):57–66.
• ²⁶
  Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Rambaldi A, et al. Long-term follow-up of Blinatumomab in patients with relapsed/refractory Philadelphia chromosome–positive B-cell precursor acute lymphoblastic leukaemia: final analysis of ALCANTARA study. Eur J Cancer. 2021;146:107–14
• ²⁷
  Dombret H, Topp MS, Schuh AC, Wei AH, Durrant S, Bacon CL, et al. Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cell precursor acute lymphoblastic leukemia. Leuk Lym. 2019;60(9):2214–22.
• ²⁸
  Rambaldi A, Ribera JM, Kantarjian HM, Dombret H, Ottmann OG, Stein AS, et al. Blinatumomab compared with standard of care for the treatment of adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia. Cancer. 2020;126(2):304–10.
• ²⁹
  Locatelli F, Zugmaier G, Rizzari C, Morris JD, Gruhn B, Klingebiel T, et al. Effect of Blinatumomab vs chemotherapy on event-free survival among children with high-risk first-relapse B-cell acute lymphoblastic leukemia: a randomized clinical trial. Jama. 2021;325(9):843–54.
• ³⁰
  Badar T, Szabo A, Advani A, Wadleigh M, Arslan S, Khan MA, et al. Real-world outcomes of adult B-cell acute lymphocytic leukemia patients treated with Blinatumomab. Blood Adv. 2020;4(10):2308–16.
• ³¹
  Turtle CJ, Hanafi L-A, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126(6):2123–38.
• ³²
  Alfayez M, Kantarjian HM, Short NJ, Assi R, Khouri M, Ravandi F, et al. Safety and efficacy of Blinatumomab in patients with central nervous system (CNS) disease: a single institution experience. Blood. 2018;132:2702.
• ³³
  Frey N. Cytokine release syndrome: who is at risk and how to treat. Best Pract Res Clin Haematol. 2017;30(4):336–40.
• ³⁴
  Stein AS, Larson RA, Schuh AC, Stevenson W, Lech-Maranda E, Tran Q, et al. Exposure-adjusted adverse events comparing Blinatumomab with chemotherapy in advanced acute lymphoblastic leukemia. Blood Adv. 2018;2(13):1522–31.
• ³⁵
  Brandi C, Haas C, d’Argouges S, Fisch T, Kufer P, Brischwein K, et al. The effect of dexamethasone on polyclonal T cell activation and redirected target cell lysis as induced by a CD19/CD3-bispecific single-chain antibody construct. Cancer Immunol Iimmunother. 2007;56(10):1551–63.
• ³⁶
  Klinger M, Brandi C, Zugmaier G, Hijazi Y, Bargou RC, Topp MS, et al. Immunopharmacologic response of patients with B-line-age acute lymphoblastic leukemia to continuous infusion of T cell-engaging CD19/CD3-bispecific BiTE antibody Blinatumomab. Blood. 2012;119(26):6226–33.
• ³⁷
  Iyer SS, Cheng G. Role of interleukin 10 transcriptional regulation in inflammation and autoimmune disease. Crit Rev Immunol. 2012;32(1).
• ³⁸
  Maude SL, Barrett D, Teachey DT, et al. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J (Sudbury, Mass). 2014;20(2):119.
• ³⁹
  Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. N Engl J Med. 2013;368(16):1509–18.
• ⁴⁰
  Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after Blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood. 2013;121 (26)5154–7.
• ⁴¹
  Singh JA, Beg S, Lopez-Olivo MA. Tocilizumab for rheumatoid arthritis: a Cochrane systematic review. J Rheumatol. 2011;38 (l):10–20.
• ⁴²
  De Benedetti F, Brunner HI, Ruperto N, Kenwright A, Wright S, Calvo I, et al. Randomized trial of tocilizumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012;367(25):2385–95.
• ⁴³
  Liu D, Zhao J. Cytokine release syndrome: grading, modeling, and new therapy. J Hematol Oncol. 2018;11(1):1–7.
• ⁴⁴
  Giavridis T, van der Stegen SJ, Eyquem J, Hamieh M, Piersigilli A, Sadelain M. CAR T cell–induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24(6):731–8.
• ⁴⁵
  Norelli M, Camisa B, Barbiera G, Falcone L, Purevdorj A, Genua M, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24(6):739–48.
• ⁴⁶
  Jabbour E, Düll J, Yilmaz M, Khoury JD, Ravandi F, Jain N, et al. Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after Blinatumomab failure: no change in the level of CD19 expression. Am J Hematol. 2018;93 (3):371–4.
• ⁴⁷
  Haddox C, Mangaonkar A, Chen D, Shi M, He R, Oliveira J, et al. Blinatumomab-induced lineage switch of B-ALL with t (4: 11) (q21; q23) KMT2A/AFF1 into an aggressive AML: pre-and post-switch phenotypic, cytogenetic and molecular analysis. Blood Cancer J. 2017;7(9):e607-e.
• ⁴⁸
  He RR, Nayer Z, Hogan M, Cuevo RS, Woodward K, Heyer D, et al. Immunotherapy-(Blinatumomab-) related lineage switch of KMT2A/AFF1 rearranged B-lymphoblastic leukemia into acute myeloid leukemia/myeloid sarcoma and subsequently into B/myeloid mixed phenotype acute leukemia. Case Rep Hematol. 2019;2019.
• ⁴⁹
  Wölfl M, Rasche M, Eyrich M, Schmid R, Reinhardt D, Schlegel PG. Spontaneous reversion of a lineage switch following an initial Blinatumomab-induced ALL-to-AML switch in MLL-rearranged infant ALL. Blood Adv. 2018;2(12):1382.
• ⁵⁰
  Zoghbi A, Zur Stadt U, Winkler B, Müller I, Escherich G. Lineage switch under Blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement. Ped Blood Cancer. 2017;64(11):e26594.
• ⁵¹
  Feucht J, Kayser S, Gorodezki D, Hamieh M, Döring M, Blaeschke F, et al. T-cell responses against CD19+ pediatric acute lymphoblastic leukemia mediated by bispecific T-cell engager (BiTE) are regulated contrarily by PD-L1 and CD80/CD86 on leukemic blasts. Oncotarget. 2016;7 (47):76902.
• ⁵²
  Badar T, Szabo A, Dinner S, Liedtke M, Burkart M, Shallis RM, et al. Sequencing of novel agents in relapsed/refractory B-cell acute lymphoblastic leukemia: blinatumomab and inotuzumab ozogamicin may have comparable efficacy as first or second novel agent therapy in relapsed/refractory acute lymphoblastic leukemia. Cancer. 2021;127(7):1039–48.
• ⁵³
  Kobayashi T, Ubukawa K, Fujishima M, Takahashi N. Correlation between increased immune checkpoint molecule expression and refractoriness to Blinatumomab evaluated by longitudinal T cell analysis. Int J Hematol. 2021;113 (4):600–5.
• ⁵⁴
  Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, et al. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody Blinatumomab in patients with B-precursor ALL. Leukemia. 2017;31 (10):2181–90.
• ⁵⁵
  Aldoss I, Song J, Stiller T, Nguyen T, Palmer J, O’Donnell M, et al. Correlates of resistance and relapse during Blinatumomab therapy for relapsed/refractory acute lymphoblastic leukemia. Am J Hematol. 2017;92(9):858–65.
• ⁵⁶
  Braig F, Brandt A, Goebeler M, Tony H-P, Kurze A-K, Nollau P. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood. 2017;129(1):100–4.

Publication Dates

• Publication in this collection
  01 July 2024
• Date of issue
  2024

History

• Received
  11 Dec 2022
• Accepted
  07 June 2023
• Published
  31 July 2023