Phase I/Phase II Study of Blinatumomab in Pediatric Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia

TL;DR: This trial, which to the best of the authors' knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL.

Abstract: Purpose Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lymphoblasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Methods This open-label study enrolled children < 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles (phase II). Results We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was 15 µg/m2/d. Blinatumomab pharmacokinetics was linear across dosage levels and consistent among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 µg/m2/d for the first 7 days, followed by 15 µg/m2/d thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27% to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved complete minimal residual disease response. The most frequent grade ≥ 3 adverse events were anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%) interrupted treatment after grade 2 seizures. Conclusion This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated antileukemic activity of single-agent blinatumomab with complete minimal residual disease response in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.

Summary

INTRODUCTION

• Acute lymphoblastic leukemia (ALL) is the most common malignant disease in children, with an annual incidence of approximately three cases per 100,000 persons.
• 4, 5 Children with second or greater relapse or refractory disease have a dismal prognosis even when treated with intensive combination chemotherapy and allogeneic hematopoietic stem-cell transplantation .
• Immunotherapy constitutes an important new antileukemic treatment strategy.
• 10 Blinatumomab is a bispecific T-cell engager (BiTE) antibody construct that directs CD3-positive effector memory T cells to CD19-positive target cells, triggering cell death.
• 11, 12 In a large phase II study in adults with relapsed/refractory BCP-ALL, the response rate after single-agent blinatumomab treatment was 43%.

Patients

• The disease was primary refractory, in first relapse after full salvage induction regimen, in second or later relapse, or in any relapse after alloHSCT.
• Patients with Philadelphia chromosomepositive ALL were eligible; those with active acute or extensive chronic graft-versus-host disease after HSCT, or active CNS or testicular involvement, were excluded.
• Further eligibility criteria are available in the study protocol (Data Supplement).
• Each center's institutional review board or an independent ethics committee approved the study protocol.
• The patients' legal representatives gave written informed consent.

Study Design and Assessments

• The study included a dosage-finding phase I part and a phase II part evaluating safety and efficacy at the recommended dosage proposed by an independent Data Safety Monitoring Board (DSMB) on the basis of the dosage-finding part.
• After determining the recommended dosage (stepwise 5/15 mg/m 2 /d), the authors treated additional patients to further assess pharmacokinetics and safety across three age groups ( Patients received blinatumomab as a 4-week continuous intravenous infusion, followed by a 2-week treatment-free interval.
• To prevent cytokine-release syndrome (CRS), dexamethasone or hydroxyurea for 4 days was recommended during the first treatment week and was required if baseline bone marrow blasts were .
• Hematologic responses were assessed locally and were confirmed by central reference laboratory.
• All AEs occurring from treatment start until 30 days after the last infusion were recorded and graded according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03.

End Points

• The primary phase I end point was the maximum-tolerated dosage (MTD), the maximal dosage at which one or fewer of six patients experienced a DLT.
• Secondary end points included pharmacokinetics and AE incidence.
• The primary phase II end point was the CR rate within the first two cycles.
• Secondary end points included AE incidence, proportion of patients undergoing alloHSCT after blinatumomab treatment, relapse-free survival (RFS), and overall survival (OS).
• MRD response and complete MRD response were exploratory end points in both phases.

Statistical Analysis

• The proportion of responders with exact 95% CIs was calculated.
• RFS and OS (time from enrollment to first relapse or death, respectively) were estimated using the Kaplan-Meier method.
• The authors conducted separate primary analyses for both study phases (Data Supplement).
• Pooled analysis of data from patients who received the recommended dosage in phases I or II was exploratory.
• Pharmacokinetic parameters were estimated using noncompartmental methods with Phoenix WinNonlin version 6.3 software on Citrix (Pharsight, St. Louis, MO).

Patient Characteristics

• Patients were considered very high risk on the basis of baseline tumor load, multiple prior relapses, short interval between latest treatment and start of blinatumomab, previous alloHSCT, and/or cytogenetic profile.
• Most patients were refractory to their last treatment (Table 1 ).
• At the date of study completion (May 24, 2016), all patients had completed the 2-year follow-up, had withdrawn from study, or had died.

Phase I Dosage-Finding Part and Pharmacokinetics

• This patient experienced febrile neutropenia and pneumonia shortly before infusion start.
• Considering the MTD and overall toxicity profile, and to reduce the risk of CRS, the independent DSMB recommended the stepwise dosage of 5/15 mg/m 2 /d for further evaluation.
• Steady-state concentration was similar at a given dosage across age groups and was similar to adult reference data (Data Supplement).
• ‡Relapse during the efficacy follow-up (no chemotherapy or alloHSCT between end of blinatumomab treatment and relapse).
• Occurred would have met the definition of a DLT.

Efficacy at the Recommended Dosage

• At the day 15 assessment, three patients who ultimately responded still had M3 marrow, two had M2 marrow; all other responders had either hypocellular or M1 marrow.
• Among 10 patients , 2 years of age (eight with MLL translocations), six (60%) achieved CR (including five with MLL translocations; Data Supplement), with four (40%) proceeding to alloHSCT in remission.
• Complete MRD response rates were similar across subgroups, with different peripheral counts at response assessment (Data Supplement).
• Thirteen of the 27 patients (48%) received alloHSCT in blinatumomabinduced remission (seven of whom had received alloHSCT previously).
• At the end of the 2-year follow-up, eight were still alive.

AEs at the Recommended Dosage

• Most AEs occurred in the first few days of cycle 1 (data not shown).
• Six of 70 patients had fatal AEs; three died after alloHSCT after blinatumomab-induced remission (Table 3 ).
• No patient developed anti-blinatumomab antibodies during the study.
• Three patients had grade 3 and one patient had grade 4 CRS.

A

• Three patients (4%) experienced grade 3 neurologic events: somnolence (two patients) and neuralgia (one patient).
• The patient, who failed to respond to blinatumomab, stopped treatment after cycle 1 and developed disease progression.
• In nine patients (13%), neurologic events, primarily tremor and dizziness, were considered to be treatment related.
• There were no permanent discontinuations caused by neurologic events.
• Elevations were seen during the first week of infusion and were transient, typically returning to baseline values within the first cycle.

DISCUSSION

• 18, 19 Among patients receiving 5/15 mg/m 2 /d, 39% achieved CR within the first two cycles, with most responders achieving complete MRD response.
• Most studies have reported low cytologic CR rates, with as few as 17% of patients with refractory first relapse achieving CR.
• 29, 30 In both CD19targeted approaches, blinatumomab and CD19 CAR T cells, CD19negative relapses have been reported.
• This study supports further evaluation of blinatumomab in children with BCP-ALL, including those with first-relapse or newly diagnosed disease at high risk of treatment failure because of significant MRD burden or unfavorable cytogenetics.

Figures

Fig 1. Study profile.

Table 3. Adverse Events Occurring in Patients who Received the Recommended Dosage

Table 1. Demographic and Baseline Characteristics

Table 2. Efficacy Outcomes and Ability to Proceed to Transplantation for Patients who Received the Recommended Dosage

Full text

JOURNAL OF CLINICAL ONCOLOGY
ORIGINAL REPORT
Phase I/Phase II Study of Blinatumomab in Pediatric Patients
With Relapsed/Refractory Acute Lymphoblastic Leukemia
Arend von Stackelberg, Franco Locatelli, Gerhard Zugmaier, Rupert Handgretinger, Tanya M. Trippett,
Carmelo Rizzari, Peter Bader, Maureen M. O’Brien, Benoˆıt Brethon, Deepa Bhojwani, Paul Gerhardt Schlegel,
Arndt Borkhardt, Susan R. Rheingold, Todd Michael Cooper, Christian M. Zwaan, Phillip Barnette,
Chiara Messina, G´erard Michel, Steven G. DuBois, Kuolung Hu, Min Zhu, James A. Whitlock, and Lia Gore
ABSTRACT
Purpose
Blinatumomab is a bispecific T-cell engager antibody construct targeting CD19 on B-cell lympho-
blasts. We evaluated the safety, pharmacokinetics, recommended dosage, and potential for efficacy
of blinatumomab in children with relapsed/refractory B-cell precursor acute lymphoblastic leukemia
(BCP-ALL).
Methods
This open-label study enrolled children , 18 years old with relapsed/refractory BCP-ALL in a phase I
dosage-escalation part and a phase II part, using 6-week treatment cycles. Primary end points
were maximum-tolerated dosage (phase I) and complete remission rate within the first two cycles
(phase II).
Results
We treated 49 patients in phase I and 44 patients in phase II. Four patients had dose-limiting
toxicities in cycle 1 (phase I). Three experienced grade 4 cytokine-release syndrome (one attributed
to grade 5 cardiac failure); one had fatal respiratory failure. The maximum-tolerated dosage was
15 mg/m
2
/d. Blinatumoma b pharm acokineti cs was l inear ac ross do sage lev els and consistent
among age groups. On the basis of the phase I data, the recommended blinatumomab dosage for
children with relapsed/refractory ALL was 5 mg/m
2
/d for the first 7 days, followed by 15 mg/m
2
/d
thereafter. Among the 70 patients who received the recommended dosage, 27 (39%; 95% CI, 27%
to 51%) achieved complete remission within the first two cycles, 14 (52%) of whom achieved
complete minimal residual disease response. The most frequent grade $ 3 adverse events were
anemia (36%), thrombocytopenia (21%), and hypokalemia (17%). Three patients (4%) and one
patient (1%) had cytokine-release syndrome of grade 3 and 4, respectively. Two patients (3%)
interrupted treatment after grade 2 seizures.
Conclusion
This trial, which to the best of our knowledge was the first such trial in pediatrics, demonstrated
antileukemic activity of single-agent blinatumomab with complete minimal residual disease re-
sponse in children with relapsed/refractory BCP-ALL. Blinatumomab may represent an important
new treatment option in this setting, requiring further investigation in curative indications.
J Clin Oncol 34. © 2016 by American Society of Clinical Oncology
INTRODUCTION
Acute lymphoblastic leukemia (ALL) is the most
common malignant disease in children, with an
annual incidence of approximately three cases per
100,000 persons.
1
When treated with contemporary
combination chemotherapy , approximately 15% of
patients relapse and 10% die.
2,3
P atien ts who relapse
have a cure rate ranging from 10% to 70%, mainly
depending on site of and time to relapse.
4,5
Children
with second or greater relapse or refractory dis-
ease have a dismal prog nosis even when treated
with intensive combination chemotherapy and
allogeneic hematopoietic stem-cell transplantation
(alloHSCT).
6,7
Targeted treatments are needed
to overcome disease resistance and to replace
nonspecific toxic chemotherapy, even in children with
chemosensitive ALL. Immunotherapy constitutes an
important new antileukemic treatment strategy .
CD19 is expressed on B-lineage cells
8,9
and
is a therapeutic target for B-cell precursor ALL
Author affiliations appear at the end of this
article.
Published online ahead of print at
www.jco.org on October 3, 2016.
Supported by Amgen. A.v.S. and F.L.
received funding from the European
Union’s Seventh Framework Program for
Research, Technological Development
and Demonstration under Grant
Agreement No. 278514-IntReALL.
Amgen also funded the work of Miranda
Tradewell, PhD, and Ali Hassan, PhD
(Complete Healthcare Communications,
LLC, Chadds Ford, PA), who developed an
initial draft of the methods and results and
who assisted with formatting.
A.v.S., F.L., and G.Z. contributed equally
to this work.
Presented in abstract form at the 49th
Annual Meeting of the American Society
of Clinical Oncology, Chicago, IL, May
31-June 3, 2013; the 56th Annual Meeting
of the American Society of Hematology,
San Francisco, CA, December 6-9, 2014;
the 46th Congress of the International
Society of Paediatric Oncology, Toronto,
Canada, October 22-25, 2014; and the
American Society for Blood and Marrow
Transplantation, San Diego, CA, February
11-14, 2015.
Authors’ disclosures of potential conflicts
of interest are found in the article online at
www.jco.org. Author contributions are
found at the end of this article.
Clinical trial information: NCT01471782.
Corresponding author: Arend von
Stackelberg, MD, Charit
´
e Campus
Virchow-Klinikum, Augustenburger Platz 1,
13353 Berlin, Germany; e-mail: arend.
stackelberg@charite.de.
© 2016 by American Society of Clinical
Oncology
0732-183X/16/3499-1/$20.00
DOI: 10.1200/JCO.2016.67.3301
© 2016 by American Society of Clinical Oncology
1
http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2016.67.3301The latest version is at
Published Ahead of Print on October 3, 2016 as 10.1200/JCO.2016.67.3301
Copyright 2016 by American Society of Clinical Oncology
207.162.240.147
Information downloaded from jco.ascopubs.org and provided by at Weill Cornell Medical Library on October 6, 2016 from
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

(BCP-ALL).
10
Blinatumomab is a bispecific T -c ell engager (BiTE)
antibody construct that directs CD3-positive effector memory T cells
to CD19-positiv e ta rget cells, triggering cell death.
11,12
In a large phase
II study in adults with relapsed/r efractory BCP -ALL, the response rate
after single-agent blinatumomab treatment was 43%.
13
We report the
results of an international phase I/II study of immunotherapy bli-
natumomab in children and adolescents with BCP-ALL that was
refractory , in second overt relapse, and/or in relapse after alloHSCT.
METHODS
Patients
We conducted an open-label, single-arm phase I/II study at 26
European and US centers. Eligible patients were , 18 years of age (2 to
17 years of age in phase I dosage escalation) and had BCP-ALL with . 25%
bone marrow blasts. The disease was primary refractory, in first relapse
after full salvage induction regimen, in second or later relapse, or in any
Phase I pharmacokinetic expansion
Recommended dosage evaluation
Blinatumomab 5/15 μg/m
2
/d
Patients who started treatment
(n = 26)
Received cycle 1 (n = 26)
Received cycle 2 (n = 11)
Received cycle 3 (n = 2)
Patients with intensive
pharmacokinetic assessments (n = 18 of 26)
Age groups
Patients 7 to 17 y (n = 9)
Patients 2 to 6 y (n = 9)
Patients < 2 y
(n = 8)
Phase II
Recommended dosage
Blinatumomab 5/15 μg/m
2
/d
Patients who started treatment (n = 44)
Received cycle 1 (n = 41)
Received cycle 2 (n = 11)
Received cycle 3 (n = 5)
Received cycle 4 (n = 3)
Received cycle 5 (n = 3)
Received retreatment (n = 1)
Age groups
Patients 7 to 17 y
(n = 31)
Patients 2 to 6 y
(n = 11)
Patients < 2 y
(n = 2)
Recommended dosage evaluation
(N = 70)
Blinatumomab 5/15 μg/m
2
/d
At completion of the study
Completed the 2-y follow-up (n = 14)
Ended study participation
(n = 56)
Died (n = 48)
Withdrawn consent (n = 6)
Physician decision (n = 1)
Lost to follow-up
(n = 1)
Age groups
Patients 7 to 17 y
(n = 40)
Patients 2 to 6 y
(n = 20)
Patients < 2 y
(n = 10)
Patients included in analysis of efficacy (n = 70)
Patients included in analysis of safety (n = 70)
Cohort 2
Blinatumomab 15 μg/m
2
/d
Patients who started treatment
(n = 7)
Received cycle 1 (n = 7)
Received cycle 2 (n = 3)
Received cycle 3 (n = 2)
Received cycle 4 (n = 1)
Received cycle 5 (n = 1)
Cohort 3
Blinatumomab 30 μg/m
2
/d
Patients who started treatment
(n = 5)
Received cycle 1 (n = 2)
Received cycle 2 (n = 2)
Received cycle 3 (n = 1)
Cohort 4
Blinatumomab 15/30 μg/m
2
/d
Patients who started treatment
(n = 6)
Received cycle 1 (n = 6)
Received cycle 2 (n = 3)
Received cycle 3 (n = 2)
Received cycle 4 (n = 2)
Received cycle 5 (n = 1)
Received retreatment
(n = 1)
Cohort 1
Blinatumomab 5 μg/m
2
/d
Patients who started treatment
(n = 5)
Received cycle 1 (n = 5)
Received cycle 2 (n = 4)
Received cycle 3 (n = 1)
Patients screened (n = 64)
Patients ineligible (n = 15)
Phase I dosage escalation and safety/pharmacokinetic evaluation
Patients screened (n = 59)
Phase II recommended dosage evaluation
Patients ineligible (n = 15)
Fig 1. Study profile.
2
© 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
von Stackelberg et al
207.162.240.147
Information downloaded from jco.ascopubs.org and provided by at Weill Cornell Medical Library on October 6, 2016 from
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

relapse after alloHSCT. Patients had Karnofsky or Lansky (age , 16 years)
performance status of $ 50%. Patients with Philadelphia chromosome‒
positive ALL were eligible; those with active acute or extensive chronic
graft-versus-host disease after HSCT, or active CNS or testicular in-
volvement, were excluded. Further eligibility criteria are available in the
study protocol (Data Supplement). Each center’s institutional review board
or an independent ethics committee approved the study protocol. The
patients’ legal representatives gave written informed consent.
Study Desig n and Assessments
The study included a dosage-finding phase I part and a phase II part
evaluating safety and efficacy at the recommended dosage proposed by an
independent Data Safety Monitoring Board (DSMB) on the basis of the
dosage-finding part. In phase I, we tested blinatumomab dosages of 5, 15,
and 30 mg/m
2
/d and a stepwise dosage of 15/30 mg/m
2
/d (15 mg/m
2
/d for
the first 7 days and 30 mg/m
2
/d thereafter). After determining the rec-
ommended dosage (stepwise 5/15 mg/m
2
/d), we treated additional patients
to further assess pharmacokinetics and safety across three age g roups (7 to
17 years; 2 to 6 years; , 2 years) before beginning phase II (Appendix Fig A1,
online only).
Patients received blinatumomab as a 4-week continuous intravenous
infusion, followed by a 2-week treatment-free interval. For stepwise dosing
(5/15 or 15/30 mg/m
2
/d), the lower dose was administered for the first
week of the first cycle followed by the higher dose for the remaining
3 weeks and subsequent cycles. Infusion was administered in the hospital
during week 1 of cycle 1 and during the first 2 days of cycle 2, and in an
outpatient setting thereafter. Patients achieving complete remission (CR)
within the first two cycles could receive up to three additional cycles or be
withdrawn from treatment to receive consolidation chemotherapy or HSCT
per the investigator’s choice. To prevent cytokine-release syndrome (CRS),
dexamethasone or hydroxyurea for 4 days was recommended during the
first treatment week and was required if baseline bone marrow blasts were
. 50%. P atients received prophylactic dexamethas one 10 mg/m
2
6to12hours
before and 5 mg/m
2
within 30 minutes of each infusion start. CNS prophylaxis
accor ding to institutional/national standards was adm inister ed at age-adj usted
doses before treatment, at day 15 of cycle 1, and at the day 29 bone marrow
assessment. Neurologic events were treated with dexamethasone at 0.2 to
0.4 mg/kg/d (maximum, 24 mg/d) for up to 3 days.
Patients discontinued treatment permanently if they experienced
adverse events (AEs) meeting the criteria for dose-limiting toxicities (DLT;
Data Supplement), irrespective of their timing; a neurologic event re-
quiring . 1 week to resolve to grade # 1; disease progression or
hematologic/extramedullary relapse; or treatment interruption/delay of
. 2 weeks or more than two discontinuations for AEs during one cycle.
For other blinatumomab-related AEs not meeting DLT criteria but re-
quiring infusion interruption, treatment could be restarted one dosage
level lower after resolution to grade # 1.
Bone marrow aspiration (and/or biopsy) for response assessment
was performed dur i ng screening, at day 15 of cycle 1, and at the end of
each 28-day cycle. Hematologi c responses were assessed locally and were
confirmed by central reference labor atory. CR was defined as no evidence
of circulating blasts or extramedullar y disease and , 5% blasts in bone
marrow(M1).CRwassubclassified on the basis of recovery of peripheral
blood counts. Minimal residual disease (MRD) response was assessed by
central laboratories; data presented are based on flow cytometr y. MRD
response was defined as , 10
24
detectable blasts; complete MRD re-
sponse was defined as n o detectable blasts. All AEs occurr ing from
treatment start until 30 days after the last infusion were recorded and
graded according to Nation al Cancer Institute Common Terminology
Criteria for Adverse Events version 4.03.
14
Anti-blinatumomab anti-
bodies were assessed.
End Points
The primary phase I end point was the maximum-tolerated dos-
age (MTD), the maximal dosage at which one or fewer of six patients
experienced a DLT. Secondary end points included pharmacokinetics and
AE incidence. The primary phase II end point was the CR rate within the
first two cycles. Secondary end points included AE incidence, proportion of
patients undergoing alloHSCT after blinatumomab treatment, relapse-free
survival (RFS), and overall survival (OS). MRD response and complete
MRD response were exploratory end points in both phases.
Statistical Analysis
Phase I followed a rolling six design.
15
The phase II sample size was
based on a Simon-like two-stage design.
16
A minimum of 40 patients (first
stage, n = 21; second stage, n = 19) was estimated to be needed to provide
80% power to test the null hypothesis, with two-sided a = 0.05, that
achievement of CR within the first two cycles was # 10% versus the
alternative hypothesis of 27.5%. The proportion of responders with exact
Table 1. Demographic and Baseline Characteristics
Characteristic
All Patients in
Phase I
(n = 49)
All Patients in
Phase II
(n = 44)
All Patients at
Recommended
Dosage* (n = 70)
Sex
Male 28 (57) 32 (73) 47 (67)
Female 21 (43) 12 (27) 23 (33)
Geographic region
European Union 34 (69) 31 (71) 48 (69)
United States 15 (31) 13 (30) 22 (31)
Age group, years
, 2 8 (16) 2 (5) 10 (14)
2-6 23 (47) 11 (25) 20 (29)
7-17 18 (37) 31 (71) 40 (57)
Age, median (range),
years
6(, 1-16) 10.5 (, 1-17) 8 (, 1-17)
Genetic abnormalities
MLL total 10 (20) 2 (5) 10 (14)†
MLL-AF4.t(4;11) 7 (14) 2 (5) 8 (11)
Other MLL 3 (6) 0 2 (3)
BCR-ABL 2(4) 1(2) 2(3)
Hypodiploidy 1 (2) 3 (7) 4 (9)
Constitutional trisomy 21 1 (2) 1 (2) 2 (3)
Previous alloHSCT
Yes 30 (61) 25 (57) 40 (57)
No 19 (39) 19 (43) 30 (43)
Previous relapses
02(4)02(3)
1 17 (35) 22 (50) 31 (44)
2 23 (47) 19 (43) 29 (41)
$ 3 7 (14) 3 (7) 8 (11)
Refractory disease 26 (53) 26 (59) 39 (56)
Time between last
relapse and first
blinatumomab
infusion, median
(range), months
1.8 (0.1-16.1) 1.9 (0.2-13.7) 2.9 (0.4-49.8)
Relapse within 6 months
after last prior
treatment attempt
——50 (71)
Bone marrow blast count
per central
laboratory, %
, 50 7 (14) 12 (27) 18 (26)
$ 50 42 (86) 32 (73) 52 (74)
NOTE. Data are prese nted as No. (%) unless otherwise indicated.
Abbreviations: alloHSCT, allogeneic hematopoietic stem-cell transplantation;
BCR-ABL, breakpoint cluster region-Abelson murine leukemia viral oncogene
homolog 1 gene; MLL, mixed-lineage leukemia gene.
*All patients treated at the stepwise dosage of 5/15 mg/m
2
/d in phase I or
phase II.
†Eight patients with MLL translocations were , 2 years old: six had MLL with
the fusion partner AF4.t(4;11); two had other MLL abnormalities.
www.jco.org © 2016 by American Society of Clinical Oncology 3
Blinatumomab in Children With Relapsed/Refractory ALL
207.162.240.147
Information downloaded from jco.ascopubs.org and provided by at Weill Cornell Medical Library on October 6, 2016 from
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

95% CIs was calculated. RFS and OS (time from enrollment to first
relapse or death, respectively) were estimated using the Kaplan-Meier
method. We conducted sep arate primar y analyses fo r both study
phases (Data Supplement). Pooled analysis of data from patients who
received the recomm ended do sage in phases I or II was e xplor-
atory. Efficacy/safety analyses were based on the full-analysis set (all
patients who received any blinatumomab infusion). Pharmacoki-
netic parameters were estimated using noncompar tmental methods
with Phoenix WinNonlin version 6.3 software on Citrix (Pharsight,
St. Louis, MO).
RESULTS
Patient Characteristics
Between January 30, 2012, and June 3, 2014, we treated
49 patients in phase I and 44 patients in phase II ( Fig 1). Patients
were considered very high risk on the basis of baseline tumor load,
multiple prior relapses, shor t interval between latest treatment and
start of blinatumomab, previous alloHSCT, and/or cytogenetic
profile. Most patients were refractory to their last treatment
(Table 1). At the date of study completion (May 24, 2016), all
patients had completed the 2-year follow-up, had withdrawn from
study, or had died.
Phase I Dos age-Finding Part and Pharmacokinetics
Four DLTs (two fatal) occurred in phase 1 (Data Supplement):
one g rade 4 CRS deemed to be related to grade 4 GI hemorrhage
at 15 mg/m
2
/d; two g rade 4 CRS at 30 mg/m
2
/d (one attributed
to grade 5 cardiac failure and the other treated successfully
with tocilizum ab
17
); and one case of grade 5 respirator y failure
(15/30 mg/m
2
/d) with cardiac arrest after hy potoni a and muscle
weakness after 7 days of infusion with blinatumomab at 15 mg/m
2
/d
(30 mg/m
2
/d was not administered). This patient experienced
febrile neutropenia and pneumonia shortly before infusion start.
Thus, the MTD was determined to be 15 mg/m
2
/d. Across dosage
cohorts, the incidence of AEs not considered DLTs was also dosage
dependent (Data Supplement). Considering the MTD and overall
toxicity profile, and to reduce the risk of CRS, the independent
DSMB recommended the stepwise dosage of 5/15 mg/m
2
/d for
further evaluation.
Twenty-six patients in three age groups (those , 2yearsold
were enrolled last) were then assessed at 5/15 mg/m
2
/d in the
phase I pharmacokinetic expansion. Blinatumomab had ap-
proxim a t e ly l inear pharmacokinetics. Steady-state concentration
was similar at a given dosage across age groups and was similar to
adult reference data (Data Supplement). Although DLTs were not
collected formally in the pharmacokinetic expansion, no AEs that
Table 2. Efficacy Outcomes and Ability to Proceed to Transplantation for Patients who Received the Recommended Dosage
Efficacy Outcomes and Ability to Proceed to alloHSCT
Patients in Phase II (n = 44)*
All Patients at Recommended
Dosage
(n = 70)*
Patients , 2 Years at
Recommended Dosage
(n = 10)*
No. % 95% CI No. % 95% CI No. % 95% CI
Hematologic response
CR within the first two cycles 14 32 19 to 48 27 39 27 to 51 6 60 26 to 88
Nonresponders (did not achieve CR)
Partial remission 3 7 4 6 0 0
Blast-free hypoplastic or aplasti c bone marrow 0 0 2 3 0 0
Progressive disease 8 18 10 14 2 20
No response 14 32 21 30 2 20
No response assessment† 511 69 NANA
CR within the first two cycles by baseline bone
marrow blast count
, 50% blasts at baseline 5 of 12 42 15 to 72 10 of 18 56 31 to 79 2 of 2 100 16 to 100
$ 50% blasts at baseline 9 of 32 28 14 to 47 17 of 52 33 20 to 47 4 of 8 50 16 to 84
Relapse or death after CR‡ 10 of 14 71 7 of 27 26 4 of 6 67
MRD response in patients who achieved CR within
the first two cycles
MRD response 8 of 14 57 29 to 82 14 of 27 52 32 to 71 3 of 6 50 12 to 88
Complete MRD response 8 of 14 57 29 to 82 14 of 27 52 32 to 71 3 of 6 50
No MRD response 6 of 14 43 12 44 3 of 6 50
No data available 0 0 1 4 0 0
Ability to proceed to HSCT
Patients who received alloHSCT 13 30 24 34 4 10
Patients in blinatumomab-induced CR 5 11 13 19 4 40
Patients in CR who received only blinatumomab 2 5 8 11 2 20
100-day mortality rate§ NE NE 25 7 to 69 NE NE
Nonresponders who received subsequent treatmentsk 818 1116 NANA
Abbreviations: alloHSCT, allogeneic hematopoietic stem-cell transplantation; CR, complete remission; HSCT, hematopoietic stem-cell transplantation; MRD, minimal
residual disease; NA, not applicable; NE, not evaluated.
*All patients treated at 5/15 mg/m
2
/d in phase I or II.
†Patients died (n = 5) or withdrew consent (n = 1) before the first response assessment.
‡Relapse during the effi cacy follow-up (no chemotherapy or alloHSCT between end of blinatumomab treatment and relapse).
§Calculated from the date of alloHSCT for all patients who received only blinatumomab at the recommended dose. Not calculated for the other two patient groups
because of limited sample size.
kPatients who were refractory to blinatumomab but who received subsequent treatments and then proceeded to alloHSCT.
4 © 2016 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY
von Stackelberg et al
207.162.240.147
Information downloaded from jco.ascopubs.org and provided by at Weill Cornell Medical Library on October 6, 2016 from
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

occurred would have met the definition of a DLT. The nature and
incidence of AEs were consistent w ith previous blinatumomab
experience (Data Supplement). After review of the toxicity data,
the DSMB confirme d 5/15 mg/m
2
/d as the recommended dosage
for phase I I.
In phase I, seven of 23 patients (30%) in the dosage-escalation
part achieved CR within the first two cycles, with all responders
achieving a complete MRD response (Data Supplement). Responses
were observed at all dosage levels.
Efficacy at the Recommended Dosage
On the basis of the pr imary anal ysis ( Januar y 12, 2015), 14
of 44 patients (32%; 95% CI, 19% to 48%) in phase II who
received the recommended dosage of 5/15 mg/m
2
/d achieved CR
within the first two cycles ( Table 2). Overall, 70 patients received
this dosage in phase I (n = 26) or phase II (n = 44). Twenty-seven
patients (39%; 95% CI, 27% to 51%) achieved CR within the first
two cycles ( Table 2), 20 (74%) w ithin cycle 1 and eight of those
(30%) by day 15 of cycle 1. At the day 15 assessment, three
patients who ultimately responded still had M3 marrow, two had
M2 marrow; all other responders had either hypocellular or M 1
marrow.
Prespecified analyses showed that CRs had been achieved
across subgroups (Fig 2 ). The CR rate was 56% among patients
with , 50% bone marrow blasts at baseline versus 33% among
those w ith $ 50% blasts. Two of three Ph-positive patients and
one of four patients with hypodiploidy achieved CR (Data Sup-
plement). One of two patients with constitutional trisomy 21
had partial remission. Among 10 patients , 2 years of age (eight
with MLL translocations), six (60%) achieved CR (including five
with MLL translocations; Data Supplement), with four (40%)
proceeding to alloHSCT in remission. Of the 27 responders treated
with blinatumomab 5/15 mg/m
2
/d, four were still in remission at
the end of the 2-year follow-up, two had relapsed but were still
alive, three had withdrawn consent (one patient in CR and two
after relapse), three had died in CR after alloHSCT, and 15 had
relapsed and died (four with a CD19-negative clone).
Fourteen of 27 responders (52%) had a complete MRD re-
sponse, 13 (48%) b y day 15 of cycle 1 . Complete MR D response
rates we re similar across subg roups, wit h different per ipheral
counts at response assessment ( Data Supplement). Thirteen of
the 27 patients (48%) received alloHSCT in blinatumomab-
induced remission (seven of whom had received alloHSCT
previously).
Forty-three patients did not achieve CR within the first two
cycles. At the end of the 2-year follow-up, eight were still alive.
Eleven nonresponders received postblinatumomab alloHSCT. Mean
cumulative prophylaxis and treatment dexamethasone dose did not
differ between responders and nonresponders (72.4 mg/m
2
v 76.3,
respectively).
Median RFS was 4.4 months (95% CI, 2.3 to 7.6 months)
among patients receiving the recommended dosage who achieved
CR, with a median follow-up of 23.1 months (Fig 3A). The RFS rate
at 6 months was 42%. Median RFS was longer for patients with
a complete MRD response (7.3 months; 95% CI, 2.7 to 16.4 months;
n=14)thanforthosewithout(1.9months;95%CI,0.8to
6.0 months; n = 1 2; Fig 3B). Median OS for all 70 patients was
7.5 months (95% CI, 4.0 to 11.8 months) with a median follow-up
of 23.8 months (Fig 3C).
AEs at the Recommended Dosage
Among the 70 patients who received blinatumomab
5/15 mg/m
2
/d, the most common AEs, regardless of causality, were
pyrexia (80%), anemia (41%), nausea (33%), and headache (30%;
Geographic region
United States
Europe
Bone marrow blasts at baseline
≥ 50%
< 50%
Age group, years
All patients
Previous HSCT
Refractory disease
Yes
Previous relapses
0
0 20 40 80 10060
n/N CR (95% CI)
27/70 38.6% (27.2 to 51.0)
39.6% (25.8 to 54.7)
36.4% (17.2 to 59.3)
0.0% (0.0 to 84.2)
30.8% (17.0 to 47.6)
55.6% (30.8 to 78.5)
32.7% (20.3 to 47.1)
19/48
8/22
< 2 60.0% (26.2 to 87.8)6/10
2 to 6 40.0% (19.1 to 63.9)
8/20
7 to 17
32.5% (18.6 to 49.1)
13/40
No 26.7% (12.3 to 45.9)8/30
Yes 47.5% (31.5 to 63.9)
19/40
0/2
1
32.3% (16.7 to 51.4)10/31
2 48.3% (29.4 to 67.5)14/29
≥ 3 37.5% (8.5 to 75.5)
3/8
No
48.4% (30.2 to 66.9)
15/31
12/39
10/18
17/52
CR Within First Two Cycles, % (95% CI)
Fig 2. Complete remission (CR) rates
within two treatment cycles among patient
subgroups (prespecified analysis). The point
estimate for CR for all patients who received
the recommended dosage is indicated by
a dashed line. HSCT, hematopoietic stem-cell
transplantation.
www.jco.org
© 2016 by American Society of Clinical Oncology 5
Blinatumomab in Children With Relapsed/Refractory ALL
207.162.240.147
Information downloaded from jco.ascopubs.org and provided by at Weill Cornell Medical Library on October 6, 2016 from
Copyright © 2016 American Society of Clinical Oncology. All rights reserved.

Frequently asked questions

Q1. What are the contributions mentioned in the paper "Phase i/phase ii study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia" ?

This open-label study enrolled children, 18 years old with relapsed/refractory BCP-ALL in a phase I dosage-escalation part and a phase II part, using 6-week treatment cycles. On the basis of the phase I data, the recommended blinatumomab dosage for children with relapsed/refractory ALL was 5 mg/m/d for the first 7 days, followed by 15 mg/m/d thereafter. Blinatumomab may represent an important new treatment option in this setting, requiring further investigation in curative indications.