2.5.1 Aseptic Preparation

Strictly observe aseptic technique when preparing the solution for infusion since BLINCYTO vials do not contain antimicrobial preservatives. To prevent accidental contamination, prepare BLINCYTO according to aseptic standards, including but not limited to:

• Prepare BLINCYTO in a USP <797> compliant facility.
• Prepare BLINCYTO in an ISO Class 5 laminar flow hood or better.
• Ensure that the admixing area has appropriate environmental specifications, confirmed by periodic monitoring.
• Ensure that personnel are appropriately trained in aseptic manipulations and admixing of oncology drugs.
• Ensure that personnel wear appropriate protective clothing and gloves.
• Ensure that gloves and surfaces are disinfected.

2.5.2 Package Content

1 package BLINCYTO includes 1 vial of BLINCYTO and 1 vial of IV Solution Stabilizer.

• Do not use IV Solution Stabilizer for reconstitution of BLINCYTO. IV Solution Stabilizer is provided with the BLINCYTO package and is used to coat the intravenous bag prior to addition of reconstituted BLINCYTO to prevent adhesion of BLINCYTO to intravenous bags and intravenous tubing.
• More than 1 package of BLINCYTO may be needed to prepare the recommended dose.

2.5.3 Incompatibility Information

BLINCYTO is incompatible with di-ethylhexylphthalate (DEHP) due to the possibility of particle formation, leading to a cloudy solution.

• Use polyolefin, DEHP-free PVC, or ethyl vinyl acetate (EVA) infusion bags/pump cassettes.
• Use polyolefin, DEHP-free PVC, or EVA intravenous tubing sets.

2.6.1 Reconstitution of BLINCYTO for 24-Hour or 48-Hour Infusion

• Determine the number of BLINCYTO vials needed for a dose and infusion duration.
• Reconstitute each BLINCYTO vial with 3 mL of preservative-free Sterile Water for Injection, USP by directing the water along the walls of the BLINCYTO vial and not directly on the lyophilized powder. The resulting concentration per BLINCYTO vial is 12.5 mcg/mL.
  • Do not reconstitute BLINCYTO vials with IV Solution Stabilizer.
• Gently swirl contents to avoid excess foaming.
  • Do not shake.
• Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow.
  • Do not use if solution is cloudy or has precipitated.

2.6.2 Preparation of BLINCYTO Infusion Bag for 24-Hour or 48-Hour Infusion

Verify the prescribed dose and infusion duration for each BLINCYTO infusion bag. To minimize errors, use the specific volumes described in Tables 5 and 6 to prepare the BLINCYTO infusion bag.

• Table 5 for patients weighing 45 kg or more
• Table 6 for patients weighing less than 45 kg
  • Aseptically add 270 mL 0.9% Sodium Chloride Injection, USP to the empty intravenous bag.
  • Aseptically transfer 5.5 mL IV Solution Stabilizer to the intravenous bag containing 0.9% Sodium Chloride Injection, USP. Gently mix the contents of the bag to avoid foaming. Discard the vial containing the unused IV Solution Stabilizer.
  • Aseptically transfer the required volume of reconstituted BLINCYTO solution into the intravenous bag containing 0.9% Sodium Chloride Injection, USP and IV Solution Stabilizer. Gently mix the contents of the bag to avoid foaming.
    • Refer to Table 5 for patients weighing 45 kg or more for the specific volume of reconstituted BLINCYTO.
    • Refer to Table 6 for patients weighing less than 45 kg (dose based on BSA) for the specific volume of reconstituted BLINCYTO.
    • Discard the vial containing unused BLINCYTO.
  • Under aseptic conditions, attach the intravenous tubing to the intravenous bag with the sterile 0.2 micron in-line filter. Ensure that the intravenous tubing is compatible with the infusion pump.
  • Remove air from the intravenous bag. This is particularly important for use with an ambulatory infusion pump.
  • Prime the intravenous tubing only with the solution in the bag containing the FINAL prepared BLINCYTO solution for infusion.
  • Store refrigerated at 2°C to 8°C (36°F to 46°F) if not used immediately [see Dosage and Administration (2.8)].

Table 5. For Patients Weighing 45 kg or More: Volumes to Add to Intravenous Bag

0.9% Sodium Chloride Injection, USP (starting volume)			270 mL
IV Solution Stabilizer (fixed volume for 24-hour and 48-hour infusion durations)			5.5 mL
Infusion Duration	Dose	Infusion Rate	Reconstituted BLINCYTO
			Volume	Vials
24 hours	9 mcg/day	10 mL/hour	0.83 mL	1
	28 mcg/day	10 mL/hour	2.6 mL	1
48 hours	9 mcg/day	5 mL/hour	1.7 mL	1
	28 mcg/day	5 mL/hour	5.2 mL	2

Table 6. For Patients Weighing Less Than 45 kg: Volumes to Add to Intravenous Bag

0.9% Sodium Chloride Injection, USP (starting volume)				270 mL
IV Solution Stabilizer (fixed volume for 24-hour and 48-hour infusion)				5.5 mL
Infusion Duration	Dose	Infusion Rate	BSA (m2)	Reconstituted BLINCYTO
				Volume	Vials
24 hours	5 mcg/m2/day	10 mL/hour	1.5 – 1.59	0.7 mL	1
			1.4 – 1.49	0.66 mL	1
			1.3 – 1.39	0.61 mL	1
			1.2 – 1.29	0.56 mL	1
			1.1 – 1.19	0.52 mL	1
			1 – 1.09	0.47 mL	1
			0.9 – 0.99	0.43 mL	1
			0.8 – 0.89	0.38 mL	1
			0.7 – 0.79	0.33 mL	1
			0.6 – 0.69	0.29 mL	1
			0.5 – 0.59	0.24 mL	1
			0.4 – 0.49	0.2 mL	1
24 hours	15 mcg/m2/day	10 mL/hour	1.5 – 1.59	2.1 mL	1
			1.4 – 1.49	2 mL	1
			1.3 – 1.39	1.8 mL	1
			1.2 – 1.29	1.7 mL	1
			1.1 – 1.19	1.6 mL	1
			1 – 1.09	1.4 mL	1
			0.9 – 0.99	1.3 mL	1
			0.8 – 0.89	1.1 mL	1
			0.7 – 0.79	1 mL	1
			0.6 – 0.69	0.86 mL	1
			0.5 – 0.59	0.72 mL	1
			0.4 – 0.49	0.59 mL	1
48 hours	5 mcg/m2/day	5 mL/hour	1.5 – 1.59	1.4 mL	1
			1.4 – 1.49	1.3 mL	1
			1.3 – 1.39	1.2 mL	1
			1.2 – 1.29	1.1 mL	1
			1.1 – 1.19	1 mL	1
			1 – 1.09	0.94 mL	1
			0.9 – 0.99	0.85 mL	1
			0.8 – 0.89	0.76 mL	1
			0.7 – 0.79	0.67 mL	1
			0.6 – 0.69	0.57 mL	1
			0.5 – 0.59	0.48 mL	1
			0.4 – 0.49	0.39 mL	1
48 hours	15 mcg/m2/day	5 mL/hour	1.5 – 1.59	4.2 mL	2
			1.4 – 1.49	3.9 mL	2
			1.3 – 1.39	3.7 mL	2
			1.2 – 1.29	3.4 mL	2
			1.1 – 1.19	3.1 mL	2
			1 – 1.09	2.8 mL	1
			0.9 – 0.99	2.6 mL	1
			0.8 – 0.89	2.3 mL	1
			0.7 – 0.79	2 mL	1
			0.6 – 0.69	1.7 mL	1
			0.5 – 0.59	1.4 mL	1
			0.4 – 0.49	1.2 mL	1

2.6.3 Administration of BLINCYTO for 24-Hour or 48-Hour Infusion

• Administer BLINCYTO as a continuous intravenous infusion at a constant flow rate using an infusion pump. 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) to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO.
• Infuse prepared BLINCYTO final infusion solution according to the instructions on the pharmacy label on the prepared bag at one of the following constant infusion rates:
  • -Infusion rate of 10 mL/hour for a duration of 24 hours, OR
  • -Infusion rate of 5 mL/hour for a duration of 48 hours
• Administer prepared BLINCYTO final infusion solution using intravenous tubing that contains a sterile, non-pyrogenic, low protein-binding, 0.2 micron in-line filter. For 7-day bag administration information see section 2.7.3 below [see Dosage and Administration (2.7)].
• Important Note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, infuse BLINCYTO through a dedicated lumen.
• At the end of the infusion, discard any unused BLINCYTO solution in the intravenous bag and intravenous tubing in accordance with local requirements.

2.7.1 Reconstitution of BLINCYTO for 7-Day Infusion

• Determine the number of BLINCYTO vials needed for a dose.
• Reconstitute each BLINCYTO vial with 3 mL of preservative-free Sterile Water for Injection, USP by directing the water along the walls of the BLINCYTO vial and not directly on the lyophilized powder. The resulting concentration per BLINCYTO vial is 12.5 mcg/mL.
  • Do not reconstitute BLINCYTO vials with the IV Solution Stabilizer.
• Gently swirl contents to avoid excess foaming.
  • Do not shake.
• Visually inspect the reconstituted solution for particulate matter and discoloration during reconstitution and prior to infusion. The resulting solution should be clear to slightly opalescent, colorless to slightly yellow.
  • Do not use if solution is cloudy or has precipitated.

2.7.2 Preparation of BLINCYTO Infusion Bag for 7-Day Infusion

Verify the prescribed dose and infusion duration for each BLINCYTO infusion bag. To minimize errors, use the specific volumes described in Table 7 to prepare the BLINCYTO infusion bag.

• Aseptically add 90 mL Bacteriostatic 0.9% Sodium Chloride Injection, USP to the empty intravenous bag.
• Aseptically transfer 2.2 mL IV Solution Stabilizer to the intravenous bag containing Bacteriostatic 0.9% Sodium Chloride Injection, USP. Gently mix the contents of the bag to avoid foaming. Discard the vial containing the unused IV Solution Stabilizer.
• Aseptically transfer the required volume of reconstituted BLINCYTO solution into the intravenous bag containing Bacteriostatic 0.9% Sodium Chloride Injection, USP and IV Solution Stabilizer. Gently mix the contents of the bag to avoid foaming.
  • Refer to Table 7 for the specific volume of reconstituted BLINCYTO. Discard the vial containing unused BLINCYTO.
• Aseptically add the required volume of 0.9% Sodium Chloride Injection, USP to the intravenous bag to obtain a final volume of 110 mL. Gently mix the contents of the bag to avoid foaming.
  • Refer to Table 7 for the specific volume of 0.9% Sodium Chloride Injection, USP.
• Under aseptic conditions, attach the intravenous tubing to the intravenous bag.
  • Ensure that the intravenous tubing is compatible with the infusion pump.
  • Do not use an in-line filter for a 7-day bag.
• Remove air from the intravenous bag. This is particularly important for use with an ambulatory infusion pump.
• Prime the intravenous tubing only with the solution in the bag containing the FINAL prepared BLINCYTO solution for infusion.
• Store refrigerated at 2°C to 8°C (36°F to 46°F) if not used immediately [see Dosage and Administration (2.8)].

Table 7. For 7-Day Infusion: Volumes to Add to Intravenous Bag for 28 mcg/day and 15 mcg/m²/day

Bacteriostatic 0.9% Sodium Chloride Injection, USP (starting volume)				90 mL
IV Solution Stabilizer (fixed volume for 7-day infusion)				2.2 mL
Reconstituted BLINCYTO				Specific volume listed below in table
Quantity Sufficient (q.s.) with 0.9% Sodium Chloride Injection, USP to a Final Volume of 110 mL				Specific volume listed below in table
Infusion Duration				7 days
Infusion Rate				0.6 mL/hour
Patient Weight	Dose	BSA (m2)The safety of the administration of BLINCYTO at a BSA of less than 0.4 m2 has not been established.	Reconstituted BLINCYTO		Volume of 0.9% Sodium Chloride Injection, USP needed to q.s. to a Final Volume of 110 mL
			Volume	Vials
Fixed-Dose
45 kg or More	28 mcg/day	N/A	16.8 mL	6	1 mL
BSA-Based Dose
Less than 45 kg	15 mcg/m2/day	1.5 – 1.59	14 mL	5	3.8 mL
		1.4 – 1.49	13.1 mL	5	4.7 mL
		1.30 – 1.39	12.2 mL	5	5.6 mL
		1.20 – 1.29	11.3 mL	5	6.5 mL
		1.10 – 1.19	10.4 mL	4	7.4 mL
		1 – 1.09	9.5 mL	4	8.3 mL
		0.9 – 0.99	8.6 mL	4	9.2 mL
		0.8 – 0.89	7.7 mL	3	10.1 mL
		0.7 – 0.79	6.8 mL	3	11 mL
		0.6 – 0.69	5.9 mL	3	11.9 mL
		0.5 – 0.59	5 mL	2	12.8 mL
		0.4 – 0.49	4.1 mL	2	13.7 mL

2.7.3 Administration of BLINCYTO as a 7-Day Infusion

• Administer BLINCYTO as a continuous intravenous infusion at a constant flow rate using an infusion pump. The pump should be programmable, lockable, non-elastomeric, and have an alarm.
• The final volume of infusion solution (110 mL) will be more than the volume administered to the patient (100 mL) to account for the priming of the intravenous tubing and to ensure that the patient will receive the full dose of BLINCYTO.
• Do not use an in-line filter for a 7-day bag.
• Infuse prepared BLINCYTO final infusion solution according to the instructions on the pharmacy label on the prepared bag at an infusion rate of 0.6 mL/hour for a duration of 7 days.
• Important Note: Do not flush the BLINCYTO infusion line or intravenous catheter, especially when changing infusion bags. Flushing when changing bags or at completion of infusion can result in excess dosage and complications thereof. When administering via a multi-lumen venous catheter, infuse BLINCYTO through a dedicated lumen.
• At the end of the infusion, dispose of any unused BLINCYTO solution in the intravenous bag and intravenous tubing in accordance with local requirements.

MRD-positive B-cell Precursor ALL

The safety of BLINCYTO in patients with MRD-positive B-cell precursor ALL was evaluated in two single-arm clinical studies in which 137 adult patients were treated with BLINCYTO. The median age of the study population was 45 years (range: 18 to 77 years).

The most common adverse reactions (≥ 20%) were pyrexia, infusion-related reactions, headache, infections (pathogen unspecified), tremor, and chills. Serious adverse reactions were reported in 61% of patients. The most common serious adverse reactions (≥ 2%) included pyrexia, tremor, encephalopathy, aphasia, lymphopenia, neutropenia, overdose, device related infection, seizure, and staphylococcal infection. Adverse reactions of Grade 3 or higher were reported in 64% of patients. Discontinuation of therapy due to adverse reactions occurred in 17% of patients; neurologic events were the most frequently reported reasons for discontinuation. There were 2 fatal adverse reactions that occurred within 30 days of the end of BLINCYTO treatment (atypical pneumonia and subdural hemorrhage).

Table 9 summarizes the adverse reactions occurring at a ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher.

Table 9. Adverse Reactions Occurring at ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher in BLINCYTO-treated Adult Patients with MRD-Positive B-cell Precursor ALL

Adverse Reaction	BLINCYTO (N = 137)
	Any GradeGrading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. n (%)	Grade ≥ 3 n (%)
Blood and lymphatic system disorders
NeutropeniaNeutropenia includes febrile neutropenia, neutropenia, and neutrophil count decreased.	21 (15)	21 (15)
LeukopeniaLeukopenia includes leukopenia and white blood cell count decreased.	19 (14)	13 (9)
ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia.	14 (10)	8 (6)
Cardiac disorders
ArrhythmiaArrhythmia includes bradycardia, sinus arrhythmia, sinus bradycardia, sinus tachycardia, tachycardia and ventricular extrasystoles.	17 (12)	3 (2)
General disorders and administration site conditions
PyrexiaPyrexia includes body temperature increased and pyrexia.	125 (91)	9 (7)
Chills	39 (28)	0 (0)
Infections and infestations
Infections - pathogen unspecified	53 (39)	11 (8)
Injury, poisoning and procedural complications
Infusion-related reactionInfusion-related reaction is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and the event lasted ≤ 2 days: cytokine release syndrome, eye swelling, hypertension, hypotension, myalgia, periorbital edema, pruritus generalized, pyrexia, and rash.	105 (77)	7 (5)
Investigations
Decreased immunoglobulinsDecreased immunoglobulins includes blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, hypogammaglobulinemia, hypoglobulinemia, and immunoglobulins decreased.	25 (18)	7 (5)
Weight increased	14 (10)	1 (< 1)
HypertransaminasemiaHypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, and hepatic enzyme increased.	13 (9)	9 (7)
Musculoskeletal and connective tissue disorders
Back pain	16 (12)	1 (< 1)
Nervous system disorders
HeadacheMay represent ICANS.	54 (39)	5 (4)
Tremor , Tremor includes essential tremor, intention tremor, and tremor.	43 (31)	6 (4)
Aphasia	16 (12)	1 (< 1)
Dizziness	14 (10)	1 (< 1)
Encephalopathy , Encephalopathy includes cognitive disorder, depressed level of consciousness, disturbance in attention, encephalopathy, lethargy, leukoencephalopathy, memory impairment, somnolence, and toxic encephalopathy.	14 (10)	6 (4)
Psychiatric disorders
Insomnia , Insomnia includes initial insomnia, insomnia, and terminal insomnia.	24 (18)	1 (< 1)
Respiratory, thoracic and mediastinal disorders
Cough	18 (13)	0 (0)
Skin and subcutaneous tissue disorders
RashRash includes dermatitis contact, eczema, erythema, rash, and rash maculopapular.	22 (16)	1 (< 1)
Vascular disorders
Hypotension	19 (14)	1 (< 1)

Additional adverse reactions in adult patients with MRD-positive ALL that did not meet the threshold criteria for inclusion in Table 9 were:

Blood and lymphatic system disorders: anemia

General disorders and administration site conditions: edema peripheral, pain, and chest pain (includes chest pain and musculoskeletal chest pain)

Hepatobiliary disorders: blood bilirubin increased

Immune system disorders: hypersensitivity and cytokine release syndrome

Infections and infestations: viral infectious disorders, bacterial infectious disorders, and fungal infectious disorders

Injury, poisoning and procedural complications: medication error and overdose (includes overdose and accidental overdose)

Investigations: blood alkaline phosphatase increased

Musculoskeletal and connective tissue disorders: pain in extremity and bone pain

Nervous system disorders: seizure (includes seizure and generalized tonic-clonic seizure), speech disorder, and hypoesthesia

Psychiatric disorders: confusional state, disorientation, and depression

Respiratory, thoracic and mediastinal disorders: dyspnea and productive cough

Vascular disorders: hypertension (includes blood pressure increased and hypertension) flushing (includes flushing and hot flush), and capillary leak syndrome

Relapsed or Refractory B-cell Precursor ALL

The safety of BLINCYTO was evaluated in a randomized, open-label, active-controlled clinical study (TOWER Study) in which 376 adult patients with Philadelphia chromosome-negative relapsed or refractory B-cell precursor ALL were treated with BLINCYTO (n = 267) or standard of care (SOC) chemotherapy (n = 109). The median age of BLINCYTO-treated patients was 37 years (range: 18 to 80 years), 60% were male, 84% were White, 7% Asian, 2% were Black or African American, 2% were American Indian or Alaska Native, and 5% were Multiple/Other.

The most common adverse reactions (≥ 20%) in the BLINCYTO arm were infections (bacterial and pathogen unspecified), pyrexia, headache, infusion-related reactions, anemia, febrile neutropenia, thrombocytopenia, and neutropenia. Serious adverse reactions were reported in 62% of patients. The most common serious adverse reactions (≥ 2%) included febrile neutropenia, pyrexia, sepsis, pneumonia, overdose, septic shock, CRS, bacterial sepsis, device related infection, and bacteremia. Adverse reactions of Grade 3 or higher were reported in 87% of patients. Discontinuation of therapy due to adverse reactions occurred in 12% of patients treated with BLINCYTO; neurologic events and infections were the most frequently reported reasons for discontinuation of treatment due to an adverse reaction. Fatal adverse events occurred in 16% of patients. The majority of the fatal events were infections.

The adverse reactions occurring at a ≥ 10% incidence for any grade or ≥ 5% incidence for Grade 3 or higher in the BLINCYTO-treated patients in first cycle of therapy are summarized in Table 10.

Table 10. Adverse Reactions Occurring at ≥ 10% Incidence for Any Grade or ≥ 5% Incidence for Grade 3 or Higher in BLINCYTO-Treated Patients in First Cycle of Therapy for Adult Patients with Relapsed or Refractory B-cell Precursor ALL (TOWER Study)

Adverse Reaction	BLINCYTO (N = 267)		Standard of Care (SOC) Chemotherapy (N = 109)
	Any GradeGrading based on NCI Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. n (%)	Grade ≥ 3 n (%)	Any Grade n (%)	Grade ≥ 3 n (%)
Blood and lymphatic system disorders
NeutropeniaNeutropenia includes agranulocytosis, febrile neutropenia, neutropenia, and neutrophil count decreased.	84 (31)	76 (28)	67 (61)	61 (56)
AnemiaAnemia includes anemia and hemoglobin decreased.	68 (25)	52 (19)	45 (41)	37 (34)
ThrombocytopeniaThrombocytopenia includes platelet count decreased and thrombocytopenia.	57 (21)	47 (18)	42 (39)	40 (37)
LeukopeniaLeukopenia includes leukopenia and white blood cell count decreased.	21 (8)	18 (7)	9 (8)	9 (8)
Cardiac disorders
ArrhythmiaArrhythmia includes arrhythmia, atrial fibrillation, atrial flutter, bradycardia, sinus bradycardia, sinus tachycardia, supraventricular tachycardia, and tachycardia.	37 (14)	5 (2)	18 (17)	0 (0)
General disorders and administration site conditions
Pyrexia	147 (55)	15 (6)	43 (39)	4 (4)
EdemaEdema includes face edema, fluid retention, edema, edema peripheral, peripheral swelling, and swelling face.	48 (18)	3 (1)	20 (18)	1 (1)
Immune system disorders
Cytokine release syndromeCytokine release syndrome includes cytokine release syndrome and cytokine storm.	37 (14)	8 (3)	0 (0)	0 (0)
Infections and infestations
Infections - pathogen unspecified	74 (28)	40 (15)	50 (46)	35 (32)
Bacterial infectious disorders	38 (14)	19 (7)	35 (32)	21 (19)
Viral infectious disorders	30 (11)	4 (1)	14 (13)	0 (0)
Fungal infectious disorders	27 (10)	13 (5)	15 (14)	9 (8)
Injury, poisoning and procedural complications
Infusion-related reactionInfusion-related reaction is a composite term that includes the term infusion-related reaction and the following events occurring with the first 48 hours of infusion and the event lasted ≤ 2 days: pyrexia, cytokine release syndrome, hypotension, myalgia, acute kidney injury, hypertension, and rash erythematous.	79 (30)	9 (3)	9 (8)	1 (1)
Investigations
HypertransaminasemiaHypertransaminasemia includes alanine aminotransferase increased, aspartate aminotransferase increased, hepatic enzyme increased, and transaminases increased.	40 (15)	22 (8)	13 (12)	7 (6)
Nervous system disorders
HeadacheMay represent ICANS.	61 (23)	1 (< 1)	30 (28)	3 (3)
Skin and subcutaneous tissue disorders
RashRash includes erythema, rash, rash erythematous, rash generalized, rash macular, rash maculo-papular, rash pruritic, skin exfoliation, and toxic skin eruption.	31 (12)	2 (1)	21 (19)	0 (0)

Selected laboratory abnormalities worsening from baseline Grade 0-2 to treatment-related maximal Grade 3-4 in first cycle of therapy are shown in Table 11.

Table 11. Selected Laboratory Abnormalities Worsening from Baseline Grade 0-2 to Treatment-related Maximal Grade 3-4Includes only patients who had both baseline and at least one laboratory measurement during first cycle of therapy available. in First Cycle of Therapy for Adult Patients with Relapsed or Refractory B-cell Precursor ALL (TOWER Study)

	BLINCYTO Grade 3 or 4 (%)	SOC Chemotherapy Grade 3 or 4 (%)
Hematology
Decreased lymphocyte count	80	83
Decreased white blood cell count	53	97
Decreased hemoglobin	29	43
Decreased neutrophil count	57	68
Decreased platelet count	47	85
Chemistry
Increased ALT	11	11
Increased bilirubin	5	4
Increased AST	8	4

Other important adverse reactions from pooled relapsed or refractory B-cell precursor ALL studies were:

Blood and lymphatic system disorders: lymphadenopathy, hematophagic histiocytosis, and leukocytosis (includes leukocytosis and white blood cell count increased)

General disorders and administration site conditions: chills, chest pain (includes chest discomfort, chest pain, musculoskeletal chest pain, and non-cardiac chest pain), pain, body temperature increased, hyperthermia, and systemic inflammatory response syndrome

Hepatobiliary disorders: hyperbilirubinemia (includes blood bilirubin increased and hyperbilirubinemia)

Immune system disorders: hypersensitivity (includes hypersensitivity, anaphylactic reaction, angioedema, dermatitis allergic, drug eruption, drug hypersensitivity, erythema multiforme, and urticaria)

Injury, poisoning and procedural complications: medication error and overdose (includes overdose, medication error, and accidental overdose)

Investigations: weight increased, decreased immunoglobulins (includes immunoglobulins decreased, blood immunoglobulin A decreased, blood immunoglobulin G decreased, blood immunoglobulin M decreased, and hypogammaglobulinemia), blood alkaline phosphatase increased, and hypertransaminasemia

Metabolism and nutrition disorders: tumor lysis syndrome

Musculoskeletal and connective tissue disorders: back pain, bone pain, and pain in extremity

Nervous system disorders: tremor (resting tremor, intention tremor, essential tremor, and tremor), altered state of consciousness (includes altered state of consciousness, depressed level of consciousness, disturbance in attention, lethargy, mental status changes, stupor, and somnolence), dizziness, memory impairment, seizure (includes seizure, and atonic seizure), aphasia, cognitive disorder, speech disorder, hypoesthesia, encephalopathy, paresthesia, and cranial nerve disorders (trigeminal neuralgia, trigeminal nerve disorder, sixth nerve paralysis, cranial nerve disorder, facial nerve disorder, and facial paresis)

Psychiatric disorders: insomnia, disorientation, confusional state, and depression (includes depressed mood, depression, suicidal ideation, and completed suicide)

Respiratory, thoracic and mediastinal disorders: dyspnea (includes acute respiratory failure, dyspnea, dyspnea exertional, respiratory failure, respiratory distress, bronchospasm, bronchial hyperreactivity, tachypnea, and wheezing), cough, and productive cough

Vascular disorders: hypotension (includes blood pressure decreased, hypotension, hypovolemic shock, and circulatory collapse), hypertension (includes blood pressure increased, hypertension, and hypertensive crisis), flushing (includes flushing and hot flush), and capillary leak syndrome

B-cell Precursor ALL in the Consolidation Phase

Risk Summary

Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1)]. There are no available data on the use of BLINCYTO in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, a murine surrogate molecule administered to pregnant mice crossed the placental barrier (see Data).

Blinatumomab causes T-cell activation and cytokine release; immune activation may compromise pregnancy maintenance. In addition, based on expression of CD19 on B-cells and the finding of B-cell depletion in non-pregnant animals, blinatumomab can cause B-cell lymphocytopenia in infants exposed to blinatumomab in-utero. Advise pregnant women of the potential risk to a fetus.

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, respectively.

Clinical Considerations

Data

Risk Summary

There is no information regarding the presence of blinatumomab in human milk, the effects on the breastfed infant, or the effects on milk production. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in breastfed infants from BLINCYTO, including B-cell lymphocytopenia, advise patients not to breastfeed during treatment with BLINCYTO and for 48 hours after the last dose.

Pregnancy Testing

Verify the pregnancy status of females of reproductive potential prior to initiating BLINCYTO treatment.

Contraception

Minimal Residual Disease (MRD)-Positive B-cell Precursor ALL

The safety and efficacy of BLINCYTO for the treatment of CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1% have been established in pediatric patients one month and older. Use of BLINCYTO is supported by evidence from two randomized, controlled trials (Study AALL1331, NCT02101853 and Study 20120215, NCT02393859) [see Clinical Studies (14.3)] in pediatric patients with first relapsed B-cell precursor ALL. Both studies included pediatric patients with MRD-positive B-cell precursor ALL. The studies included pediatric patients treated with BLINCYTO in the following age groups: 6 infants (1 month up to less than 2 years), 165 children (2 years up to less than 12 years), and 70 adolescents (12 years to less than 17 years). In general, the adverse reactions in BLINCYTO-treated pediatric patients were similar in type to those seen in adult patients with MRD-positive ALL [see Adverse Reactions (6.1)], and no differences in safety were observed between the different pediatric age subgroups.

Relapsed or Refractory B-cell Precursor ALL

The safety and efficacy of BLINCYTO have been established in pediatric patients one month and older with relapsed or refractory B-cell precursor ALL. Use of BLINCYTO is supported by a single-arm trial in pediatric patients with relapsed or refractory B-cell precursor ALL. This study included pediatric patients in the following age groups: 10 infants (1 month up to less than 2 years), 40 children (2 years up to less than 12 years), and 20 adolescents (12 years to less than 18 years). No differences in efficacy were observed between the different age subgroups [see Clinical Studies (14.2)].

In general, the adverse reactions in BLINCYTO-treated pediatric patients with relapsed or refractory ALL were similar in type to those seen in adult patients with relapsed or refractory B-cell precursor ALL [see Adverse Reactions (6.1)]. Adverse reactions that were observed more frequently (≥ 10% difference) in the pediatric population compared to the adult population were pyrexia (80% vs. 61%), hypertension (26% vs. 8%), anemia (41% vs. 24%), infusion-related reaction (49% vs. 34%), thrombocytopenia (34% vs. 21%), leukopenia (24% vs. 11%), and weight increased (17% vs. 6%).

In pediatric patients less than 2 years old (infants) with relapsed or refractory ALL, the incidence of neurologic toxicities was not significantly different than for the other age groups, but its manifestations were different; the only event terms reported were agitation, headache, insomnia, somnolence, and irritability. Infants also had an increased incidence of hypokalemia (50%) compared to other pediatric age cohorts (15-20%) or adults (17%).

B-cell Precursor ALL in the Consolidation Phase

The safety and efficacy of BLINCYTO for the treatment of Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase have been established in pediatric patients one month and older. Use of BLINCYTO for this indication is supported by extrapolation from a randomized controlled study in adults (Study E1910, NCT02003222) and evidence from two randomized, controlled studies in pediatric patients (Study 20120215 and Study AALL1331) [see Adverse Reactions (6.1), Use in Specific Populations (8.4), Clinical Pharmacology (12.3), and Clinical Studies (14.3)].

Benzyl Alcohol Toxicity in Neonates

Serious and fatal adverse reactions, including "gasping syndrome," can occur in very low birth weight (VLBW) neonates born weighing less than 1500 g, and early preterm neonates (infants born less than 34 weeks gestational age) treated with benzyl alcohol-preserved drugs intravenously. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high concentrations of benzyl alcohol and its metabolite in the blood and urine (blood concentration of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known [see Warnings and Precautions (5.12)].

Use the preservative-free formulations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) in neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative). The BLINCYTO 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL [see Warnings and Precautions (5.12)].

Benzyl alcohol administration may contribute to metabolic acidosis in pediatric patients, particularly those with immaturity of the metabolic pathway for alcohol, or those with underlying conditions or receiving concomitant medications that could predispose to acid base imbalance. Monitor these patients during use of BLINCYTO (with preservative) for new or worsening metabolic acidosis.

Distribution

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

Elimination

The estimated mean (SD) systemic clearance with continuous intravenous infusion in patients receiving blinatumomab in clinical studies was 3.10 (2.94) L/hour. The mean (SD) half-life was 2.20 (1.34) hours. Negligible amounts of blinatumomab were excreted in the urine at the tested clinical doses.

Specific Populations

There were no clinically meaningful differences in the pharmacokinetics of blinatumomab based on age (0.6 to 80 years of age), sex, race (72% White, 17% Asian, 3% Black), ethnicity, Philadelphia chromosome status or mild (total bilirubin ≤ upper limit of normal [ULN] and AST > ULN or total bilirubin > 1 to 1.5 × ULN and any AST) or moderate hepatic impairment (total bilirubin > 1.5 to 3 × ULN and any AST). The effect of other races or severe hepatic impairment (total bilirubin > 3 × ULN, any AST) on the pharmacokinetics of blinatumomab is unknown. Body surface area (0.4 to 2.9 m²) influences the pharmacokinetics of blinatumomab, supporting BSA-based dosing in patients < 45 kg.

Drug Interaction Studies

Transient elevation of cytokines may suppress CYP450 enzyme activities [see Drug Interactions (7) and Clinical Pharmacology (12.2)].

BLAST Study

The efficacy of BLINCYTO was evaluated in an open-label, multicenter, single-arm study (BLAST Study) [NCT01207388] that included patients who were ≥ 18 years of age, had received at least 3 chemotherapy blocks of standard ALL therapy, were in hematologic complete remission (defined as < 5% blasts in bone marrow, absolute neutrophil count > 1 Gi/L, platelets > 100 Gi/L) and had MRD at a level of ≥ 0.1% using an assay with a minimum sensitivity of 0.01%. BLINCYTO was administered at a constant dose of 15 mcg/m²/day (equivalent to the recommended dosage of 28 mcg/day) intravenously for all treatment cycles. Patients received up to 4 cycles of treatment. Dose adjustment was possible in case of adverse events.

The treated population included 86 patients in first or second hematologic complete remission (CR1 or CR2). The demographics and baseline characteristics are shown in Table 14. The median number of treatment cycles was 2 (range: 1 to 4). Following treatment with BLINCYTO, 45 out of 61 (73.8%) patients in CR1 and 14 out of 25 (56.0%) patients in CR2 underwent allogeneic hematopoietic stem cell transplantation in continuous hematologic complete remission.

Table 14. Demographics and Baseline Characteristics in BLAST Study

Characteristics	BLINCYTO (N = 86)
Age
Median, years (min, max)	43 (18, 76)
≥ 65 years, n (%)	10 (12)
Males, n (%)	50 (58)
Race, n (%)
Asian	1 (1)
Other (mixed)	0 (0)
White	76 (88)
Unknown	9 (11)
Philadelphia chromosome disease status, n (%)
Positive	1 (1)
Negative	85 (99)
Relapse history, n (%)
Patients in 1st CR	61 (71)
Patients in 2nd CR	25 (29)
MRD level at baselineAssessed centrally using an assay with minimum sensitivity of 0.01%., n (%)
≥ 10%	7 (8)
≥ 1% and < 10%	34 (40)
≥ 0.1% and < 1%	45 (52)

Efficacy was based on achievement of undetectable MRD within one cycle of BLINCYTO treatment and hematological relapse-free survival (RFS). The assay used to assess MRD response had a sensitivity of 0.01% for 6 patients and ≤ 0.005% for 80 patients. Overall, undetectable MRD was achieved by 70 patients (81.4%: 95% CI: 71.6%, 89.0%). The median hematological RFS was 22.3 months. Table 15 shows the MRD response and hematological RFS by remission number.

Table 15. Efficacy Results in Patients ≥ 18 Years of Age with MRD-positive B-cell Precursor ALL (BLAST Study)

	Patients in CR1 (n = 61)	Patients in CR2 (n = 25)
Complete MRD responseComplete MRD response was defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity of 0.01%, n (%), [95% CI]	52 (85.2) [73.8, 93.0]	18 (72.0) [50.6, 87.9]
Median hematological relapse-free survivalRelapse was defined as either hematological or extramedullary relapse, secondary leukemia, or death due to any cause; Includes time after transplantation; Kaplan-Meier estimate in months (range)	35.2 (0.4, 53.5)	12.3 (0.7, 42.3)

Undetectable MRD was achieved by 65 of 80 patients (81.3%: 95% CI: 71.0%, 89.1%) with an assay sensitivity of at least 0.005%. The estimated median hematological RFS among the 80 patients using the higher sensitivity assay was 24.2 months (95% CI: 17.9, NE).

TOWER Study

The efficacy of BLINCYTO was compared to standard of care (SOC) chemotherapy in a randomized, open-label, multicenter study (TOWER Study) [NCT02013167]. Eligible patients were ≥ 18 years of age with relapsed or refractory B-cell precursor ALL [> 5% blasts in the bone marrow and refractory to primary induction therapy or refractory to last therapy, untreated first relapse with first remission duration < 12 months, untreated second or later relapse, or relapse at any time after allogeneic hematopoietic stem cell transplantation (alloHSCT)]. BLINCYTO was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for Cycles 2-5 in 42-day cycles and for Cycles 6-9 in 84-day cycles. Dose adjustment was possible in case of adverse events. SOC chemotherapy included fludarabine, cytarabine arabinoside, and granulocyte colony-stimulating factor (FLAG); high-dose cytarabine arabinoside (HiDAC); high-dose methotrexate- (HDMTX) based combination; or clofarabine/clofarabine-based regimens.

There were 405 patients randomized 2:1 to receive BLINCYTO or investigator-selected SOC chemotherapy. Randomization was stratified by age (< 35 years vs. ≥ 35 years of age), prior salvage therapy (yes vs. no), and prior alloHSCT (yes vs. no) as assessed at the time of consent. The demographics and baseline characteristics were well-balanced between the two arms (see Table 16).

Table 16. Demographics and Baseline Characteristics in TOWER Study

Characteristics	BLINCYTO (N = 271)	Standard of Care (SOC) Chemotherapy (N = 134)
Age
Median, years (min, max)	37 (18, 80)	37 (18, 78)
< 35 years, n (%)	124 (46)	60 (45)
≥ 35 years, n (%)	147 (54)	74 (55)
≥ 65 years, n (%)	33 (12)	15 (11)
≥ 75 years, n (%)	10 (4)	2 (2)
Males, n (%)	162 (60)	77 (58)
Race, n (%)
American Indian or Alaska Native	4 (2)	1 (1)
Asian	19 (7)	9 (7)
Black (or African American)	5 (2)	3 (2)
Multiple	2 (1)	0
Native Hawaiian or Other Pacific Islander	1 (0)	1 (1)
Other	12 (4)	8 (6)
White	228 (84)	112 (84)
Prior salvage therapy	171 (63)	70 (52)
Prior alloHSCTalloHSCT = allogeneic hematopoietic stem cell transplantation.	94 (35)	46 (34)
Eastern Cooperative Group Status - n (%)
0	96 (35)	52 (39)
1	134 (49)	61 (46)
2	41 (15)	20 (15)
Unknown	0	1 (1)
Refractory to salvage treatment - n (%)
Yes	87 (32)	34 (25)
No	182 (67)	99 (74)
Unknown	2 (1)	1 (1)
Maximum of central/local bone marrow blasts - n (%)
≤ 5%	0	0
> 5 to < 10%	9 (3)	7 (5)
10 to < 50%	60 (22)	23 (17)
≥ 50%	201 (74)	104 (78)
Unknown	1 (0)	0

Of the 271 patients randomized to the BLINCYTO arm, 267 patients received BLINCYTO treatment. The median number of treatment cycles was two (range: 1 to 9 cycles); 267 (99%) received Cycles 1-2 (induction), 86 (32%) received Cycles 3-5 (consolidation), and 27 (10%) received Cycles 6-9 (continued therapy). Of the 134 patients on the SOC arm, 25 dropped out prior to start of study treatment, and 109 patients received a median of 1 treatment cycle (range: 1 to 4 cycles).

The determination of efficacy was based on overall survival (OS). The study demonstrated statistically significant improvement in OS for patients treated with BLINCYTO as compared to SOC chemotherapy.

See Figure 1 and Table 17 below for efficacy results from the TOWER Study.

Figure 1. Kaplan-Meier Curve of Overall Survival in TOWER Study

Figure 1

Table 17. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Negative Relapsed or Refractory B-cell Precursor ALL (TOWER Study)

	BLINCYTO (N = 271)	SOC Chemotherapy (N = 134)
Overall Survival
Number of deaths (%)	164 (61)	87 (65)
Median, months [95% CI]	7.7 [5.6, 9.6]	4.0 [2.9, 5.3]
Hazard Ratio [95% CI]Based on stratified Cox's model.	0.71 [0.55, 0.93]
p-valueThe p-value was derived using stratified log rank test.	0.012
Overall Response
CRCR (complete remission) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter)./CRh*CRh* (complete remission with partial hematologic recovery) was defined as ≤ 5% blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter)., n (%) [95% CI]	115 (42) [37, 49]	27 (20) [14, 28]
Treatment difference [95% CI]	22 [13, 31]
p-valueThe p-value was derived using Cochran-Mantel-Haenszel test.	< 0.001
CR, n (%) [95% CI]	91 (34) [28, 40]	21 (16) [10, 23]
Treatment difference [95% CI]	18 [10, 26]
p-value	< 0.001
MRD Response MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry < 1 × 10-4 (0.01%). for CR/CRh*
n1/n2 (%)n1: number of patients who achieved MRD response and CR/CRh*; n2: number of patients who achieved CR/CRh* and had a postbaseline assessment. [95% CI]	73/115 (64) [54, 72]	14/27 (52) [32, 71]

Study MT103-211

Study MT103-211 [NCT01466179] was an open-label, multicenter, single-arm study. 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 within 12 months of alloHSCT, and had ≥ 10% blasts in bone marrow).

BLINCYTO was administered as a continuous intravenous infusion. The recommended dose for this study was determined to be 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. The treated population included 185 patients who received at least 1 infusion of BLINCYTO; the median number of treatment cycles was 2 (range: 1 to 5). Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO. Among treated patients, the median age was 39 years (range: 18 to 79 years), 63 out of 185 (34.1%) had undergone HSCT prior to receiving BLINCYTO, and 32 out of 185 (17.3%) had received more than 2 prior salvage therapies.

Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with BLINCYTO. Table 18 shows the efficacy results from this study. The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77).

Table 18. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Negative Relapsed or Refractory B-cell Precursor ALL (Study MT103-211)

	N = 185
	CRCR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter).	CRh*CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter).	CR/CRh*
n (%) [95% CI]	60 (32.4) [25.7, 39.7]	17 (9.2) [5.4, 14.3]	77 (41.6) [34.4, 49.1]
MRD responseMRD (minimal residual disease) response was defined as MRD by PCR < 1 × 10-4 (0.01%).
n1/n2 (%)n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. Six CR/CRh* responders with missing MRD data were considered as MRD-nonresponders. [95% CI]	48/60 (80.0) [67.7, 89.2]	10/17 (58.8) [32.9, 81.6]	58/77 (75.3) [64.2, 84.4]
DOR/RFSDOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. Relapse was defined as hematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse.
Median (months) (range)	6.7 (0.46 – 16.5)	5.0 (0.13 – 8.8)	5.9 (0.13 – 16.5)

ALCANTARA Study

The efficacy of BLINCYTO for treatment of Philadelphia chromosome-positive B-cell precursor ALL was evaluated in an open-label, multicenter, single-arm study (ALCANTARA Study) [NCT02000427]. Eligible patients were ≥ 18 years of age with Philadelphia chromosome-positive B-cell precursor ALL, relapsed or refractory to at least 1 second generation or later tyrosine kinase inhibitor (TKI), or intolerant to second generation TKI, and intolerant or refractory to imatinib mesylate.

BLINCYTO was administered at 9 mcg/day on Days 1-7 and 28 mcg/day on Days 8-28 for Cycle 1, and 28 mcg/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events.

The treated population included 45 patients who received at least one infusion of BLINCYTO; the median number of treatment cycles was 2 (range: 1 to 5). The demographics and baseline characteristics are shown in Table 19.

Table 19. Demographics and Baseline Characteristics in ALCANTARA Study

Characteristics	BLINCYTO (N = 45)
Age
Median, years (min, max)	55 (23, 78)
≥ 65 years and < 75 years, n (%)	10 (22)
≥ 75 years, n (%)	2 (4)
Males, n (%)	24 (53)
Race, n (%)
Asian	1 (2)
Black (or African American)	3 (7)
Other	2 (4)
White	39 (87)
Disease History
Prior TKI treatmentNumber of patients that failed ponatinib = 23 (51%), n (%)
1	7 (16)
2	21 (47)
≥ 3	17 (38)
Prior salvage therapy	31 (62)
Prior alloHSCTalloHSCT = allogeneic hematopoietic stem cell transplantation	20 (44)
Bone marrow blastscentrally assessed
≥ 50% to < 75%	6 (13)
≥ 75%	28 (62)

Efficacy was based on the complete remission (CR) rate, duration of CR, and proportion of patients with an MRD-negative CR/CR with partial hematological recovery (CR/CRh*) within 2 cycles of treatment with BLINCYTO. Table 20 shows the efficacy results from ALCANTARA Study. Five of the 16 responding (31%) patients underwent allogeneic HSCT in CR/CRh* induced with BLINCYTO. There were 10 patients with documented T315I mutation; four achieved CR within 2 cycles of treatment with BLINCYTO.

Table 20. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Positive Relapsed or Refractory B-cell Precursor ALL (ALCANTARA Study)

	N = 45
	CRCR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter).	CRh*CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter).	CR/CRh*
n (%) [95% CI]	14 (31) [18, 47]	2 (4) [1, 15]	16 (36) [22, 51]
MRD responseMRD (minimal residual disease) response was defined as MRD by PCR < 1 × 10-4 (0.01%).
n1/n2 (%)n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. Six CR/CRh* responders with missing MRD data were considered as MRD-nonresponders. [95% CI]	12/14 (86) [57, 98]	2/2 (100) [16, 100]	14/16 (88) [62, 98]
DOR/RFSDOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. Relapse was defined as hematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse.
Median (months) (range)	6.7 (3.6 – 12.0)	NENE = not estimable (3.7 – 9.0)	6.7 (3.6 – 12.0)

Study MT103-205

Study MT103-205 [NCT01471782] was an open-label, multicenter, single-arm study in pediatric patients with relapsed or refractory B-cell precursor ALL (second or later bone marrow relapse, any marrow relapse after allogeneic HSCT, or refractory to other treatments, and had > 25% blasts in bone marrow). BLINCYTO was administered at 5 mcg/m²/day on Days 1-7 and 15 mcg/m²/day on Days 8-28 for Cycle 1, and 15 mcg/m²/day on Days 1-28 for subsequent cycles. Dose adjustment was possible in case of adverse events. Patients who responded to BLINCYTO but later relapsed had the option to be retreated with BLINCYTO.

Among the 70 treated patients, the median age was 8 years (range: 7 months to 17 years), 40 out of 70 (57.1%) had undergone allogeneic HSCT prior to receiving BLINCYTO, and 39 out of 70 (55.7%) had refractory disease. The median number of treatment cycles was 1 (range: 1 to 5).

Twenty-three out of 70 (32.9%) patients achieved CR/CRh* within the first 2 treatment cycles with 17 out of 23 (73.9%) occurring within Cycle 1 of treatment. See Table 21 for the efficacy results from the study. The HSCT rate among those who achieved CR/CRh* was 48% (11 out of 23).

Table 21. Efficacy Results in Patients < 18 Years of Age with Relapsed or Refractory B-cell Precursor ALL (Study MT103-205)

	N = 70
	CRCR (complete remission) was defined as ≤ 5% of blasts in the bone marrow, no evidence of circulating blasts or extra-medullary disease, and full recovery of peripheral blood counts (platelets > 100,000/microliter and absolute neutrophil counts [ANC] > 1,000/microliter).	CRh*CRh* (complete remission with partial hematological recovery) was defined as ≤ 5% of blasts in the bone marrow, no evidence of circulating blasts or extramedullary disease, and partial recovery of peripheral blood counts (platelets > 50,000/microliter and ANC > 500/microliter).	CR/CRh*
n (%) [95% CI]	12 (17.1) [9.2, 28.0]	11 (15.7) [8.1, 26.4]	23 (32.9) [22.1, 45.1]
MRD responseMRD (minimal residual disease) response was defined as MRD by PCR or flow cytometry < 1 × 10-4 (0.01%).
n1/n2 (%)n1: number of patients who achieved MRD response and the respective remission status; n2: number of patients who achieved the respective remission status. One CR/CRh* responder with missing MRD data was considered as a MRD-nonresponder. [95% CI]	6/12 (50.0) [21.1, 78.9]	4/11 (36.4) [10.9, 69.2]	10/23 (43.5) [23.2, 65.5]
DOR/RFSDOR (duration of response)/RFS (relapse-free survival) was defined as time since first response of CR or CRh* to relapse or death, whichever is earlier. Relapse was defined as hematological relapse (blasts in bone marrow greater than 5% following CR) or an extramedullary relapse.
Median (months) (range)	6.0 (0.5 – 12.1)	3.5 (0.5 – 16.4)	6.0 (0.5 – 16.4)

Study E1910

The efficacy of BLINCYTO was evaluated in a randomized, controlled study in adult patients with newly diagnosed Philadelphia chromosome-negative B-cell precursor ALL (Study E1910) [NCT02003222]. Eligible patients in hematologic complete remission (CR) or CR with incomplete peripheral blood count recovery (CRi) following induction and intensification chemotherapy were randomized 1:1 to receive a consolidation regimen comprised of multiple cycles of BLINCYTO monotherapy in addition to multiple cycles of intensive chemotherapy (BLINCYTO arm) or to intensive chemotherapy alone (chemotherapy arm). Randomization was stratified by age (< 55 years versus ≥ 55 years), CD20 status, rituximab use, and intent to undergo allogeneic stem cell transplantation (HSCT).

The postremission treatment consisted of a BFM-like chemotherapy regimen adapted from the E2993/UKALLXII clinical trial. Patients randomized to the BLINCYTO arm were to receive 2 cycles of BLINCYTO followed by 3 cycles of consolidation chemotherapy, then a third cycle of BLINCYTO followed by the fourth cycle of chemotherapy and a fourth cycle of BLINCYTO (total 8 cycles). BLINCYTO was administered as a continuous intravenous infusion at 28 mcg/day on Days 1-28. Patients randomized to the chemotherapy arm of the study were to receive 4 cycles of chemotherapy alone (total 4 cycles). Patients on the BLINCYTO arm could go to HSCT after 1 - 2 cycles of BLINCYTO and up to 2 cycles of consolidation chemotherapy, and patients randomized to the chemotherapy arm could go to HSCT after intensification and up to 3 cycles of consolidation chemotherapy. All patients who completed consolidation but did not go to HSCT received maintenance therapy through 2 1/2 years from the start of intensification.

The demographics and baseline characteristics are provided in Table 22.

Table 22. Demographics and Baseline Characteristics in Study E1910

Characteristic	Consolidation Consisting of
	BLINCYTO Cycles + Chemotherapy Cycles (n=112)	Chemotherapy Cycles Alone (n=112)
Age
Median, years (min, max)	52 (31, 69)	50 (30, 70)
Males, n (%)	55 (49)	56 (50)
Race, n (%)
American Indian or Alaska Native	2 (2)	1 (1)
Asian	3 (3)	2 (2)
Black (or African American)	9 (8)	4 (4)
Native Hawaiian or Other Pacific Islander	1 (1)	0
White	87 (78)	89 (79)
Not Reported	5 (4)	6 (5)
Unknown	5 (4)	10 (9)
Ethnicity, n (%)
Hispanic or Latino	13 (12)	10 (9)
Not Hispanic or Latino	95 (85)	95 (85)
Not Reported	1 (1)	2 (2)
Unknown	3 (3)	5 (4)
Stratification Factors, n (%)
Age < 55 years at randomization	65 (58)	65 (58)
CD20 positive	45 (40)	46 (41)
Rituximab use	33 (29)	36 (32)
Planned allogeneic SCTallogeneic SCT = allogeneic stem cell transplantation.	36 (32)	35 (31)

Efficacy was established on the basis of overall survival (OS). The results with a median follow-up of 3.6 years are shown in Figure 2 and Table 23.

Figure 2. Kaplan-Meier for Overall Survival in Study E1910

KM = Kaplan-Meier. CI = Confidence Interval. N = Number of patients in the analysis set. Censor indicated by vertical bar.

Figure 2

Table 23. Overall Survival in Study E1910

	BLINCYTO + Chemotherapy	Chemotherapy
CI = Confidence interval. Overall survival (OS) is calculated from time of randomization until death due to any cause.
Number of patients	112	112
Overall Survival
3-year Kaplan-Meier estimate (%) [95% CI]	84.8 [76.3, 90.4]	69.0 [58.7, 77.2]
Hazard ratio [95% CI]The hazard ratio estimates are obtained from a stratified Cox regression model at the 3rd interim analysis.	0.42 [0.24, 0.75]
p-valueThe p-value was derived using the stratified log rank test.	0.003

In a later analysis with a median follow-up of 4.5 years, the 5-year OS was 82.4 % [95% CI (73.7, 88.4)] in the BLINCYTO + chemotherapy arm and 62.5 % [95% CI (52.0, 71.3)] in the chemotherapy arm. The hazard ratio was 0.44 [95% CI (0.25, 0.76)].

Study 20120215

The efficacy of BLINCYTO compared to consolidation chemotherapy was evaluated in a randomized, controlled, open-label, multicenter study (Study 20120215) [NCT02393859]. Eligible patients were 28 days to 18 years old and had high-risk, first-relapsed, Philadelphia chromosome-negative B-cell precursor ALL with < 25% blasts in the bone marrow after induction and 2 cycles of consolidation chemotherapy. Patients were randomized 1:1 to receive BLINCYTO or the IntReALLHR2010 HC3 intensive combination chemotherapy as the third cycle of consolidation. Patients in the BLINCYTO arm received one cycle of BLINCYTO as a continuous intravenous infusion at 15 mcg/m²/day over 4 weeks (maximum daily dose was not to exceed 28 mcg/day). Randomization was stratified by age, minimal residual disease status determined at the end of induction based on local assessment, and bone marrow status determined at the end of the second block of consolidation chemotherapy. Patients were to proceed to HSCT after this cycle of consolidation.

There were 54 patients randomized to the BLINCYTO arm and 57 to the chemotherapy arm. The demographics and baseline characteristics are shown in Table 24.

Table 24. Demographics and Baseline Characteristics in Study 20120215

Characteristics	Consolidation Cycle 3
	BLINCYTO (N = 54)	Chemotherapy (N = 57)
N = number of patients in the analysis set; n = number of patients with observed data; MRD = minimal residual disease; PCR = polymerase chain reaction.
Age, n (%)
Median, (range)	6 (1, 17)	5 (1, 17)
< 1 year	0	0
1 to 9 years	39 (72)	41 (72)
≥ 10 to 18 years	15 (28)	16 (28)
Males, n (%)	30 (56)	23 (40)
Race, n (%)
American Indian or Alaska Native	0	0
Asian	1 (2)	3 (5)
Black (or African American)	0	3 (5)
Native Hawaiian or Other Pacific Islander	0	0
Other	3 (6)	5 (9)
White	50 (93)	46 (81)
Cytomorphology at randomization, n (%)
Blasts < 5%	54 (100)	54 (95)
Blasts ≥ 5% and < 25%	0	2 (4)
Blasts ≥ 25% blasts	0	0
Not evaluable	0	1 (2)
MRD PCR value at randomization, n (%)
≥ 10-3	11 (20)	16 (28)
< 10-3 and ≥ 10-4	15 (28)	6 (11)
< 10-4	20 (37)	23 (40)
Unknown	8 (15)	12 (21)
Time from first diagnosis to relapse (month), n (%)
< 18 months	19 (35)	22 (39)
≥ 18 months and ≤ 30 months	32 (59)	31 (54)
> 30 months	3 (6)	4 (7)

Efficacy was established on the basis of overall survival (OS) and relapse-free survival (RFS). See Table 25, Figure 3, and Figure 4 for results of OS and RFS from Study 20120215.

Table 25. Efficacy Results in Pediatric Patients with High-Risk First Relapsed B-cell Precursor ALL (Study 20120215)

	Consolidation Cycle 3
	BLINCYTO (N = 54)	Chemotherapy (N = 57)
NE = Not estimable. CI = Confidence interval.
Overall Survival
Number of deaths (%)	11 (20.4)	28 (49.1)
5-year KM estimate (%) [95% CI]Months were calculated as days from randomization date to event/censor date, divided by 30.5.	78.4 [64.2, 87.4]	41.4 [26.3, 55.9]
Hazard Ratio [95% CI]The hazard ratio estimates are obtained from the Cox proportional hazard model.	0.35 [0.17, 0.70]
Relapse-free Survival
Events, n (%)	20 (37.0)	37 (64.9)
5-year KM estimate (%) [95% CI]	61.1 [46.3, 72.9]	27.6 [16.2, 40.3]
Hazard Ratio [95% CI]	0.38 [0.22, 0.66]

The median follow-up time for OS was 55.2 months for the overall population. Figure 3 presents a Kaplan-Meier plot comparing OS between treatment arms for the overall population.

Figure 3. Kaplan-Meier for Overall Survival (Study 20120215)

KM = Kaplan-Meier. CI = Confidence Interval. N = Number of patients in the analysis set. Censor indicated by vertical bar.

Figure 3

Figure 4. Kaplan-Meier for Relapse-free Survival (Study 20120215)

KM = Kaplan-Meier. CI = Confidence Interval. N = Number of patients in the analysis set. Censor indicated by vertical bar.

Figure 4