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Leukemia & Lymphoma

ISSN: 1042-8194 (Print) 1029-2403 (Online) Journal homepage: http://www.tandfonline.com/loi/ilal20

Blinatumomab: a CD19/CD3 bispecific T cellengager (BiTE) with unique anti-tumor efficacy

Maria-Elisabeth Goebeler & Ralf Bargou

To cite this article: Maria-Elisabeth Goebeler & Ralf Bargou (2016): Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with unique anti-tumor efficacy, Leukemia & Lymphoma,DOI: 10.3109/10428194.2016.1161185

To link to this article: http://dx.doi.org/10.3109/10428194.2016.1161185

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Blinatumomab: a CD19/CD3 bispecific T cell engager (BiTE) with uniqueanti-tumor efficacy

Maria-Elisabeth Goebelera,b and Ralf Bargoua

aComprehensive Cancer Center Mainfranken, University Hospital W€urzburg, W€urzburg, Germany; bDepartment of Internal Medicine II,University Hospital W€urzburg, W€urzburg, Germany

ABSTRACTBlinatumomab is a member of a novel class of T cell-engaging bispecific antibodies, so-calledBispecific T cell Engager (BiTEs). It is directed against the B cell differentiation antigen CD19 andintended for treatment of B cell malignancies. In clinical phase I/II trials, blinatumomab showedremarkable single-agent activity in patients with relapsed and/or refractory (R/R) non-Hodgkinlymphoma and R/R B cell precursor acute lymphoblastic leukemia (B-precursor ALL). Cytokinerelease syndrome and neurological side effects were dose-limiting. Adverse effects were wellmanageable and transient in nature. Based on results of an international phase II trial, blinatumo-mab received FDA approval for the treatment of R/R B-precursor ALL in December 2014.Ongoing and future trials will contribute to further optimization of blinatumomab-based T celltherapy and have to show that integration of blinatumomab in current and innovative treatmentprotocols improves overall survival and quality of life of patients with B cell malignancies.

ARTICLE HISTORYReceived 9 October 2015Revised 21 February 2016Accepted 26 February 2016

KEYWORDSB-precursor ALL; BiTEVR ;blinatumomab; immunother-apy; NHL

Introduction

Over the past two decades immunotherapy has becomea promising treatment modality for a broad range ofmalignancies including leukemia and lymphoma.Compared to conventional chemotherapy monoclonalantibodies (mAbs) that specifically bind to cell surfaceantigens of tumor cells offer the opportunity of a moreselective and less toxic immune-mediated treatmentapproach. The first anti-tumor mAb recognizing the Bcell antigen CD20, i.e. rituximab, achieved US FDAapproval in 1997 due to significant improvement ofclinical outcomes of patients with indolent lymph-oma.[1,2] By now, rituximab has become an integralpart of treatment concepts for all types of B cell non-Hodgkin lymphoma (NHL). Since then mAbs againstother targets such as EGFR, VEGF, CD30, and HER-2have been approved and could significantly change theoutcome of patients in various cancer entities.[3–8]

Monoclonal Abs exert their anti-tumor activity eitherby direct inhibition of important growth factors orgrowth factor receptors or activation of the innateimmune system via their Fc-receptor. However, mAbsare not able to recruit cytotoxic T lymphocytes(CTL),[9] which are thought to be the most powerfuleffector cells of the immune system.

After the introduction of mAbs in routine clinicalpractice in the late nineties of the twentieth century, ittook more than another decade until we learned toutilize the power of the T cell system for cancer ther-apy. Especially, two T cell-engaging strategies weresuccessfully translated into the clinic during the pastfew years: (i) the activation of endogenous tumor-directed T cell clones by check-point antibodies ordrugs that block inhibitory T cell pathways. Theseinclude mAbs blocking CTLA-4 and PD-1 recep-tors.[10–12] (ii) The active redirection of T-cells in a tar-geted and MHC-independent manner by eitherbispecific T cell-engaging (BiTE) antibodies or by adop-tive cell transfer therapy with genetically engineeredchimeric antigen receptor T cells (CAR T cells).[13,14] Incontrast to the checkpoint inhibitors, CARs and BiTEsare able to induce a T cell response in a completelyMHC-independent manner thereby circumventing com-mon escape mechanisms (e.g. absence of stable tumorantigens and loss of intracellular peptide transportersTAP-1 and -2;[15] downregulation of major histocom-patibility class (MHC) I molecules;[16,17] loss of co-stimulatory molecules or up-regulation of anti-apop-totic proteins [18–20]). By selecting a particular surfaceantigen the therapeutic potential of T cell engagementby either the CAR or the BiTE approach can in principle

CONTACT Dr Maria-Elisabeth Goebeler goebeler_m@ukw.de Comprehensive Cancer Center Mainfranken, University Hospital W€urzburg,Oberd€urrbacherstr. 6, ZIM A4-1.445, 97080 W€urzburg, Germany� 2016 Informa UK Limited, trading as Taylor & Francis Group

LEUKEMIA & LYMPHOMA, 2016http://dx.doi.org/10.3109/10428194.2016.1161185

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be applied to a broad array of malignant diseases.However, until today this approach was mainly suc-cessful in CD19-positive B cell malignancies. BiTE anti-bodies targeting EpCAM, Her2/neu, EGFR, CEA, CD33,EphA2, PSMA, BCMA, and MCSP (or HMW-MAA) are inclinical development.[21] Convincing clinical data forthe latter BiTE-based treatment approaches are yetlacking. Therefore, this review is focused on CD19 astarget for the treatment of B cell malignancies. We willreview the structural and functional features of blinatu-momab, its pharmacologic profile and first clinical datafor treatment of NHL and ALL.

Blinatumomab, a murine anti-human CD3 � anti-human CD19 single-chain antibody, is the so far clinic-ally most advanced BiTE antibody (previously desig-nated in the literature as bscCD19xCD3, MT103,AMG103; trade name BlincytoVR ). The non-proprietaryname blinatumomab was given by the World HealthOrganization and refers to its specificity: B cell lineagespecific anti-tumor mouse monoclonal antibody.Blinatumomab was designed and pioneered in a closecollaboration between the German biotech companyMicromet and academic centers in Germany.[22]

The bispecific single chain formatand pre-clinical characteristics

The first paper on blinatumomab was published in2000,[23] followed by detailed reports on its in vitrocharacteristics and on the mode of T cell activation.[24]The mode of action of blinatumomab is based on atandem arrangement of the antigen-binding domainsof two single chain antibodies (scFvs) that are cova-lently linked by a flexible linker peptide, which is facili-tating a simultaneous binding to the CD3e/T cellreceptor (TCR) complex and the pan-B cell antigenCD19 [Figure 1]. Consequently, this BiTE antibody iscompletely devoid of the constant antibody regionsresulting in a relatively small fusion protein with amolecular weight of 55 kDa.[23,25,26] This particulardesign allows for optimal rotation and kinking of thetwo binding arms and enables a close and efficaciousinteraction between the T cell and tumor cell targets. Itfacilitates simultaneous binding of two different anti-gens on two separate cells and thus efficiently triggerstarget cell-specific cytolytic toxicity. As blinatumomabis monovalent for the TCR, T cell activation appearsonly in the presence of CD19-positive target cells.[27]Vice versa, tumor cell lysis was never observed in theabsence of T cells showing that the cytotoxic effect ofblinatumomab is absolutely T cell-dependent.[28]

Blinatumomab is a recombinant fusion protein pro-duced by eukaryotic mammalian cells (Chinese hamster

ovary cells) with high protein stability and homogen-eity. A C-terminal hexahistidine tag is used for purifica-tion from the cell culture medium by affinitychromatography. The variable binding domains of bli-natumomab were derived from mouse mAbs againstCD19 and the e chain of the T cell receptor/CD3 com-plex. The monovalent binding affinity for CD19 is1� 10�9 M (equilibrium dissociation constant KD), forCD3 the KD value is 1� 10�7 M. Due to its favorablebinding affinity to CD19 versus CD3 and its particularmolecular structure, only picomolar concentrations arenecessary to induce T cell-mediated cytotoxic damageof target cells.[28–31]

Blinatumomab is able to establish very tight cyto-lytic synapses between effector cells and CD19 tar-get cells.[28,32,33] The formation of this transientBiTE-induced cytolytic synapse is followed by a per-forin/granzyme-mediated cell destruction via proteo-lytic activation of caspases 3 and 7 in tumor cellsand serial lysis of the latter.[34,35] As perforin, apore-forming protein of cytotoxic T cells, plays acentral role in this lytic process cytotoxic T cell activ-ity might be inhibited by concanamycin A, an inhibi-tor of perforin.[34,35] In the presence of CD19-positive target cells, blinatumomab induces a poly-clonal T cell activation followed by a strong prolifer-ation of the T cell compartment. In response to BiTEstimulation, the vast majority of CD8þ and CD4þ Tcells start to express CD25 and CD69 as well as sur-face expression of cell adhesion molecules (e.g. CD2,LFA-1).[26,28] Thus, all CD8þ or CD4þ T cell subpo-pulations with the exception of na€ıve T-cells can getinvolved in redirected target cell lysis. In a large ser-ies of in vitro cytotoxicity assays in no case T cellsrequired additional pre- or co-stimulatory signals.Blinatumomab-activated T cells transiently releaseinflammatory cytokines (especially IL-6, IL-10, andinterferon-c), the cytokine peak concentrations beingdose-dependent.[30,36,37]

In summary, pre-clinical characterization of blinatu-momab revealed remarkable anti-lymphoma activity invitro, which was superior to other monoclonal or bispe-cific antibody constructs. Blinatumomab induced T cell-mediated target cells lysis at extremely low concentra-tions, i.e. at the pico- to femto-molar range [24] as wellas at very low effector to target ratios. Blinatumomabis able to utilize the T cell inherent seek-and-destroymechanism and induces serial killing followed by astrong polyclonal expansion of the cytotoxic T cellcompartment. The strong T cell-mediated anti-lymph-oma activity found in vitro could be confirmed in vivoin a SCID mouse model.[29]

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Advantage of targeting CD19

The human CD19 antigen is a 95 kDa transmembraneglycoprotein belonging to the immunoglobulin super-family.[38] CD19 as B cell-restricted cell surface antigenis stably expressed on normal and malignant B cellswith the exception of hematopoietic stem cells (HSC)and terminally differentiated plasma cells.[4,39–41] Incontrast to other B cell antigens such as CD20 orCD22, CD19 is expressed on all stages of B-lineage ALLas well as all NHL subtypes including CLL. CD19-medi-ated signaling seems to be important for growth andsurvival of normal and malignant B cells. Its ability toact as critical co-receptor for B cell receptor (BCR) sig-nal transduction, its potency to amplify the activationof Src-family tyrosine kinases and to enhance BCR

signaling via recruitment of PI3 and AKT kinases couldrecently be demonstrated.[42,43] Due to its functionalrole for B cell survival, CD19 antigen escape of malig-nant cells upon selective CD19-targeted treatmentpressure appears to be unlikely.[31,43–46]

Experience in indolent and aggressive NHL

First clinical phase I trials were performed in patientswith relapsed/refractory (R/R) NHL (summarized byNagorsen et al. [31]). In three phase I dose escalationtrials (MT103 1/01-2001, MT103 1/01-2002, and MT1031/01-2003), blinatumomab was administered as shortterm infusion over 2–4 h in a total of 21 patients.Daily doses ranged from 0.75 to 13 lg/m2. Major side

Figure 1. Proposed mechanism of action of BiTE antibody blinatumomab. For details, refer to the text (adapted from Zimmermanet al., 2015 [65]).

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effects were fever, chills, fatigue, cytokine release syn-drome (CRS), and neurologic AEs including aphasia,ataxia, seizure, and disorientation. Pharmacokineticanalyses revealed a short serum half-life of blinatumo-mab of about 2 h. In none of the 22 patients testedin the three short-term infusion trials, an objectiveclinical response could be documented. Based onassessments of the overall benefit/risk profile, all thethree short-term infusion trials were discontinuedprematurely.

The experience with short-term infusions suggestedthat a prolonged steady state concentration isrequired to improve efficacy and tolerability.Considering the short serum half-life of blinatumomabin patients and its mode of action relying on a con-tinuous seek-and-destroy mechanism, a new phase Itrial was started using a continuous intravenous infu-sion (CIV) mode of application over 4–8 weeks percycle (MT103-104 phase I). First clinical data on thistrial have been published in 2008 [47] and updatedin 2016 [48]. The BiTE antibody was infused via aportable mini pump-port system, which allowedpatients to be treated even in an outpatient setting.Doses applied ranged from 0.5 to 90 lg/m2/day andled to the identification of 60 lg/m2/day as the max-imum tolerated dose (MTD) level. Originally, the trialwas designed as a classic dose-escalating phase I trialfor patients with R/R indolent NHL, but was lateramended to confirm safety and efficacy of the dose-escalating part in an extension part and to alsoinclude patients with R/R diffuse large B-cell lymph-oma (DLBCL). Overall, 76 patients with R/R NHL wereenrolled, the majority (n¼ 62) had indolent (low-grade) lymphomas, including follicular lymphoma(n¼ 28), and mantle cell lymphoma (n¼ 24); 14 hadDLBCL. The median number of previous therapies was3. Around half of the patients had received fludara-bine and 93% rituximab before treatment with theBiTE antibody. Most common AEs were flu-like symp-toms such as fever, chills, headache, and fatigue whilelymphopenia and CRP increase turned out to be themost common laboratory AEs. The majority of AEswere observed during the first 72 h of treatment andmainly resolved upon continued application of theBiTE antibody. AEs such as lymphocytopenia, leuko-penia or increase of CRP could primarily be attributedto the mode of action of blinatumomab.

The clinically most relevant (grade 3) and dose-limit-ing toxicities were side effects of the central nervoussystem (CNS) such as encephalopathy, aphasia, tremor,disorientation, and seizure. Overall, 13 patients had todiscontinue treatment due to grade 3 neurologicevents, no grade 4 or 5 of such events were reported.

All neurological AEs in this trial were transient innature and completely reversible. Several mitigationstrategies have been explored to reduce CNS AEs ofwhich stepwise dose-escalation (5–15–60 lg/m2) andtherapeutic intervention with dexamethasone seemedto be effective.

Pharmacokinetic analyses showed stable serum lev-els of blinatumomab at predicted levels, which weremaintained during the whole time of continuous infu-sion and confirmed the short serum half-time of 2 h.Pharmacodynamic analyses revealed a transient andmodest increase of inflammatory cytokines, includingIFN-c, TNF, IL-2, Il-6, and IL-10 in many patients uponstart of blinatumomab. A rapid and sustained deple-tion of B cells within a few days after initiation oftreatment was observed in all patients treated atdose levels of 5 lg/m2/day and higher. The decreaseof B cells was paralleled by a transient increase ofthe apoptotic B cell fraction confirming the mode ofaction of the BiTE antibody in patients. T cells in theperipheral blood also declined but much faster thanB cells and recovered within 2 weeks. Thereby, T cellactivation markers such as CD69 and CD25 werefound to be increased in the recovering T cellfraction.

While first evidence of B cell depletion wasobserved at doses of 5 lg/m2/day, the first objectiveclinical responses as assessed by Cheson criteria andindependent central review were documented at adose level of 15 lg/m2/day, and at this dose level alsoa clearance of bone marrow infiltration was reported infive out of six patients.[47] Dose escalation to 60 lg/m2

raised the overall response rate to 69% (37% CRs;Table 1). Objective responses were reported across dif-ferent histological subtypes with a formal overallresponse rate (ORR) of 80% for follicular lymphoma,71% for mantle cell lymphoma, and 55% for DLBCL.Follow-up analysis showed ongoing remissions afterinitial blinatumomab monotherapy that have reachedmore than 4 years in some patients.

Efficacy of blinatumomab in R/R DLBCL observed inthe phase I MT103-104 trial was confirmed by a subse-quent phase II study (MT103-208 trial).[49] In this trial,a stepwise dosing regimen (9, 28, and 112 lg/day) wasestablished as the preferred dosing for blinatumomabin DLBCL. Treatment with blinatumomab resulted inobjective and durable responses in heavily pretreatedpatients with R/R DLBCL (median number of threeprior treatments). Among 21 evaluable patients whoreceived blinatumomab 112 lg/day for at least 1 week,the ORR was 53%. As in the previous MT103-104 phaseI trial, neurologic AEs were the clinically most relevantside effects.

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Experience in adult minimal residual (MRDþ)ALL

Persisting or recurrent minimal residual disease (MRD)in patients with B-precursor ALL after inductionchemotherapy is known to be a risk factor for rapidclinical relapse within a few months. Patients withMRD-positive B-precursor ALL have a very poor out-come.[50] Therefore, a phase II trial with blinatumomabwas started in 2008 for patients with MRD persistenceor relapse after induction and consolidation chemo-therapy (MT103-202 phase II) to evaluate the efficacyof blinatumomab. As the phase I MT103-104 trial coulddemonstrate that a dose of 15 lg/m2/day is sufficientto clear the bone marrow from malignant B cell infiltra-tion, this dose level was chosen for the phase II MRDtrial. Patients were treated at 15 lg/m2/day CIV over 4

weeks, additional consolidation cycles (median of 3)were spaced by a treatment-free break of 2 weeks. Theprimary efficacy endpoint of this trial was conversionfrom MRD-positive to MRD-negative disease.[51]Sixteen out of 20 evaluable patients (80%) achieved acomplete MRD response (i.e. tumor cells below thedetection limit of 10�4) after the first treatment cycle.After a median follow-up observation time of 33months, leukemia-free survival of the whole studypopulation was 60%.[52] Four out of six patients werelong-term survivors, who did not require subsequenttreatment after blinatumomab monotherapy. Two ofthe long-term survivors had Ph* ALL and received sub-sequent tyrosine kinase inhibitor (TKI) treatment.

Overall, blinatumomab was well tolerated. Most fre-quent grade 3 and 4 AEs were lymphocytopenia, whichwas completely reversible and thought to reflect the

Table 1. Completed and currently recruiting clinical trials on blinatumomab.Trial Phase Indication Dosing Patients (n) Results References

MT 103-I/01-2001MT 103-I/01-2002MT 103-I/01-2003

I r/r NHL/CLL Short term infusion for2–4 h up to 13 lg/m2 up to3 times per week

22 No objectiveresponses

Nagorsen et al. [31]

MT 103-104NCTZ00274742

I r/r NHLFL 37%MCL 32%DLBCL 18%Other indolent NHL13%

Dose escalation part:0.5–90 lg/m2/day for 4–8weeks Dose expansion part:60 lg/m2/day in one ordouble step application

76 ORR: 69% (at targetdose 60 lg/m2/day)ORR: 55% in DLBCL

Goebeler et al. [48]

MT 103-208NCT01741792

II r/r DLBCL 112 lg/m2/day in doublestep dosing

19 ORR: 53% (at targetdose 112 lg/day forat least 1 week)

Viardot et al. [49]

Median OS:MT 103-202NCT00560794

II MRDþ r/r BCP- ALL 15 lg/m2/day 21 MRD negativity: 80% Topp et al. [51]Median RFS: 61%Median follow-up forRFS: 33 months

Topp et al. [52]

MT 103-203NCT01207388

pivotal MRDþ r/r BCP-ALL 15 lg/m2/day Ongoing Interim analysis (116patients)

G€okbuget et al. [53]

EU 2014:III MRD negativity: 78%

Median RFS: data inevaluation

MT 103-206NCT01209286

II r/r BCP-ALL 5–15 lg/m2/day 36 CR/CRh: 69% Topp et al. [54]MRD response: 88%Median OS: 9.8monthsMedian RFS: 7.6months

MT 103-211NCT01466179

pivotal r/r BCP-ALL 9–28 lg/day 189 CR/CRh: 43% Topp et al. [55]II Median OS: 6.1

months-MRD responders:11.5 months-MRD non-responders:6.7 months

311 TowerNCT02013167

III r/r BCP-ALL 9–28 lg/day Ongoing Analysis ongoing

216 AlcantaraNCT02000427

II r/r Phþ BCP-ALL 9–28 lg/day Ongoing Analysis ongoing

ECOG1910NCT02003222

III ALL 28 lg/day Ongoing Analysis ongoing

MT103-205NCT01471782

I/II r/r pediatric ALL 5–15 lg/m2/day Phase I: 41Phase II: ongoing

Analysis ongoing

MRD: minimal residual disease; ORR: overall response rate; OS: overall survival; RFS: relapse-free survival.

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mode of action of blinatumomab. Two patients had todiscontinue treatment due to CNS events, which werecompletely reversible within a few days after treatmentdiscontinuation. As the data of this trial successfullydemonstrated the potency of blinatumomab to eradi-cate even chemotherapy-resistant malignant B cells aconfirmatory trial in patients with MRD-positive ALLacross several countries in Europe was started (BLASTtrial, MT103-203). Between 2010 and 2013, 116 patientswere enrolled and treated. A first interim analysis wasrecently reported and confirmed the high MRDresponse rate of trial MT103-202.[53]

Experiences in adult relapsed and refractoryALL

Based on these promising results in patients with MRD-positive B-precursor ALL, a phase 2 single-arm doseescalation trial (MT103-206 phase II) of blinatumomab inadults with R/R B-precursor ALL was initiated in cooper-ation with the German ALL study group (GMALL).[54]Primary endpoint was CR or CR with partial hematologicrecovery (CRh), secondary endpoints included MRDresponse, realization of hematopoietic stem cell trans-plantation (HSCT), relapse-free survival, overall survival(OS), and incidence of AEs. Thirty-six patients with B-precursor ALL were included and entered a short dose-optimizing run-in phase determining stepwise dosing asthe preferred treatment schedule (5 to >15 lg/m2 perday). The CR rate was 69% with 88% of the respondersachieving a MRD response. CRS and neurologic symp-toms appeared as the clinically most relevant AEs andled to temporary or permanent discontinuation of treat-ment. Stepwise dosing along with a short pre-phasetreatment (dexamethasoneþ cyclophosphamide) inpatients with high tumor burden was chosen to preventsevere CRS. Patients with seizure had to interrupt treat-ment but successfully resumed treatment with anti-epi-leptic prophylaxis.

In a subsequent large confirmatory phase II trial(MT103-211 phase II), 189 patients with R/R B-precursorALL were enrolled between 2010 and 2013.[55] In con-trast to the exploratory trial, only patients with eitherearly relapse, refractory disease or relapse after at leastone salvage therapy were included into the trial. Thereported CR rate after two cycles of blinatumomabtreatment was 41%. After a median follow-up of 8.9months, 45% of patients who had achieved a CR werestill alive and in remission. Forty percentages ofpatients who achieved a CR underwent allogeneicHSCT. The most frequent� grade 3 adverse eventswere febrile neutropenia (25%), neutropenia (16%) andanemia (14%). Two percentages experienced a grade 3

CRS, 11% and 2% of patients had a neurologic eventgrade 3 and 4, respectively.

These data compare favorably to historical controlsof this patient cohort with poor prognosis. Of note,there was a significant correlation between tumor bur-den and response rate in this trial. CR occurred in 73%of patients with less than 50% bone marrow blasts atbaseline compared with 29% CR rate in patients with50% or more bone marrow blasts. Based on the resultsof this confirmatory MT103-211 trial, the FDA approvedblinatumomab for the treatment of patients with‘‘Philadelphia chromosome-negative relapsed/refractoryB-cell precursor acute lymphoblastic leukemia’’ inDecember 2014. The European Medicines Agency(EMA) approved blinatumomab for the same indicationon 24 November 2015.

The patient population in the confirmatory trial wasdifferent from the patients in the pilot trials in terms ofpretreatment and refractoriness with more than 50%of patients at �2nd relapse in the confirmatory trial incomparison to 19% at �2nd relapse in the exploratorytrial. Although the comparison of different trials is diffi-cult, this might explain the different CR rates in bothtrials. Overall, the data from the different ALL trialsshow a clear correlation between response rates andtumor load or intensity of pretreatment suggestingthat blinatumomab has its highest value first-line or ina MRD setting.

Experiences in childhood relapsed/refractoryB-precursor ALL

The first clinical experience with blinatumomab inchildhood B-precursor ALL were published byHandgretinger and colleagues,[56] who treated threechildren with R/R ALL with blinatumomab on a com-passionate use basis. In 2014, Schlegel et al. reportedon blinatumomab treatment of further nine post-trans-plant-relapsed pediatric patients with B-precursor ALLwith no other treatment options. These nine patientsreceived a total of 18 cycles of treatment, six patientsachieved a complete remission, four after one cycle ofblinatumomab only. Four patients could be bridged toa second transplant. After a median follow-up of 398days, the probability of hematologic event-free survivalwas 30%.[57] CRS grade 3 occurred in two patients,neurologic AEs in terms of grade 3 seizures were docu-mented in one patient.

To date, results of two trials in R/R pediatric B-pre-cursor ALL (phase I and phase II) have been pub-lished.[58–60] Overall, a similar toxicity profile as seenin adult ALL was found and the same stepwise dosingwas determined as the preferred mode of application

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(5 to >15 lg/m2). About one third of heavily pre-treated patients achieved a CR. A list of all completedand ongoing trials with blinatumomab is shown inTable 1.

Specific toxicity of blinatumomab

The clinically most relevant CNS events usually occurat the onset of treatment and are fully reversible andwell manageable [26,61] (Table 2). CNS events includeseizures or convulsions, encephalopathy or confusionand cerebellar symptoms. All events were reversiblewhen withholding blinatumomab infusion or applyingdexamethasone. While not entirely comprehended, bli-natumomab-associated neurologic AEs are thought tobe induced by transient neuroinflammatory irritationsof the CNS. Adherence of blinatumomab-activated Tcells to the endothelium is considered as a pre-requis-ite and first pathogenic step of CNS toxicity. ActivatedT cells are supposed to transmigrate across the bloodbrain barrier and to enter the CNS where they inducea T-cell mediated toxic inflammation of the CNS. Ofnote, similar neurotoxicity is seen upon treatment withCAR T-cells.[14,61,62] So far, patients with tumor mani-festations of the CNS or a history of CNS disorders

should not be exposed to blinatumomab. For the man-agement of neurological events, premedication withdexamethasone 20 mg intravenously 1 h prior to thefirst dose of blinatumomab of each cycle, prior to astep dose (such as cycle 1 day 8), or when restartingan infusion after an interruption of 4 or more hours isrecommended (Table 3). In the case of disappearanceof the neurological AE patients might be re-exposedwith a reduced dose, patients with grade 4 neuro-logical events should be permanently discontinued.Exploiting agents that interfere with T cell adherenceto the endothelium or local cytokine release mightcontribute to mitigation strategies of blinatumomab-associated CNS events. Definition of predictive factorsfor CNS toxicity should facilitate identification ofpatients at risk for CNS events.

Severe CRS, usually characterized by fever andchills, hypotension, and shortness of breath in severecases, is an occasionally observed adverse event ofblinatumomab therapy (6% in MT103-206 trial, 2% inMT103-211 trial), that is especially seen during thefirst days of treatment of patients with R/R B-precur-sor ALL. CRS is thought to be induced by rapid killingof large tumor masses during the initial infusion. Afew patients developed more fulminant CRS withmultisystem organ failure. Decrease of the initial doseof blinatumomab (5 lg/m2/day starting dose in thefirst treatment cycle) followed by stepwise dose escal-ation and the addition of dexamethasone could suc-cessfully reduce the incidence of CRS in a series ofpatients with R/R B-precursor ALL.[55] CRS has onlybeen observed during the first cycle of treatmentand its occurrence is not correlating with treatmentresponse.[63] Recent data demonstrate that IL-10, IL-6, and IFN-c are the most highly elevated cytokinesin patients who developed CRS upon blinatumomabtreatment similar to patients treated with CD19 CART cells.[42] Severe CRS occurs preferentially inpatients with high blast counts. Patients with B-pre-cursor ALL and more than 50% blasts or a peripheralblast count over 15� 109/L should therefore receivepre-phase dexamethasone (10 lg/m2 up to 5 days)with or without cyclophosphamide (200 mg/m2 up to3 days) in order to reduce the risk of CRS.[55] Pre-phase dexamethasone does not significantly affectthe rate of CR. Overall, pre-phase dexamethasonetogether with dose reduction of blinatumomab to5 lg/m2/day (or 9 lg/day) in the first week of the firstcycle efficiently prevents the development of clinicallyrelevant CRS. A summary on frequency and kind ofadverse events according to the prescription informa-tion for BlincytoVR (blinatumomab) is provided inTable 2.

Table 2. Frequency and kind of adverse events (ae) appearingduring blinatumomab exposure in clinical trials and patientswith B-cell precursor all.Severity and frequencyof AE Kind of adverse events

All AE � 20% Pyrexia 62%Headache 36%Peripheral edema (25%), febrile neutropenia (25%)Nausea (25%)Hypokalemia (23%)Rash (21%)Tremor (20%)Constipation (20%)

SAE (� 2%) Febrile neutropeniaPyrexiaPneumonia, sepsisNeutropeniaDevice-related infectionsTremorEncephalopathyInfectionOverdoseConfusionStaphylococcal bacteremiaHeadache

Leukoencephalopathy Although the clinical significance is unknown,cranial magnetic resonance imaging (MRI)changes showing leukoencephalopathy havebeen observed in patients receiving BLINCYTOVR ,especially in patients previously treated withcranial irradiation andanti-leukemic chemothera

According to BlincytoVR (blinatumomab) prescribing information 7/2015,AMGEN (www.blincyto.com/static/pdf/pharmacy_brochure.pdf, accessed on4 January 2016).

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Prediction of efficacy and mechanisms ofescape

Efforts have been made to find predictive markers forthe efficacy of blinatumomab treatment. In an analysisof 31 patients with R/R ALL treated with blinatumomabat a single center, T regulatory (Treg) lymphocytes ofthe T cell compartment were monitored by flowcytometry and a logistic regression model was devel-oped to delineate responders versus non-responders toblinatumomab. A high percentage of Treg (>12.5%)and high serum lactate dehydrogenase levels werefound to be independent predictors of lack ofresponse to blinatumomab.[64] Furthermore, the per-centage of bone marrow blasts in R/R B-precursor ALLseems to be predictive for response. Within theMT103-211 pivotal trial,[55] 73% of patients with lessthan 50% bone marrow blasts achieved a CR com-pared with 29% of patients with more than 50% bonemarrow blasts at baseline.

Mechanisms of resistance or escape to blinatumo-mab treatment are poorly understood. In the explora-tory MT103-202 MRD ALL trial, a small number ofpatients relapsed with CD19-negative disease or atextramedullary sites (testis, CNS).[52] In the exploratoryMT 103-206 R/R ALL trial, 3 out of 10 reported relapseswere CD19-negative including one extramedullary

relapse.[54] The therapeutic pressure induced by blina-tumomab appears to select for CD19-negative ALLclones as well as for clones that are capable to homeat sites which are less accessible for T cells. The ‘‘loss’’of CD19 as immune escape may explain resistance toblinatumomab in a subgroup of ALL patients and willtrigger strategies to further improve blinatumomab-based therapies. A better understanding of the fre-quency of this immune escape and the underlyingmechanisms are of importance in order to optimizetreatment approaches. Likewise, the cause for primaryresistance also remains to be clarified.

Cost effectiveness

Blinatumomab has a price tag of USD $178.000 (USD$89.000 per cycle, see Table 4 ). Amgen, the supplierof blinatumomab, said in an e-mailed statement that‘‘the price reflects the significant clinical, economic,and humanistic value of the product and to patientsand the healthcare system, for an ultra-orphan popula-tion with a dramatic impact on a serious illness’’(http://www.fiercepharmamarketing.com/story/amgen-slaps-record-breaking-178k-price-rare-leukemia-drug-blincyto/-12-18). Future trials and outcome analyseshave to show whether blinatumomab has a major

Table 3. Instruction for dose interruption, dose modification and steroid application in the case of adverse events (AE).Toxicity Grade Action Co-medication

Cytokine releasesyndrome

Grade 3* Withhold blinatumomab until resolved, then re-startblinatumomab at 9 lg/day. Escalate to 28 lg/day after 7days if the toxicity does not recur.If the interruption of blinatumomab is no longer than 7days continue blinatumomab application to a total of 28days. If the AE lasts longer than 7 days, start a newtreatment cycle after the AE resolved.

20 mg dexamethasone i.v. 1 hr before start of treatmentand at any dose step

Grade 4* Discontinue blinatumomab permanentlyNeurologicaltoxicity

Seizure Discontinue blinatumomab permanently if more than 1seizure occurs

Grade 3* Withhold blinatumomab until no more than grade 1 (mild)and for at least 3 days, then re-start blinatumomab at 9 lg/day. Escalate to 28 lg/day after 7 days if the toxicity doesnot recur.If the interruption of blinatumomab is no longer than 7days continue blinatumomab application to a total of 28days. If the AE lasts longer than 7 days, start a newtreatment cycle after the AE resolved.If the toxicity occurred at 9 lg/day or if the toxicity takesmore than 7 days discontinue blinatumomab permanently

Grade 4* discontinue blinatumomab permanentlyOther clinicallyrelevant adverseevents

Grade 3* Withhold blinatumomab until no more than grade 1 (mild)and for at least 3 days, then re-start blinatumomab at 9 lg/day. Escalate to 28 lg/day after 7 days if the toxicity doesnot recur, If the interruption of blinatumomab is no longerthan 7 days continue blinatumomab application to a total of28 days. If the AE lasts longer than 7 days, start a newtreatment cycle after the AE resolved.If the toxicity occured at 9 lg/day or if the toxicity takesmore than 14 days to resolve discontinue blinatumomabpermanently

Grade 4* discontinue blinatumomab permanently

Based on the Common Toxicity Criteria for Adverse Eevents (CTCAE) version 4.1. Grade 3¼ severe, Grade 4¼ life-threating (according to BlincytoVR (blinatu-momab) prescribing information 7/2015, AMGEN, (www.blincyto.com/static/pdf/pharmacy_brochure.pdf, accessed on 4 January 2016).

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impact on the overall survival and quality of life of ALLpatients. Such data are urgently needed to assesswhether the current price tag is justified and cost-effective.

Conclusions and outlook

The BiTE antibody blinatumomab is the first example toshow that redirecting T cells to cancer cells in an active,MHC-independent and targeted manner is clinicallyfeasible and might lead to impressive responses in can-cer patients refractory to conventional therapies. Theclinical efficacy of this new therapeutic principle hasbeen confirmed by related approaches such as the CAR-T cell approach. Long-term follow-up analyses of thefirst phase I and II trials suggest that blinatumomabmonotherapy has curative potential in a subgroup ofpatients with R/R NHL, and MRDþ or R/R B-precursorALL. The high CR rate and the improved overall andrelapse-free survival compared to historical controls inheavily pre-treated patients with B-precursor ALL led toapproval of blinatumomab for the treatment of R/R B-precursor ALL by the FDA in December 2014 and theEMA in November 2015. A global phase III trial of blina-tumomab versus investigator’s choice of chemotherapyin patients with R/R ALL (NCT02013167) is currentlyevaluating in a prospective and randomized mannerwhether blinatumomab improves overall survival com-pared to conventional salvage therapies. Studies evalu-ating blinatumomab in the first-line treatment settingare in preparation (NCT02143414 and NCT02003222).

Although the first clinical data are encouraging,there is space for improvement. Many questions are

unresolved, e.g. what is the best time point of startingblinatumomab treatment? Should blinatumomab beintegrated into first line treatment of ALL? Can the effi-cacy of BITE treatment be improved in combinationwith chemotherapy or targeted therapies? The superiorresponse rates in patient cohorts with less pretreat-ment and lower tumor burden and the relatively highproportion of long-term survivors in the MRD trials incomparison to the poorer outcome in the R/R B-pre-cursor ALL trials suggest that blinatumomab may haveits optimal impact on the overall outcome of ALLpatients if integrated into first-line treatment strategies.Studies in the first line setting are in progress.

The role of blinatumomab for treatment of NHL needsstill to be determined. Phase I and phase II data showsubstantial activity, but further studies are warranted.Patients with high-risk disease such as CLL with 17p-dele-tion or p53 mutation or patients with high-risk or refrac-tory DLBCL may benefit from blinatumomab therapy.

The data from the phase I MT103-104 trial implicatethat the efficacy of blinatumomab is dose-dependent.Therefore, one might speculate that improved mitiga-tion strategies for the dose-limiting toxicities will allowfor higher dosing that may result in deeper remissionsand improved overall survival.

Another way to further improve efficacy is thesequential or concomitant combination of blinatumo-mab with therapies that are compatible or synergisticwith its mode of action. For example, preclinical stud-ies have shown that blinatumomab acts in concertwith rituximab suggesting that the combination of dif-ferent immunotherapies with different modes of actioncould be a promising approach to overcome immuneescape and resistance and to improve clinical efficacy.The relapse of CD19-negative ALL patients implies thata combination of different BiTEs with different targetspecificity may be another attractive approach.Preliminary results from few patients with PhþALLwho were treated with blinatumomab and subsequentTKI therapy in the exploratory MT103-202 trial suggestcombinatorial strategies of BiTEs and classical targetedapproaches with small molecules in the future.

To date, T cell-engaging approaches have been suc-cessfully tested in patients with CD19-positive B cellmalignancies. Whether BiTEs and CARs will also suc-ceed in other cancers, particularly in solid tumors, willbe one of the most exciting topics in the future.

Potential conflict of interest: Disclosure forms pro-vided by the authors are available with the full text ofthis article at http://dx.doi.org/10.3109/10428194.2016.1161185.

Table 4. Quick drug profile blincytoVR (blinatumomab).Drug name BlincytoVR (Blinatumomab, AMG103)Company AMGEN, Thousand Oaks, California, USAOther names AMG 103MoA Bi-specific T-cell Engager (BiTE antibody)MoR N.A.MTD

112 lg/day, continuous intravenous administration(c.i.v.)

DLT Neurologic adverse events, cytokine release syndromeSchedulea

9 lg/day c.i.v. starting dose days 1–7, 28 lg/day c.i.v.weeks 2–4 (¼ one cycle), 2-week treatment-freeinterval; cycles 2–5: start at 28 lg/day c.i.v. weeks 1–4,each cycle followed by a 2-week treatment-freeinterval.

Plasma half-life 2 hCosts USD $ 89.000 per cycleAny other uniquefeature

Induction of T cell-mediated target cells lysis atextremely low concentrations

MoA: Mechanism of action; MoR: Mechanism of resistance; MTD: Maximumtolerated dose; DLT: Dose limiting toxicity.aAccording to BlincytoVR (blinatumomab) prescribing information 7/2015,AMGEN, (www.blincyto.com/static/pdf/pharmacy_brochure.pdf, accessed on4 January 2016).

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