14 CLINICAL STUDIES

14.1 MRD-positive B-cell Precursor ALL

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 11. 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 11. Demographics and Baseline Characteristics in BLAST Study
Characteristics	BLINCYTO (N = 86)
* Assessed centrally using an assay with minimum sensitivity of 0.01%.
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 baseline*, 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 12 shows the MRD response and hematological RFS by remission number.

Table 12. 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 response was defined as the absence of detectable MRD confirmed in an assay with minimum sensitivity of 0.01% † Relapse was defined as either hematological or extramedullary relapse, secondary leukemia, or death due to any cause; Includes time after transplantation; Kaplan-Meier estimate
Complete MRD response*, n (%), [95% CI]	52 (85.2) [73.8, 93.0]	18 (72.0) [50.6, 87.9]
Median hematological relapse-free survival† 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).

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]

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 15 shows the efficacy results from this study. The HSCT rate among those who achieved CR/CRh* was 39% (30 out of 77).

Table 15. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Negative Relapsed or Refractory B-cell Precursor ALL (Study MT103-211)
	N = 185
	CR*	CRh*†	CR/CRh*
* CR (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* (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). ‡ MRD (minimal residual disease) response was defined as MRD by PCR < 1 × 10-4 (0.01%). § 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. ¶ DOR (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.
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 response‡
n1/n2 (%)§ [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/RFS¶
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 16.

Table 16. Demographics and Baseline Characteristics in ALCANTARA Study
Characteristics	BLINCYTO (N = 45)
* Number of patients that failed ponatinib = 23 (51%) † alloHSCT = allogeneic hematopoietic stem cell transplantation ‡ centrally assessed
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 treatment*, n (%)
1	7 (16)
2	21 (47)
≥ 3	17 (38)
Prior salvage therapy	31 (62)
Prior alloHSCT†	20 (44)
Bone marrow blasts‡
≥ 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 17 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 17. Efficacy Results in Patients ≥ 18 Years of Age with Philadelphia Chromosome-Positive Relapsed or Refractory B-cell Precursor ALL (ALCANTARA Study)
	N = 45
	CR*	CRh*†	CR/CRh*
* CR (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* (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). ‡ MRD (minimal residual disease) response was defined as MRD by PCR < 1 × 10-4 (0.01%). § 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. ¶ DOR (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. # NE = not estimable
n (%) [95% CI]	14 (31) [18, 47]	2 (4) [1, 15]	16 (36) [22, 51]
MRD response‡
n1/n2 (%)§ [95% CI]	12/14 (86) [57, 98]	2/2 (100) [16, 100]	14/16 (88) [62, 98]
DOR/RFS¶
Median (months) (range)	6.7 (3.6 – 12.0)	NE# (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 18 for the efficacy results from the study. The HSCT rate among those who achieved CR/CRh* was 48% (11 out of 23).

Table 18. Efficacy Results in Patients < 18 Years of Age with Relapsed or Refractory B-cell Precursor ALL (Study MT103-205)
	N = 70
	CR*	CRh*†	CR/CRh*
* CR (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* (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). ‡ MRD (minimal residual disease) response was defined as MRD by PCR or flow cytometry < 1 × 10-4 (0.01%). § 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. ¶ DOR (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.
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 response‡
n1/n2 (%)§ [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/RFS¶
Median (months) (range)	6.0 (0.5 – 12.1)	3.5 (0.5 – 16.4)	6.0 (0.5 – 16.4)

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

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 19.

Table 19. Demographics and Baseline Characteristics in Study E1910
Characteristics	Consolidation Consisting of
Characteristics	BLINCYTO Cycles + Chemotherapy Cycles (n = 112)	Chemotherapy Cycles Alone (n = 112)
* allogeneic SCT = allogeneic stem cell transplantation.
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 SCT*	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 20.

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.

Table 20. 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.
* The hazard ratio estimates are obtained from a stratified Cox regression model at the 3rd interim analysis. † The p-value was derived using the stratified log rank test.
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]*	0.42 [0.24, 0.75]
p-value†	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 21.

Table 21. Demographics and Baseline Characteristics in Study 20120215
Characteristics	Consolidation Cycle 3
Characteristics	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 22, Figure 3, and Figure 4 for results of OS and RFS from Study 20120215.

Table 22. 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.
* Months were calculated as days from randomization date to event/censor date, divided by 30.5. † The hazard ratio estimates are obtained from the Cox proportional hazard model.
Overall Survival
Number of deaths (%)	11 (20.4)	28 (49.1)
5-year KM estimate (%) [95% CI]*	78.4 [64.2, 87.4]	41.4 [26.3, 55.9]
Hazard Ratio [95% CI]†	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 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.