Confirmatory Phase II Study of Blinatumomab (MT103) in Patients With Minimal Residual Disease of B-precursor Acute Lymphoblastic Leukemia (ALL)

At the end of the first treatment cycle (Day 29) a bone marrow aspiration/biopsy was performed and evaluated by the central MRD laboratory. Complete MRD response is defined as no polymerase chain reaction (PCR) amplification of individual rearrangements of immunoglobulin (Ig)- or T-cell receptor (TCR)-genes detected after completion of the first cycle.

Time frame: During the first cycle (6 weeks)

Population: Primary endpoint full analysis set (Prim EP FAS) included all participants with an Ig TCR PCR MRD assay with the minimum required sensitivity of 1 x 10\^-4 at central lab established at Baseline.

The mortality rate within 100 days after allogeneic HSCT was defined as the Kaplan-Meier estimate of the percentage of participants dying within 100 days after the day of the first allogeneic HSCT.

Time frame: 100 days after HSCT, as of the data cut-off date of 05 August 2015

Population: Full analysis set participants who underwent HSCT prior to relapse (hematological or extramedullary) excluding Philadelphia-positive participants

The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) is a 30-question tool used to assess the overall quality of life in cancer patients. It consists of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, Role, Cognitive, Emotional, Social), and 9 symptom scales/items (Fatigue, Nausea and Vomiting, Pain, Dyspnea, Insomnia, Appetite Loss, Constipation, Diarrhea, Financial Impact). For each of these scales, scores range from 0 to 100. For the GHS and 5 functional scales a high score indicates better global health status/functioning and a positive change from baseline indicates improvement. For the 9 symptom scales, a high score indicates a higher level of symptoms, and a negative change from Baseline indicates an improvement in symptoms. The maximum changes from baseline to cycles 1 through 4 and the change from baseline to the end of the core study are reported.

Time frame: Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).

Population: FAS with available data at relevant time points. For maximum change, the change from baseline was calculated using subset of FAS with available data (baseline and post-baseline) at the end of each cycle. The number analyzed are the number of subjects with available data at the time point at which maximum change from baseline was observed.

The EQ-5D is a self-administered questionnaire which captures 3 basic types of information: a descriptive profile (health state index) and the overall health rating using a visual analog scale. The health state index measures mobility, self-care, usual activities, pain/discomfort and anxiety/depression on scales from no problems (score = 1), some problems (score = 2), to extreme problems (score = 3). For each dimension the mean change from baseline was calculated at the end of each treatment cycle and at the end of the core study. The maximum observed change from baseline during cycles 1 to 4 and the change from baseline at the end of the core study are reported for each dimension.

Time frame: Baseline and the end of each treatment cycle (day 29 of each cycle) and 30 days after end of the last infusion (end of the core study, a maximum of 26 weeks).

Population: FAS with available data at relevant time points. For maximum change, the change from baseline was calculated using subset of FAS with available data (baseline and post-baseline) at the end of each cycle. The number analyzed are the number of subjects with available data at the time point at which maximum change from baseline was observed.

MRD level was measured by polymerase chain reaction (PCR) performed on bone marrow and assessed by the central laboratory. An MRD level of 10\^-n corresponds to residual leukemia cells at a frequency of 1 per 10ⁿ bone marrow cells.

Time frame: Baseline and end of cycle 1 (6 weeks)

Population: Full analysis set participants who were in hematological complete remission at treatment start, with no MRD Response in the first treatment cycle, excluding Philadelphia-positive participants.

The duration of MRD response was analyzed as the time from onset of MRD negativity until MRD or hematological relapse or date of last confirmation of negative MRD status. Participants who received chemotherapy or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse were censored at the start of chemotherapy or HSCT, respectively. MRD relapse is defined as the reappearance of individual rearrangements of Ig- or TCR-genes ≥ lower limit of quantification (LLOQ) for at least 1 individual marker measured by an assay with a sensitivity of minimum 10\^-4. Hematological relapse is defined as the unequivocal detection of \> 5% leukemia cells in bone marrow as measured by cytological or microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia.

Time frame: Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.

Population: Full analysis set participants who were in hematological complete remission at treatment start, excluding Philadelphia-positive participants, who had an MRD complete response at cycle 1

Hematological RFS was measured from first dose of blinatumomab until the first assessment of documented relapse (either hematological or extramedullary), secondary leukemia, or death due to any cause. Participants without a documented relapse, or death due to any cause were censored at the time of their last hematological assessment. Participants who received chemotherapy for relapsed or persistent MRD or for any other reason after treatment with blinatumomab, or HSCT after treatment with blinatumomab, before hematological or extramedullary relapse, or death occurred were censored at the start of chemotherapy or HSCT, respectively. Hematological relapse was defined as unequivocal detection of \> 5% leukemia cells in bone marrow as measured by cytological, microscopic assessment, presence of circulating leukemia blasts, or extramedullary leukemia (whichever occurred first). The 18-month Kaplan-Meier estimate of hematological RFS is reported.

Time frame: 18 months, up to the data cut-off date of 05 August 2015

Population: Full analysis set participants who were in hematological complete remission at treatment start, excluding Philadelphia-positive participants.

Adverse events (AEs) were evaluated for severity according to 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, required or prolonged inpatient hospitalization, resulted in persistent or significant incapacity or substantial disruption to conduct normal life functions, was a congenital anomaly or birth defect or was a medically important condition.

Time frame: From the first dose of blinatumomab until 30 days after last dose; the median treatment duration was 55 days.

Population: All participants who received any infusion of blinatumomab.

Overall survival was measured from the first treatment with blinatumomab until death due to any cause. Participants who did not die were censored at their last contact date.

Time frame: Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.

Population: Full analysis set

Time frame: From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months.

Population: Full analysis set

Time frame: From first dose of study drug through the end of follow-up; median (minimum, maximum) time on study was 33.8 (1, 62) months

Population: Full analysis set

Time to hematological relapse was measured from the start of treatment with blinatumomab until hematological or extramedullary relapse. Participants who died or received HSCT or post-blinatumomab chemotherapy after treatment with blinatumomab were censored at their last hematological assessment prior to death or HSCT or post-blinatumomab chemotherapy (whichever occurred first).

Time frame: Until the data cut-off date of 05 August 2015; median time on study was 18.3 months.

Population: Full analysis set participants who were in hematological complete remission at treatment start, excluding Philadelphia-positive participants.