1.1 MRD-positive B-cell Precursor ALL

BLINCYTO is indicated 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% in adult and pediatric patients one month and older.

1.2 Relapsed or Refractory B-cell Precursor ALL

BLINCYTO is indicated for the treatment of relapsed or refractory CD19-positive B-cell precursor acute lymphoblastic leukemia (ALL) in adult and pediatric patients one month and older.

1. 3 B-cell Precursor ALL in the Consolidation Phase

BLINCYTO is indicated for the treatment of CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (ALL) in the consolidation phase of multiphase chemotherapy in adult and pediatric patients one month and older.

2.1 Treatment of MRD-positive B-cell Precursor ALL

• A treatment course consists of 1 cycle of BLINCYTO for induction followed by up to 3 additional cycles for consolidation.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• See Table 1 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose. For patients weighing less than 45 kg, the dose is calculated using the patient's body surface area (BSA).

• Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with prednisone or equivalent for MRD-positive B-cell Precursor ALL:
  • For adult patients, premedicate with prednisone 100 mg intravenously or equivalent (e.g., dexamethasone 16 mg) 1 hour prior to the first dose of BLINCYTO in each cycle.
  • For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
  • See Instructions for Use for infusion over 24 hours or 48 hours.
  • See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg.

2.2 Treatment of Relapsed or Refractory B-cell Precursor ALL

• A treatment course consists of up to 2 cycles of BLINCYTO for induction followed by 3 additional cycles for consolidation and up to 4 additional cycles of continued therapy.
• A single cycle of treatment of BLINCYTO induction or consolidation consists of 28 days of continuous intravenous infusion followed by a 14-day treatment-free interval (total 42 days).
• A single cycle of treatment of BLINCYTO continued therapy consists of 28 days of continuous intravenous infusion followed by a 56-day treatment-free interval (total 84 days).
• See Table 2 for the recommended dose by patient weight and schedule. Patients weighing 45 kg or more receive a fixed-dose and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA.

• Hospitalization is recommended for the first 9 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with dexamethasone:
  • For adult patients, premedicate with 20 mg of dexamethasone intravenously or orally 1 hour prior to the first dose of BLINCYTO of each cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours.
  • For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg, prior to the first dose of BLINCYTO in the first cycle, prior to a step dose (such as Cycle 1 Day 8), and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
  • See Instructions for Use for infusion over 24 hours or 48 hours.
  • See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg.

2.3 Treatment of B-cell Precursor ALL in the Consolidation Phase

• A single cycle of BLINCYTO monotherapy in consolidation is 28 days of continuous infusion followed by a 14-day treatment-free interval (total 42 days) [see Table 3 and Clinical Studies (14.3)].
• Patients weighing 45 kg or more receive a fixed-dose, and for patients weighing less than 45 kg, the dose is calculated using the patient's BSA (see Table 3).

• Hospitalization is recommended for the first 3 days of the first cycle and the first 2 days of the second cycle. For all subsequent cycle starts and re-initiations (e.g., if treatment is interrupted for 4 or more hours), supervision by a healthcare professional or hospitalization is recommended.
• Intrathecal chemotherapy prophylaxis is recommended before and during BLINCYTO therapy to prevent central nervous system ALL relapse.
• Premedicate with dexamethasone:
  • For adult patients, premedicate with dexamethasone 20 mg intravenously within 1 hour prior to the first dose of BLINCYTO of each cycle.
  • For pediatric patients, premedicate with 5 mg/m2 of dexamethasone intravenously or orally, to a maximum dose of 20 mg prior to the first dose of BLINCYTO in the first cycle and when restarting an infusion after an interruption of 4 or more hours in the first cycle.
• For administration of BLINCYTO:
  • See Instructions for Use for infusion over 24 hours or 48 hours.
  • See Instructions for Use for infusion over 72 hours, 96 hours, or 7 days using Bacteriostatic 0.9% Sodium Chloride Injection (containing 0.9% benzyl alcohol). The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg.

2.4 Dosage Modifications for Adverse Reactions

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

2.5 Preparation and Administration of BLINCYTO

It is very important that the instructions for preparation (including admixing) and administration provided in this section are strictly followed to minimize medication errors (including underdose and overdose) [see Warnings and Precautions (5.10)].

BLINCYTO can be infused over 24 hours (preservative-free), 48 hours (preservative-free), 72 hours (with preservative), 96 hours (with preservative), or 7 days (with preservative). The choice between these options for the infusion duration should be made by the treating healthcare provider considering the frequency of the infusion bag changes and the weight of the patient. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg.

For preparation, reconstitution, and administration of BLINCYTO:

The BLINCYTO Instructions for Use contains more detailed instructions on the preparation of infusion [see Instructions for Use].

The preparation steps differ based on the infusion duration. Follow the steps specific to the infusion duration you are preparing.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Call 1-800-77-AMGEN (1-800-772-6436) if you have questions about the reconstitution and preparation of BLINCYTO.

2.6 Storage of Reconstituted BLINCYTO

The information in Table 5 indicates the storage time for the reconstituted BLINCYTO vial and prepared infusion bag.

5.1 Cytokine Release Syndrome

Cytokine Release Syndrome (CRS), which may be life-threatening or fatal, occurred in patients receiving BLINCYTO. The median time to onset of CRS was 2 days after the start of infusion and the median time to resolution of CRS was 5 days among cases that resolved. Manifestations of CRS include fever, headache, nausea, asthenia, hypotension, increased alanine aminotransferase (ALT), increased aspartate aminotransferase (AST), increased total bilirubin, and disseminated intravascular coagulation (DIC). The manifestations of CRS after treatment with BLINCYTO overlap with those of infusion reactions, capillary leak syndrome (CLS), and hemophagocytic histiocytosis/macrophage activation syndrome (MAS). Using all of these terms to define CRS in clinical trials of BLINCYTO, CRS was reported in 15% of patients with relapsed or refractory ALL, in 7% of patients with MRD-positive ALL, and in 16% of patients receiving BLINCYTO cycles in the consolidation phase of therapy [see Adverse Reactions (6.1)].

Monitor patients for signs or symptoms of these events. Advise outpatients on BLINCYTO to contact their healthcare professional for signs and symptoms associated with CRS. If severe CRS occurs, interrupt BLINCYTO until CRS resolves. Discontinue BLINCYTO permanently if life-threatening CRS occurs. Administer corticosteroids for severe or life-threatening CRS [see Dosage and Administration (2.4)].

5.2 Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome

BLINCYTO can cause serious or life-threatening neurologic toxicity, including ICANS [see Adverse Reactions 6.1].

The incidence of neurologic toxicities in clinical trials was approximately 65% [see Adverse Reactions (6.1)]. Among patients that experienced a neurologic toxicity, the median time to the first event was within the first 2 weeks of BLINCYTO treatment. The most common (≥ 10%) manifestations of neurological toxicity were headache, and tremor; the neurological toxicity profile varied by age group [see Use in Specific Populations (8.4, 8.5)]. Grade 3 or higher neurological toxicities following initiation of BLINCYTO administration occurred in approximately 13% of patients and included encephalopathy, convulsions, speech disorders, disturbances in consciousness, confusion and disorientation, and coordination and balance disorders. Manifestations of neurological toxicity included cranial nerve disorders. The majority of neurologic toxicities resolved following interruption of BLINCYTO, but some resulted in treatment discontinuation.

The incidence of signs and symptoms consistent with ICANS in clinical trials was 7.5%. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

There is limited experience with BLINCYTO in patients with active ALL in the central nervous system (CNS) or a history of neurologic events. Patients with a history or presence of clinically relevant CNS pathology were excluded from clinical studies. Patients with Down Syndrome may have a higher risk of seizures with BLINCYTO therapy.

Monitor patients receiving BLINCYTO for signs and symptoms of neurological toxicities, including ICANS. Advise outpatients on BLINCYTO to contact their healthcare professional if they develop signs or symptoms of neurological toxicities. Management of neurologic toxicity may require interruption or discontinuation of BLINCYTO as recommended and/or treatment with corticosteroids [see Dosage and Administration (2.4)].

5.3 Infections

In patients with ALL receiving BLINCYTO in clinical studies, serious infections such as sepsis, pneumonia, bacteremia, opportunistic infections, and catheter-site infections were observed in approximately 25% of patients, some of which were life-threatening or fatal [see Adverse Reactions (6.1)]. As appropriate, administer prophylactic antibiotics and employ surveillance testing during treatment with BLINCYTO. Monitor patients for signs and symptoms of infection and treat appropriately.

5.4 Tumor Lysis Syndrome

Tumor lysis syndrome (TLS), which may be life-threatening or fatal, has been observed in patients receiving BLINCYTO [see Adverse Reactions (6.1)]. Appropriate prophylactic measures, including pretreatment nontoxic cytoreduction and on-treatment hydration, should be used for the prevention of TLS during BLINCYTO treatment. Monitor for signs or symptoms of TLS. Management of these events may require either temporary interruption or discontinuation of BLINCYTO [see Dosage and Administration (2.4)].

5.5 Neutropenia and Febrile Neutropenia

Neutropenia and febrile neutropenia, including life-threatening cases, have been observed in patients receiving BLINCYTO [see Adverse Reactions (6.1)]. Monitor laboratory parameters (including, but not limited to, white blood cell count and absolute neutrophil count) during BLINCYTO infusion. Interrupt BLINCYTO if prolonged neutropenia occurs.

5.6 Effects on Ability to Drive and Use Machines

Due to the potential for neurologic events, including seizures and ICANS, patients receiving BLINCYTO are at risk for loss of consciousness [see Warnings and Precautions (5.2)]. Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered.

5.7 Elevated Liver Enzymes

Treatment with BLINCYTO was associated with transient elevations in liver enzymes [see Adverse Reactions (6.1)]. In patients with ALL receiving BLINCYTO in clinical studies, the median time to onset of elevated liver enzymes was 3 days.

The majority of these transient elevations in liver enzymes were observed in the setting of CRS. For the events that were observed outside the setting of CRS, the median time to onset was 19 days. Grade 3 or greater elevations in liver enzymes occurred in approximately 7% of patients outside the setting of CRS and resulted in treatment discontinuation in less than 1% of patients.

Monitor alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and total blood bilirubin prior to the start of and during BLINCYTO treatment. Interrupt BLINCYTO if the transaminases rise to greater than 5 times the upper limit of normal or if total bilirubin rises to more than 3 times the upper limit of normal.

5.8 Pancreatitis

Fatal pancreatitis has been reported in patients receiving BLINCYTO in combination with dexamethasone in clinical studies and the postmarketing setting [see Adverse Reactions (6.2)].

Evaluate patients who develop signs and symptoms of pancreatitis. Management of pancreatitis may require either temporary interruption or discontinuation of BLINCYTO and dexamethasone [see Dosage and Administration (2.4)].

5.9 Leukoencephalopathy

Cranial magnetic resonance imaging (MRI) changes showing leukoencephalopathy have been observed in patients receiving BLINCYTO, especially in patients with prior treatment with cranial irradiation and antileukemic chemotherapy (including systemic high-dose methotrexate or intrathecal cytarabine). The clinical significance of these imaging changes is unknown.

5.10 Preparation and Administration Errors

Preparation and administration errors have occurred with BLINCYTO treatment. Follow instructions for preparation (including admixing) and administration strictly to minimize medication errors (including underdose and overdose) [see Dosage and Administration (2.5) and Instructions for Use].

5.11 Immunization

The safety of immunization with live viral vaccines during or following BLINCYTO therapy has not been studied. Vaccination with live virus vaccines is not recommended for at least 2 weeks prior to the start of BLINCYTO treatment, during treatment, and until immune recovery following last cycle of BLINCYTO.

5.12 Benzyl Alcohol Toxicity in Neonates

Serious adverse reactions, including fatal reactions and the "gasping syndrome," have been reported 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) who received intravenous drugs containing benzyl alcohol as a preservative. Early preterm VLBW neonates may be more likely to develop these reactions, because they may be less able to metabolize benzyl alcohol [see Use in Specific Populations (8.4)].

Use the preservative-free preparations of BLINCYTO where possible in neonates. When prescribing BLINCYTO (with preservative) for neonatal patients, consider the combined daily metabolic load of benzyl alcohol from all sources including BLINCYTO (with preservative), other products containing benzyl alcohol or other excipients (e.g., ethanol, propylene glycol) which compete with benzyl alcohol for the same metabolic pathway.

Monitor neonatal patients receiving BLINCYTO (with preservative) for new or worsening metabolic acidosis. The minimum amount of benzyl alcohol at which serious adverse reactions may occur in neonates is not known. The BLINCYTO 72-Hour bag (with preservative) and 96-Hour bag (with preservative) contain 2.5 mg of benzyl alcohol per mL, and the 7-Day bag (with preservative) contains 7.4 mg of benzyl alcohol per mL. The administration of BLINCYTO as a 72-hour, 96-hour, and 7-day infusion is not recommended for patients weighing less than 5.4 kg [see Use in Specific Populations (8.4)].

5.13 Embryo-Fetal Toxicity

Based on its mechanism of action, BLINCYTO may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose [see Use in Specific Populations (8.1, 8.3)].

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The safety of BLINCYTO in adult and pediatric patients one month and older with MRD-positive B-cell precursor ALL (n = 137), relapsed or refractory B-cell precursor ALL (n = 267), and Philadelphia chromosome-negative B-cell precursor ALL in consolidation (n = 165) was evaluated in clinical studies. The most common adverse reactions (≥ 20%) to BLINCYTO in this pooled population were pyrexia, infusion-related reactions, headache, infection, musculoskeletal pain, neutropenia, nausea, anemia, thrombocytopenia, and diarrhea.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of BLINCYTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

• Fatal pancreatitis in patients receiving BLINCYTO in combination with dexamethasone.

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

BLINCYTO may cause fetal harm when administered to a pregnant woman [see Use in Specific Populations (8.1)].

8.4 Pediatric Use

The safety and efficacy of BLINCYTO in pediatric patients less than 1 month of age have not been established for any indication [see Indications and Usage (1)].

8.5 Geriatric Use

There were 158 (7%) patients 65 years and older in clinical studies of BLINCYTO for patients with MRD positive, CD19-positive B-cell precursor ALL in first or second complete remission, relapsed or refractory CD19-positive B-cell precursor ALL, and CD19-positive, Philadelphia-chromosome negative B-cell precursor ALL in the consolidation phase. Of the total number of BLINCYTO-treated patients in these studies, 123 (8%) were 65 years of age and older and 21 (1%) were 75 years of age or older. No overall differences in safety or effectiveness were observed between these patients and younger patients, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. However, elderly patients experienced a higher rate of serious infections and neurological toxicities, including cognitive disorder, encephalopathy, and confusion [see Warnings and Precautions (5.2, 5.3)].

12.1 Mechanism of Action

Blinatumomab is a bispecific CD19-directed CD3 T-cell engager that binds to CD19 expressed on the surface of cells of B-lineage origin and CD3 expressed on the surface of T-cells. It activates endogenous T-cells by connecting CD3 in the T-cell receptor (TCR) complex with CD19 on benign and malignant B-cells. Blinatumomab mediates the formation of a synapse between the T-cell and the tumor cell, upregulation of cell adhesion molecules, production of cytolytic proteins, release of inflammatory cytokines, and proliferation of T-cells, which result in redirected lysis of CD19+ cells.

12.2 Pharmacodynamics

During the continuous intravenous infusion over 4 weeks, the pharmacodynamic response was characterized by T-cell activation and initial redistribution, reduction in peripheral B-cells, and transient cytokine elevation.

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

Peripheral B-cell counts decreased to less than or equal to 10 cells/microliter during the first treatment cycle at doses ≥ 5 mcg/m2/day or ≥ 9 mcg/day in the majority of patients. No recovery of peripheral B-cell counts was observed during the 2-week BLINCYTO-free period between treatment cycles. Incomplete depletion of B-cells occurred at doses of 0.5 mcg/m2/day and 1.5 mcg/m2/day and in a few patients at higher doses.

Cytokines including IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, TNF-α, and IFN-γ were measured, and IL-6, IL-10, and IFN-γ were elevated. The highest elevation of cytokines was observed in the first 2 days following start of BLINCYTO infusion. The elevated cytokine levels returned to baseline within 24 to 48 hours during the infusion. In subsequent treatment cycles, cytokine elevation occurred in fewer patients with lesser intensity compared to the initial 48 hours of the first treatment cycle.

12.3 Pharmacokinetics

The pharmacokinetics of blinatumomab appear linear over a dose range from 5 to 90 mcg/m2/day (approximately equivalent to 9 to 162 mcg/day) in adult patients. Following continuous intravenous infusion, the steady-state serum concentration (Css) was achieved within a day and remained stable over time. The increase in mean Css values was approximately proportional to the dose in the range tested. At the clinical doses of 9 mcg/day and 28 mcg/day for the treatment of relapsed or refractory ALL, the mean (SD) Css was 228 (356) pg/mL and 616 (537) pg/mL, respectively. The pharmacokinetics of blinatumomab in adult patients with MRD-positive B-cell precursor ALL and in adult patients with B-cell precursor ALL in the consolidation phase were similar to adult patients with relapsed or refractory ALL.

12.6 Immunogenicity

The observed incidence of anti-drug antibody is highly dependent on the sensitivity and specificity of the assay. Differences in assay methods preclude meaningful comparisons of the incidence of anti-drug antibody in the studies described below with the incidence of anti-drug antibodies in other studies, including those of BLINCYTO.

The immunogenicity of BLINCYTO has been evaluated using either an electrochemiluminescence detection technology (ECL) or an enzyme-linked immunosorbent assay (ELISA) screening immunoassay for the detection of binding anti-blinatumomab antibodies. For patients whose sera tested positive in the screening immunoassay, an in vitro biological assay was performed to detect neutralizing antibodies.

In clinical studies, less than 2% of patients treated with BLINCYTO tested positive for binding anti-blinatumomab antibodies. Of patients who developed anti-blinatumomab antibodies, 7 out of 9 (78%) had in vitro neutralizing activity. Anti-blinatumomab antibody formation may affect pharmacokinetics of BLINCYTO.

Overall, the totality of clinical evidence supports the finding that anti-blinatumomab antibodies are not suggestive of any clinical impact on the safety or effectiveness of BLINCYTO.

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

No carcinogenicity or genotoxicity studies have been conducted with blinatumomab.

No studies have been conducted to evaluate the effects of blinatumomab on fertility. A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat-dose toxicity study in mice.

14.1 MRD-positive B-cell Precursor ALL

14.2 Relapsed/Refractory B-cell Precursor ALL

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 13).

Table 13. Demographics and Baseline Characteristics in TOWER Study

Characteristics	BLINCYTO (N = 271)	Standard of Care (SOC) Chemotherapy (N = 134)
* alloHSCT = allogeneic hematopoietic stem cell transplantation.
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 alloHSCT*	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 14 below for efficacy results from the TOWER Study.

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

Table 14. 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)
* Based on stratified Cox's model. † The p-value was derived using stratified log rank test. ‡ CR (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* (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). ¶ The p-value was derived using Cochran-Mantel-Haenszel test. # MRD (minimum residual disease) response was defined as MRD by PCR or flow cytometry < 1 × 10-4 (0.01%). Þ n1: number of patients who achieved MRD response and CR/CRh*; n2: number of patients who achieved CR/CRh* and had a postbaseline assessment.
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]*	0.71 [0.55, 0.93]
p-value†	0.012
Overall Response
CR‡/CRh*§, n (%) [95% CI]	115 (42) [37, 49]	27 (20) [14, 28]
Treatment difference [95% CI]	22 [13, 31]
p-value¶	< 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# for CR/CRh*
n1/n2 (%)Þ [95% CI]	73/115 (64) [54, 72]	14/27 (52) [32, 71]

14.3 Philadelphia Chromosome-Negative B-cell Precursor ALL in the Consolidation Phase

Store BLINCYTO and IV Solution Stabilizer vials in the original package refrigerated at 2°C to 8°C (36°F to 46°F) and protect from light until time of use. Do not freeze.

BLINCYTO and IV Solution Stabilizer vials may be stored for a maximum of 8 hours at room temperature [23°C to 27°C (73°F to 81°F)] in the original carton to protect from light.

Cytokine Release Syndrome (CRS)

Advise patients of the risk of CRS and infusion reactions, and to contact their healthcare professional for signs and symptoms associated with CRS or infusion reactions (pyrexia, fatigue, nausea, vomiting, chills, hypotension, rash, and wheezing) [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)].

Neurological Toxicities, including Immune Effector Cell-Associated Neurotoxicity Syndrome

Advise patients of the risk of neurological toxicities, including ICANS, and to contact their healthcare professional for signs and symptoms associated with this event (including convulsions, speech disorders, and confusion) [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)].

Infections

Advise patients of the risk of infections, and to contact their healthcare professional for signs or symptoms of infection [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)].

Inform patients of the importance of keeping the skin clean around the intravenous catheter to reduce the risk of infection.

Pancreatitis

Advise patients of the risk of pancreatitis and to contact their healthcare provider for signs or symptoms of pancreatitis, which include severe and persistent stomach pain, with or without nausea and vomiting [see Warnings and Precautions (5.8) and Adverse Reactions (6.2)].

Driving and Engaging in Hazardous Occupations

Advise patients to refrain from driving and engaging in hazardous occupations or activities such as operating heavy or potentially dangerous machinery while BLINCYTO is being administered. Patients should be advised that they may experience neurological events, including seizures and ICANS [see Warnings and Precautions (5.6)].

Infusion Pump Errors

Inform patients they should not adjust the setting on the infusion pump. Any changes to pump function may result in dosing errors. If there is a problem with the infusion pump or the pump alarms, patients should contact their doctor or nurse immediately.

Embryo-Fetal Toxicity

Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to inform their healthcare provider if they are pregnant or become pregnant [see Warnings and Precautions (5.13) and Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with BLINCYTO and for 48 hours after the last dose [see Warnings and Precautions (5.13) and Use in Specific Populations (8.3)].

Lactation

Advise women not to breastfeed during treatment with BLINCYTO and for 48 hours after the last dose [see Use in Specific Populations (8.2)].