1 Introduction

The most common form of acute lymphoblastic leukaemia (ALL) is B cell precursor ALL (BCP-ALL), which accounts for 80 % of ALL cases [1]. BCP-ALL is hard to treat successfully, as after an initial response to intensive acute and consolidation phase multi-agent chemotherapy, patients are highly likely to experience relapse. As a result, despite an 80–90 % complete response rate with initial treatment, only 20–40 % of patients will be in remission after 5 years. Patients with a complete response to treatment who have persistent minimal residual disease (MRD) measured by flow cytometry or polymerase chain reaction are at an increased risk of relapse and of reduced survival [1]. Similarly, patients who are Philadelphia chromosome (Ph)-positive have a negative clinical course [2]. Ph-positive patients have a genetic abnormality consisting of fusion of the Abelson oncogene on long arm of chromosome 9 with the breakpoint cluster on chromosome 22 (BCR-ABL1 oncogene). In adult ALL, 25 % of patients are Ph-positive and 50 % of patients aged >50 years have this abnormality [2]. New treatments are required for all varieties of relapsed or refractory BCP-ALL, including in patients who are Ph-positive or MRD-positive.

Blinatumomab (Blincyto™) is a first-in-class, bispecific T-cell engaging (BiTE®) antibody that has been developed by Amgen Inc. for the treatment of haematological cancers originating from B-cell lines, in particular BCP-ALL and non-Hodgkin lymphoma (NHL). In both the USA and the EU, blinatumomab has orphan drug status as a treatment for BCP-ALL [3]. The US FDA granted accelerated approval for blinatumomab for the treatment of Ph-negative, relapsed or refractory BCP-ALL in December 2014 [4]. The FDA had previously designated blinatumomab as a breakthrough therapy, and continuation of this approval may be contingent on confirmation of benefit in subsequent trials. The US prescribing information contains a black box warning regarding the possibility of the occurrence of life-threatening or fatal CRS and of severe, life-threatening or fatal neurological toxicities [5]. A Marketing Authorization Application (MAA) was submitted to the European Medicines Agency (EMA) in October 2014, seeking approval for the use of blinatumomab in the treatment of BCP-ALL [6].

Features and properties of blinatumomab

Alternative names

AMG 103; AMG-103; AMG103; Blincyto™; MEDI 538; MEDI-538; MT 103; MT-103; MT103

Class

Bispecific antibodies; monoclonal antibodies

Mechanism of action

Immunostimulant, T lymphocyte stimulant

Route of administration

Intravenous

Pharmacodynamics

Lyses tumour cells by binding to cluster of differentiation (CD) 19 antigens and to the CD3/T cell receptor complex, physically linking T cells with malignant B cells, while also triggering the T-cell receptor signalling cascade

Pharmacokinetics

Following continuous intravenous infusion, blinatumomab pharmacokinetics were linear at dosages ranging from 5 to 90 μg/m2/day, with steady-state concentrations reached within a day. The mean blinatumomab elimination half-life was 2.1 h

Adverse events

 Most frequent

Pyrexia, headache, peripheral oedema, nausea, febrile neutropenia, hypokalaemia, constipation

 Most frequent serious adverse events

Febrile neutropenia, pyrexia, pneumonia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteraemia, headache

 Rare

Severe CNS adverse events, cytokine release syndrome, clinically-important increases in liver enzymes

ATC codes

 WHO ATC code

L01X-C (monoclonal antibodies)

 EphMRA ATC code

L1X3 (antineoplastic monoclonal antibodies)

Chemical name

Immunoglobulin scFv-scFv, anti- [Homo sapiens CD19 (B lymphocyte surface antigen B4, Leu-12)] /anti- [Homo sapiens CD3 epsilon (CD3E, Leu-4)] Mus musculus monoclonal antibody bispecific single chain

Molecular formula

C2367 H3577 N649 O772 S19

1.1 Company Agreements

In June 2003, MedImmune entered into an agreement with Micromet AG to jointly develop blinatumomab and create up to six drug candidates using the BiTE® product platform. MedImmune Ventures, Inc., a wholly owned subsidiary of MedImmune, made an investment in Micromet, assuming responsibility for clinical development, registration and commercialisation of blinatumomab, and acquired product rights for its use in North America. The two companies planned to begin a research programme for the development of this new BiTE® antibody for the treatment of haematological cancers. However, in November 2009 Micromet bought out MedImmune’s remaining rights to blinatumomab in North America and terminated the agreement signed in 2003 [7–10].

Micromet Inc. was formed in May 2006 from the merger of CancerVax Corporation and Micromet AG. As of March 2012, Micromet Inc. became a wholly owned subsidiary of Amgen, and shares of the former ceased to be traded. In May 2013, Amgen entered into a long-term collaborative agreement with Astellas Pharma for the development of five Amgen pipeline medicines, including blinatumomab, AMG 145, romosozumab, rilotumumab and AMG 377. Under the terms of the agreement, the companies will co-develop and co-commercialise blinatumomab for the treatment of ALL and NHL. In addition, in October 2013 the companies established a joint venture company in Japan, which initiated operations under the name Amgen Astellas BioPharma KK. Amgen Astellas BioPharma KK plans to become a wholly owned Amgen affiliate as soon as 2020, with the long-term collaboration between Amgen and Astellas extending to 2032 [11–14].

In January 2011, Micromet also entered into a Cooperative Research and Development Agreement (CRADA) with the National Cancer Institute (NCI) to broaden the development of blinatumomab for the treatment of ALL and various lymphoma subtypes. Under the terms of the CRADA, both parties are to evaluate the safety and efficacy of blinatumomab in clinical trials in patients with B-cell derived haematological malignancies. The NCI have agreed to sponsor trials evaluating blinatumomab as a first-line therapy in patients with newly diagnosed ALL, older patients with ALL and in patients with Waldenstrom’s macroglobulinemia [15].

Manufacturing agreements: Micromet entered into a manufacturing agreement with Lonza in November 2009. Lonza will manufacture blinatumomab for clinical trials and will develop the commercial scale process for the drug. According to Micromet’s Form 10-K (filed 2 March 2012), Micromet also entered into an agreement with Boehringer Ingelheim for the production of finished blinatumomab product from quantities of blinatumomab manufactured by Lonza [16].

2 Scientific Summary

2.1 Pharmacodynamics

Blinatumomab is a BiTE® antibody, manufactured in Chinese hamster ovary cells, that consists of the variable antibody binding domains of two maternal antibodies, but that lacks the constant region of common monoclonal antibodies [17]. One arm of the antibody binds to cluster of differentiation (CD) 19 antigens while the other binds to the CD3/T cell receptor complex; CD19 is expressed on cells of B-lineage origin, including on cancer cells [2, 5, 18]. As a result, blinatumomab physically links T cells with malignant B cells, while also triggering the T-cell receptor signalling cascade [2, 18]. This signalling cascade has the effect of recruiting polyclonal T cells, which are then only activated if the BiTE® antibody is also bound to the tumour cell surface [2]. Blinatumomab also increases cell adhesion molecules, the production of cytolytic proteins and the release of inflammatory cytokines, which in tandem with the increased proliferation of T cells results in the lysis of CD19-expressing (CD19+) cells [5].

In phase I/II studies in adults [17] and children [19] with refractory/relapsed BCP-ALL, continuous infusion of blinatumomab induced haematological, molecular and morphological remissions in substantial proportions of patients. In a phase I study, in patients with relapsed B cell-NHL, the partial or complete remission rate achieved with blinatumomab therapy was dose-dependent [17].

Lymphocyte responses to blinatumomab were evaluated in a phase II study in patients with BCP-ALL in haematological complete remission but who were molecularly relapsed or refractory (n = 20) (NCT00560794) [18]. Patients were treated with a continuous infusion of blinatumomab 15 μg/m2/day over 4 weeks followed by a 2-week treatment-free period (followed by up to three consolidation cycles). Within a mean 2 days of the initiation of the infusion, B-cell counts were reduced to <1 B cell/μL and were essentially undetectable over the ensuing treatment period. T-cell counts declined reaching a nadir in less than one day, recovered to baseline within a few days, and then increased over 2–3 weeks, on average doubling in numbers. Expression of the T-cell activation marker CD69 was increased on a large proportion of T cells. During the infusion, redirected lysis resulted in a durable depletion of CD19+ target B cells. At the initiation of the first infusion, some patients had increased cytokine release [particularly interleukin (IL)-10, IL-6 and interferon-γ], but such increases were not detected at initiation of a second cycle [18].

In cell culture studies using a B-cell leukaemia cell line, T-cell cytotoxicity induced by blinatumomab was stronger than the antibody dependent cellular cytotoxicity (ADCC) induced by rituximab [20]. Blinatumomab-mediated T cell cytotoxicity and rituximab-mediated ADCC both resulted in the same pro-apoptotic reaction (potent activation of pro-caspases 3 and 7) in target cells; dose-dependent activation of caspases correlated with tumour cell lysis. The combination of the two agents increased the efficacy of rituximab in lysing leukaemia cells, due to an additive effect that was especially evident at low effector-to-target cell ratios and when antibody concentrations were low. The simultaneous targeting of different antigens by the two agents was proposed as a possible therapeutic option for exploration [20].

In a study using peripheral blood mononuclear cells from either treatment-naïve or previously-treated patients with chronic lymphocytic leukaemia (CLL), blinatumomab induced T-cell proliferation and activation, cytokine secretion and granzyme B release, and induced tumour cell death at very low T-cell: tumour cell ratios [21]. These findings suggest that blinatumomab may be of use in overcoming immunodeficiency in the treatment of CLL [21]. Blinatumomab may also have therapeutic potential in acute myeloid leukaemia (AML), as in blast cell cultures from patients with AML, the presence of blinatumomab resulted in a decrease in CD33+ AML blasts and of CD33+ monocytes, along with an increase in activation markers on the vast majority of CD4+ and CD8+ T cells, and lysis of CD33+ target blast cells [22].

2.2 Pharmacokinetics

Blinatumomab pharmacokinetics in adult patients appears to be linear at dosages ranging from 5 to 90 μg/m2/day [5]. Steady-state concentrations with continuous intravenous infusion were reached within a day and remained stable. Over the dosage range tested, the increase in the mean steady-state blinatumomab concentration was approximately proportional to dosage. The mean (standard deviation) steady-state concentration was 211 (258) pg/mL at a dosage of 9 μg/m2/day and 621 (502) pg/mL at 28 μg/m2/day. The mean volume of distribution (estimated for the terminal phase) was 4.52 L (2.89).

Although the metabolism of blinatumomab has not been elucidated, it is assumed to be degraded into small peptides and amino acids by cellular catabolic pathways common to the breakdown of other antibodies [5]. In clinical studies, after continuous infusion of blinatumomab, the estimated mean systemic clearance (CL) was 2.92 (2.83) L/h and the mean elimination half-life was 2.1 h.

Based on population pharmacokinetic studies, sex, age (18–80 years), body weight (44–134 kg) and body surface area (1.39–2.57 m2) do not affect blinatumomab pharmacokinetics [5]. No formal studies have been conducted to evaluate blinatumomab pharmacokinetics in patients with renal impairment. However, mean blinatumomab CL values in patients with moderate renal impairment [creatinine clearance (CLCR) 30–59 mL/min; n = 21] showed an approximately twofold difference to those of patients with normal renal function (CLCR >90 mL/min; n = 215). There was high inter-patient variability and CL values remained essentially within the same range as patients with normal renal function. There are no pharmacokinetic data available for patients with severe renal impairment (CLCR <30 mL/min), or in patients undergoing dialysis.

Blinatumomab causes a transient increase in cytokines, which may suppress hepatic cytochrome P450 enzymes, potentially leading to drug interactions with agents with a narrow therapeutic window that are substrates of these enzymes (e.g. warfarin, cyclosporine) [5]. The highest risk for interactions is during the first 9 days of cycle 1 and during the first 2 days of cycle 2.

2.3 Therapeutic Trials

Adult clinical studies of blinatumomab generally included patients aged ≥18 years. In the studies discussed below, blinatumomab was administered as a continuous intravenous infusion, generally for at least one cycle of 4 weeks, followed by consolidation therapy, consisting of up to three further cycles. When indicated, patients underwent chemotherapy and/or allogeneic human stem cell transplantation (HSCT), but not before completing at least one blinatumomab treatment cycle.

2.3.1 In Adults with B-Cell Precursor Acute Lymphoblastic Leukaemia

The US approval of blinatumomab in relapsed or refractory BCP-ALL is based in large part on clinical findings from a single-arm, multinational phase II study in patients who were Ph-negative (n = 185 evaluable patients) (NCT01466179) [5]. Patients were treated with blinatumomab 9 μg/day for 1 week followed by 28 μg/day for 3 weeks (cycle 1); blinatumomab 28 μg/day was administered in subsequent cycles. The dosage was adjusted as required when adverse events occurred. After 1 or 2 blinatumomab treatment cycles, 77 (42 %) patients achieved complete remission (CR) or complete remission with partial haematological recovery (CRh*) (CR/CRh*) (primary endpoint); 81 % of remissions occurred during cycle 1. Among those achieving CR/CRh*, 30 (39 %) patients underwent subsequent HSCT and 75 % of patients met the MRD response criterion (MRD by PCR <1 × 10−4); the median duration of response (time from response to relapse or death) in this group was 5.9 months [5].

The efficacy of blinatumomab in patients with relapsed or refractory MRD-positive BCP-ALL was also evaluated in a single-arm, German multicentre, phase II study (n = 21) (NCT00560794) [23]. Patients were treated with blinatumomab 15 μg/m2/24 h over 4–8 weeks, followed by a 2-week treatment-free period. Responders could receive three further cycles as consolidation therapy. One patient was not evaluable as a result of treatment discontinuation because of a grade 3 adverse event. Of the remaining patients, 16 became MRD-negative after one treatment cycle, 12 of whom had previously been refractory to chemotherapy. After a median of 405 days follow-up, the haematological relapse-free probability was 78 %. Four patients relapsed, all of whom had not undergone allogeneic HSCT [23]. At a later follow-up after 33 months, the probability of remaining haematologically relapse-free was 61 % (65 % in nine patients who had undergone allogeneic HSCT); in six responders who were Ph-negative, four were in ongoing haematological and molecular remission [24]. In this study, depletion of B cells and blasts with blinatumomab treatment was associated with decreased concentrations of circulating immunoglobulins, with reductions described as being more pronounced than with chemotherapy [25].

A further, single-arm, German multicentre phase II study of blinatumomab was conducted in three sequential cohorts of patients with Ph-negative, relapsed or refractory BCP-ALL who received different dosage regimens (n = 36) (NCT01209286) [26]. Patients were treated with two initial blinatumomab cycles to induce remission, and responders received three additional cycles unless they were undergoing HSCT. In all, 25 (69 %) of patients reached CR/CRh*, among whom 88 % had an MRD response; 13 (52 %) patients went on to receive HSCT. The median overall survival was 9.8 months and the median relapse-free survival was 7.6 months [26].

Results are recently available from a confirmatory, single arm, multinational phase II study in patients with relapsed or refractory MRD-positive BCP-ALL (n = 116) (NCT01207388; BLAST study) [27]. Patients received blinatumomab 15 μg/m2/24 h over 4 weeks followed by a 2-week treatment-free period. Responders could receive up to four cycles or undergo HSCT after one cycle. At the analysis cutoff (February 2014), 106 patients had concluded treatment; 74 patients completed treatment and 32 had discontinued because of adverse events, disease relapse or investigator decision. After one blinatumomab cycle, 88/113 (78 %; 95 % CI 69–85) of patients had a complete MRD response, exceeding the a priori null response rate of 44 % for the lower bound of the 95 % CI [27].

2.3.2 In Adults with Non-Hodgkin Lymphoma

Final results are available from an open-label, dose-escalation, phase I study in adult patients with relapsed or refractory B-cell NHL (NCT00274742) [28, 29]. Interim results are also available from an open-label, phase II study that is evaluating stepwise versus constant blinatumomab dosing strategies (NCT01741792) [30]. In the phase I study, heavily pre-treated patients with NHL (including patients with mantle cell lymphoma and diffuse large B cell lymphoma) (n = 76) were treated with blinatumomab in dosages ranging from 0.5 to 90 μg/m2/day. Across all NHL subtypes, for patients receiving the maximum tolerated dosage of blinatumomab 60 μg/m2/day (n = 35), 69 % had an objective response during either the dose escalation or extension phases (37 % of patients had a complete response) [29]. In the ongoing phase II study, among patients evaluable for response (n = 16), the objective response rate was 44 % [30].

2.3.3 In Children and Adolescents with Acute Lymphoblastic Leukaemia

A dosage-finding, phase I/II study conducted in children (<18 years of age) with relapsed or refractory BCP-ALL (n = 41) evaluated five different blinatumomab dosage regimens (NCT01471782) [31]. The maximum tolerated blinatumomab dosage was estimated to be 15 μg/m2/day and stepwise dosages of 5–15 μg/m2/day were recommended for use in this population [31]. In the phase II stage of this study (n = 18), the remission rate was 37 % after 1 or 2 cycles at the recommended dosage, and 30 % reached MRD negativity [32]. Overall, 8 of 15 patients who were blinatumomab responders underwent HSCT during a complete response.

Further evidence for the efficacy of blinatumomab in patients aged 4–19 years was obtained in a study in patients with post-HSCT, relapsed BCP-ALL who were consistently CD19+ (n = 9) [33]. Patients were treated with blinatumomab at initial dosages of 5 or 15 μg/m2/day for 28 days followed by a 7–14 day treatment-free interval. Patients with non-response with this first treatment cycle received a second cycle at 15 μg/m2/day, with or without prior stem cell boost. Remission was achieved in four patients during cycle 1 and, after receiving chemotherapy to reduce blast load, a further two patients during cycle 2. Four patients subsequently underwent successful HSCT. Three patients were non-responsive to blinatumomab.

Key phase I–III studies of blinatumomab in acute lymphoblastic leukaemia and non-Hodgkin lymphoma

Indication

Phase

Agents

Status

Location(s)

Identifier

In adult patients

BCP-ALL (r/r; Ph −ve)

II

BLI

Completed

Multinational

NCT01466179 (MT103-211)a

BCP-ALL (r/r; MRD +ve)

II

BLI

Completed

Germany

NCT00560794 (MT103-202)b

BCP-ALL (MRD +ve; Ph −ve)

II

BLI

Completed

Multinational

NCT01207388 (MT103-203)a

BCP-ALL (r/r; Ph −ve)

II

BLI

Completed

Germany

NCT01209286 (MT103-206)b

BCP-ALL (r/r; Ph +ve)

II

BLI

Recruiting

Multinational

NCT02000427a

BCP-ALL (new dx; Ph −ve; ≥65 years)

II

BLI plus CT

Initiated

USA

NCT02143414 (NCI-2014-01047)c

BCP-ALL (r/r; Ph −ve)

III

BLI vs. CT

Recruiting

Multinational

NCT02013167 (00103311)a

BCP-ALL (new dx; Ph −ve)

III

BLI plus CT vs. CT

Recruiting

USA

NCT02003222 (NCI-2013-02229)c

DLBCL (r/r)

II

BLI

Ongoing

Germany

NCT01741792 (MT103-208)b

NHL including MCL/DLBCL (r)

I

BLI

Completed

Germany

NCT00274742 (MT103-104)b

In younger adults and children (aged 1–30 years)

BCP-ALL (Ph–ve, r)

III

BLI plus-CT vs. CT

Recruiting

USA

NCT02101853 (NCI-2014-00631)c

In children/adolescents

BCP-ALL (r/r)

I/II

BLI

Recruitment complete

Multinational

NCT01471782 (MT103-205)a

  1. BCP-ALL B cell precursor acute lymphoblastic leukaemia, BLI blinatumomab, CT standard-of-care combination chemotherapy, DLBCL diffuse large B-cell lymphoma, dx diagnosis, MCL mantle cell lymphoma, MRD minimal residual disease, NCI US National Cancer Institute, NHL non-Hodgkin lymphoma, Ph Philadelphia chromosome, r relapsed, r/r relapsed or refractory
  2. aSponsored by Amgen Inc.
  3. bSponsored by Amgen Inc. in collaboration with the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL)
  4. cSponsored by the US NCI

2.4 Adverse Events

The US prescribing information includes pooled tolerability/safety data from clinical trials in which adult patients with relapsed or refractory ALL received at least one dose of blinatumomab (in dosages up to 28 μg/m2/day) (n = 212) [5]. Based on these data, grade 3 or higher severity adverse events occurred in 80 % of patients, while 18 % of patients discontinued treatment because of adverse events, most frequently because of encephalopathy and sepsis. Fatal adverse events (mostly infections) were reported in 15 % of patients; however, in patients in remission no deaths were attributed to adverse events. The most commonly occurring adverse events observed in at least 20 % of patients were pyrexia (62 % of patients), headache (36 %), peripheral oedema (25 %), nausea (25 %), febrile neutropenia (25 %), hypokalemia (23 %) and constipation (20 %). Serious adverse events (SAEs) occurred in 65 % of patients; the most frequently occurring SAEs were febrile neutropenia, pyrexia, pneumonia, sepsis, neutropenia, device-related infection, tremor, encephalopathy, infection, overdose, confusion, Staphylococcal bacteremia and headache [5].

Similar tolerability findings were reported in small clinical studies in adult patients with NHL, with CNS adverse events being among the most common clinically important adverse events [29, 30].

In the dosage-finding phase I/II study in children with relapsed or refractory BCP-ALL (NCT01471782), cytokine release syndrome (CRS) was a dose-limiting adverse effect in the phase I stage of the study and was fatal in two patients [31]. During the phase II stage, which adopted a stepwise dosing strategy, CRS occurred in 1 (6 %) of 18 patients (grade 3 level of severity). In the full study population (n = 41), the most common adverse events were pyrexia (70 % of patients), headache (37 %), hypertension (32 %) and anaemia (29 %); neurological adverse events occurred in 46 % of patients and were grade 1 or 2 in severity in all cases but one [31].

Less common, but clinically important, adverse events that have occurred in patients receiving blinatumomab include severe neurological toxicities and liver enzyme abnormalities [5]. Neurological toxicities may manifest as encephalopathy, seizures, speech disorders, reduced consciousness, confusion and disorientation, and coordination/balance disturbances. Independent of CRS, transient elevations in liver enzymes can occur with blinatumomab therapy; in patients without CRS, ≈6 % of patients had ≥grade 3 elevations in liver enzymes and <1 % of patients discontinued blinatumomab because of elevations in liver enzymes [5].

2.5 Ongoing Clinical Studies

Ongoing phase II studies of blinatumomab in patients with BCP-ALL that are yet to report findings include: an open-label, single-arm, multinational study in adult patients with relapsed or refractory, Ph-positive disease (NCT02000427); an open-label, non-randomized, parallel-groups, US multicentre study in newly diagnosed patients aged ≥65 that is evaluating blinatumomab plus two different chemotherapy regimens, prednisone, vincristine sulfate, methotrexate, mercaptopurine (POMP) or prednisone plus dasatinib (NCT02143414); and a multinational, phase I/II study in children and adolescents aged 1–17 years with relapsed or refractory disease (NCT01471782).

Two phase III studies are also currently recruiting patients. These are an open-label, randomized, multinational trial in patients with relapsed or refractory, Ph-negative BCP-ALL, in which blinatumomab as monotherapy will be compared with one of four possible standard of care chemotherapy regimens (NCT02013167), and an open-label, randomized, US multicentre trial in patients with newly diagnosed Ph-negative BCP-ALL, in which combination therapy with blinatumomab plus chemotherapy will be compared with induction chemotherapy alone (NCT02003222).

A further phase III, open-label, randomized, parallel-groups, US multicentre trial is now recruiting young adults and children (patients aged 1–30 years) with relapsed BCP-ALL (NCT02101853). This study will compare blinatumomab plus four different chemotherapy regimens in patient groups stratified according to whether the patient is considered at low-risk or at intermediate- or high-risk for having a poor prognosis, based on clinical and laboratory features.

3 Current Status

Blinatumomab was approved in the USA for the treatment of Ph-negative, relapsed or refractory BCP-ALL on 3 December 2014 [4]. Blinatumomab is awaiting approval for the treatment of BCP ALL in the EU [6].