BLINCYTO 38.5mcg powder for concentrate and solution infusion solution medication leaflet

BLINCYTO 38.5 micrograms powder for concentrate and solution for solution for infusion.

One vial of powder contains 38.5 micrograms blinatumomab.

Reconstitution with water for injections results in a final blinatumomab concentration of12.5 micrograms/mL.

Blinatumomab is produced in Chinese hamster ovary cells by recombinant DNA technology.

For the full list of excipients, see section 6.1.

Powder for concentrate and solution for solution for infusion.

BLINCYTO powder (powder for concentrate): White to off-white powder.

Solution (stabiliser): Colourless-to-slightly yellow, clear solution with a pH of 7.0.

BLINCYTO is indicated as monotherapy for the treatment of adults with CD19 positive relapsed orrefractory B-cell precursor acute lymphoblastic leukaemia (ALL). Patients with Philadelphiachromosome-positive B-cell precursor ALL should have failed treatment with at least 2 tyrosinekinase inhibitors (TKIs) and have no alternative treatment options.

BLINCYTO is indicated as monotherapy for the treatment of adults with Philadelphia chromosome-negative CD19 positive B-cell precursor ALL in first or second complete remission with minimalresidual disease (MRD) greater than or equal to 0.1%.

BLINCYTO is indicated as monotherapy for the treatment of paediatric patients aged 1 month or olderwith Philadelphia chromosome-negative CD19 positive B-cell precursor ALL which is refractory or inrelapse after receiving at least two prior therapies or in relapse after receiving prior allogeneichaematopoietic stem cell transplantation.

BLINCYTO is indicated as monotherapy for the treatment of paediatric patients aged 1 month or olderwith high-risk first relapsed Philadelphia chromosome-negative CD19 positive B-cell precursor ALLas part of the consolidation therapy (see section 4.2).

BLINCYTO is indicated as monotherapy as part of consolidation therapy for the treatment of adultpatients with newly diagnosed Philadelphia chromosome negative CD19 positive B-cell precursor

ALL.

Treatment should be initiated under the direction of and supervised by physicians experienced in thetreatment of haematological malignancies. Patients treated with BLINCYTO should be given the

Educational Brochure for Patients and Caregivers and the Patient Card.

For the treatment of relapsed or refractory B-cell precursor ALL, hospitalisation is recommended forinitiation at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle.

For the treatment of Philadelphia chromosome-negative MRD positive B-cell precursor ALL,hospitalisation is recommended at a minimum for the first 3 days of the first cycle and the first 2 daysof subsequent cycles.

For the treatment of B-cell precursor ALL in the consolidation phase, hospitalisation is recommendedfor the first 3 days of the first cycle and the first 2 days of the second cycle.

In patients with a history or presence of clinically relevant central nervous system (CNS) pathology(see section 4.4), hospitalisation is recommended at a minimum for the first 14 days of the first cycle.

In the second cycle, hospitalisation is recommended at a minimum for 2 days, and clinical judgementshould be based on tolerance to BLINCYTO in the first cycle. Caution should be exercised as cases oflate occurrence of first neurological events have been observed.

For all subsequent cycle starts and reinitiation (e.g. if treatment is interrupted for 4 or more hours),supervision by a healthcare professional or hospitalisation is recommended.

Relapsed or refractory B-cell precursor ALL

Patients with relapsed or refractory B-cell precursor ALL, may receive 2 cycles of treatment. A singlecycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated bya 14-day (2 weeks) treatment-free interval.

Patients who have achieved complete remission (CR/CRh*) after 2 treatment cycles may receive up to3 additional cycles of BLINCYTO consolidation treatment, based on an individual benefits-risksassessment.

Recommended daily dose is by body weight (see table 1). Patients greater than or equal to 45 kgreceive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s bodysurface area (BSA).

Table 1. BLINCYTO recommended dosage for relapsed or refractory B-cell precursor ALL

Body weight Cycle 1 Subsequent cycles

Days 1-7 Days 8-28 Days 29-42 Days 1-28 Days 29-42

Greater than 9 mcg/day via 28 mcg/day 14-day 28 mcg/day via 14-dayor equal to continuous via continuous treatment- continuous treatment-free45 kg infusion infusion free interval infusion interval(fixed-dose)

Less than 5 mcg/m2/day 15 mcg/m2/day 15 mcg/m2/day45 kg via continuous via continuous via continuous(BSA-based infusion infusion infusiondose) (not to exceed (not to exceed (not to exceed9 mcg/day) 28 mcg/day) 28 mcg/day)

Premedication and additional medication recommendations

In adult patients, dexamethasone 20 mg intravenous should be administered 1 hour prior to initiationof each cycle of BLINCYTO therapy.

In paediatric patients, dexamethasone 10 mg/m2 (not to exceed 20 mg) should be administered orallyor intravenously 6 to 12 hours prior to the start of BLINCYTO (cycle 1, day 1). This should befollowed by dexamethasone 5 mg/m2 orally or intravenously within 30 minutes prior to the start of

BLINCYTO (cycle 1, day 1).

Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of eachtreatment cycle.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy toprevent central nervous system ALL relapse.

Pre-phase treatment for patients with high tumour burden

For patients with ≥ 50% leukaemic blasts in bone marrow or > 15 000/microlitre peripheral bloodleukaemic blast counts treat with dexamethasone (not to exceed 24 mg/day).

MRD positive B-cell precursor ALL

When considering the use of BLINCYTO as a treatment for Philadelphia chromosome-negative

MRD positive B-cell precursor ALL, quantifiable MRD should be confirmed in a validated assay withminimum sensitivity of 10-4 (see section 5.1). Clinical testing of MRD, regardless of the choice oftechnique, should be performed by a qualified laboratory familiar with the technique, following wellestablished technical guidelines.

Patients may receive 1 cycle of induction treatment followed by up to 3 additional cycles of

BLINCYTO consolidation treatment. A single cycle of treatment of BLINCYTO induction orconsolidation is 28 days (4 weeks) of continuous intravenous infusion followed by a 14-day (2 weeks)treatment-free interval (total 42 days). The majority of patients who respond to blinatumomab achievea response after 1 cycle (see section 5.1). Therefore, the potential benefit and risks associated withcontinued therapy in patients who do not show haematological and/or clinical improvement after1 treatment cycle should be assessed by the treating physician. See table 2 for the recommended dailydose.

Table 2. BLINCYTO recommended dosage for adult patients with MRD-positive B-cellprecursor ALL

Body weight Treatment cycle(s)

Days 1-28 Days 29-42

Greater than or equal14-day treatment freeto 45 kg 28 mcg/dayinterval(fixed-dose)

Less than 45 kg 15 mcg/m2/day 14-day treatment-free(BSA-based dose) (not to exceed 28 mcg/day) interval

Premedication and additional medication recommendations

Prednisone 100 mg intravenously or equivalent (e.g. dexamethasone 16 mg) should be administered1 hour prior to initiation of each cycle of BLINCYTO therapy.

Anti-pyretic use (e.g. paracetamol) is recommended to reduce pyrexia during the first 48 hours of eachtreatment cycle.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy toprevent central nervous system ALL relapse.

B-cell precursor ALL in the consolidation phase

BLINCYTO is administered as a continuous intravenous infusion delivered at a constant flow rateusing an infusion pump. A single cycle of treatment is 28 days (4 weeks) of continuous infusionfollowed by a 14-day (2-week) treatment-free interval. Patients may receive up to 4 cycles of

BLINCYTO consolidation treatment.

See table 3 for the recommended daily dose by body weight for adults. Patients weighing greater thanor equal to 45 kg receive a fixed-dose, and for patients weighing less than 45 kg, the dose is calculatedusing the patient’s body surface area (BSA).

Table 3. BLINCYTO recommended dosage for B-cell precursor ALL for Adults in theconsolidation phase

Body weight Consolidation cycles (Cycles 1-4)

Days 1-28 Days 29-42

Greater than or equal to 45 kg 28 mcg/day 14 day treatment-free interval(fixed-dose)

Less than 45 kg 15 mcg/m2/day 14 day treatment-free interval(BSA-based dose) (not to exceed 28 mcg/day)

High-risk first relapsed B-cell precursor ALL

Paediatric patients with high-risk first relapsed B-cell precursor ALL may receive 1 cycle of

BLINCYTO treatment after induction and 2 blocks of consolidation chemotherapy. A single cycle oftreatment is 28 days (4 weeks) of continuous infusion. See table 4 for the recommended daily dose bybody weight for paediatric patients.

Table 4. BLINCYTO recommended dosage for paediatric patients with high-risk first relapsed

B-cell precursor ALL post-induction chemotherapy

Body weight greater than or Body weight less than 45 kg

One consolidation cycle equal to 45 kg (BSA-based dose)(fixed-dose)

Days 1-28 28 mcg/day 15 mcg/m2/day(not to exceed 28 mcg/day)

Premedication and additional medication recommendations

In adult patients, dexamethasone 20 mg intravenous should be administered within 1 hour prior toinitiation of each cycle of BLINCYTO therapy.

In paediatric patients, dexamethasone 5 mg/m2 (not to exceed 20 mg) should be administered prior tothe first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4or more hours in the first cycle.

Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy toprevent central nervous system ALL relapse.

Consideration to discontinue BLINCYTO temporarily or permanently as appropriate should be madein the case of the following severe (grade 3) or life-threatening (grade 4) toxicities (see section 4.4):

cytokine release syndrome, tumour lysis syndrome, neurological toxicity, elevated liver enzymes andany other clinically relevant toxicities.

If the interruption of treatment after an adverse reaction is no longer than 7 days, continue the samecycle to a total of 28 days of infusion inclusive of days before and after the interruption in that cycle.

If an interruption due to an adverse reaction is longer than 7 days, start a new cycle. If the toxicitytakes more than 14 days to resolve, discontinue BLINCYTO permanently, except if describeddifferently in the table 5 below.

Table 5. Recommendations for toxicity management (excluding ICANS)

Toxicity Grade* Action for patients weighing Action for patients weighinggreater than or equal to 45 kg less than 45 kg

Cytokine Grade 3 Interrupt BLINCYTO until Interrupt BLINCYTO untilrelease resolved, then restart resolved, then restartsyndrome, BLINCYTO at 9 mcg/day. BLINCYTO at 5 mcg/m2/day.

tumour lysis Escalate to 28 mcg/day after Escalate to 15 mcg/m2/day aftersyndrome 7 days if the toxicity does not 7 days if the toxicity does notrecur. recur.

Grade 4 Discontinue BLINCYTO Discontinue BLINCYTOpermanently. permanently.

Neurological Grade 3 Interrupt BLINCYTO until no Interrupt BLINCYTO until notoxicity more than grade 1 (mild) and for more than grade 1 (mild) and for(excluding at least 3 days, then restart at least 3 days, then restart

ICANS) BLINCYTO at 9 mcg/day. BLINCYTO at 5 mcg/m2/day.

Escalate to 28 mcg/day after Escalate to 15 mcg/m2/day after7 days if the toxicity does not 7 days if the toxicity does notrecur. For reinitiation, recur. If the toxicity occurred atpremedicate with a 24 mg dose 5 mcg/m2/day, or if the toxicityof dexamethasone. Then reduce takes more than 7 days todexamethasone step-wise over resolve, discontinue4 days. If the toxicity occurred BLINCYTO permanently.

at 9 mcg/day, or if the toxicitytakes more than 7 days toresolve, discontinue

BLINCYTO permanently.

Grade 4 Discontinue BLINCYTO Discontinue BLINCYTOpermanently. permanently.

Elevated liver Grade 3 If clinically relevant, interrupt If clinically relevant, interruptenzymes BLINCYTO until no more than BLINCYTO until no more thangrade 1 (mild), then restart grade 1 (mild), then restart

BLINCYTO at 9 mcg/day. BLINCYTO at 5 mcg/m2/day.

Escalate to 28 mcg/day after Escalate to 15 mcg/m2/day after7 days if the toxicity does not 7 days if the toxicity does notrecur. recur.

Grade 4 Consider discontinuing Consider discontinuing

BLINCYTO permanently. BLINCYTO permanently.

Toxicity Grade* Action for patients weighing Action for patients weighinggreater than or equal to 45 kg less than 45 kg

Other Grade 3 Interrupt BLINCYTO until no Interrupt BLINCYTO until noclinically more than grade 1 (mild), then more than grade 1 (mild), thenrelevant (as restart BLINCYTO at restart BLINCYTO atdetermined by 9 mcg/day. Escalate to 5 mcg/m2/day. Escalate totreating 28 mcg/day after 7 days if the 15 mcg/m2/day after 7 days ifphysician) toxicity does not recur. the toxicity does not recur.

adverse Grade 4 Consider discontinuing Consider discontinuingreactions BLINCYTO permanently. BLINCYTO permanently.

* Based on the NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Grade 3 is severe,and grade 4 is life-threatening.

Table 6. Recommendations for management of immune effector cell-associated neurotoxicitysyndrome (ICANS)

Gradea Presenting symptomsb Actions

Grade 1 ICE score 7-9c Interrupt BLINCYTO until ICANS resolves. For

CAPD score 1-8* reinitiation, premedicate with up to 20 mgor depressed level of dexamethasone 1-3 hours before blinatumomabconsciousnessd: awakens restart.

spontaneously.

Monitor neurologic symptoms and considerconsultation with a neurologist for furtherevaluation and management.

Consider non-sedating, antiseizure medicinalproducts (e.g., levetiracetam) for seizureprophylaxis.

Action for patients ≥ 45 kg:

Consider treatment with dexamethasone up to8 mg/dose up to 3 doses administered over24 hours.

Action for patients < 45 kg:

Consider treatment with dexamethasone at a totaldaily dose up to 0.2-0.4 mg/kg/day (up to amaximum 24 mg/day).

Gradea Presenting symptomsb Actions

Grade 2 ICE score 3-6c Interrupt BLINCYTO.

CAPD score 1-8* Administer dexamethasone:

or depressed level ofconsciousnessd: awakens to voice. For patients ≥ 45 kg:

Administer dexamethasone 8 mg/dose up to3 doses/day (24 mg/day maximum) for up to2 days or until event resolution, whichever issooner.

For patients < 45 kg:

Administer dexamethasone at a total daily dose ofat least 0.2-0.4 mg/kg/day (maximum 24 mg perday) administered over 3 doses for up to 2 days oruntil event resolution, whichever is sooner.

Monitor neurologic symptoms and considerconsultation with a neurologist and otherspecialists for further evaluation and management.

Consider non-sedating, antiseizure medicinalproducts (e.g., levetiracetam) for seizureprophylaxis.

Action for patients ≥ 45 kg:

Interrupt BLINCYTO until ICANS resolves, thenrestart BLINCYTO at 9 mcg/day. Escalate to28 mcg/day after 7 days if the toxicity does notrecur. For reinitiation, premedicate with up to20 mg dexamethasone 1-3 hours beforeblinatumomab restart.

Action for patients < 45 kg:

Interrupt BLINCYTO until ICANS resolve, thenrestart BLINCYTO at 5 mcg/m2/day. Escalate to15 mcg/m2/day after 7 days if the toxicity does notrecur. For reinitiation, premedicate with 5 mg/m2dexamethasone (maximum 20 mg dose) 1-3 hoursbefore blinatumomab restart.

Gradea Presenting symptomsb Actions

Grade 3 ICE score 0-2c Interrupt BLINCYTO.

CAPD ≥ 9 Administer dexamethasone:

or depressed level ofconsciousnessd: For patients ≥ 45 kg:

* awakens only to tactile Administer dexamethasone 8 mg/dose 3 doses/daystimulus, (24 mg/day maximum) until event resolution tograde 1 or less and then taper as clinicallyor seizuresd, either: indicated.

* any clinical seizure, focalor generalised, that resolves For patients < 45 kg:

rapidly, or Administer dexamethasone at a total daily dose of

* non-convulsive seizures on at least 0.2-0.4 mg/kg/day (maximum 24 mg perelectroencephalogram day) until event resolution to grade 1 or less and(EEG) that resolve with then taper as clinically indicated.

intervention,

Monitor neurologic symptoms and consideror raised intracranial pressure: consultation with a neurologist and other

* focal/local oedema on specialists for further evaluation and management.

neuroimagingd

Consider non-sedating, antiseizure medicinalproducts (e.g., levetiracetam) for seizureprophylaxis.

Provide supportive therapy, which may includeintensive care.

Action for patients ≥ 45 kg:

Interrupt BLINCYTO until ICANS resolves, thenrestart BLINCYTO at 9 mcg/day. Escalate to28 mcg/day after 7 days if the toxicity does notrecur. For reinitiation, premedicate with up to20 mg dexamethasone 1-3 hours beforeblinatumomab restart. If the toxicity occurred at9 mcg/day, or if the toxicity takes more than7 days to resolve, discontinue BLINCYTOpermanently.

Action for patients < 45 kg:

Interrupt BLINCYTO until ICANS resolves, thenrestart BLINCYTO at 5 mcg/m2/day. Escalate to15 mcg/m2/day after 7 days if the toxicity does notrecur. For reinitiation, premedicate with 5 mg/m2dexamethasone (maximum 20 mg/day) 1-3 hoursbefore blinatumomab restart. If the toxicityoccurred at 5 mcg/m2/day, or if the toxicity takesmore than 7 days to resolve, discontinue

BLINCYTO permanently.

Action for all patients

Permanently discontinue BLINCYTO if morethan one seizure occurs.

Gradea Presenting symptomsb Actions

Grade 4 ICE score 0c Permanently discontinue BLINCYTO.

Unable to perform CAPD* Administer dexamethasone:

or, depressed level ofconsciousnessd either: For patients ≥ 45 kg:

* patient is unarousable or Administer dexamethasone 8 mg/dose 3 doses/dayrequires vigorous or until event resolution to grade 1 or less and thenrepetitive tactile stimuli to taper as clinically indicated.

arouse, or Alternatively, consider administration of

* stupor or coma, methylprednisolone 1000 mg per dayintravenously for 3 days; taper as clinicallyor seizuresd, either: indicated.

* life-threatening prolongedseizure (> 5 minutes), or For patients < 45 kg:

* repetitive clinical or Administer dexamethasone at a total daily dose ofelectrical seizures without at least 0.2-0.4 mg/kg/day until event resolution toreturn to baseline in grade 1 or less and then taper as clinicallybetween, indicated.

Alternatively, consider administration ofor motor findingsd: methylprednisolone 30 mg/kg/day (maximum

* deep focal motor weakness 1000 mg/day) in divided doses intravenously forsuch as hemiparesis or 3 days; taper as clinically indicated.

paraparesis,

Monitor neurologic symptoms and consideror raised intracranial consultation with a neurologist and otherpressure/cerebral oedemad, with specialists for further evaluation and management.

signs/symptoms such as:

* diffuse cerebral oedema on Consider non-sedating, antiseizure medicinalneuroimaging, or products (e.g., levetiracetam) for seizureprophylaxis.

* decerebrate or decorticateposturing, or

Provide supportive therapy, which may include

* cranial nerve VI palsy, orintensive care.

* papilledema, or

* Cushing’s triad

Utilise ICE-Immune effector cell-associated encephalopathy score for patients aged ≥ 12 years of age

Utilise the CAPD- Cornell Assessment of Paediatric Delirium tool for patients aged < 12 years of age. Fordetails on CAPD assessment please refer to Lee, et al, 2019.a Based on American Society for Transplantation and Cellular Therapy (ASTCT) 2019 grading for ICANS.b Management is determined by the most severe event, not attributable to any other cause.c If patient is arousable and able to perform ICE assessment, assess:

Orientation (oriented to year, month, city, hospital = 4 points); Naming (name 3 objects, e.g., point to clock, pen,button = 3 points); Following commands (e.g., “show me 2 fingers” or “close your eyes and stick out yourtongue” = 1 point); Writing (ability to write a standard sentence = 1 point); and Attention (count backwards from100 by ten = 1 point). If patient is unarousable and unable to perform ICE assessment (Grade 4

ICANS) = 0 points.d Not attributable to any other cause.e All references to dexamethasone administration are dexamethasone or equivalent medicinal products.

* Scores between 1-8 may represent no impairment, grade 1 or grade 2 ICANS and must be combined withclinical assessment.

No dose adjustment is necessary in elderly patients (≥ 65 years of age), see section 5.1. There islimited experience with BLINCYTO in patients ≥ 75 years of age.

Based on pharmacokinetic analyses, dose adjustment is not necessary in patients with mild tomoderate renal dysfunction (see section 5.2). The safety and efficacy of BLINCYTO have not beenstudied in patients with severe renal impairment.

Based on pharmacokinetic analyses, no effect of baseline liver function on blinatumomab exposure isexpected and adjustment of the initial dose is not necessary (see section 5.2). The safety and efficacyof BLINCYTO have not been studied in patients with severe hepatic impairment.

There is limited experience with BLINCYTO in children < 1 year of age. Currently available data inchildren are described in sections 4.8 and 5.1.

BLINCYTO is for intravenous use.

For instructions on the handling and preparation of the medicinal product before administration, seesection 6.6.

Administer BLINCYTO as a continuous intravenous infusion delivered at a constant flow rate usingan infusion pump over a period of up to 96 hours. The pump should be programmable, lockable,non-elastomeric, and have an alarm.

The starting volume (270 mL) is more than the volume administered to the patient (240 mL) toaccount for the priming of the intravenous tubing and to ensure that the patient will receive the fulldose of BLINCYTO.

Infuse prepared BLINCYTO final infusion solution according to the instructions on the pharmacylabel on the prepared bag at one of the following constant infusion rates:

* Infusion rate of 10 mL/h for a duration of 24 hours

* Infusion rate of 5 mL/h for a duration of 48 hours

* Infusion rate of 3.3 mL/h for a duration of 72 hours

* Infusion rate of 2.5 mL/h for a duration of 96 hours

Administer prepared BLINCYTO final infusion solution using intravenous tubing that contains asterile, non-pyrogenic, low protein-binding 0.2 micrometre in-line filter.

Important note: Do not flush the BLINCYTO infusion line, especially when changing infusion bags.

Flushing when changing bags or at completion of infusion can result in excess dosage andcomplications thereof. When administering via a multi-lumen venous catheter, BLINCYTO should beinfused through a dedicated lumen.

The choice of the infusion duration should be made by the treating physician considering thefrequency of the infusion bag changes and the weight of the patient. The target therapeutic dose of

BLINCYTO delivered does not change.

Change of infusion bag

The infusion bag must be changed at least every 96 hours by a healthcare professional for sterilityreasons.

- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

- Breast-feeding (see section 4.6).

In order to improve the traceability of biological medicinal products, the name and the batch numberof the administered product should be clearly recorded.

Neurologic events including ICANS

Neurologic events including events with a fatal outcome have been observed. Grade 3 (CTCAEversion 4.0) or higher (severe or life-threatening) neurologic events including ICANS followinginitiation of blinatumomab administration included encephalopathy, seizures, speech disorders,disturbances in consciousness, confusion and disorientation, and coordination and balance disorders.

Among patients that experienced a neurologic event, the median time to the first event was within thefirst 2 weeks of treatment and the majority of events resolved after treatment interruption andinfrequently led to BLINCYTO treatment discontinuation.

Elderly patients may be more susceptible to serious neurologic events such as cognitive disorder,encephalopathy, and confusion.

Patients with a medical history of neurologic signs and symptoms (such as dizziness, hypoaesthesia,hyporeflexia, tremor, dysaesthesia, paraesthesia and memory impairment) demonstrated a higher rateof neurologic events (such as tremor, dizziness, confusional state, encephalopathy and ataxia). Amongthese patients, the median time to the first neurologic event was within the first cycle of treatment.

There is limited experience in patients with a history or presence of clinically relevant CNS pathology(e.g. epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson’s disease,cerebellar disease, organic brain syndrome and psychosis) as they were excluded from clinical studies.

There is a possibility of a higher risk of neurologic events in this population. The potential benefits oftreatment should be carefully weighed against the risk of neurologic events and heightened cautionshould be exercised when administering BLINCYTO to these patients.

There is limited experience with blinatumomab in patients with documented active ALL in the CNS orcerebrospinal fluid (CSF). However, patients have been treated with blinatumomab in clinical studiesafter clearance of CSF blasts with CNS directed therapy (such as intrathecal chemotherapy).

Therefore, once the CSF is cleared, treatment with BLINCYTO may be initiated.

It is recommended that a neurological examination be performed in patients prior to starting

BLINCYTO therapy and that patients be clinically monitored for signs and symptoms of neurologicevents including ICANS (e.g. writing test which could be part of a comprehensive neurologicalassessment). Management of these signs and symptoms to resolution may require either temporaryinterruption or permanent discontinuation of BLINCYTO and/or treatment with corticosteroids (seesection 4.2). In the event of a seizure, secondary prophylaxis with appropriate anticonvulsantmedicinal products (e.g. levetiracetam) is recommended.

In patients receiving blinatumomab, serious infections, including sepsis, pneumonia, bacteraemia,opportunistic infections and catheter site infections have been observed, some of which werelife-threatening or fatal. Adult patients with Eastern Cooperative Oncology Group (ECOG)performance status at baseline of 2 experienced a higher incidence of serious infections compared topatients with ECOG performance status of < 2. There is limited experience with BLINCYTO inpatients with an active uncontrolled infection.

Patients receiving BLINCYTO should be clinically monitored for signs and symptoms of infectionand treated appropriately. Management of infections may require either temporary interruption ordiscontinuation of BLINCYTO (see section 4.2).

Cytokine release syndrome and infusion reactions

Cytokine release syndrome (CRS) which may be life-threatening or fatal (grade ≥ 4) has been reportedin patients receiving BLINCYTO (see section 4.8).

Serious adverse reactions that may be signs and symptoms of CRS included pyrexia, asthenia,headache, hypotension, total bilirubin increased, and nausea; uncommonly, these events led to

BLINCYTO discontinuation. The median time to onset of a CRS event was 2 days. Patients should beclosely monitored for signs or symptoms of these events.

Disseminated intravascular coagulation (DIC) and capillary leak syndrome (CLS, e.g. hypotension,hypoalbuminaemia, oedema and haemoconcentration) have been commonly associated with CRS (seesection 4.8). Patients experiencing capillary leak syndrome should be managed promptly.

Haemophagocytic histiocytosis/macrophage activation syndrome (MAS) has been uncommonlyreported in the setting of CRS.

Infusion reactions may be clinically indistinguishable from manifestations of CRS (see section 4.8).

The infusion reactions were generally rapid, occurring within 48 hours after initiating infusion.

However, some patients reported delayed onset of infusion reactions or in later cycles. Patients shouldbe observed closely for infusion reactions, especially during the initiation of the first and secondtreatment cycles and treated appropriately. Anti-pyretic use (e.g. paracetamol) is recommended to helpreduce pyrexia during the first 48 hours of each cycle. To mitigate the risk of CRS, it is important toinitiate BLINCYTO (cycle 1, days 1-7) at the recommended starting dose in section 4.2.

Management of these events may require either temporary interruption or discontinuation of

BLINCYTO (see section 4.2).

Tumour lysis syndrome (TLS), which may be life-threatening or fatal (grade ≥ 4) has been observed inpatients receiving BLINCYTO.

Appropriate prophylactic measures including aggressive hydration and anti-hyperuricaemic therapy(such as allopurinol or rasburicase) should be used for the prevention and treatment of TLS during

BLINCYTO treatment, especially in patients with higher leukocytosis or a high tumour burden.

Patients should be closely monitored for signs or symptoms of TLS, including renal function and fluidbalance in the first 48 hours after the first infusion. In clinical studies, patients with moderate renalimpairment showed an increased incidence of TLS compared with patients with mild renal impairmentor normal renal function. Management of these events may require either temporary interruption ordiscontinuation of BLINCYTO (see section 4.2).

Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patientsreceiving BLINCYTO. Laboratory parameters (including, but not limited to white blood cell countand absolute neutrophil count) should be monitored routinely during BLINCYTO infusion, especiallyduring the first 9 days of the first cycle, and treated appropriately.

Treatment with BLINCYTO was associated with transient elevations in liver enzymes. The majorityof the events were observed within the first week of treatment initiation and did not requireinterruption or discontinuation of BLINCYTO (see section 4.8).

Monitoring of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyltransferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatmentespecially during the first 48 hours of the first 2 cycles should be performed. Management of theseevents may require either temporary interruption or discontinuation of BLINCYTO (see section 4.2).

Pancreatitis, life-threatening or fatal, has been reported in patients receiving BLINCYTO in clinicalstudies and the post-marketing setting. High-dose steroid therapy may have contributed, in some cases,to the pancreatitis.

Patients should be closely monitored for signs and symptoms of pancreatitis. Patient evaluation mayinclude physical examination, laboratory evaluation for serum amylase and serum lipase, andabdominal imaging, such as ultrasound and other appropriate diagnostic measures. Management ofpancreatitis may require either temporary interruption or discontinuation of BLINCYTO (seesection 4.2).

Leukoencephalopathy including progressive multifocal leukoencephalopathy

Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have beenobserved in patients receiving BLINCYTO, especially in patients with prior treatment with cranialirradiation and anti-leukaemic chemotherapy (including systemic high-dose methotrexate orintrathecal cytarabine). The clinical significance of these imaging changes is unknown.

Due to the potential for progressive multifocal leukoencephalopathy (PML), patients should bemonitored for signs and symptoms. In case of suspicious events consider consultation with aneurologist, brain MRI and examination of cerebral spinal fluid (CSF), see section 4.8.

CD19-negative relapse

CD19-negative B-cell precursor ALL has been reported in relapsed patients receiving BLINCYTO.

Particular attention should be given to assessment of CD19 expression at the time of bone marrowtesting.

Lineage switch from ALL to acute myeloid leukaemia (AML)

Lineage switch from ALL to AML has been rarely reported in relapsed patients receiving

BLINCYTO, including those with no immunophenotypic and/or cytogenetic abnormalities at initialdiagnosis. All relapsed patients should be monitored for presence of AML.

The safety of immunisation with live viral vaccines during or following BLINCYTO therapy has notbeen studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to thestart of BLINCYTO treatment, during treatment, and until recovery of B-lymphocytes to normalranges following last treatment cycle.

Due to the potential depletion of B-cells in newborns following exposure to blinatumomab duringpregnancy, newborns should be monitored for B-cell depletion and vaccinations with live virusvaccines should be postponed until the infant’s B-cell count has recovered (see section 4.6).

Women of childbearing potential have to use effective contraception during and for at least 48 hours,after treatment with BLINCYTO (see section 4.6).

Medication errors have been observed with BLINCYTO treatment. It is very important that theinstructions for preparation (including reconstitution and dilution) and administration are strictlyfollowed to minimise medication errors (including underdose and overdose) (see section 4.2).

This medicinal product contains less than 1 mmol (23 mg) sodium over a 24 hour infusion, that is tosay essentially ‘sodium-free’.

No formal drug interaction studies have been performed. Results from an in vitro test in humanhepatocytes suggest that blinatumomab did not affect CYP450 enzyme activities.

Initiation of BLINCYTO treatment causes transient release of cytokines during the first days oftreatment that may suppress CYP450 enzymes. Patients who are receiving medicinal products that are

CYP450 and transporter substrates with a narrow therapeutic index should be monitored for adverseeffects (e.g. warfarin) or drug concentrations (e.g. cyclosporine) during this time. The dose of theconcomitant medicinal product should be adjusted as needed.

Women of childbearing potential have to use effective contraception during and for at least 48 hoursafter treatment with blinatumomab (see section 4.4).

Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetaldevelopmental toxicity study conducted in mice, the murine surrogate molecule crossed the placentaand did not induce embryotoxicity, or teratogenicity (see section 5.3). The expected depletions of

B- and T-cells were observed in the pregnant mice but haematological effects were not assessed infoetuses.

There are no data from the use of blinatumomab in pregnant women.

Blinatumomab should not be used during pregnancy unless the potential benefit outweighs thepotential risk to the foetus.

In case of exposure during pregnancy, depletion of B-cells may be expected in newborns due to thepharmacological properties of the product. Consequently, newborns should be monitored for B-celldepletion and vaccinations with live virus vaccines should be postponed until the infant’s B-cell counthas recovered (see section 4.4).

It is unknown whether blinatumomab or metabolites are excreted in human milk. Based on itspharmacological properties, a risk to the suckling child cannot be excluded. Consequently, as aprecautionary measure, breast-feeding is contraindicated during and for at least 48 hours aftertreatment with blinatumomab.

No studies have been conducted to evaluate the effects of blinatumomab on fertility. No adverseeffects on male or female mouse reproductive organs in 13-week toxicity studies with the murinesurrogate molecule (see section 5.3).

Blinatumomab has major influence on the ability to drive and use machines. Confusion anddisorientation, coordination and balance disorders, risk of seizures and disturbances in consciousnesscan occur (see section 4.4). Due to the potential for neurologic events, patients receivingblinatumomab should refrain from driving, engaging in hazardous occupations or activities such asdriving or operating heavy or potentially dangerous machinery while blinatumomab is beingadministered. Patients must be advised that they may experience neurologic events.

The adverse reactions described in this section were identified in clinical studies of patients with

B-cell precursor ALL (N = 1 045).

The most serious adverse reactions that may occur during blinatumomab treatment include: infections(22.6%), neurologic events (12.2%), neutropenia/febrile neutropenia (9.1%), cytokine releasesyndrome (2.7%), and tumour lysis syndrome (0.8%).

The most common adverse reactions were: pyrexia (70.8%), infections - pathogen unspecified(41.4%), infusion-related reactions (33.4%), headache (32.7%), nausea (23.9%), anaemia (23.3%),thrombocytopenia (21.6%), oedema (21.4%), neutropenia (20.8%), febrile neutropenia (20.4%),diarrhoea (19.7%), vomiting (19.0%), rash (18.0%), hepatic enzyme increased (17.2%), cough(15.0%), bacterial infectious disorders (14.1%), tremor (14.1%), cytokine release syndrome (13.8%),leukopenia (13.8%), constipation (13.5%), decreased immunoglobulins (13.4%), viral infectiousdisorders (13.3%), hypotension (13.0%), back pain (12.5%), chills (11.7%), abdominal pain (10.6%),tachycardia (10.6%), insomnia (10.4%), pain in extremity (10.1%), and fungal infectious disorders(9.6%).

Adverse reactions are presented below by system organ class and frequency category. Frequencycategories were determined from the crude incidence rate reported for each adverse reaction in clinicalstudies of patients with B-cell precursor ALL (N = 1 045). Within each frequency grouping, adversereactions are presented in order of decreasing seriousness.

MedDRA system Very common Common Uncommonorgan class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100)

Infections and Bacterial infectionsa, b Sepsisinfestations Viral infectionsa, b Pneumonia

Infections - pathogen Fungal infectionsa, bunspecifieda, b

Blood and lymphatic Febrile neutropenia Leukocytosis5 Lymphadenopathysystem disorders Anaemia1 Lymphopenia6 Histiocytosis

Neutropenia2 haematophagic

Thrombocytopenia3

Leukopenia4

MedDRA system Very common Common Uncommonorgan class (≥ 1/10) (≥ 1/100 to < 1/10) (≥ 1/1 000 to < 1/100)

Immune system Cytokine release Hypersensitivity Cytokine stormdisorders syndromea

Metabolism and Tumour lysis syndromenutrition disorders

Psychiatric disordersa Insomnia18 Confusional state18

Disorientation18

Nervous system Headache18 Encephalopathy18 Speech disorder18disordersa Tremor18 Aphasia18

Paraesthesia18

Seizure18

Cognitive disorder18

Memory impairment

Dizziness18

Somnolence18

Hypoaesthesia18

Cranial nerve disorderb

Ataxia18

Immune effector cell-associated neurotoxicitysyndrome (ICANS)

Cardiac disorders Tachycardia7

Vascular disorders Hypotension8 Flushing Capillary leak

Hypertension9 syndrome

Respiratory, thoracic Cough Dyspnoea Dyspnoea exertionaland mediastinal Productive cough Acute respiratorydisorders Respiratory failure failure

Wheezing

Gastrointestinal Nausea Pancreatitisadisorders Diarrhoea

Abdominal pain

Hepatobiliary Hyperbilirubinaemiaa, 10disorders

Skin and subcutaneous Rash11tissue disorders

Musculoskeletal and Back pain Bone painconnective tissue Pain in extremitydisorders

General disorders and Pyrexia12 Chest pain14administration site Chills Painconditions Oedema13

Investigations Hepatic enzyme Weight increasedincreaseda, 15 Blood alkaline

Decreased phosphatase increasedimmunoglobulins16

Injury, poisoning and Infusion-relatedprocedural reactions17complicationsa Additional information is provided in “Description of selected adverse reactions”.b MedDRA high level group terms (MedDRA version 23.0).

Event terms that represent the same medical concept or condition were grouped together and reported as a singleadverse reaction in the table above. The terms contributing to the relevant adverse reaction are indicated below:1 Anaemia includes anaemia and haemoglobin decreased.

2 Neutropenia includes neutropenia and neutrophil count decreased.3 Thrombocytopenia includes platelet count decreased and thrombocytopenia.4 Leukopenia includes leukopenia and white blood cell count decreased.5 Leukocytosis includes leukocytosis and white blood cell count increased.6 Lymphopenia includes lymphocyte count decreased and lymphopenia.7 Tachycardia includes sinus tachycardia, supraventricular tachycardia, tachycardia, atrial tachycardia andventricular tachycardia.8 Hypotension includes blood pressure decreased and hypotension.9 Hypertension includes blood pressure increased and hypertension.10 Hyperbilirubinaemia includes blood bilirubin increased and hyperbilirubinaemia.11 Rash includes erythema, rash, rash erythematous, rash generalised, rash macular, rash maculo-papular, rashpruritic, catheter site rash, rash pustular, genital rash, rash papular and rash vesicular.12 Pyrexia includes body temperature increased and pyrexia.13 Oedema includes bone marrow oedema, periorbital oedema, eyelid oedema, eye oedema, lip oedema, faceoedema, localised oedema, generalised oedema, oedema, oedema peripheral, infusion site oedema, oedematouskidney, scrotal oedema, oedema genital, pulmonary oedema, laryngeal oedema, angioedema, circumoral oedemaand lymphoedema.14 Chest pain includes chest discomfort, chest pain, musculoskeletal chest pain and non-cardiac chest pain.15 Hepatic enzyme increased includes alanine aminotransferase increased, aspartate aminotransferase increased,gamma-glutamyl transferase increased, hepatic enzyme increased, liver function test increased and transaminasesincreased.16 Decreased immunoglobulins includes blood immunoglobulin G decreased, blood immunoglobulin Adecreased, blood immunoglobulin M decreased, globulins decreased, hypogammaglobulinaemia,hypoglobulinaemia and immunoglobulins decreased.17 Infusion-related reactions is a composite term that includes the term infusion-related reaction and thefollowing events occurring with the first 48 hours of infusion and event lasted ≤ 2 days: pyrexia, cytokine releasesyndrome, hypotension, myalgia, acute kidney injury, hypertension, rash, tachypnoea, swelling face, faceoedema and rash erythematous.18 Events may represent ICANS.

Neurologic events including ICANS

In the randomised phase III clinical study (N = 267) and the single-arm phase II clinical study(N = 189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor

ALL treated with BLINCYTO, 66.0% of patients experienced one or more neurologic adversereactions (including psychiatric disorders), primarily involving the CNS. Serious and grade ≥ 3neurologic adverse reactions were observed in 11.6% and 12.1% of patients respectively, of which themost common serious adverse reactions were encephalopathy, tremor, aphasia, and confusional state.

The majority of neurologic events (80.5%) were clinically reversible and resolved followinginterruption of BLINCYTO. The median time to the first event was within the first 2 weeks oftreatment. One case of fatal encephalopathy has been reported in an earlier phase II clinical single-armstudy.

Neurologic events were reported for 62.2% of adult patients with Philadelphia chromosome-positiverelapsed or refractory B-cell precursor ALL (N = 45). Serious and grade ≥ 3 neurologic events werereported at 13.3% each in adult patients with Philadelphia chromosome-positive relapsed or refractory

B-cell precursor ALL.

Neurologic events were reported for 71.5% of adult patients with MRD positive B-cell precursor ALL(N = 137), 22.6% of patients experienced serious events. Grade ≥ 3 and grade ≥ 4 events, respectively,were reported for 16.1% and 2.2% of adult patients with MRD positive B-cell precursor ALL.

Neurologic events were reported in 61.2% of adult patients in CD19-positive B-cell precursor ALL inthe consolidation phase where BLINCYTO was administered alternating with chemotherapy(N = 147). Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 28.6% and 2.0% of adultpatients with CD19-positive B-cell precursor ALL in the consolidation phase.

ICANS, including Grade 3 and higher ICANS, were reported in clinical trials and with post-marketingexperience. The most frequent clinical manifestations of ICANS were confusional state, aphasia,disorientation, altered state of consciousness, dysarthria, encephalopathy, seizure, mental statuschanges, somnolence and dysgraphia.

The observed time to onset of ICANS ranged from 0 to 299 days with the majority of ICANSoccurring within the first three weeks.

For clinical management of neurologic events and ICANS, see section 4.2.

Life-threatening or fatal (grade ≥ 4) viral, bacterial and fungal infections have been reported inpatients treated with BLINCYTO. In addition, reactivations of virus infection (e.g. Polyoma (BK))have been observed in the phase II clinical study in adults with Philadelphia chromosome-negativerelapsed or refractory B-cell precursor ALL. Patients with Philadelphia chromosome-negative relapsedor refractory B-cell precursor ALL with ECOG performance status at baseline of 2 experienced ahigher incidence of serious infections compared to patients with ECOG performance status of < 2.

Infections were reported in 34.7% of adult patients with CD19-positive B-cell precursor ALL in theconsolidation phase where BLINCYTO was administered alternating with chemotherapy (N = 147).

Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 28.6% and 10.2% of adult patientswith CD19-positive B-cell precursor ALL in the consolidation phase.

For clinical management of infections, see section 4.4.

In the randomised phase III clinical study (N = 267) and the single-arm phase II clinical study(N = 189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor

ALL treated with BLINCYTO, 14.7% of patients experienced CRS. Serious CRS reactions werereported in 2.4% of patients with a median time to onset of 2 days.

Cytokine release syndrome was reported in 8.9% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL (N = 45), 2.2% of patients experienced seriousevents. No grade ≥ 3 or ≥ 4 events were reported.

Cytokine release syndrome was reported in 2.9% of adult patients with MRD positive B-cell precursor

ALL (N = 137). Grade 3 and serious events were reported for 1.5% each of adult patients with MRDpositive B-cell precursor ALL; no grade ≥ 4 events were reported.

Cytokine release syndrome was reported in 15.6% of adult patients with CD19-positive B-cellprecursor ALL in the consolidation phase where BLINCYTO was administered alternating withchemotherapy (N = 147). Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 4.1% and0.7% of adult patients with CD19-positive B-cell precursor ALL in the consolidation phase.

Capillary leak syndrome was observed in 1 patient in the phase II clinical study in adult patients with

Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL and in 1 patient in thephase II clinical study in adult patients with MRD positive B-cell precursor ALL. Capillary leaksyndrome was not observed in adult patients in the phase II clinical study in patients with Philadelphiachromosome-positive relapsed or refractory B-cell precursor ALL. Capillary leak syndrome wasreported in 1 patient (0.7%) with CD19-positive B-cell precursor ALL in the consolidation phasewhere BLINCYTO was administered alternating with chemotherapy (N = 147); the event was grade 3.

For clinical management of CRS, see section 4.4.

In the randomised phase III clinical study (N = 267) and the single-arm phase II clinical study(N = 189) in patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor

ALL treated with BLINCYTO, 22.4% of patients reported elevated liver enzymes and associatedsigns/symptoms. Serious and grade ≥ 3 adverse reactions (such as ALT increased, AST increased, andblood bilirubin increased) were observed in 1.5% and 13.6% of patients respectively. The median timeto onset to the first event was 4 days from the start of BLINCYTO treatment initiation.

Elevated liver enzyme events were reported for 17.8% of adult patients with Philadelphiachromosome-positive relapsed or refractory B-cell precursor ALL (N = 45), 2.2% of patientsexperienced serious events. Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 13.3% and6.7% of adult patients with Philadelphia chromosome-positive relapsed or refractory B-cell precursor

ALL.

Elevated liver enzyme events were reported for 12.4% of adult patients with MRD positive B-cellprecursor ALL (N = 137). Grade ≥ 3 and grade ≥ 4 events, respectively, were reported for 8.0% and4.4% of adult patients with MRD positive B-cell precursor ALL.

Elevated liver enzyme events were reported in 15.6% of adult patients with CD19-positive B-cellprecursor ALL in the consolidation phase where BLINCYTO was administered alternating withchemotherapy (N = 147). Grade ≥ 3 and Grade ≥ 4 events, respectively, were reported -for 8.8% and2.7 % of adult patients with CD-19 positive B-cell precursor ALL in the consolidation phase.

The duration of hepatic adverse reactions has generally been brief and with rapid resolution, oftenwhen continuing uninterrupted treatment with BLINCYTO.

For clinical management of elevated liver enzymes, see section 4.4.

Pancreatitis, life-threatening or fatal, has been reported in patients receiving BLINCYTO in theclinical studies and the post-marketing settings. The median time to onset was 7.5 days. For clinicalmanagement of pancreatitis, see section 4.4.

Leukoencephalopathy including progressive multifocal leukoencephalopathy

Leukoencephalopathy has been reported. Patients with brain MRI/CT findings consistent withleukoencephalopathy experienced concurrent serious adverse reactions including confusional state,tremor, cognitive disorder, encephalopathy, and convulsion. Although there is a potential for thedevelopment of progressive multifocal leukoencephalopathy (PML), no confirmed case of PML hasbeen reported in the clinical studies.

The safety and effectiveness of BLINCYTO have been evaluated in paediatric patients with

Philadelphia chromosome negative relapsed or refractory B-cell precursor ALL in two open labelstudies: a single-arm Phase I/II study (MT103-205) and a randomised, controlled Phase IIIstudy (20120215).

Study MT103-205 was a dose escalation/evaluation study in paediatric patients with relapsed orrefractory B-cell precursor ALL in a phase I/II, single-arm dose escalation/evaluation study (MT103-205), in which 70 patients, aged 7 months to 17 years, were treated with the recommended dosageregimen.

The most frequently reported serious adverse reactions were pyrexia (11.4%), febrile neutropenia(11.4%), cytokine release syndrome (5.7%), sepsis (4.3%), device-related infection (4.3%), overdose(4.3%), convulsion (2.9%), respiratory failure (2.9%), hypoxia (2.9%), pneumonia (2.9%), andmulti-organ failure (2.9%).

The adverse reactions in BLINCYTO-treated paediatric patients were similar in type to those seen inadult patients. Adverse reactions that were observed more frequently (≥ 10% difference) in thepaediatric population compared to the adult population were anaemia, thrombocytopenia, leukopenia,pyrexia, infusion-related reactions, weight increase, and hypertension.

The type and frequency of adverse reactions were similar across different paediatric subgroups(gender, age and geographic region).

At a dose higher than the recommended dose in study MT103-205, a case of fatal cardiac failureoccurred in the setting of life-threatening cytokine release syndrome (CRS) and tumour lysissyndrome (TLS), see section 4.4.

BLINCYTO has also been evaluated in paediatric patients with high-risk first relapsed B-cellprecursor ALL in a randomised, controlled, open-label phase III study (20120215), in which54 patients, aged 1 to 18 years, were treated with the recommended dosage regimen for high-risk firstrelapsed B-cell precursor ALL. The safety profile of BLINCYTO in study 20120215 is consistent withthat of the studied paediatric relapsed or refractory B-cell precursor ALL population.

There is limited experience with BLINCYTO in patients ≥ 75 years of age. Generally, safety wassimilar between elderly patients (≥ 65 years of age) and patients less than 65 years of age treated with

BLINCYTO. However, elderly patients may be more susceptible to serious neurologic events such ascognitive disorder, encephalopathy and confusion.

Elderly patients with MRD positive ALL treated with BLINCYTO may have an increased risk ofhypogammaglobulinaemia compared to younger patients. It is recommended that immunoglobulinlevels are monitored in elderly patients during treatment with BLINCYTO.

The safety of BLINCYTO has not been studied in patients with severe renal impairment.

In clinical studies of adult ALL patients treated with BLINCYTO, less than 2% tested positive foranti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, the majorityhad in vitro neutralising activity. No anti-blinatumomab antibodies were detected in clinical studies ofpaediatric patients with relapsed or refractory ALL treated with blinatumomab.

Anti-blinatumomab antibody formation may affect the pharmacokinetics of BLINCYTO.

Overall, the totality of clinical evidence supports the finding that anti-blinatumomab antibodies are notsuggestive of any clinical impact on the safety or effectiveness of BLINCYTO.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Overdoses have been observed including one patient who received 133-fold the recommendedtherapeutic dose of BLINCYTO delivered over a short duration. Overdoses resulted in adversereactions which were consistent with the reactions observed at the recommended therapeutic dose andincluded fever, tremors, and headache. In the event of overdose, the infusion should be temporarilyinterrupted and patients should be monitored. Reinitiation of BLINCYTO at the correct therapeuticdose should be considered when all toxicities have resolved and no earlier than 12 hours afterinterruption of the infusion (see section 4.2).

Pharmacotherapeutic group: Antineoplastic agents, other monoclonal antibodies and antibody drugconjugates, ATC code: L01FX07.

Blinatumomab is a bispecific T-cell engager molecule that binds specifically to CD19 expressed onthe surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activatesendogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benignand malignant B-cells. The anti-tumour activity of blinatumomab immunotherapy is not dependent on

T-cells bearing a specific TCR or on peptide antigens presented by cancer cells, but is polyclonal innature and independent of human leukocyte antigen (HLA) molecules on target cells. Blinatumomabmediates the formation of a cytolytic synapse between the T-cell and the tumour cell, releasingproteolytic enzymes to kill both proliferating and resting target cells. Blinatumomab is associated withtransient upregulation of cell adhesion molecules, production of cytolytic proteins, release ofinflammatory cytokines, and proliferation of T-cells, and results in elimination of CD19+ cells.

Consistent immune-pharmacodynamic responses were observed in patients studied. During thecontinuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterised by

T-cell activation and initial redistribution, rapid peripheral B-cell depletion, and transient cytokineelevation.

Peripheral T-cell redistribution (i.e. T-cell adhesion to blood vessel endothelium and/or transmigrationinto tissue) occurred after start of blinatumomab infusion or dose escalation. T-cell counts initiallydeclined within 1 to 2 days and then returned to baseline levels within 7 to 14 days in the majority ofpatients. Increase of T-cell counts above baseline (T-cell expansion) was observed in few patients.

Peripheral B-cell counts decreased rapidly to an undetectable level during treatment at doses≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell countswas observed during the 2-week treatment-free period between treatment cycles. Incomplete depletionof B-cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few non-responders athigher doses.

Peripheral lymphocytes were not measured in paediatric subjects.

Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α and IFN-γ were measured and, IL-6,

IL-10 and IFN-γ were most elevated. Transient elevation of cytokines was observed in the first 2 daysfollowing start of blinatumomab infusion. The elevated cytokine levels returned to baseline within24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred infewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.

Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL

A total of 456 patients aged ≥ 18 years of age with relapsed or refractory B-cell precursor ALL wereexposed to BLINCYTO during the phase II and phase III clinical studies described below.

The safety and efficacy of BLINCYTO compared to standard of care (SOC) chemotherapy wereevaluated in a randomised, open-label, multicentre, phase III study (TOWER). Eligible patients were≥ 18 years of age and ECOG status ≤ 2 with relapsed or refractory B-cell precursor ALL (had> 5% blasts in the bone marrow and either relapse at any time after allogeneic HSCT, untreated firstrelapse with first remission duration < 12 months, or refractory to last therapy).

Patients were randomised 2:1 to receive BLINCYTO or 1 of 4 prespecified, investigator-selected,

SOC backbone chemotherapy regimens. Randomisation was stratified by age (< 35 years versus≥ 35 years of age), prior salvage therapy (yes versus no), and prior allogeneic HSCT (yes versus no) asassessed at the time of consent. The demographics and baseline characteristics were well-balancedbetween the two arms (see table 7).

Table 7. Demographics and baseline characteristics in phase III study (TOWER)

BLINCYTO SOC chemotherapy

Characteristic(N = 271) (N = 134)

Median, years (min, max) 37 (18, 80) 37 (18, 78)

Mean, years (SD) 40.8 (17.1) 41.1 (17.3)≥ 65 years, n (%) 33 (12.2) 15 (11.2)

Prior salvage therapy 164 (60.5) 80 (59.7)0 114 (42.1) 65 (48.5)1 91 (33.6) 43 (32.1)≥ 2 66 (24.3) 26 (19.4)

Prior alloHSCT 94 (34.7) 46 (34.3)

ECOG status - n (%)0 96 (35.4) 52 (38.8)1 134 (49.4) 61 (45.5)2 41 (15.1) 20 (14.9)

Refractory status - n (%)

Primary refractory 46 (17.0) 27 (20.1)

Refractory to salvage therapy 87 (32.1) 34 (25.4)

Maximum of central/local bone marrow blasts - n (%)≥ 50% 201 (74.2) 104 (77.6)alloHSCT = allogeneic haematopoietic stem cell transplantation

SOC = standard of care

BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dosewas 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The target dose of 28 mcg/daywas administered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose adjustmentwas possible in case of adverse reactions. Of the 267 patients who received BLINCYTO, the meannumber of completed treatment cycles was 2.0; of the 109 patients who received SOC chemotherapy,the mean number of treatment cycles was 1.3.

The primary endpoint was overall survival (OS). The median OS was 4.0 months (95% CI: 2.9, 5.3) inthe SOC chemotherapy arm compared with 7.7 months (95% CI: 5.6, 9.6) in the BLINCYTO arm.

The hazard ratio (95% CI) was 0.71 (0.55, 0.93) between treatment arms favouring BLINCYTO,indicated a 29% reduction in hazard rate in the BLINCYTO arm (p-value = 0.012 (stratified log-ranktest)), see figure 1. Consistency in OS results was shown in subgroups by stratification factors.

Consistent results were observed after censoring at the time of HSCT; median OS, censored at thetime of HSCT, was 6.9 months (95% CI: 5.3, 8.8) in the BLINCYTO group and 3.9 months(95% CI: 2.8, 4.9) in the SOC group (HR, 0.66; 95% CI: 0.50, 0.88; p-value = 0.004). The mortalityrate following alloHSCT among all responders who did not receive anti-leukaemic therapy was10/38 (26.3%; 95% CI: 13.4, 43.1) in the BLINCYTO group and 3/12 (25%; 95% CI: 5.5, 57.2) in the

SOC group; such mortality rate at 100 days post alloHSCT was 4/38 (12.4%; 95% CI: 4.8%, 29.9%)in the BLINCYTO group and 0/12 (0%; 95% CI: not estimable) in the SOC group. Efficacy resultsfrom other key endpoints in the study are summarised in table 8.

Figure 1. Kaplan-Meier curve of overall survival

BLIN CYTO SOC Chemo1.0 (N=271) (N=134)0.9

Median OS, mo 7.7 (5.6, 9.6) 4.0 (2.9, 5.3)0.8 HR (BLINCYTO/SOC Chemo) (95% CI) 0.71 (0.55, 0.93)0.7 p-value (2-sided) 0.0120.60.50.40.30.20.10.00 3 6 9 12 15 18 21 24 27

Months

BLINCYTO SOC Chemo

Number of subjects at Risk

BLINCYTO 271 176 124 79 45 27 9 4 0 0

SOC Chemo 134 71 41 27 17 7 4 1 0 0

A censored subject is indicated by a Vertical Bar l. GRH0358 v1

Table 8. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome-negativerelapsed or refractory B-cell precursor ALL (TOWER)

BLINCYTO SOC chemotherapy(N = 271) (N = 134)

Complete remission (CR)

CRa/CRh*b/CRic, n (%) [95% CI] 119 (43.9) (37.9, 50.0) 33 (24.6) (17.6, 32.8)

Treatment difference [95% CI] 19.3 (9.9, 28.7)p-value < 0.001

CR, n (%) [95% CI] 91 (33.6) (28.0, 39.5) 21 (15.7) (10.0, 23.0)

Treatment difference [95% CI] 17.9 (9.6, 26.2)p-value < 0.001

Event-free survivald6-month estimate % [95% CI] 30.7 (25.0, 36.5) 12.5 (7.2, 19.2)18-months estimate % [95% CI] 9.5 (5.1, 15.6) 7.9 (3.7, 14.2)

HR [95% CI] 0.55 (0.43, 0.71)

Duration of haematological response-

Median time to event [95% CI]

CR 8.3 (5.7, 10.7) 7.8 (2.2, 19.0)

CR/CRh*/CRi 7.3 (5.8, 9.9) 4.6 (1.8, 19.0)

MRDe response for CR/CRh*/CRi

MRD evaluable patients (%)74/97 (76.3) (66.6, 84.3) 16/33 (48.5) (30.8, 66.5)[95% CI]f

Duration of MRD response-4.5 months (3.6, 9.0) 3.8 months (1.9, 19.0)

Median time to event [95% CI]

Survival Probability

BLINCYTO SOC chemotherapy(N = 271) (N = 134)

Postbaseline alloHSCT - n (%)

Overall subjects 65 (24) 32 (23.9)

Haematological responders50 (42.0) 18 (54.5)(CR/CRh*/CRi)

Time to alloHSCT among alltransplanted patients 3.7 months (3.0, 5.3) 3.1 months (2.6, pct. 4.3)

Median time to event (N = 65) (N = 32)(Interquartile range)

Time to alloHSCT among

CR/CRh*/CRi responders 11.3 months (5.2, NE) 3.6 months (2.3, 7.2)

Median time to event [95% CI] (N = 119) (N = 33)(KM estimate)100 day mortality after alloHSCTn/N (%), [95% CI] 4/38, 12.4% (4.8, 29.9) 0/12, 0.0% (0.0, NE)a CR was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheralblood counts (platelets > 100 000/microlitre and absolute neutrophil counts [ANC] > 1 000/microlitre).b CRh* (complete remission with partial haematologic recovery) was defined as ≤ 5% blasts in the bone marrow,no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50 000/microlitre and

ANC > 500/microlitre).c CRi (complete remission with incomplete haematologic recovery) was defined as ≤ 5% blasts in the bonemarrow, no evidence of disease, and incomplete recovery of peripheral blood counts(platelets > 100 000/microlitre or ANC > 1 000/microlitre).d EFS time was calculated from the time of randomisation until the date of disease assessment indicating arelapse after achieving a CR/CRh*/CRi or death, whichever is earlier. Subjects who fail to achieve a

CR/CRh*/CRi within 12 weeks of treatment initiation are considered treatment failures and assigned an EFSduration of 1 day.e MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry < 1 × 10-4.f Patients who achieved CR/CRh*/CRi and had an evaluable post baseline MRD assessment.

In this open-label study, Health related quality of life (HRQoL) reported by patients were measuredusing the European Organisation for Research and Treatment of Cancer Quality of Life

Questionnaire - Core 30 (EORTC QLQ-C30). In a post-hoc sensitivity analysis, compared to SOC,

BLINCYTO consistently delayed the time to clinically meaningful deterioration of HRQoL(≥ 10-points worsening from baseline) for global health status [median BLINCYTO versus SOC:

8.1 months versus 1.0 month; HR = 0.60 (95% CI = 0.42, 0.85)], functional scales, symptom scalesand individual items. Because the health-related quality of life results are based on a post-hocsensitivity analysis, the results should be interpreted with caution.

BLINCYTO was also evaluated in an open-label, multicentre, single-arm phase II study of189 patients (MT103-211). Eligible patients were ≥ 18 years of age with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL (relapsed with first remission duration of≤ 12 months in first salvage, or relapsed or refractory after first salvage therapy, or relapsed within12 months of allogeneic HSCT, and had ≥ 10% blasts in bone marrow).

Premedication, BLINCYTO dose per treatment cycle and route of administration were identical tothose in the phase III study. Patients were premedicated with a mandatory cerebrospinal fluidprophylaxis consisting of an intrathecal regimen according to institutional or national guidelineswithin 1 week prior to start of BLINCYTO treatment. BLINCYTO was administered as a continuousintravenous infusion. In the first cycle, the initial dose was 9 mcg/day for week 1, then 28 mcg/day forthe remaining 3 weeks. The target dose of 28 mcg/day was administered in cycle 2 and subsequentcycles starting on day 1 of each cycle. Dose adjustment was possible in the case of adverse reactions.

The treated population included 189 patients who received at least 1 infusion of BLINCYTO; themean number of cycles per patient was 1.6. Patients who responded to BLINCYTO but later relapsedhad the option to be retreated with BLINCYTO. Among treated patients, the median age was 39 years(range: 18 to 79 years, including 25 patients ≥ 65 years of age), 64 of 189 (33.9%) had undergone

HSCT prior to receiving BLINCYTO and 32 of 189 (16.9%) had received more than 2 prior salvagetherapies.

The primary endpoint was the complete remission/complete remission with partial haematologicalrecovery (CR/CRh*) rate within 2 cycles of treatment with BLINCYTO. Eighty-one of 189 (42.9%)patients achieved CR/CRh* within the first 2 treatment cycles with the majority of responses(64 of 81) occurring within 1 cycle of treatment. In the elderly population (≥ 65 years of age) 11 of25 patients (44.0%) achieved CR/CRh* within the first 2 treatment cycles (see section 4.8 for safety inelderly). Four patients achieved CR during consolidation cycles, resulting in a cumulative CR rate of35.4% (67/189; 95% CI: 28.6% - 42.7%). Thirty-two of 189 (17%) patients underwent allogeneic

HSCT in CR/CRh* induced with BLINCYTO (see table 9).

Table 9. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome-negativerelapsed or refractory B-cell precursor ALL (MT103-211)n (%) 95% CIn = 189

Complete remission (CR)1/Complete remission 81 (42.9%) [35.7% - 50.2%]with partial haematological recovery (CRh*)2

CR 63 (33.3%) [26.7% - 40.5%]

CRh* 18 (9.5%) [5.7% - 14.6%]

Blast free hypoplastic or aplastic bone marrow3 17 (9.0%) [5.3% - 14.0%]

Partial remission4 5 (2.6%) [0.9% - 6.1%]

Relapse5-free survival (RFS) for CR/CRh* 5.9 months [4.8 to 8.3 months]

Overall survival 6.1 months [4.2 to 7.5 months]1 CR was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheralblood counts (platelets > 100 000/microlitre and absolute neutrophil counts [ANC] > 1 000/microlitre).2 CRh* was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery ofperipheral blood counts (platelets > 50 000/microlitre and ANC > 500/microlitre).3 Blast free hypoplastic or aplastic bone marrow was defined as bone marrow blasts ≤ 5%, no evidence ofdisease, insufficient recovery of peripheral blood counts: platelets ≤ 50 000/microlitre and/or

ANC ≤ 500/microlitre.4 Partial remission was defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline.5 Relapse was defined as haematological relapse (blasts in bone marrow greater than 5% following CR) or anextramedullary relapse.

In a prespecified exploratory analysis, 60 of 73 MRD evaluable patients with CR/CRh* (82.2%) alsohad a MRD response (defined as MRD by PCR < 1 × 10-4).

Patients with prior allogeneic HSCT had similar response rates to those without prior HSCT, olderpatients had similar response rates to younger patients, and no substantial difference was observed inremission rates based on the number of lines of prior salvage treatment.

In patients with non-CNS/non-testes extramedullary disease (defined as at least 1 lesion ≥ 1.5 cm) atscreening (N = 8/189) clinical response rates (25% [95% CI: 3.2-65.1]) were lower compared withpatients with no evidence of extramedullary disease (N = 181, 43.6% [95% CI: 36.3 - 51.2]) (seefigure 2).

Patients with the highest tumour burden as measured by the percentage of bone marrow blast cells atbaseline (≥ 90%) still had a clinically meaningful response with a CR/CRh* rate of 21.6%(95% CI: 12.9 - 32.7) (see figure 2). Patients with low tumour burden (< 50%) responded best to

BLINCYTO treatment with CR/CRh* rate of 72.9% (95% CI: 59.7 - 83.6).

Figure 2. Forest plot of CR/CRh* rate during the first 2 cycles for study MT103-211 (primaryanalysis set)

Subgroup Rate and 95% Confidence Interval (CI) n/N Rate (95% CI)

Bone Marrow Blast Infiltration(Central Lab)<50% 43/59 72.9% (59.7%-83.6%)≥50% to <75% 8/25 32.0% (14.9%-53.5%)≥75% to <90% 14/31 45.2% (27.3%-64.0%)≥90% 16/74 21.6% (12.9%-32.7%)

Extramedullary Disease at Baseline

Yes 2/8 25.0% (3.2%-65.1%)

No 79/181 43.6% (36.3%-51.2%)

Overall 81/189 42.9% (35.7%-50.2%)0 20 40 60 80 100

Percent Achieving CR/CRh*

GRH0148v3n = number of patients who achieved CR or CRh* in the first 2 cycles of treatment in the specified subgroup.

N = total number of patients in the specified subgroup.

There is limited data in patients with late first relapse of B-cell precursor ALL defined as a relapseoccurring more than 12 months after first remission or more than 12 months after HSCT in the firstremission. In clinical phase II studies, 88.9% (8/9) of patients with late first relapse as defined in theindividual studies achieved CR/CRh* within the first 2 treatment cycles with 62.5% (6/9) achieving

MRD response and 37.5% (3/9) undergoing allogeneic HSCT after treatment with BLINCYTO. Themedian overall survival (OS) was 17.7 months (95% CI: 3.1 - not estimable).

In the randomised, open-label, multicentre, phase III study (TOWER), 70% (7/10) of post-transplantpatients in late first relapse treated with BLINCYTO compared to 20% (1/5) treated with SOCchemotherapy achieved CR/CRh* within the first 2 treatment cycles. Fifty percent (5/10) compared to0% (0/5) achieved MRD response and 20% (2/10) compared to 40% (2/5) underwent allogeneic HSCTafter treatment. The median OS was 15.6 months (95% CI: 5.5 - not estimable) for the BLINCYTOgroup and 5.3 months (95% CI: 1.1 - not estimable) for the SOC chemotherapy group.

Philadelphia chromosome-positive relapsed or refractory B-cell precursor ALL in adult patients

The safety and efficacy of BLINCYTO were evaluated in an open-label, multicentre, single-armphase II study (ALCANTARA). Eligible patients were ≥ 18 years of age with Philadelphiachromosome-positive B-cell precursor ALL: relapsed or refractory to at least 1 second generation orlater tyrosine kinase inhibitor (TKI); OR intolerant to second generation TKI, and intolerant orrefractory to imatinib mesylate.

BLINCYTO was administered as a continuous intravenous infusion. In the first cycle, the initial dosewas 9 mcg/day for week 1, then 28 mcg/day for the remaining 3 weeks. The dose of 28 mcg/day wasadministered in cycle 2 and subsequent cycles starting on day 1 of each cycle. Dose adjustment waspossible in case of adverse reactions. The treated population included 45 patients who received at leastone infusion of BLINCYTO; the mean number of treatment cycles was 2.2 (see table 10 for patientdemographics and baseline characteristics).

Table 10. Demographics and baseline characteristics in phase II study (ALCANTARA)

BLINCYTO

Characteristic(N = 45)

Median, years (min, max) 55 (23, 78)

Mean, years (SD) 52.8 (15)≥ 65 years and < 75 years, n (%) 10 (22.2)≥ 75 years, n (%) 2 (4.4)

Males, n (%) 24 (53.3)

Race, n (%)

Asian 1 (2.2)

Black (or African American) 3 (6.7)

Other 2 (4.4)

White 39 (86.7)

Disease History, n (%)

Prior TKI treatmenta1 7 (15.6)2 21 (46.7)≥ 3 17 (37.8)

Prior salvage therapy 31 (61.9)

Prior alloHSCTb 20 (44.4)

Bone marrow blastsc, n (%)≥ 50% to < 75% 6 (13.3)≥ 75% 28 (62.2)a Number of patients that failed ponatinib = 23 (51.1%)b alloHSCT = allogeneic haematopoietic stem cell transplantationc centrally assessed

The primary endpoint was the CR/CRh* rate within 2 cycles of treatment with BLINCYTO. Sixteenout of 45 (35.6%) patients achieved CR/CRh* within the first 2 treatment cycles. Of the 16 patientswith CR/CRh* in the first 2 cycles, 12 of 14 (85.7%) patients with a CR and 2 of 2 (100%) patientswith a CRh* also achieved an MRD complete response (see table 11).

Two patients achieved CR during subsequent cycles, resulting in a cumulative CR rate of35.6% (16 out of 45; 95% CI: 21.9 - 51.2). Five out of 16 (31.3%) patients underwent allogeneic

HSCT in CR/CRh* induced with BLINCYTO.

Table 11. Efficacy results in patients ≥ 18 years of age with Philadelphia chromosome-positiverelapsed or refractory B-cell precursor acute lymphoblastic leukaemia (ALL) (ALCANTARA)

N = 45

Complete remission (CR)a/Complete remission with partial 16 (35.6) [21.9, 51.2]haematological recovery (CRh*)b, n (%) [95% CI]

CR 14 (31.1) [18.2, 46.6]

CRh* 2 (4.4) [0.5, 15.1]

CRic (without CRh*), n (%) [95% CI] 2 (4.4) [0.5, 15.1]

Blast free hypoplastic or aplastic bone marrow (without CRi)d, n (%) 3 (6.7) [1.4, 18.3][95% CI]

Partial remissione, n (%) [95% CI] 2 (4.4) [0.5, 15.1]

Complete MRD responsef, n (%) [95% CI] 18 (40.0) [25.7, 55.7]

Median Relapseg-free survival (RFS) for CR/CRh* [95% CI] 6.7 months [4.4 to NEh]

Median Overall survival [95% CI] 7.1 months [5.6 to NEh]a CR was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheralblood counts (platelets > 100 000/microlitre and absolute neutrophil counts [ANC] > 1 000/microlitre).

b CRh* was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery ofperipheral blood counts (platelets > 50 000/microlitre and ANC > 500/microlitre).c CRi (complete remission with incomplete haematologic recovery) was defined as ≤ 5% blasts in the bonemarrow, no evidence of disease, and incomplete recovery of peripheral blood counts(platelets > 100 000/microlitre or ANC > 1 000/microlitre).d Blast free hypoplastic or aplastic bone marrow was defined as bone marrow blasts ≤ 5%, no evidence ofdisease, insufficient recovery of peripheral counts: platelets ≤ 50 000/microlitre and/or ANC ≤ 500/microlitre.e Partial remission was defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline.f Complete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimumsensitivity of 10-4.g Relapse was defined as haematological relapse (blasts in bone marrow greater than 5% following CR) or anextramedullary relapse.h NE = not estimable.

Patients with the higher tumour burden as measured by the percentage of bone marrow blast cells atbaseline (≥ 50%) still had a clinically meaningful response with a CR/CRh* rate of26.5% (95% CI: 12.9 - 44.4). Patients with low tumour burden (< 50%) responded best to

BLINCYTO treatment with CR/CRh* rate of 63.6% (95% CI: 30.8 - 89.1). For patients with highperipheral white blood cell counts (≥ 3.0 × 109/L), response rate was 27.3% (95% CI: 10.7 - 50.2)while percentage of response for those with a lower white blood cell count (< 3.0 × 109/L) was43.5% (95% CI: 23.2 - 65.5).

Treatment effects in evaluable subgroups (e.g. mutation status, number of prior TKIs, prior HSCTstatus, and relapse without prior HSCT) were in general consistent with the results in the overallpopulation. Patients with T315I mutation, other mutations, or additional cytogenetic abnormalitiesresponded with a similar rate as compared to those that did not have these mutations or abnormalities.

MRD positive B-cell precursor ALL

The safety and efficacy of BLINCYTO in adult patients with MRD positive B-cell precursor ALLwere evaluated in an open-label, multicentre, single-arm phase II study (BLAST). Eligible patientswere ≥ 18 years of age with no prior HSCT, had received at least 3 blocks of standard ALL inductiontherapy, were in complete haematologic remission (defined as < 5% blasts in bone marrow, absoluteneutrophil count ≥ 1 000/microlitres, platelets ≥ 50 000/microlitres, and haemoglobin level ≥ 9 g/dL)and had molecular failure or molecular relapse (defined as MRD ≥ 10-3), see table 12. MRD status atscreening was determined from bone marrow aspirations using flow cytometry or polymerase chainreaction (PCR) at a minimum sensitivity of 10-4 based on local site evaluations. A central laboratorysubsequently confirmed MRD levels by PCR. Final interpretation of MRD results followed EuroMRD

Consortium guidelines.

Table 12. Demographics and baseline characteristics in MRD study (BLAST)

BLINCYTO

Characteristic(N = 116)

Median, years (min, max) 45 (18, 76)

Mean, years (SD) 44.6 (16.4)≥ 65 years, n (%) 15 (12.9)

Males, n (%) 68 (58.6)

Race, n (%)

Asian 1 (0.9)

Other (mixed) 1 (0.9)

White 102 (87.9)

Unknown 12 (10.3)

BLINCYTO

Characteristic(N = 116)

Relapse history, n (%)

Patients in 1st CR 75 (64.7)

Patients in 2nd CR 39 (33.6)

Patients in 3rd CR 2 (1.7)

MRD level at baseline*, n (%)≥ 10-1 and < 1 9 (7.8)≥ 10-2 and < 10-1 45 (38.8)≥ 10-3 and < 10-2 52 (44.8)< 10-3 3 (2.6)

Below lower limit of quantification 5 (4.3)

Unknown 2 (1.7)

* Centrally assessed in an assay with minimum sensitivity of 10-4

BLINCYTO was administered as a continuous intravenous infusion. Patients received BLINCYTO ata constant dose of 15 mcg/m2/day (equivalent to the recommended dosage of 28 mcg/day) for alltreatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in caseof adverse reactions. The treated population included 116 patients who received at least one infusionof BLINCYTO; the mean number of completed treatment cycles was 1.8 (range: 1 to 4).

The primary endpoint was the proportion of patients who achieved a complete MRD response withinone cycle of BLINCYTO treatment. Eighty-eight out of 113 (77.9%) evaluable patients achieved acomplete MRD response after one cycle of treatment; see table 13. Two subjects achieved a complete

MRD response with 1 additional cycle of BLINCYTO. MRD response rates by age and MRD level atbaseline subgroups were consistent with the results in the overall population. RFS in patients with

Philadelphia chromosome-negative B-cell precursor ALL at 18 months censored at HSCT orpost-BLINCYTO chemotherapy was 54% (33%, 70%). RFS at 18 months not censored at HSCT orpost-BLINCYTO chemotherapy was 53% (44%, 62%).

Table 13. Efficacy results in patients ≥ 18 years of age with MRD positive B-cell precursor ALL(BLAST)

Complete MRD responsea, n/N (%), [95% CI] 88/113b (77.9) [69.1-85.1]≥ 65 years old 12/15 (80.0) [51.9-95.7]

Patients in 1st CR 60/73 (82.2) [71.5-90.2]

Patients in 2nd CR 27/38 (71.1) [54.1-84.6]

Patients in 3rd CR 1/2 (50.0) [1.3-98.7]

Duration of complete MRD response [95% CI] 17.3 months [12.6-23.3]a Complete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimumsensitivity of 10-4.b One hundred thirteen patients (97.4%; 113/116) were included in the primary endpoint full analysis set.

B-cell precursor ALL in the consolidation phase

The efficacy of BLINCYTO in consolidation phase treatment of B-cell precursor ALL in adult andpaediatric patients was evaluated in study E1910 and study 20120215. The efficacy results from Study

E1910 are described below and the paediatric and young adult studies are described in sectionpaediatric population.

In study E1910 (20129152), the safety and efficacy of BLINCYTO were evaluated in a Phase III,randomised, controlled study in adult patients with newly diagnosed Philadelphia chromosomenegative B-cell precursor ALL. Eligible patients received induction chemotherapy. After induction,patients in haematologic complete remission (CR) or CR with incomplete peripheral blood countrecovery (CRi) continued on study and received intensification chemotherapy. After intensificationtherapy, 286 patients were randomised or assigned to receive BLINCYTO alternating withconsolidation chemotherapy (n = 152) or standard of care (SOC) consolidation chemotherapy alone(n = 134). The chemotherapy regimens used in Study E1910 were based on the

UKALL12/ECOG2993 protocol. Each arm received maintenance therapy at a total treatment durationof 2.5 years after the start of intensification. Randomisation was stratified by MRD status (MRDnegativity defined as < 1 × 10-4), age (< 55 years versus ≥ 55 years), CD20 status, rituximab use, andintent to receive allogeneic stem cell transplant (SCT).

Study treatment in the BLINCYTO arm consisted of 4 cycles of blinatumomab and 4 cycles ofchemotherapy in the following sequence. It included 2 cycles of BLINCYTO (each cycle consisted of28 mcg/day BLINCYTO administered as continuous intravenous infusion for 28 days, with a 14-daytreatment-free interval between cycles), followed by 3 cycles of consolidation chemotherapy, a thirdcycle of BLINCYTO followed by an additional cycle of consolidation chemotherapy, and then afourth cycle of BLINCYTO. In a posthoc analysis in subjects who did not receive HSCT, numericallygreater OS was observed in patients who received 4 cycles vs 1-2 cycles of BLINCYTO in frontlineconsolidation. Patients received an average of 3.04 cycles of BLINCYTO. If a patient proceeded toallogeneic SCT, it was strongly encouraged that patients randomized to blinatumomab receive bothcycles of blinatumomab therapy before proceeding to allogeneic SCT. The SOC arm of the studyconsisted of 4 cycles of consolidation chemotherapy. Patients in each arm received the same numberof cycles and doses of consolidation chemotherapy. Patients who were randomised to the SOC armcould proceed directly to allogeneic SCT or to consolidation chemotherapy.

Baseline demographics and characteristics were similar between the treatment arms. Demographicsand characteristics information is provided in table 14.

Table 14. Demographics and characteristics (E1910)

BLINCYTO arm SOC arma

Characteristic(N = 152) (N = 134)

MRD MRD MRD MRD

Positive Negative Positive Negative(N = 40) (N = 112) (N = 22) (N = 112)

Mean, years (min, max) 49.6 (30, 69) 50.2 (30, 70)

Males, n (%) 69 (45.4) 70 (52.2)

Race, n (%)

American Indian or Alaska Native 2 (1.3) 1 (0.7)

Asian 4 (2.6) 2 (1.5)

Black (or African American) 12 (7.9) 5 (3.7)

Hispanic (or Latino) 21 (13.8) 15 (11.2)

Native Hawaiian or Other Pacific Islander 1 (0.7) 0 (0.0)

White 117 (77.0) 110 (82.1)

Received allogeneic SCTb, n (%) 37 (24.3) 28 (20.9)

Mean number of BLINCYTO cycles inpatients who received allogeneic SCTb, n 15 (1.93) 22 (1.95)(cycles)

Mean number of BLINCYTO cycles inpatients who did not receive allogeneic 21 (2.90) 89 (3.30)

SCTb, n (cycles)a SOC = Standard of care.b allogeneic SCT = allogeneic stem cell transplantation.

The primary endpoint was overall survival (OS) in patients who were MRD-negative. Secondaryendpoints included relapse-free survival (RFS) in patients who were MRD-negative, OS and RFS inpatients who were MRD-positive.

The study demonstrated improvement in OS and RFS. The stratified hazard ratios and Kaplan-Meierestimates for OS and RFS in patients who were MRD-negative, MRD-positive, and all patientscombined regardless of MRD status are provided in table 15. The Kaplan Meier plot for OS in patientswho were MRD negative is provided in figure 3. The Kaplan Meier plot for OS in all patientscombined regardless of MRD status is provided in figure 4.

Figure 3. Kaplan-Meier for overall survival in patients who were MRD negative atrandomisation (prior to start of consolidation) (E1910)1.0 Stratified Log Rank: p = 0.0010.9 Hazard ratio (95% CI) from stratified Cox regression: 0.44 (0.25, 0.76)0.80.70.60.50.40.30.20.10.0

Number of Subjects at Risk:

1: 112 107 100 89 60 32 16 4 02: 112 97 86 71 45 30 10 4 00 1 2 3 4 5 6 7 8 9 10

Years

Treatment (N = xx): 5 year KM estimate % (95% CI)1: Blincyto (N = 112): 82.4 (73.7, 88.4) 2: SOC Chemotherapy (N = 112): 62.5 (52.0, 71.3)

SOC = Standard of Care, KM = Kaplan-Meier, CI = Confidence Interval, N = Number of patients in the analysisset, Censor indicated by vertical bar.

Figure 4. Kaplan-Meier for overall survival combining patients who were MRD-positive and

MRD-negative at randomisation (prior to start of consolidation) (E1910)1.0

Hazard ratio (95% CI) from stratified Cox regression: 0.47 (0.30, 0.74)0.90.80.70.60.50.40.30.20.10.0

Number of Subjects at Risk:

1: 152 142 130 117 78 43 26 10 02: 134 109 96 80 53 25 13 4 00 1 2 3 4 5 6 7 8 9 10

Years

Treatment (N = xx): 5 year KM estimate % (95% CI)1: Blincyto (N = 152): 79.1 (71.4, 85.0) 2: SOC Chemotherapy (N = 134): 58.3 (48.8, 66.7)

SOC = Standard of Care, KM = Kaplan-Meier, CI = C onfidence Interval, N = Number of patients in the analysisset, Censor indicate d by vertical bar.

Survival Probability Survival Probability

GRH2607v2

GRH2609 v2

Table 15. Overall survival and relapse-free survival in MRD-negative and MRD-positivepatients (E1910)

BLINCYTO Arm SOC Arm

MRD-Negative

Number of patients 112 112

Median follow-up time (years)a, b 4.5 4.5

Overall Survival5-year Kaplan-Meier estimate (%) [95% CI] 82.4 [73.7, 88.4] 62.5 [52.0, 71.3]

Hazard ratio [95% CI]c 0.44 [0.25, 0.76]p-value 0.003

Relapse-free Survival5-year Kaplan-Meier estimate (%) [95% CI] 77.0 [67.8, 83.8] 60.5 [50.1, 69.4]

Hazard ratio [95% CI]d 0.53 [0.32, 0.88]

MRD-Positive

Number of patients 40 22

Median follow-up time (years)e, b 4.6 5.0

Overall Survival5-year Kaplan-Meier estimate (%) [95% CI] 70.1 [52.0, 82.5] 37.8 [17.8, 57.7]

Hazard ratio [95% CI]f 0.40 [0.14, 1.12]

Relapse-free Survival5-year Kaplan-Meier estimate (%) [95% CI] 71.8 [54.8, 83.3] 39.4 [19.3, 59.0]

Hazard ratio (95% CI)g 0.37 [0.13, 1.03]

Combined MRD-Negative and MRD-Positive

Number of patients 152 134

Median follow-up time (years)a, b, e 4.5 4.5

Overall Survival5-year Kaplan-Meier estimate (%) [95% CI] 79.1 [71.4, 85.0] 58.3 [48.8, 66.7]

Hazard ratio [95% CI]f 0.47 [0.30, 0.74]

Relapse-free Survival5-year Kaplan-Meier estimate (%) [95% CI] 75.6 [67.8, 81.8] 57.2 [47.9, 65.4]

Hazard ratio (95% CI)g 0.53 [0.35, 0.81]

Full analysis set includes all randomised or assigned patients who are assessed as MRD-negative or MRD-positive centrally after induction and intensification chemotherapy. CI = Confidence interval. Relapse-freesurvival (RFS) is calculated from time of randomisation or registration until relapse or death due to any cause.

Overall survival (OS) is calculated from time of randomisation or registration until death due to any cause.

MRD-positive defined as MRD value ≥ 1 × 10-4 and MRD-negative defined as MRD value < 1 × 10-4.a Years are calculated as days from randomisation date to event/censor date, divided by 365.25.b Time to censoring measures follow-up time calculated by reversing the status indicator for censored and events.c The hazard ratio estimates are obtained from a stratified Cox regression model. A hazard ratio < 1.0 indicates alower average death rate and a longer survival for patients in the BLINCYTO arm relative to patients in the SOCarm.d The hazard ratio estimates are obtained from a stratified Cox regression model. A hazard ratio < 1.0 indicates alower average event rate and a longer relapse-free survival for patients in the BLINCYTO arm relative topatients in the SOC arm.e Years are calculated as days from randomisation or registration date to event/censor date, divided by 365.25.f The hazard ratio estimates are obtained from a stratified Cox proportional hazards model. A hazard ratio < 1.0indicates a lower average death rate and a longer survival for patients in the BLINCYTO arm relative to patientsin the SOC arm.

g The hazard ratio estimates are obtained from a stratified Cox proportional hazards model. A hazard ratio < 1.0indicates a lower average event rate and a longer relapse-free survival for patients in the BLINCYTO armrelative to patients in the SOC arm.

The safety and effectiveness of BLINCYTO have been established in paediatric patients with

Philadelphia chromosome negative relapsed or refractory B-cell precursor ALL in two open labelstudies: a single-arm Phase I/II study (MT103-205) and a randomised, controlled Phase IIIstudy (20120215).

The safety and efficacy of BLINCYTO compared to standard of care (SOC) consolidationchemotherapy were evaluated in a randomised, controlled, open-label, multicentre study (20120215).

Eligible patients were between 28 days and 18 years of age with high-risk first relapsed Philadelphiachromosome-negative B-cell precursor ALL and had < 25% blasts in the bone marrow. High-riskpatients were defined as per IntReALL criteria. Patients with clinically relevant CNS pathologyrequiring treatment (e.g. unstable epilepsy) or evidence of current CNS involvement by ALL wereexcluded from the study. Patients were enrolled and randomised after induction and 2 blocks ofconsolidation chemotherapy.

Patients were randomised 1:1 to receive BLINCYTO or a third block of SOC consolidationchemotherapy (High-risk consolidation 3, HC3). Patients in the BLINCYTO arm received one cycleof BLINCYTO as a continuous intravenous infusion at 15 mcg/m2/day over 4 weeks (maximum dailydose was not to exceed 28 mcg/day). Dose adjustment was possible in case of adverse reactions.

Randomisation was stratified by age (< 1 year, 1 to 9 years, and > 9 years), bone marrow statusdetermined at the end of the second block of consolidation chemotherapy and MRD status determinedat the end of induction (blasts < 5% with MRD level < 10-3, blasts < 5% with MRD level ≥ 10-3, andblasts ≥ 5% and < 25%). The demographics and baseline characteristics were well-balanced betweenthe two arms (see table 16). No subject had prior HSCT.

Table 16. Demographics and baseline characteristics in study 20120215

BLINCYTO SOC Chemotherapy

Characteristics(N = 54) (N = 54)

Age, n (%)< 1 year 0 (0.0) 0 (0.0)1 to 9 years 39 (72.2) 38 (70.4)≥ 10 to 18 years 15 (27.8) 16 (29.6)

Males, n (%) 30 (55.6) 22 (40.7)

Race, n (%)

American Indian or Alaska Native 0 (0.0) 0 (0.0)

Asian 1 (1.9) 3 (5.6)

Black (or African American) 0 (0.0) 3 (5.6)

Native Hawaiian or Other Pacific Islander 0 (0.0) 0 (0.0)

Other 3 (5.6) 5 (9.3)

White 50 (92.6) 43 (79.6)

Occurrence and type of any genetic abnormality, n (%)

No 34 (63.0) 29 (53.7)

Yes 20 (37.0) 25 (46.3)

Hyperdiploidy 6 (11.1) 6 (11.1)

Hypodiploidy 1 (1.9) 0 (0.0)t(v;11q23)/MLL rearranged 0 (0.0) 4 (7.4)t(12;21)(p13;q22)/TEL-AML1 2 (3.7) 3 (5.6)t(1;19)(q23;p13.3)/E2A-PBX1 2 (3.7) 2 (3.7)t(5;14)(q31;32)/IL3-IGH 0 (0.0) 0 (0.0)

Other 9 (16.7) 10 (18.5)

BLINCYTO SOC Chemotherapy

Characteristics(N = 54) (N = 54)

Extramedullary disease at relapse, n (%)

No 44 (81.5) 40 (74.1)

Yes 10 (18.5) 14 (25.9)

Cytomorphology, n (%)

Blasts < 5% 54 (100.0) 51 (94.4)

Blasts ≥ 5% and < 25% 0 (0.0) 2 (3.7)

Blasts ≥ 25% 0 (0.0) 0 (0.0)

Not evaluable 0 (0.0) 1 (1.9)

MRD PCR value, n (%)≥ 10-4 10 (18.5) 13 (24.1)< 10-4 20 (37.0) 22 (40.7)

Time from first diagnosis to relapse (month), n (%)< 18 months 19 (35.2) 22 (40.7)≥ 18 months and ≤ 30 months 32 (59.3) 28 (51.9)> 30 months 3 (5.6) 4 (7.4)

N = number of patients in the analysis set; n = number of patients with observed data; MRD = minimal residualdisease; PCR = polymerase chain reaction.

The primary endpoint was event-free survival (EFS). The study demonstrated statistically significantimprovement in EFS for patients treated with BLINCYTO as compared to SOC consolidationchemotherapy. Treatment effects in subgroups (e.g. age, tumour burden/MRD status, time from firstdiagnosis to relapse) were in general consistent with the results in the overall population. See figure 5and table 17 for primary analysis efficacy results from study 20120215.

Figure 5. Kaplan-Meier curve of event-free survival1.00.9 Stratified Log Rank: p = <0.001

Hazard ratio (95% CI) from stratified Cox regression: 0.36 (0.19, 0.66)0.80.70.60.50.40.30.20.10.0

Number of Subjects at Risk1: 54 35 22 17 13 11 9 8 5 5 5 5 4 2 02: 54 49 37 28 24 22 21 19 15 12 10 7 4 1 00 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48

Months

Treatment (N), Median (95% CI) 1: HC3 (N = 54), 7.4 (4.5, 12.7) 2: Blinatumomab (N = 54), NE (12.0, NE)

CI = confidence interval, HC3 = High-risk consolidation 3, N = number of patients in the analysis set, NE = notevaluable.

Survival Probability

GRH2386 v1

Table 17. Efficacy results in paediatric patients with high-risk first relapsed B-cell precursor

ALL (20120215)

BLINCYTO SOC Chemotherapy(N = 54) (N = 54)

Event-free survivala

Events (%) 18 (33.3) 31 (57.4)

Median, months [95% CI] NEb [12.0, NEb] 7.4 [4.5, 12.7]

Hazard ratio [95% CI]c 0.36 [0.19, 0.66]p-valued < 0.001

Overall survival

Number of deaths (%) 8 (14.8) 16 (29.6)36-month estimate (%) [95% CI] 81.1 [65.5, 90.2] 55.8 [36.9, 71.0]

Hazard ratio [95% CI]c,d 0.43 [0.18, 1.01]p-valuee,f 0.047

MRD responseg

Number of MRD response, n1/n2h (%) 44/49 (89.8) 26/48 (54.2)[95% CI] [77.8, 96.6] [39.2, 68.6]p-valuef,i < 0.001

Note: Efficacy results from primary analysis (data cut-off of 17 July 2019).a EFS time was calculated from the time of randomisation until the date of relapse or tumour burden of ≥ 5% and< 25% blasts after having achieved a complete remission (CR), failure to achieve a CR at the end of treatment,secondary malignancy, or death due to any cause, whichever occurs first.b NE = not estimable.c Based on stratified Cox’s model.d The updated hazard ratio for OS (data cut-off of 14 September 2020) was 0.33 (95% CI: 0.15 to 0.72).e The p-value was derived using a stratified log-rank test.f Endpoint not formally tested. The p-value was not adjusted for multiplicity.g MRD (minimum residual disease) response was defined as MRD by PCR < 1 × 10-4.h n1: number of patients who achieved a MRD response after having a baseline MRD ≥ 10-4 or < 10-4;n2: number of patients assessed.i The p-value was derived using Cochran Mantel Haenszel test.

The overall median follow-up time for EFS was 51.9 months (95% CI: 47.2, 62.1). In patients whoreceived the SOC consolidation chemotherapy (HC3), the 5-year Kaplan-Meier estimate of EFS, was27.6% (95% CI: 16.2, 40.3) compared to 57.8% (95% CI: 42.5, 70.4) in patients who received

BLINCYTO and the hazard ratio (95% CI) was 0.35 (0.20, 0.61).

The median follow-up time for OS was 55.2 months for the overall population and was similarbetween treatment arms. The 5-year Kaplan-Meier estimate of OS was 41.4% (95% CI: 26.3 to 55.9)in the chemotherapy (HC3) arm and 78.4% (95% CI: 64.2 to 87.4) in the BLINCYTO arm and thehazard ratio (95% CI) was 0.33 (0.16, 0.66). The median time to transplant was 1.7 months (range: 1to 4 months) in the HC3 arm and 1.9 months (range: 1 to 3 months) in the BLINCYTO arm.

A numerically higher incidence of postbaseline alloHSCT was reported in the BLINCYTO armcompared with the HC3 arm; 82.5% of subjects (47 of 57) in the HC3 arm and 94.4% of subjects (51of 54) in the BLINCYTO arm. In the HC3 arm, 39 of 57 subjects (68.4%) received a transplant whilein complete remission, whereas 51 of 54 subjects (94.4%) in the BLINCYTO arm received atransplant while in complete remission.

At time of 100 days post-transplant, the mortality rates reached 3.9% (95% CI: 1.0 to 14.8) in the

BLINCYTO arm and 5.1% (95% CI: 1.3 to 19.0) in the chemotherapy (HC3) arm. The Kaplan-Meiermedian time to death was 1558.0 days in the HC3 arm (95% CI: 431.0 days to NE) and not reached inthe blinatumomab arm (95% CI: NE, NE).

The safety and efficacy of BLINCYTO were also evaluated in an open-label, multicentre, single-armstudy in 93 paediatric patients with relapsed or refractory B-cell precursor ALL (second or later bonemarrow relapse, in any marrow relapse after allogeneic HSCT, or refractory to other treatments, andalso with > 25% blasts in bone marrow) (MT103-205). This was a two-part study, a dose-finding partto determine the appropriate dosing regimen, followed by a single-arm efficacy part using thisregimen.

BLINCYTO was administered as a continuous intravenous infusion. In the dose-finding part of thestudy, doses of up to 30 mcg/m2/day were evaluated. The recommended dose for thepharmacokinetics (PK) expansion and efficacy parts of the study was determined to be 5 mcg/m2/dayon days 1-7 and 15 mcg/m2/day on days 8-28 for cycle 1, and 15 mcg/m2/day on days 1-28 forsubsequent cycles. Dose adjustment was possible in case of adverse reactions. Patients who respondedto BLINCYTO but later relapsed had the option to be retreated with BLINCYTO.

The treated population (in the dose-finding, PK expansion, and efficacy parts) included 70 patientswho received at least 1 infusion of BLINCYTO at the recommended dose; the mean number oftreatment cycles was 1.5. Among treated patients, the median age was 8 years (range: 7 months to17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and39 out of 70 (55.7%) had refractory disease. Most patients had a high tumour burden(≥ 50% leukaemic blasts in bone marrow) at baseline with a median of 75.5% bone marrow blasts.

Twenty out of 70 (28.6%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 outof 20 (85%) occurring within cycle 1 of treatment. Four patients achieved M1 bone marrow but didnot meet the peripheral blood count recovery criteria for CR or CRh*. Eleven of the 20 patients (55%)who achieved CR/CRh* received an allogeneic HSCT. The CR/CRh* for patients less than 2 years ofage was 40.0% (4/10), for patients 2 to 6 years was 30.0% (6/20); and for patients aged 7 to 17 yearswas 25.0% (10/40). Three patients < 1 year of age refractory to prior treatment and without prioralloHSCT received one cycle of BLINCYTO at a dose of 5-15 mcg/m2/day. None of the 3 subjects< 1 year old achieved a CR/CRh*, 1 patient had progressive disease (OS 2.3 months) and 2 werenon-responders (OS 1.1 months and 8.7 months, respectively). The type of adverse reactions observedin infants were similar to those observed in the overall paediatric population. See table 18 for theefficacy results.

Table 18. Efficacy results in patients < 18 years of age with relapsed or refractory B-cellprecursor ALL (MT103-205)

N = 70

CRa/CRh*b, n (%) [95% CI] 20 (28.6%) [18.4% - 40.6%]

CR, n (%) [95% CI] 11 (15.7%) [8.1% - 26.4%]

CRh*, n (%) [95% CI] 9 (12.9%) [6.1% - 23.0%]

Complete MRD response for CR/CRh*c, n1/n2d (%) [95% CI] 11/20 (55.0%) [31.5 - 76.9]

CR, n1/n2d (%) [95% CI] 6/11 (54.5%) [23.4 - 83.3]

CRh*, n1/n2d (%) [95% CI] 5/9 (55.6%) [21.2 - 86.3]

Median relapsee-free survival (RFS)e for CR/CRh* [95% CI] 6.8 months [2.2 to 12.0 months]

Median overall survival [95% CI] 7.5 months [4.0 to 11.8 months]100-day mortality after alloHSCTfn/N (%), [95% CI] 1/6 (16.7%) [2.5% - 72.7%]a CR was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts orextramedullary disease, and full recovery of peripheral blood counts (platelets > 100 000/microlitre and absoluteneutrophil counts [ANC] > 1 000/microlitre) and no relapse within 28 days.b CRh* was defined as M1 marrow (≤ 5% of blasts in the bone marrow), no evidence of circulating blasts orextramedullary disease, and partial recovery of peripheral blood counts (platelets > 50 000/microlitre and

ANC > 500/microlitre) and no relapse within 28 days.c Complete MRD response. No detectable signal for leukaemic cells either by PCR or flow cytometry.d n1: number of patients who achieved MRD response and the respective remission status; n2: number of patientswho achieved the respective remission status. One CR /CRh* responder with missing MRD data was consideredas a MRD-nonresponder.

e Relapse was defined as haematological relapse (blasts in bone marrow greater than 25% following CR) or anextramedullary relapse.

f Only patients with HSCT in CR/CRh* remission (with no anti-leukaemia agents used prior to HSCT) areincluded.

The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day(approximately equivalent to 9-162 mcg/day) in adult patients. Following continuous intravenousinfusion, the steady state serum concentration (Css) was achieved within a day and remained stableover time. The increase in mean Css values was approximately proportional to the dose in the rangetested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed or refractory

ALL, the mean (SD) Css was 228 (356) pg/mL and 616 (537) pg/mL, respectively. Thepharmacokinetics of blinatumomab in patients with MRD positive B-cell precursor ALL were similarto patients with relapsed or refractory ALL. The pharmacokinetics of blinatumomab in theconsolidation phase in adults with B-cell precursor ALL, including patients with newly diagnosed

ALL and first relapsed ALL, were similar to adult patients with relapsed or refractory ALL.

The estimated mean (SD) volume of distribution based on terminal phase (Vz) was 5.27 (4.37) L withthe continuous intravenous infusion of blinatumomab.

The metabolic pathway of blinatumomab has not been characterised. Like other protein therapeutics,blinatumomab is expected to be degraded into small peptides and amino acids via catabolic pathways.

The estimated mean (SD) systemic clearance with continuous intravenous infusion in patientsreceiving blinatumomab in clinical studies was 3.10 (2.94) L/hour. The mean (SD) half-life was2.20 (1.34) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinicaldoses.

Specific Populations

No clinically meaningful differences in the pharmacokinetics of blinatumomab were observed basedon age, sex, race, ethnicity, Philadelphia chromosome status, or mild (total bilirubin ≤ upper limit ofnormal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) or moderate hepaticimpairment (total bilirubin > 1.5 to 3 × ULN and any AST). Body surface area (0.4 to 2.9 m2)influences the pharmacokinetics of blinatumomab, supporting BSA-based dosing in patients < 45 kg.

No formal pharmacokinetic studies of blinatumomab have been conducted in patients with renalimpairment.

Pharmacokinetic analyses showed an approximately 2-fold difference in mean blinatumomabclearance values between patients with moderate renal dysfunction and normal renal function.

However since high inter-patient variability was discerned (CV% up to 98.4%), and clearance valuesin renal impaired patients were essentially within the range observed in patients with normal renalfunction, no clinically meaningful impact of renal function on clinical outcomes is expected. Theeffect of severe renal impairment on the pharmacokinetics of blinatumomab has not been studied.

No formal pharmacokinetic studies using blinatumomab have been conducted in patients with hepaticimpairment. The effect of hepatic impairment on the clearance of blinatumomab was evaluated bypopulation pharmacokinetic analysis in patients with mild and moderate hepatic dysfunction comparedto normal hepatic function using the criteria defined by the National Cancer Institute Organ

Dysfunction Working Group. No clinically meaningful differences in the clearance of blinatumomabwere observed between patients with mild and moderate hepatic dysfunction and patients with normalfunction. The effect of severe hepatic impairment on the pharmacokinetics of blinatumomab has notbeen studied.

The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 30 mcg/m2/day inpaediatric patients. At the recommended doses of 5 and 15 mcg/m2/day for the treatment of relapsed orrefractory B-cell precursor ALL, the mean (SD) steady state concentration (Css) values were 162 (179)and 533 (392) pg/mL, respectively. The estimated mean (SD) volume of distribution (Vz), clearance(CL) and terminal half-life (t1/2,z) were 4.14 (3.32) L/m2, 1.65 (1.62) L/hr/m2 and 2.14 (1.44) hours,respectively.

The pharmacokinetics of blinatumomab in the consolidation phase in paediatric patients with B-cellprecursor ALL, including patients with first relapsed B-cell precursor ALL, were similar to paediatricpatients with relapsed or refractory B-cell precursor ALL.

Repeat-dose toxicity studies conducted with blinatumomab and the murine surrogate revealed theexpected pharmacologic effects (including release of cytokines, decreases in leukocyte counts,depletion of B-cells, decreases in T-cells, decreased cellularity in lymphoid tissues). These changesreversed after cessation of treatment.

Reproductive toxicity studies have not been conducted with blinatumomab. In an embryo-foetaldevelopmental toxicity study performed in mice, the murine surrogate crossed the placenta to a limitedextent (foetal-to-maternal serum concentration ratio < 1%) and did not induce embryo-foetal toxicity orteratogenicity. The expected depletions of B- and T-cells were observed in the pregnant mice buthaematological effects were not assessed in foetuses. No studies have been conducted to evaluatetreatment-related effects on fertility. There were no effects on male or female reproductive organs intoxicity studies with the murine surrogate.

Citric acid monohydrate (E330)

Trehalose dihydrate

Lysine hydrochloride

Polysorbate 80 (E433)

Sodium hydroxide (for pH-adjustment)

Solution (stabiliser)

Citric acid monohydrate (E330)

Lysine hydrochloride

Polysorbate 80 (E433)

Sodium hydroxide (for pH-adjustment)

Water for injections

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

Unopened vials5 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 2°C - 8°C or 4 hours ator below 27°C.

From a microbiological point of view, unless the method of reconstituting precludes the risks ofmicrobial contamination, the reconstituted solution should be diluted immediately. If not dilutedimmediately, in-use storage times and conditions are the responsibility of the user.

Diluted solution (prepared infusion bag)

Chemical and physical in-use stability has been demonstrated for 10 days at 2°C - 8°C or 96 hours ator below 27°C.

From a microbiological point of view, the prepared infusion bags should be used immediately. If notused immediately, in-use storage times and conditions prior to use are the responsibility of the userand would normally not be longer than 24 hours at 2°C - 8°C, unless dilution has taken place incontrolled and validated aseptic conditions.

Store and transport refrigerated (2°C - 8°C).

Do not freeze.

Store the vials in the original package in order to protect from light.

For storage conditions after reconstitution and dilution of the medicinal product, see section 6.3.

Each BLINCYTO pack contains 1 vial of powder for concentrate for solution for infusion and 1 vialof solution (stabiliser):

* 38.5 micrograms blinatumomab powder in a vial (type I glass) with a stopper (elastomericrubber), seal (aluminium) and a flip off cap, and

* 10 mL solution in a vial (type I glass) with a stopper (elastomeric rubber), seal (aluminium) anda flip off cap.

Aseptic handling must be ensured when preparing the infusion. Preparation of BLINCYTO should be:

- performed under aseptic conditions by trained personnel in accordance with good practice rulesespecially with respect to the aseptic preparation of parenteral products.

- prepared in a laminar flow hood or biological safety cabinet using standard precautions for thesafe handling of intravenous agents.

It is very important that the instructions for preparation and administration provided in this section arestrictly followed to minimise medication errors (including underdose and overdose).

Other instructions

* BLINCYTO is compatible with polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), orethyl vinyl acetate (EVA) infusion bags/pump cassettes.

* At the end of infusion, any unused medicinal product or waste material should be disposed of inaccordance with local requirements.

Preparation of the solution for infusion

These supplies are also required, but not included in the package:

* Sterile single-use disposable syringes

* 21-23 gauge needle(s) (recommended)

* Water for injections

* Infusion bag with 250 mL sodium chloride 9 mg/mL (0.9%) solution for injection;o To minimise the number of aseptic transfers, use a 250 mL pre-filled infusion bag.

BLINCYTO dose calculations are based on a usual overfill volume of 265 to 275 mLsodium chloride 9 mg/mL (0.9%) solution for injection.

o Use only polyolefin, PVC non-di-ethylhexylphthalate (non-DEHP), or ethyl vinyl acetate(EVA) infusion bags/pump cassettes.

* Polyolefin, PVC non-DEHP, or EVA intravenous tubing with a sterile, non-pyrogenic, lowprotein-binding 0.2 micrometre in-line filter.

o Ensure that the tubing is compatible with the infusion pump.

Reconstitute BLINCYTO with water for injections. Do not reconstitute BLINCYTO vials with thesolution (stabiliser).

To prime the intravenous tubing, use only the solution in the bag containing the FINALprepared BLINCYTO solution for infusion. Do not prime with sodium chloride 9 mg/mL (0.9%)solution for injection.

Reconstitution of BLINCYTO1. Determine the number of BLINCYTO vials needed for a dose and infusion duration.

2. Using a syringe, reconstitute each vial of BLINCYTO powder for concentrate using 3 mL ofwater for injections. Direct the water along the walls of the BLINCYTO vial and not directly onthe lyophilised powder.

* Do not reconstitute BLINCYTO powder for concentrate with the solution(stabiliser).

* The addition of water for injections to the powder for concentrate results in a total volumeof 3.08 mL for a final BLINCYTO concentration of 12.5 mcg/mL.

3. Gently swirl contents to avoid excess foaming.

* Do not shake.

4. Visually inspect the reconstituted solution for particulate matter and discolouration duringreconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent,colourless-to-slightly yellow.

* Do not use if the solution is cloudy or has precipitated.

Preparation of BLINCYTO infusion bag

Verify the prescribed dose and infusion duration for each BLINCYTO infusion bag. To minimiseerrors, use the specific volumes described in tables 19 and 20 to prepare the BLINCYTO infusionbag.

* Table 19 for patients weighing greater than or equal to 45 kg

* Table 20 for patients weighing less than 45 kg1. Use an infusion bag pre-filled with 250 mL sodium chloride 9 mg/mL (0.9%) solution forinjection that usually contains a total volume of 265 to 275 mL.

2. To coat the infusion bag, using a syringe, aseptically transfer 5.5 mL of the solution (stabiliser)to the infusion bag. Gently mix the contents of the bag to avoid foaming. Discard the remainingsolution (stabiliser).

3. Using a syringe, aseptically transfer the required volume of reconstituted BLINCYTO solutioninto the infusion bag containing sodium chloride 9 mg/mL (0.9%) solution for injection and thesolution (stabiliser). Gently mix the contents of the bag to avoid foaming.

* Refer to table 19 for patients weighing greater than or equal to 45 kg for the specificvolume of reconstituted BLINCYTO.

* Refer to table 20 for patients weighing less than 45 kg (dose based on BSA) for thespecific volume of reconstituted BLINCYTO.

* Discard the vial containing any unused BLINCYTO reconstituted solution.

4. Under aseptic conditions, attach the intravenous tubing to the infusion bag with the sterile0.2 micron in-line filter. Ensure that the intravenous tubing is compatible with the infusionpump.

5. Remove air from the infusion bag. This is particularly important for use with an ambulatoryinfusion pump.

6. Prime the intravenous infusion line only with the solution in the bag containing the FINALprepared BLINCYTO solution for infusion.

7. Store refrigerated at 2°C - 8°C if not used immediately.

Table 19. For patients weighing greater than or equal to 45 kg: volumes of sodium chloride9 mg/mL (0.9%) solution for injection, solution (stabiliser), and reconstituted BLINCYTO toadd to infusion bag

Sodium chloride 9 mg/mL (0.9%) solution for injection 250 mL(starting volume) (usual overfill volume of 265 to 275 mL)

Solution (stabiliser) (fixed volume for 24, 48, 72, and5.5 mL96-hour infusion durations)

Infusion Reconstituted BLINCYTO

Dose Infusion rateduration Volume Vials9 mcg/day 10 mL/hour 0.83 mL 124 hours28 mcg/day 10 mL/hour 2.6 mL 19 mcg/day 5 mL/hour 1.7 mL 148 hours28 mcg/day 5 mL/hour 5.2 mL 29 mcg/day 3.3 mL/hour 2.5 mL 172 hours28 mcg/day 3.3 mL/hour 8 mL 39 mcg/day 2.5 mL/hour 3.3 mL 296 hours28 mcg/day 2.5 mL/hour 10.7 mL 4

Table 20. For patients weighing less than 45 kg: volumes of sodium chloride 9 mg/mL (0.9%)solution for injection, solution (stabiliser), and reconstituted BLINCYTO to add to infusion bag

Sodium chloride 9 mg/mL (0.9%) solution for injection 250 mL(starting volume) (usual overfill volume of 265 to 275 mL)

Solution (stabiliser) (fixed volume for 24, 48, 72, and 5.5 mL96-hour infusion durations)

Infusion Dose Infusion rate BSA Reconstituted BLINCYTOduration (m2)*

Volume Vials1.5 - 1.59 0.7 mL 11.4 - 1.49 0.66 mL 11.3 - 1.39 0.61 mL 11.2 - 1.29 0.56 mL 11.1 - 1.19 0.52 mL 11 - 1.09 0.47 mL 124 hours 5 mcg/m2/day 10 mL/hour0.9 - 0.99 0.43 mL 10.8 - 0.89 0.38 mL 10.7 - 0.79 0.33 mL 10.6 - 0.69 0.29 mL 10.5 - 0.59 0.24 mL 10.4 - 0.49 0.2 mL 11.5 - 1.59 2.1 mL 11.4 - 1.49 2 mL 11.3 - 1.39 1.8 mL 11.2 - 1.29 1.7 mL 11.1 - 1.19 1.6 mL 11 - 1.09 1.4 mL 124 hours 15 mcg/m2/day 10 mL/hour0.9 - 0.99 1.3 mL 10.8 - 0.89 1.1 mL 10.7 - 0.79 1 mL 10.6 - 0.69 0.86 mL 10.5 - 0.59 0.72 mL 10.4 - 0.49 0.59 mL 1

Sodium chloride 9 mg/mL (0.9%) solution for injection 250 mL(starting volume) (usual overfill volume of 265 to 275 mL)

Solution (stabiliser) (fixed volume for 24, 48, 72, and 5.5 mL96-hour infusion durations)

Infusion Dose Infusion rate BSA Reconstituted BLINCYTOduration (m2)*

Volume Vials1.5 - 1.59 1.4 mL 11.4 - 1.49 1.3 mL 11.3 - 1.39 1.2 mL 11.2 - 1.29 1.1 mL 11.1 - 1.19 1 mL 11 - 1.09 0.94 mL 148 hours 5 mcg/m2/day 5 mL/hour0.9 - 0.99 0.85 mL 10.8 - 0.89 0.76 mL 10.7 - 0.79 0.67 mL 10.6 - 0.69 0.57 mL 10.5 - 0.59 0.48 mL 10.4 - 0.49 0.39 mL 11.5 - 1.59 4.2 mL 21.4 - 1.49 3.9 mL 21.3 - 1.39 3.7 mL 21.2 - 1.29 3.4 mL 21.1 - 1.19 3.1 mL 21 - 1.09 2.8 mL 148 hours 15 mcg/m2/day 5 mL/hour0.9 - 0.99 2.6 mL 10.8 - 0.89 2.3 mL 10.7 - 0.79 2 mL 10.6 - 0.69 1.7 mL 10.5 - 0.59 1.4 mL 10.4 - 0.49 1.2 mL 1

Sodium chloride 9 mg/mL (0.9%) solution for injection 250 mL(starting volume) (usual overfill volume of 265 to 275 mL)

Solution (stabiliser) (fixed volume for 24, 48, 72, and 5.5 mL96-hour infusion durations)

Infusion Dose Infusion rate BSA Reconstituted BLINCYTOduration (m2)*

Volume Vials1.5 - 1.59 2.1 mL 11.4 - 1.49 2 mL 11.3 - 1.39 1.8 mL 11.2 - 1.29 1.7 mL 11.1 - 1.19 1.6 mL 11 - 1.09 1.4 mL 172 hours 5 mcg/m2/day 3.3 mL/hour0.9 - 0.99 1.3 mL 10.8 - 0.89 1.1 mL 10.7 - 0.79 1 mL 10.6 - 0.69 0.86 mL 10.5 - 0.59 0.72 mL 10.4 - 0.49 0.59 mL 11.5 - 1.59 6.3 mL 31.4 - 1.49 5.9 mL 31.3 - 1.39 5.5 mL 21.2 - 1.29 5.1 mL 21.1 - 1.19 4.7 mL 21 - 1.09 4.2 mL 272 hours 15 mcg/m2/day 3.3 mL/hour0.9 - 0.99 3.8 mL 20.8 - 0.89 3.4 mL 20.7 - 0.79 3 mL 20.6 - 0.69 2.6 mL 10.5 - 0.59 2.2 mL 10.4 - 0.49 1.8 mL 1

Sodium chloride 9 mg/mL (0.9%) solution for injection 250 mL(starting volume) (usual overfill volume of 265 to 275 mL)

Solution (stabiliser) (fixed volume for 24, 48, 72, and 5.5 mL96-hour infusion durations)

Infusion Dose Infusion rate BSA Reconstituted BLINCYTOduration (m2)*

Volume Vials1.5 - 1.59 2.8 mL 11.4 - 1.49 2.6 mL 11.3 - 1.39 2.4 mL 11.2 - 1.29 2.3 mL 11.1 - 1.19 2.1 mL 11 - 1.09 1.9 mL 196 hours 5 mcg/m2/day 2.5 mL/hour0.9 - 0.99 1.7 mL 10.8 - 0.89 1.5 mL 10.7 - 0.79 1.3 mL 10.6 - 0.69 1.2 mL 10.5 - 0.59 0.97 mL 10.4 - 0.49 0.78 mL 11.5 - 1.59 8.4 mL 31.4 - 1.49 7.9 mL 31.3 - 1.39 7.3 mL 31.2 - 1.29 6.8 mL 31.1 - 1.19 6.2 mL 31 - 1.09 5.7 mL 396 hours 15 mcg/m2/day 2.5 mL/hour0.9 - 0.99 5.1 mL 20.8 - 0.89 4.6 mL 20.7 - 0.79 4 mL 20.6 - 0.69 3.4 mL 20.5 - 0.59 2.9 mL 20.4 - 0.49 2.3 mL 1

BSA = body surface area

*The safety of the administration of BLINCYTO for BSA of less than 0.4 m2 has not been established.

Amgen Europe B.V.

Minervum 70614817 ZK Breda

The Netherlands

EU/1/15/1047/001

Date of first authorisation: 23 November 2015

Date of last renewal: 9 March 2023

Detailed information on this medicinal product is available on the website of the European Medicines

Agency https://www.ema.europa.eu.