Clinical Study With Blinatumomab in Patients With Relapsed/Refractory B-precursor Acute Lymphoblastic Leukemia (ALL)

Time to hematological relapse was measured for participants in remission during the core study (the time from the first infusion through 30 days after the last infusion), from the time the participant first achieved remission until first documented relapse or death due to disease progression. Participants without documented relapse (hematological or extramedullary) and who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission. Participants who died without having reported hematological relapse or without showing any clinical sign of disease progression were censored on their date of death.

Hematological relapse is defined as:

• proportion of blasts in bone marrow > 5% after documented CR/CRh* or
• blasts in peripheral blood after documented CR/CRh*.

Time to hematological relapse was analyzed by Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.

Participants who were eligible for allogeneic HSCT were those who achieved remission (complete response or complete response with partial recovery of peripheral blood counts) after 2 cycles of blinatumomab treatment, and no further anti-leukemic medication was given before HSCT.

Complete Remission was defined by the following criteria:

• bone marrow blasts ≤ 5%
• no evidence of disease
• full recovery of peripheral blood counts:
• platelets > 100,000/μL, and
• absolute neutrophil count (ANC) > 1,000/μL

Complete Remission With Partial Hematological Recovery was defined by the following criteria:

• bone marrow blasts ≤ 5%
• no evidence of disease
• partial recovery of peripheral blood counts:
• platelets > 50,000/μL, and
• ANC > 500/μL.

Partial Remission is defined as bone marrow blasts 6% to 25% with at least a 50% reduction from baseline.

Relapse-free survival was assessed for participants who achieved a complete remission or complete remission with partial hematological recovery during the core study and was measured from the time the participant first achieved remission until first documented relapse or death due to any cause. Participants without a documented relapse (hematological or extramedullary) or who did not die were censored at the time of their last bone marrow assessment or their last survival follow-up visit confirming remission.

Relapse free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.

Event-free survival was calculated from the start date of blinatumomab infusion until the date of bone marrow aspiration at which hematological relapse was first detected, or the date of diagnosis on which the hematological or extramedullary relapse was documented or the date of start of any new therapy for ALL (excluding HSCT), or the date of death, whichever was earlier. Participants who did not achieve complete remission or complete remission with partial hematological recovery during the core study were evaluated as having an event on Day 1. Participants in remission who did not experience hematological relapse, did not receive a new therapy for ALL (excluding HSCT), and did not die were censored on the date of the last available bone marrow aspiration or on the last date of survival follow-up visit, whichever was later.

Event free survival was estimated using Kaplan-Meier methods and the median observation time was calculated by the reverse Kaplan Meier method.

Overall survival was measured for all participants from the time the participant received the first treatment of blinatumomab until death due to any cause or the date of the last follow-up. Participants who did not die were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive. Overall survival was estimated using Kaplan-Meier methods. The median follow-up time with respect to overall survival was calculated by the reverse Kaplan Meier method.

Adverse events (AEs) were evaluated for severity according to the the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4, as follows: Grade 1 - Mild AE; Grade 2 - Moderate AE; Grade 3 - Severe AE; Grade 4 - Life-threatening or disabling AE; Grade 5 - Death.

The investigator used medical judgment to determine if there was a causal relationship (ie, related, unrelated) between an adverse event and blinatumomab.

An AE was considered "serious" if it resulted in death, was life-threatening, requires or prolongs inpatient hospitalization, results in persistent or significant incapacity or substantial disruption to conduct normal life functions, is a congenital anomaly or birth defect or is a medically important condition.

Progressive disease was not an adverse event, per the protocol, unless it was more severe than expected for the patient. Therefore, many deaths due to progressive disease were not counted as adverse events.

The analysis of 100-day mortality after allogeneic HSCT was assessed for all participants who received an allogeneic HSCT while in remission (CR/CRh*) following treatment with blinatumomab. 100-day mortality after allogeneic HSCT was calculated relative to the date of allogeneic HSCT.

Patients alive were censored on the last documented visit date or the date of the last phone contact when the patient was last known to have been alive.

The 100-day mortality rate after allogeneic HSCT was defined as the percentage of patients having died up to 100 days after allogeneic HSCT estimated using the estimated time to death in percent calculated by Kaplan-Meier methods.

The steady state concentration of blinatumomab was summarized as the observed concentrations collected at least 10 hours after the start of the IV infusion or dose step for cycle 1 and cycle 2, respectively. Serum concentrations of blinatumomab were measured using a validated bioassay. The lower limit of quantitation (LLOQ) = 50.0 pg/mL.

The activation of immune effector cells was monitored by the measurement of peripheral blood cytokine levels including interleukin (IL)-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α and interferon gamma (IFN)-γ using enzyme-linked immunosorbent assays or cytometric bead assays. The limit of detection of the assay (LOD) was 20 pg/mL and the limit of quantification (LOQ) was 125 pg/mL. Data below LOD were set to 10 pg/mL while data < LOQ and > LOD were reported as measured.

Serum IL-4 levels were below detection limit (< 20 pg/mL) at all time points in all participants studied.

Blast Free Hypoplastic or Aplastic Bone Marrow was defined as:

• bone marrow blasts ≤ 5%
• no evidence of disease
• insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or absolute neutrophil count (ANC) ≤ 500/μL

Complete Remission (CR):

• bone marrow blasts ≤ 5%
• no evidence of disease
• full recovery of peripheral blood counts:
• platelets > 100,000/μL, and
• absolute neutrophil count (ANC) > 1,000/μL

Complete Remission With Partial Hematological Recovery (CRh*):

• bone marrow blasts ≤ 5%
• no evidence of disease
• partial recovery of peripheral blood counts:
• platelets > 50,000/μL, and
• ANC > 500/μL

Blast Free Hypoplastic or Aplastic Bone Marrow:

• bone marrow blasts ≤ 5%
• no evidence of disease
• insufficient recovery of peripheral counts: platelets ≤ 50,000/μL and/or ANC ≤ 500/μL

Partial Remission:

• bone marrow blasts 6% to 25% with at least a 50% reduction from Baseline.