3404-Acute lymphoblastic leukaemia blinatumomab

The following have occurred in patients receiving blinatumomab:

Cytokine Release Syndrome, which may be life-threatening or fatal
Neurological toxicities, which may be severe, life-threatening, or fatal
Reactivation of JC viral infection

Interrupt or discontinue blinatumomab as recommended if any of these adverse events occur.

Patients with leukaemia should be considered for inclusion into clinical trials. Link to ALLG website and ANZCTR website.

Cycle 1

Drug	Dose	Route	Day
Blinatumomab	9 micrograms *	CIV over 24 hours	1 to 7
Blinatumomab	28 micrograms **	CIV over 24 hours	8 to 28

Cycle 2 to 5

Drug	Dose	Route	Day
Blinatumomab	28 micrograms **	CIV over 24 hours	1 to 28

* Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA) at 5 micrograms/m²/day (not exceeding 9 micrograms/day).

** Patients greater than or equal to 45 kg receive a fixed-dose and for patients less than 45 kg, the dose is calculated using the patient’s body surface area (BSA) at 15 micrograms/m²/day (not exceeding 28 micrograms/day).

Frequency:: 42 days . A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval.

Cycles:: 5. Patients who experience complete remission after 2 treatment cycles may have up to 3 additional cycles of consolidation treatment, based on an individual benefit-risk assessment.

Notes:

Hospitalisation is recommended at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle.
Dexamethasone 20 mg should also be administered as a premedication when restarting an infusion after an interruption of 4 hours or more.
Blinatumomab preparation and administration can be complex. It is important that the instruction for preparation and administration provided in the Product Information are strictly followed to minimise medication errors.
Pre-phase treatment with dexamethasone (not exceeding 24 mg/day) should be considered for patients with high tumour burden (leukaemic blasts in bone marrow ≥ 50% or peripheral blood leukaemic blast counts > 15,000/microL)
Intrathecal chemotherapy prophylaxis is recommended before and during blinatumomab therapy to prevent central nervous system ALL relapse.

Drug status:

Blinatumomab: (PBS authority)

Blinatumomab is PBS subsidised for Philadelphia chromosome negative ALL

Cost:: ~ $81,420 per cycle "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics or other supportive medications), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

The supportive therapies (e.g. antiemetics, premedications, etc.), infusion times, diluents, volumes and routes of administration, if included, are listed as defaults. They may vary between institutions and can be substituted to reflect individual institutional policy.

Antiemetics if included in the treatment schedule are based upon recommendations from national and international guidelines. These are defaults only and may be substituted to reflect individual institutional policy. Select here for recommended doses of alternative antiemetics.

Cycle 1

Day 1
Dexamethasone	20 mg (IV)	60 minutes before the start of treatment
Blinatumomab	9 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 2 to 7
Blinatumomab	9 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 8
Dexamethasone	20 mg (IV)	60 minutes before step dose (increase).
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 9 to 28
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Cycle 2 to 5

Day 1
Dexamethasone	20 mg (IV)	60 minutes before the start of treatment
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 2 to 28
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Notes:

Dexamethasone 20 mg should also be administered as a premedication when restarting an infusion after an interruption of 4 hours or more.
Blinatumomab preparation and administration can be complex. It is important that the instruction for preparation and administration provided in the Product Information are strictly followed to minimise medication errors.
Hospitalisation is recommended at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle.
Pre-phase treatment with dexamethasone (not exceeding 24 mg/day) may be considered for patients with high tumour burden (leukaemic blasts in bone marrow ≥ 50% or peripheral blood leukaemic blast counts > 15,000/microL)
Intrathecal chemotherapy prophylaxis is recommended before and during blinatumomab therapy to prevent central nervous system ALL relapse.

Frequency:: 42 days . A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval.

Cycles:: 5. Patients who experience complete remission after 2 treatment cycles may have up to 3 additional cycles of consolidation treatment, based on an individual benefit-risk assessment.

Treatment schedule - Overview

Cycle 1

Drug	Dose	Route	Day
Blinatumomab	9 micrograms *	CIV over 24 hours	1 to 7
Blinatumomab	28 micrograms **	CIV over 24 hours	8 to 28

Cycle 2 to 5

Drug	Dose	Route	Day
Blinatumomab	28 micrograms **	CIV over 24 hours	1 to 28

Frequency:: 42 days . A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval.

Cycles:: 5. Patients who experience complete remission after 2 treatment cycles may have up to 3 additional cycles of consolidation treatment, based on an individual benefit-risk assessment.

Notes:

Hospitalisation is recommended at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle.
Dexamethasone 20 mg should also be administered as a premedication when restarting an infusion after an interruption of 4 hours or more.
Blinatumomab preparation and administration can be complex. It is important that the instruction for preparation and administration provided in the Product Information are strictly followed to minimise medication errors.
Pre-phase treatment with dexamethasone (not exceeding 24 mg/day) should be considered for patients with high tumour burden (leukaemic blasts in bone marrow ≥ 50% or peripheral blood leukaemic blast counts > 15,000/microL)
Intrathecal chemotherapy prophylaxis is recommended before and during blinatumomab therapy to prevent central nervous system ALL relapse.

Drug status:

Blinatumomab: (PBS authority)

Blinatumomab is PBS subsidised for Philadelphia chromosome negative ALL

Cost:: ~ $81,420 per cycle "How this cost is calculated"
The cost displayed on the protocol is intended as rudimentary guide only for the Australian context.

The cost includes antineoplastic drugs only (not antiemetics or other supportive medications), unless otherwise indicated.

Drug unit costs are taken directly from the Pharmaceutical Benefits Scheme (PBS) website (www.pbs.gov.au), MIMS Online and other sources. These costs are reviewed and updated on eviQ at 6 monthly intervals.

Where there are differing unit costs based on vial sizes and tablet strengths, the mean unit cost is used. The cost of oral continuous therapy is based on 28 day month.

The protocol cost is derived from drug dose calculations based upon a default body surface area (BSA) of 1.8 m²; weight of 75 kg; and creatinine clearance of 75 mL/min.

One off loading doses are not included in protocol cost calculations.

The cost displayed is the actual drug cost and does not necessarily reflect the cost incurred by the patient as many antineoplastic drugs are reimbursed on the PBS.

Treatment schedule - Detail

Cycle 1

Day 1
Dexamethasone	20 mg (IV)	60 minutes before the start of treatment
Blinatumomab	9 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 2 to 7
Blinatumomab	9 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 8
Dexamethasone	20 mg (IV)	60 minutes before step dose (increase).
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 9 to 28
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Cycle 2 to 5

Day 1
Dexamethasone	20 mg (IV)	60 minutes before the start of treatment
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Day 2 to 28
Blinatumomab	28 micrograms (CIV over 24 hours)	in sodium chloride 0.9% over 24 hours as a continuous infusion

Notes:

Dexamethasone 20 mg should also be administered as a premedication when restarting an infusion after an interruption of 4 hours or more.
Blinatumomab preparation and administration can be complex. It is important that the instruction for preparation and administration provided in the Product Information are strictly followed to minimise medication errors.
Hospitalisation is recommended at a minimum for the first 9 days of the first cycle and the first 2 days of the second cycle.
Pre-phase treatment with dexamethasone (not exceeding 24 mg/day) may be considered for patients with high tumour burden (leukaemic blasts in bone marrow ≥ 50% or peripheral blood leukaemic blast counts > 15,000/microL)
Intrathecal chemotherapy prophylaxis is recommended before and during blinatumomab therapy to prevent central nervous system ALL relapse.

Frequency:: 42 days . A single cycle of treatment is 28 days (4 weeks) of continuous infusion. Each cycle of treatment is separated by a 14 day (2 week) treatment-free interval.

Cycles:: 5. Patients who experience complete remission after 2 treatment cycles may have up to 3 additional cycles of consolidation treatment, based on an individual benefit-risk assessment.

Indications and patient population

B-cell precursor acute lymphoblastic leukaemia (ALL) in patients with relapsed or refractory disease

Clinical information

Venous access	Central venous access device (CVAD) is required to administer this treatment. Read more about central venous access device line selection
Premedication	The product information states that premedication is required for this treatment. Please refer to the treatment schedule for suggested premedication regimen. This may be substituted to reflect institutional policy.
Emetogenicity LOW	Dexamethasone has been included as both an antiemetic and premedication for hypersensitivity in this protocol. Ensure that patients also have sufficient antiemetics for breakthrough emesis: Metoclopramide 10 mg three times a day when necessary (maximum of 30 mg/24 hours, up to 5 days) OR Prochlorperazine 10 mg PO or 12.5 mg IV every 6 hours when necessary. Read more about preventing antineoplastic induced nausea and vomiting
Cytokine Release Syndrome/Infusion Reactions	Potentially life-threatening cytokine release syndrome (CRS) have been reported in patients receiving blinatumomab. Infusion reactions have also occurred and may be clinically indistinguishable from manifestations of CRS. Serious adverse events included pyrexia, asthenia, headache, hypotension, elevated liver enzymes, total bilirubin increased, and nausea. In some cases, disseminated intravascular coagulation, capillary leak syndrome, and haemophagocytic lymphohistiocytosis/macrophage activation syndrome have been reported in the setting of CRS. Patients should be closely monitored for signs or symptoms of these events. Management of CRS events may require either temporary interruption or discontinuation of blinatumomab.
Neurologic toxicity	Approximately 65% of patients experienced neurological toxicity. The most common neurological symptoms were headaches and tremor. Grade 3 or higher, including fatal neurological adverse events, included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. The majority of events resolved and infrequently led to blinatumomab treatment discontinuation. Patients receiving blinatumomab should be closely monitored for signs and symptoms of neurological toxicity. If symptoms are severe blinatumomab should be temporarily interrupted or discontinued.
Leukoencephalopathy	There is a potential risk of leukoencephalopathy in patients receiving blinatumomab. Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed, especially in patients with prior treatment with cranial irradiation and anti-leukaemic chemotherapy (including systemic high dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.
Progressive multifocal leukoencephalopathy	Use of monoclonal antibodies may be associated with an increased risk of progressive multifocal leukoencephalopathy (PML), a rare but potentially fatal opportunistic viral infection of the brain. Patients must be monitored for any new or worsening neurological symptoms. Read more about progressive multifocal leukoencephalopathy and the Therapeutic Goods Administration Medicines Safety update on progressive multifocal leukoencephalopathy from the Australian Government, Department of Health.
Pancreatitis	Pancreatitis, life-threatening or fatal, have been reported in patients receiving blinatumomab. In some cases, high-dose steroid therapy may have contributed. Monitor patients who develop signs and symptoms of pancreatitis, and if severe blinatumomab may be temporary interruption or discontinued.
Tumour lysis risk	Assess patient for risk of developing tumour lysis syndrome. Read more about prevention and management of tumour lysis syndrome.
Pneumocystis jiroveci pneumonia (PJP) prophylaxis	PJP prophylaxis is recommended e.g. trimethoprim/sulfamethoxazole 160/800 mg PO one tablet twice daily, twice weekly (e.g. on Mondays and Thursdays) OR one tablet three times weekly (e.g. on Mondays, Wednesdays and Fridays). Read more about prophylaxis of pneumocystis jiroveci (carinii) in cancer patients
Antiviral prophylaxis	Read more about antiviral prophylaxis drugs and doses
Antifungal prophylaxis	Read more about antifungal prophylaxis drugs and doses.
Irradiated blood components	Irradiation of blood components is recommended. Read more about the indications for the use of irradiated blood components
Blood tests	FBC, EUC, LFTs, LDH, urate and lipase at baseline, then prior to each treatment or as clinically indicated
Hepatitis B screening and prophylaxis	Routine screening for HBsAg and anti-HBc is recommended prior to initiation of treatment. Prophylaxis should be determined according to individual institutional policy. Read more about hepatitis B screening and prophylaxis in cancer patients requiring cytotoxic and/or immunosuppressive therapy
Vaccinations	Live vaccines, including BCG, MMR, zoster and varicella vaccines, are contraindicated in cancer patients receiving immunosuppressive therapy and/or who have poorly controlled malignant disease. Refer to the recommended schedule of vaccination for immunocompromised patients, as outlined in the Australian Immunisation Handbook.
Effects of cancer treatment on fertility	Cancer treatment can have harmful effects on fertility and this should be discussed with all patients of reproductive age prior to commencing treatment. Read more about the effect of cancer treatment on fertility

Dose modifications

Evidence for dose modifications is limited, and the recommendations made on eviQ are intended as a guide only. They are generally conservative with an emphasis on safety. Any dose modification should be based on clinical judgement, and the individual patient’s situation including but not limited to treatment intent (curative vs palliative), the antineoplastic regimen (single versus combination therapy versus chemotherapy versus immunotherapy), biology of the cancer (site, size, mutations, metastases), other treatment related side effects, additional co-morbidities, performance status and patient preferences. Suggested dose modifications are based on clinical trial findings, product information and reference committee consensus. Non-haematological gradings are based on Common Terminology Criteria for Adverse Events (CTCAE) unless otherwise specified. Renal and hepatic dose modifications have been standardised where possible. For more information see dosing considerations & disclaimer.

Note:

If there are interruptions in the treatment period due to adverse effects of:
- Less than 7 days: continue the same cycle to a total of 28 days (inclusive of days before and after the interruption in that cycle)
- Greater than 7 days: start a new cycle
Dexamethasone 20 mg should also be administered as a premedication when restarting an infusion after an interruption of 4 hours or more.

Haematological toxicity
There is no information regarding dose adjustment based on haematological parameters. Neutropenia and febrile neutropenia, including life threatening cases have been reported. Monitor FBC during blinatumomab administration and interrupt blinatumomab if prolonged neutropenia occurs.

Renal impairment
There is no formal data in patients with renal impairment. However, based on pharmacokinetic analyses, dose adjustment in patients with mild to moderate renal impairment is not necessary.

Hepatic impairment
There is no formal data in patients with hepatic impairment. Since blinatumomab is a protein and not metabolised through the hepatic pathway, dose adjustment is not necessary.

C ytokine release syndrome (CRS)
Grade 3	Interrupt treatment until toxicity resolved. Then recommence at: ≥ 45 kg: 9 micrograms/day. Escalate to 28 micrograms/day after 7 days if the toxicity does not recur. < 45 kg: 5 micrograms/m²/day. Escalate to 15 micrograms/m²/day after 7 days if the toxicity does not recur.
Grade 4	Discontinue blinatumomab permanently

C ytokine release syndrome (CRS)

Grade 3

Interrupt treatment until toxicity resolved. Then recommence at:

≥ 45 kg: 9 micrograms/day. Escalate to 28 micrograms/day after 7 days if the toxicity does not recur.
< 45 kg: 5 micrograms/m²/day. Escalate to 15 micrograms/m²/day after 7 days if the toxicity does not recur.

Grade 4

Discontinue blinatumomab permanently

N eurological toxicity
Seizure	Discontinue blinatumomab permanently if more than one seizure occurs
Grade 3	Interrupt treatment until toxicity has resolved to Grade 1 or less for at least 3 days. Then recommence at: ≥ 45 kg: 9 micrograms/day. Escalate to 28 micrograms/day after 7 days if the toxicity does not recur. For reinitiation, premedication with 24 mg dexamethasone with a 4 day taper. As secondary prophylaxis, consider appropriate anticonvulsant medication. If the toxicity occurred at 9 micrograms/day, or if the toxicity takes >7 days to resolve discontinue blinatumomab permanently. < 45 kg: 5 micrograms/m²/day. Escalate to 15 micrograms/m²/day after 7 days if the toxicity does not recur. Consider appropriate anticonvulsant medication. If the toxicity occurred at 5 micrograms/m²/day, or if the toxicity takes >7 days to resolve discontinue blinatumomab permanently.
Grade 4	Discontinue blinatumomab permanently

N eurological toxicity

Seizure

Discontinue blinatumomab permanently if more than one seizure occurs

Grade 3

Interrupt treatment until toxicity has resolved to Grade 1 or less for at least 3 days. Then recommence at:

≥ 45 kg: 9 micrograms/day. Escalate to 28 micrograms/day after 7 days if the toxicity does not recur.
For reinitiation, premedication with 24 mg dexamethasone with a 4 day taper. As secondary prophylaxis, consider appropriate anticonvulsant medication.
If the toxicity occurred at 9 micrograms/day, or if the toxicity takes >7 days to resolve discontinue blinatumomab permanently.
< 45 kg: 5 micrograms/m²/day. Escalate to 15 micrograms/m²/day after 7 days if the toxicity does not recur.
Consider appropriate anticonvulsant medication. If the toxicity occurred at
5 micrograms/m²/day, or if the toxicity takes >7 days to resolve discontinue blinatumomab permanently.

Grade 4

Discontinue blinatumomab permanently

Non-Haematological toxicity
Grade 3	Interrupt treatment until toxicity has resolved to Grade 1 or less. Then recommence at: ≥ 45 kg: 9 micrograms/day. Escalate to 28 micrograms/day after 7 days if the toxicity does not recur. < 45 kg: 5 micrograms/m²/day. Escalate to 15 micrograms/m²/day after 7 days if the toxicity does not recur.
Grade 4	Discontinue blinatumomab permanently

Non-Haematological toxicity

Grade 3

Interrupt treatment until toxicity has resolved to Grade 1 or less. Then recommence at:

≥ 45 kg: 9 micrograms/day. Escalate to 28 micrograms/day after 7 days if the toxicity does not recur.
< 45 kg: 5 micrograms/m²/day. Escalate to 15 micrograms/m²/day after 7 days if the toxicity does not recur.

Grade 4

Discontinue blinatumomab permanently

Interactions

References & Disclaimer

Blinatumomab
No formal drug interaction studies have been conducted with blinatumomab. However blinatumomab is not expected to affect CYP450 enzyme activities.

General
	Interaction	Clinical management
Warfarin	Antineoplastic agents may alter the anticoagulant effect of warfarin	Monitor INR regularly and adjust warfarin dosage as appropriate; consider alternative anticoagulant (e.g. LMWH or unfractionated heparin)
Direct oral anticoagulants (DOACs) e.g. apixaban, rivaroxaban, dabigatran	Interaction with both CYP3A4 and P-gp inhibitors /inducers. DOAC and antineoplastic levels may both be altered, possibly leading to loss of efficacy or toxicity (i.e. increased bleeding).	Apixaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. If treating VTE, avoid use with strong CYP3A4 and P‑gp inducers. Rivaroxaban: avoid concurrent use with strong CYP3A4 and P‑gp inhibitors. Dabigatran: avoid combination with strong P‑gp inducers and inhibitors. If concurrent use is unavoidable, monitor closely for efficacy/toxicity of both drugs.
Digoxin	Antineoplastic agents can damage the lining of the intestine; affecting the absorption of digoxin	Monitor digoxin serum levels; adjust digoxin dosage as appropriate
Antiepileptics	Both altered antiepileptic and antineoplastic levels may occur, possibly leading to loss of efficacy or toxicity	Where concurrent use of an enzyme-inducing antiepileptic cannot be avoided, monitor antiepileptic serum levels for toxicity, as well as seizure frequency for efficacy; adjust dosage as appropriate. Also monitor closely for efficacy of the antineoplastic therapy
Antiplatelet agents and NSAIDs	Increased risk of bleeding due to treatment related thrombocytopenia	Avoid or minimise combination. If combination deemed essential, (e.g. low dose aspirin for ischaemic heart disease) monitor for signs of bleeding
Serotonergic drugs, including selective serotonin reuptake inhibitors (SSRIs e.g. paroxetine) and serotonin noradrenaline reuptake inhibitors (SNRIs e.g. venlafaxine)	Increased risk of serotonin syndrome with concurrent use of 5-HT3 receptor antagonists (e.g. palonosetron, ondansetron, granisetron, tropisetron, dolasetron, etc.)	Avoid combination. If combination is clinically warranted, monitor for signs and symptoms of serotonin syndrome (e.g. confusion, agitation, tachycardia, hyperreflexia). For more information link to TGA Medicines Safety Update
Vaccines	Diminished response to vaccines and increased risk of infection with live vaccines	Live vaccines (e.g. BCG, MMR, zoster and varicella) are contraindicated in patients on immunosuppressive therapy. Use with caution in patients on non-immunosuppressive therapy. For more information; refer to the recommended schedule of vaccination for cancer patients, as outlined in the Australian Immunisation Handbook

Administration Cycle 1

Note: Blinatumomab preparation and administration can be complex. It is important that the instruction for preparation and administration provided in the Product Information are strictly followed to minimise medication errors.

Day 1

Handling of monoclonal antibodies and waste management

Safe administration

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Access CVC.

baseline weight
baseline neurological assessment e.g. daily handwriting assessment that includes the date, time and location.

Pre treatment medication

Administer antiemetics if required

Dexamethasone

administer 60 minutes before the start of blinatumomab treatment
administer via IV infusion over 15 minutes
flush with ~ 50mL sodium chloride 0.9%.

Treatment - Time out

Blinatumomab

Prior to administration

ensure a PVC-free line is used and primed with blinatumomab only and attach a protein-sparing 0.2 micron in-line filter
dedicate a CVAD lumen solely for blinatumomab and ensure that no other drug or fluid is given through this port
ensure that the infusion is commenced at an appropriate time to facilitate outpatient infusion bag / cassette changes.

Administer blinatumomab

via continuous IV infusion
do not administer any remaining fluid once the prescribed infusion time has ceased as this may result in excess dosing
observe for signs of an infusion reaction especially cytokine release syndrome and/or neurological problems e.g. seizures,headache, confusion, slurred speech etc.

If an infusion reaction occurs notify medical officer immediately

for severe reactions stop infusion and manage as per emergency

Note: do NOT flush the blinatumomab infusion line or the dedicated CVAD lumen, especially when changing infusion bags or cassettes. Flushing when changing bags or at completion of infusion can result in an excess dosage / drug bolus and complications to the patient.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Day 2 to 7

Handling of monoclonal antibodies and waste management

Safe administration

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

regular neurological assessment e.g. daily handwriting assessment that includes the date,time and location.

Pre treatment medication

Administer antiemetics if required

Treatment - Time out

Blinatumomab

Prior to administration

ensure a PVC-free line is used and primed with blinatumomab only and attach a protein-sparing 0.2 micron in-line filter
attach infusion line with filter to the already dedicated CVAD lumen solely for blinatumomab and ensure that no other drug or fluid is given through this port

Administer blinatumomab

via continuous IV infusion
do not administer any remaining fluid once the prescribed infusion time has ceased as this may result in excess dosing
observe for signs of an infusion reaction especially cytokine release syndrome and/or neurological problems e.g. seizures,headache, confusion, slurred speech etc.

If an infusion reaction occurs notify medical officer immediately

for severe reactions stop infusion and manage as per emergency

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Day 8

Handling of monoclonal antibodies and waste management

Safe administration

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

regular neurological assessment e.g. daily handwriting assessment that includes the date,time and location.

Pre treatment medication

Administer antiemetics if required

Dexamethasone

administer 60 minutes before step dose (increase) blinatumomab
administer via IV infusion over 15 minutes
flush with ~ 50mL sodium chloride 0.9%.

Treatment - Time out

Blinatumomab

Prior to administration

ensure a PVC-free line is used and primed with blinatumomab only and attach a protein-sparing 0.2 micron in-line filter
attach infusion line with filter to the already dedicated CVAD lumen solely for blinatumomab and ensure that no other drug or fluid is given through this port

Administer blinatumomab

via continuous IV infusion
do not administer any remaining fluid once the prescribed infusion time has ceased as this may result in excess dosing
observe for signs of an infusion reaction especially cytokine release syndrome and/or neurological problems e.g. seizures,headache, confusion, slurred speech etc.

If an infusion reaction occurs notify medical officer immediately

for severe reactions stop infusion and manage as per emergency

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Day 9 to 28

Handling of monoclonal antibodies and waste management

Safe administration

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

regular neurological assessment e.g. daily handwriting assessment that includes the date,time and location.

Pre treatment medication

Administer antiemetics if required

Treatment - Time out

Blinatumomab

Prior to administration

ensure a PVC-free line is used and primed with blinatumomab only and attach a protein-sparing 0.2 micron in-line filter
attach infusion line with filter to the already dedicated CVAD lumen solely for blinatumomab and ensure that no other drug or fluid is given through this port

Administer blinatumomab

via continuous IV infusion
do not administer any remaining fluid once the prescribed infusion time has ceased as this may result in excess dosing
observe for signs of an infusion reaction especially cytokine release syndrome and/or neurological problems e.g. seizures,headache, confusion, slurred speech etc.

If an infusion reaction occurs notify medical officer immediately

for severe reactions stop infusion and manage as per emergency

Deaccess CVC.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Antiemetics

Antiemetics as prescribed.

Prophylaxis medications

Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.

Patient information

Ensure patient receives patient information sheet.

Administration Cycle 2 to 5

Day 1

Handling of monoclonal antibodies and waste management

Safe administration

General patient assessment prior to each day of treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before commencing treatment.

Prime IV line(s).

Access CVC.

baseline weight
baseline neurological assessment e.g. daily handwriting assessment that includes the date, time and location.

Pre treatment medication

Administer antiemetics if required

Dexamethasone

administer 60 minutes before the start of blinatumomab treatment
administer via IV infusion over 15 minutes
flush with ~ 50mL sodium chloride 0.9%.

Treatment - Time out

Blinatumomab

Prior to administration

ensure a PVC-free line is used and primed with blinatumomab only and attach a protein-sparing 0.2 micron in-line filter
dedicate a CVAD lumen solely for blinatumomab and ensure that no other drug or fluid is given through this port
ensure that the infusion is commenced at an appropriate time to facilitate outpatient infusion bag / cassette changes.

Administer blinatumomab

via continuous IV infusion
do not administer any remaining fluid once the prescribed infusion time has ceased as this may result in excess dosing
observe for signs of an infusion reaction especially cytokine release syndrome and/or neurological problems e.g. seizures,headache, confusion, slurred speech etc.

If an infusion reaction occurs notify medical officer immediately

for severe reactions stop infusion and manage as per emergency

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Days 2 to 28

Handling of monoclonal antibodies and waste management

Safe administration

General patient assessment prior to each treatment.

Any toxicity grade 2 or greater may require dose reduction, delay or omission of treatment and review by medical officer before recommencing treatment.

regular neurological assessment e.g. daily handwriting assessment that includes the date,time and location.

Pre treatment medication

Administer antiemetics if required

Treatment - Time out

Blinatumomab

Prior to administration

ensure a PVC-free line is used and primed with blinatumomab only and attach a protein-sparing 0.2 micron in-line filter
attach infusion line with filter to the already dedicated CVAD lumen solely for blinatumomab and ensure that no other drug or fluid is given through this port

Administer blinatumomab

via continuous IV infusion
do not administer any remaining fluid once the prescribed infusion time has ceased as this may result in excess dosing
observe for signs of an infusion reaction especially cytokine release syndrome and/or neurological problems e.g. seizures,headache, confusion, slurred speech etc.

If an infusion reaction occurs notify medical officer immediately

for severe reactions stop infusion and manage as per emergency

Deaccess CVC.

Continue safe handling precautions (reproductive risk only) for 7 days after completion of drug(s).

Discharge information

Antiemetics

Antiemetics as prescribed.

Prophylaxis medications

Prophylaxis medications (if prescribed) i.e. tumour lysis prophylaxis, PJP prophylaxis, antifungals, antivirals.

Patient information

Ensure patient receives patient information sheet.

Side effects

The side effects listed below are not a complete list of all possible side effects for this treatment. Side effects are categorised into the approximate onset of presentation and should only be used as a guide.

Immediate (onset hours to days)
Hypersensitivity reaction	Anaphylaxis and infusion related reactions can occur with this treatment. Read more about hypersensitivity reaction
Nausea and vomiting	Read more about prevention of treatment induced nausea and vomiting
Flu-like symptoms

Early (onset days to weeks)
Fever
Headache
Neutropenia	Abnormally low levels of neutrophils in the blood. This increases the risk of infection. Any fever or suspicion of infection should be investigated immediately and managed aggressively. Read more about neutropenia
Thrombocytopenia	A reduction in the normal levels of functional platelets, increasing the risk of abnormal bleeding. Read more about thrombocytopenia
Diarrhoea	Read more about treatment induced diarrhoea
Hypokalaemia	Abnormally low levels of potassium in the blood.
Fluid retention and oedema	An excess amount of fluid around the cells, tissues or serous cavities of the body, leading to swelling.
Constipation
Fatigue	Read more about fatigue
Insomnia

Late (onset weeks to months)
Anaemia	Abnormally low levels of red blood cells (RBCs) or haemoglobin in the blood. Read more about anaemia
Cognitive changes (chemo fog)	Changes in cognition characterised by memory loss, forgetfulness and feeling vague. This is also referred to as 'chemo brain' or 'chemo fog'. Read more about cognitive changes (chemo fog)
Progressive multifocal leukoencephalopathy (PML)	A rare opportunistic viral infection of the brain, usually leading to death or severe disability, can occur with monoclonal antibodies (e.g. rituximab, obinutuzumab, ofatumumab, brentuximab vedotin) and other targeted therapies (e.g. ibrutinib, ruxolitinib, idelalisib). Onset may occur up to months after the final dose. Read more about progressive multifocal leukoencephalopathy (PML)

Evidence

The evidence supporting the use of blinatumomab in this setting is provided primarily from a multicentre international phase III randomised open-label trial, the TOWER study, which compared blinatumomab monotherapy with ‘standard-of-care chemotherapy’ in patients with relapsed or refractory Philadelphia chromosome negative B-cell acute lymphoblastic leukaemia (ALL).^r

Between January 2014 and September 2015, 271 patients were randomised to receive blinatumomab and 134 patients were assigned to chemotherapy, in a 2:1 randomisation. The local investigator was able to choose one of 4 regimens for the standard-of-care chemotherapy: FLAG ± anthracycline (45% of participants); HiDAC (17% of participants); a high-dose methotrexate regimen (20% of participants); or a clofarabine based regimen (17% of participants).^r

The primary study endpoint was overall survival (OS), with secondary endpoints including achievement of complete remission and full haematologic recovery within 12 weeks (CR); achievement of CR with complete or incomplete haematologic recovery within 12 weeks (CR+CRi); event-free survival; duration of CR; measurable residual disease (MRD) remission rates; allogeneic transplant rates; and adverse events.^r

Blinatumomab resulted in a significant prolongation of overall survival compared to chemotherapy in this trial, with the median OS 7.7 months in the blinatumomab arm compared to 4.0 months in the chemotherapy arm (p=0.01). This study was stopped early by the study data and safety monitoring board after interim analysis demonstrated the OS benefit as above, which was a prespecified stopping rule.^r

On this basis blinatumomab is listed as a category 1 recommendation in the NCCN guidelines for ALL in relapsed or refractory Ph-negative B-ALL.

Efficacy

The median overall survival was 7.7 months in the blinatumomab arm and 4.0 months in the chemotherapy arm (hazard ratio (HR) for death 0.71; 95%CI 0.55-0.93, p=0.01). The median duration of follow-up was 11.7 months in the blinatumomab arm and 11.8 months in the chemotherapy arm, and median number of treatment cycles was 2 (range, 1 to 9) and 1 (range, 1 to 4) respectively.

In terms of secondary endpoints the remission rates were higher in the blinatumomab arm, with CR of 34% vs 16% (p<0.001), and CR+CRi 44% vs 25% (P<0.001). EFS rates were superior (HR 0.55, p<0.001), and 24% of patients in both groups proceeded to allogeneic transplants.^r

Outcome	Blinatumomab (n=271)	Chemotherapy (n=134)	P value	Comments
Overall survival	7.7 months	4.0 months	P=0.01	Trial stopped early
CR + CRi rates	44%	25%	P<0.001
Duration of CR	7.3 months	4.4 months	Not stated
EFS	31% at 6 months	12% at 6 months	P<0.001	Defined as events after CR

Kaplan-Meier survival curve for OS by intention-to treat analysis

Subgroup analysis forest plot

Health-related quality of life (HRQL) was assessed in the TOWER study by means of the EORTC QLQ-C30 questionnaire, and reported separately.^r Of the 405 patients randomised, 342 had baseline and ≥ 1 post-treatment assessments available, and were included in the HRQL analysis. Blinatumomab treatment was associated with improved HRQL over chemotherapy in almost all domains:

Time to clinically meaningful deterioration in HRQL analyses

Efficacy summary: improved overall survival and health-related quality of life in patients receiving blinatumomab compared to standard-of-care chemotherapy.

Toxicity

ALL therapies result in toxicities for all patients, and adverse events were recorded for 99% in both treatment arms on the TOWER study. Serious adverse events were reported in 62% of blinatumomab patients, and 45% of patients in the chemotherapy arm, including fatal events in 19% (blinatumomab) and 17% (chemotherapy). Note that this includes outcomes following allogeneic transplant. Investigator assessed deaths as being related to treatment in 3% of patients receiving blinatumomab and 7% on the chemotherapy arm. When adjusted for ‘treatment exposure’ the SAE rate for blinatumomab was 349 per 100 patient years versus 641 per 100 patient years in the chemotherapy arm. Grade ≥3 neurotoxicity, an adverse event of special interest as it was seen in previous blinatumomab studies, was reported in 9.4% and 8.3% respectively. Treatment discontinuation was seen in 12% and 8% respectively, which included neurotoxicity (4% and 1%), and cytokine release syndrome (1% and 0%).^r

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First approved:: 2 October 2018
Review due:: 31 December 2019

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21 Jan 2019

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