REGULAR ARTICLE

Inotuzumab ozogamicin in adults with relapsed or refractory

CD22-positive acute lymphoblastic leukemia: a phase 1/2 study

Daniel J. DeAngelo,1 Wendy Stock,2 Anthony S. Stein,3 Andrei Shustov,4 Michaela Liedtke,5 Charles A. Schiffer,6 Erik Vandendries,7
Katherine Liau,7 Revathi Ananthakrishnan,7 Joseph Boni,8 A. Douglas Laird,9 Luke Fostvedt,9 Hagop M. Kantarjian,10 and Anjali S. Advani11
1
Dana-Farber Cancer Institute, Boston, MA; 2University of Chicago Comprehensive Cancer Center, Chicago, IL; 3City of Hope, Duarte, CA; 4Division of Hematology, University
of Washington, Seattle, WA; 5Stanford Cancer Institute, Stanford, CA; 6Karmanos Cancer Institute, Detroit, MI; 7Pfizer Inc, Cambridge, MA; 8Pfizer Inc, Collegeville, PA; 9Pfizer
Inc, La Jolla, CA; 10MD Anderson Cancer Center, Houston, TX; and 11Cleveland Clinic, Cleveland, OH

This study evaluated the safety, antitumor activity, pharmacokinetics, and pharmacodynamics
Key Points
of inotuzumab ozogamicin (InO) for CD22-positive relapsed/refractory acute lymphoblastic
• Weekly InO 1.8 mg/m2 leukemia. In phase 1, patients received InO 1.2 (n 5 3), 1.6 (n 5 12), or 1.8 (n 5 9) mg/m2
per cycle is associated per cycle on days 1, 8, and 15 over a 28-day cycle (#6 cycles). The recommended phase 2 dose
with manageable toxic-
(RP2D) was confirmed (expansion cohort; n 5 13); safety and activity of InO were assessed in
ities and encouraging
patients receiving the RP2D in phase 2 (n 5 35) and in all treated patients (n 5 72). The RP2D
activity in patients with
was 1.8 mg/m2 per cycle (0.8 mg/m2 on day 1; 0.5 mg/m2 on days 8 and 15), with reduction to
relapsed/refractory
1.6 mg/m2 per cycle after complete remission (CR) or CR with incomplete marrow recovery (CRi).
ALL.
Treatment-related toxicities were primarily cytopenias. Four patients experienced treatment-
• Achievement of MRD
related venoocclusive disease/sinusoidal obstruction syndrome (VOD/SOS; 1 fatal). Two
negativity and disease
VOD/SOS events occurred during treatment without intervening transplant; of 24 patients
burden was not corre-
proceeding to poststudy transplant, 2 experienced VOD/SOS after transplant. Forty-nine (68%)
lated; InO may thus be
patients had CR/CRi, with 41 (84%) achieving minimal residual disease (MRD) negativity. Median
effective regardless of
baseline disease progression-free survival was 3.9 (95% confidence interval, 2.9-5.4) months; median overall
severity. survival was 7.4 (5.7-9.2) months for all treated patients, with median 23.7 (range, 6.8-29.8)
months of follow-up for all treated patients alive at data cutoff. Achievement of MRD negativity
was associated with higher InO exposure. InO was well tolerated and demonstrated high single-
agent activity and MRD-negativity rates. This trial was registered at www.clinicaltrials.gov as
#NCT01363297.

Introduction

Acute lymphoblastic leukemia (ALL) is a heterogeneous malignancy with an estimated incidence of 6250
newly diagnosed cases in 2015.1,2 Although the majority (58%) of these cases were estimated to be among
pediatric and young adult patients aged ,20 years, 26% were among adults $45 years old.1,2
Current treatments for adults with newly diagnosed B-cell ALL yield complete remission (CR) rates
ranging from 60% to 90%3-12; however, many patients eventually relapse and only ;30% to 50%
maintain extended disease-free survival for $3 years.6-10 Moreover, overall survival (OS) rate at 5 years after
relapse has been reported to be only 7%.13 For B-cell ALL that has relapsed or is refractory to standard
chemotherapy, CR rates decrease with successive salvage treatments (eg, ;30% to 40% in first and
;10% to 25% in second or later salvage).3,7,14 Because CR is required for ensuing allogeneic stem cell

Submitted 6 October 2016; accepted 27 April 2017. DOI 10.1182/ © 2017 by The American Society of Hematology
bloodadvances.2016001925.
The full-text version of this article contains a data supplement.

27 JUNE 2017 x VOLUME 1, NUMBER 15 1167

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transplant (SCT), few (5% to 30%) patients in second or later salvage included Eastern Cooperative Oncology Group (ECOG) per-
are eligible for allogeneic SCT, which remains the only potentially curative formance status 0-3; adequate liver and renal function; no isolated
option and the primary objective of treatment after relapse.3,13-16 extramedullary relapse or active central nervous system leukemia;
and no prior allogeneic hematopoietic SCT (HSCT) #4 months
Salvage therapies for B-cell ALL using cytotoxic chemotherapy
before first dose. Concurrent therapy for central nervous system
combinations possess limited efficacy and are frequently associated
prophylaxis was permitted.
with significant toxicities,16,17 which are further exacerbated by dose
intensification or by the addition of other agents.18 Targeted antibody- The protocol was conducted in accordance with the Declaration of
drug conjugate therapies can minimize exposure of normal tissues to Helsinki and International Conference on Harmonization Guidelines
a conjugated cytotoxic agent.19 Lineage-specific antigens expressed for Good Clinical Practice and was approved by Institutional Review
on the surface of leukemic cells function as targets for antibody-drug Boards at each participating institution. Participants provided
conjugate treatments and are used as diagnostic markers and for written informed consent before initiation of study-related activities.
classifying immunologic subtypes.20 CD22, a B-cell–restricted sialic
Study design
acid–recognizing immunoglobulin superfamily lectin (Siglec),21 is
expressed on leukemic blasts in .90% patients with B-cell This study was a prospective, open-label, phase 1/2 study performed
ALL22-25 and is not shed into the extracellular compartment.26,27 at 8 sites in the United States. In phase 1, patients received InO
CD22 has therefore become an important therapeutic target in B-cell (1-hour intravenous infusion) in the following dose cohorts (Table 1): total
ALL and other B-cell malignancies.28-30 dose 1.2 mg/m2 per cycle (0.8 mg/m2 [day 1]; 0.4 mg/m2 [day 15]);
1.6 mg/m2 per cycle (0.8 mg/m2 [day 1]; 0.4 mg/m2 [days 8 and 15]);
Inotuzumab ozogamicin (InO; CMC-544) is a humanized CD22
1.8 mg/m2 per cycle (0.8 mg/m2 [day 1]; 0.5 mg/m2 [days 8 and 15]).
monoclonal antibody conjugated to calicheamicin, a cytotoxic
Cycles were repeated every 28 days (contingent upon meeting
antibiotic.31-33 After binding to CD22, InO is rapidly internalized
dose-delay/redosing criteria [supplemental Materials]); treatment
into lysosomes, where calicheamicin is released to bind the minor
continued for #6 cycles or until disease progression, consent
DNA groove, leading to double-strand cleavage and subsequent
withdrawal, or prolonged/excessive toxicity. Patients with suitable
apoptosis.31,33-37 A previous single-institution phase 2 study (N 5 90)
donors could undergo allogeneic HSCT after InO treatment at the
demonstrated that InO, administered on either a single-dose
investigator’s discretion.
monthly or a weekly schedule, is active and tolerable in patients with
relapsed/refractory ALL (overall response rate, 58%; median duration of To determine the RP2D, 24 patients were enrolled into 3-patient
remission [DOR], 7 months; minimal residual disease [MRD]–negativity cohorts using a traditional 313 design for the first 2 cohorts, and the
rate among responders, 72%; median survival, 6.2 months).18,38 adaptive dose-finding method of Thall and Cook39,40 using EffTox41
for the subsequent cohorts. EffTox takes into account toxicity (dose-
This phase 1/2 multisite study consisted of a dose-escalation phase
limiting toxicity [DLT]) and efficacy (response better than progressive
1 part that determined the recommended phase 2 dose (RP2D) for
disease [PD]; see supplemental Materials for cohort assignment
evaluation of the safety and antitumor activity of InO administered
decision rules and candidate InO doses). The phase 1 expansion
on a weekly schedule to patients with CD22-positive relapsed/
cohort included 13 patients who received the RP2D (1.8 mg/m2 per
refractory B-cell ALL. The study is also the first to undertake explor-
cycle); with dose reduction to 1.6 mg/m2 per cycle for patients
atory pharmacokinetic (PK), pharmacodynamic, and pharmacoge-
achieving a CR or CR with incomplete marrow recovery (CRi).
nomic (PG) analyses to examine the following potential correlations:
Thirty-five additional patients received InO at the RP2D in phase 2.
(1) InO PK with peripheral blood B-lymphocyte depletion and re-
generation; (2) bone marrow (BM) blasts with B-lymphocyte Safety and efficacy assessments
depletion and regeneration; (3) InO PK and BM blast counts with Safety was assessed from physical examinations, vital signs, 12-lead
achievement of MRD negativity; and (4) InO treatment outcomes electrocardiograms, laboratory evaluations, and adverse events (AEs),
with expression of genes, including those involved in DNA damage graded using National Cancer Institute Common Terminology Criteria
response, apoptosis, B-cell antigen expression, glutathione me- for Adverse Events, version 3.0, and monitored throughout the study
tabolism, drug transport, and the PI3K/mTOR pathway. and for $28 days after the last dose inclusive of the end-of-treatment
Methods visit. All treatment-related AEs were monitored until resolution, return
to baseline, or stabilization. Venoocclusive disease/sinusoidal ob-
Patients struction syndrome (VOD/SOS) was reported for up to 2 years after
Eligible patients were adults ($18 years) diagnosed with CD22- the first dose (see supplemental Materials for VOD/SOS definition).
positive ALL ($20% blasts CD22-positive based on local immuno- The primary phase 2 endpoint was CR/CRi; key secondary endpoints
phenotyping and histopathologic evaluation) that was refractory included MRD negativity and cytogenetics in responders, DOR, OS,
(disease progression/no response during most recent prior therapy) progression-free survival (PFS), PK, pharmacodynamics, and PG.
or relapsed (response to most recent prior therapy with subsequent BM aspirates (and/or biopsies if clinically indicated) and disease
relapse). Patients enrolled in phase 2 were in second or later salvage. assessments were performed at screening, on day 21 (67 days) of
Patients with lymphoblastic lymphoma with BM involvement with each cycle, at the end-of-treatment visit, during follow-up visits
$5% lymphoblasts were eligible. Patients with peripheral absolute (every 12 weeks after the last disease assessment for 1 year from
lymphoblast count $25 000/mL were included if treated with first dose and every 24 weeks in year 2 until PD, initiation of
hydroxyurea or steroids within 2 weeks of the first dose to reduce poststudy anti–cancer therapy, or until achievement of 2 years of
white blood cell count to #25 000/mL; those with Philadelphia follow-up), and as clinically indicated (see supplemental Materials for
chromosome–positive ALL must have failed standard treatment definitions used for response and PD status assessments). DOR
with $1 tyrosine kinase inhibitor. Other key eligibility criteria was defined as the time from first CR/CRi to relapse after CR/CRi,

1168 DeANGELO et al 27 JUNE 2017 x VOLUME 1, NUMBER 15

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Table 1. Candidate InO doses and schedules a priori due to the outcome-adaptive nature of the Bayesian procedure
Dosing Schedule,* mg/m2 used for cohort assignment; 24 patients were ultimately enrolled. An
Total dose per
Dose level Day 1 Day 8 Day 15 Day 21 cycle, mg/m2
interim futility analysis (IA) was to be performed based on 10 evaluable
patients receiving the RP2D in the phase 1 dose escalation part:
22 0.4 0 0.4 BM evaluation performed 0.8
for disease assessment
the trial was to be stopped if none achieved CR/CRi; otherwise, 12
additional patients were to be enrolled in a dose expansion cohort (13
21 0.6 0 0.4 BM evaluation performed 1.0
for disease assessment patients were ultimately enrolled). For phase 2, a maximum sample
size of 35 patients was estimated based on a 2-stage design using
1 0.8 0 0.4 BM evaluation performed 1.2
for disease assessment swogstat.42 In an IA of the first 12 patients in stage 1, an additional 23
2 0.8 0.4 0.4 BM evaluation performed 1.6
patients were to be enrolled in stage 2 if $2 of these 12 patients
for disease assessment achieved CR/CRi (see supplemental Materials for details of hypotheses).
3 0.8 0.5 0.5 BM evaluation performed 1.8 All enrolled patients received treatment; safety and antitumor
for disease assessment
activity were assessed in all treated patients. DOR, PFS, and OS
4 1.0 0.5 0.5 BM evaluation performed 2.0 distributions were summarized using the Kaplan-Meier method. PK
for disease assessment
and pharmacodynamic analyses were based on patients with $1
*Each cycle was 28 d (#6 cycles). quantifiable InO and/or unconjugated calicheamicin concentration
or PK parameter of interest. PG analyses were based on enrolled
patients who had received $1 InO dose and with $1 sample with
treatment discontinuation due to health deterioration, or death, both a baseline and a posttreatment assessment.
whichever occurred first. MRD negativity was defined as ,0.01%
leukemic blasts per total nucleated mononuclear BM cells, analyzed Results
centrally using multiparametric flow cytometry. Patients were followed
for survival for up to 2 years. Patients
A total of 72 patients received $1 dose of InO (phase 1 dose
PK, pharmacodynamic, and PG assessments
escalation, n 5 24; phase 1 dose expansion, n 5 13; phase 2, n 5 35;
Serum InO and unconjugated calicheamicin concentrations were supplemental Figure 1). The median age was 45 (range, 20-79) years;
determined from blood samples drawn during days 1 and 15 of cycles 22% had Ph1 disease, and 32% had received prestudy SCT; 78%
1 and 2 (at 0, 1, and 3 hours), and day 1 of cycle 4 (at 0 and 1 hour). had received $2 salvage treatments; 21% had complex cytogenetics
Samples were analyzed using a validated liquid chromatography ($5 chromosomal aberrations); 60% had first CR duration ,12
coupled to tandem mass spectrometry procedure (Pharmaceutical months; and 74% had ECOG performance status score 0-1 (Table 2).
Product Development Laboratories, Richmond, VA; lower limit of
Patients completed median 3 (range, 1-6) treatment cycles. Median
quantitation [LLOQ] 5 1 ng/mL for InO; LLOQ 5 50 pg/mL for
treatment duration was 2.1 (range, 0.02-9.5) months; median
unconjugated calicheamicin).
follow-up was 12.1 (range, 6.8-12.8) months for patients in phase 2
Circulating B-lymphocyte count was determined in blood samples alive at the time of data cutoff and 23.7 (range, 6.8-29.8) months for
collected on days 1, 8, 15, and 21 of cycles 1 through 6, at the end of all treated patients alive at the time of data cutoff. As of the data cutoff
treatment, and for 4 to 6 weeks after the last dose. CD22 expression date (30 January 2015), 96% of patients had discontinued treatment,
on circulating CD191 B-lymphocytes was determined in blood most commonly due to PD/relapse (42%), proceeding to HSCT
samples collected predose, at the end of infusion on days 1 and 15 (25%), or AEs (18%); 18 patients were alive.
of cycles 1 and 2, and on day 1 of cycle 4.
RP2D determination and confirmation
For assessments of InO PK and pharmacodynamic effects on the
achievement of MRD negativity (defined as above), BM aspirates were Details of patient enrollment and associated DLTs in the phase 1
collected at screening, day 28 of cycles 1 through 6, and at the end of dose-escalation portion are presented in supplemental Materials;
treatment. Dose-normalized maximum (Cmax, dn) and minimum (Cmin, dn) briefly, no DLTs occurred in the 1.2- and 1.6-mg/m2 per cycle
serum InO concentrations were determined from the PK samples cohorts and 1 DLT occurred in the 1.8-mg/m2 per cycle cohort
collected on days 1 and 15 of each cycle. (grade 4 elevated lipase). For the 1.2-, 1.6-, and 1.8-mg/m2 per
cycle cohorts, respectively, the CR/CRi rates were 67% (n 5 2/3
To examine correlations between clinical outcome and gene expres- [95% confidence interval (CI) 9% to 99%]), 75% (n 5 9/12 [43%
sion, peripheral whole blood samples were collected in PAXgene tubes to 95%]), and 89% (n 5 8/9 [52% to 100%]), of whom 2, 8, and
(QIAGEN, Valencia, CA) on days 1 and 15 of cycle 1 (each at predose 8 patients achieved MRD negativity (overall: 95% [n 5 18/19]).
and postdose time points). Messenger RNA (mRNA) levels were Based on considerations of CR/CRi, MRD-negativity rates, and DLTs,
determined using custom 96-gene format TaqMan Low Density Array the RP2D was determined to be 1.8 mg/m2 per cycle (0.8 mg/m2 [day 1];
cards (Thermo Fisher Scientific, Waltham, MA). Reference genes used 0.5 mg/m2 [days 8 and 15]) as a starting dose. Subsequent dose
were ACTB, B2M, GAPDH, and PGK1; mRNA levels for each target reduction to 1.6 mg/m2 per cycle (0.8 mg/m2 [day 1]; 0.4 mg/m2
gene were reported as a normalized value, 22DCt, where DCt 5 Ct [days 8 and 15]) was recommended upon achievement of CR/CRi,
target gene 2 Ct reference genes, averaged. based on the previous observations: (1) InO exposure increases with
subsequent doses following remission,43 (2) tumor burden or blast
Statistical analysis count may be related to exposure, (3) dose modifications are common
The estimated maximum sample size for the phase 1 dose-escalation later in therapy, and (4) 7/9 (78%) patients in the 1.8 mg/m2 per cycle
part was 36 patients. However, this could not be precisely determined cohort experienced AEs leading to dose delay.

27 JUNE 2017 x VOLUME 1, NUMBER 15 INOTUZUMAB OZOGAMICIN FOR CD22-POSITIVE ALL 1169

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 1170
Table 2. Patient characteristics
Phase 1 part
Dose escalation

DeANGELO et al
Characteristic 1.2 mg/m2 (n 5 3) 1.6 mg/m2 (n 5 12) 1.8 mg/m2 (n 5 9) Dose expansion 1.8 mg/m2 (n 5 13) Phase 2 part (n 5 35) All treated (n 5 72)

Age, median, y (range) 64.0 (62-65) 43 (23-69) 42 (23-67) 57 (24-75) 34 (20-79) 45 (20-79)
,65, n (%) 2 (67) 10 (83) 8 (89) 10 (77) 31 (89) 61 (85)

Male, n (%) 3 (100) 11 (92) 3 (33) 7 (54) 27 (77) 51 (71)

Race, n (%)

White 3 (100) 9 (75) 8 (89) 10 (77) 25 (71) 55 (76)

Asian 0 0 1 (11) 1 (8) 4 (11) 6 (8)

Black 0 1 (8) 0 1 (8) 0 2 (3)

Other/unspecified 0 2 (17) 0 1 (8) 6 (17) 9 (13)

ECOG performance status, n (%)

0 0 4 (33) 1 (11) 4 (31) 3 (9) 12 (17)
1 2 (67) 5 (42) 5 (56) 7 (54) 22 (63) 41 (57)

2 1 (33) 3 (25) 3 (33) 1 (8) 8 (23) 16 (22)

3 0 0 0 1 (8) 2 (6) 3 (4)

Salvage status, n (%)

1 0 4 (33) 3 (33) 7 (54) 2 (6)* 16 (22)

2 1 (33) 5 (42) 3 (33) 4 (31) 16 (46) 29 (40)

3 2 (67) 2 (17) 2 (22) 1 (8) 11 (31) 18 (25)

4 0 0 0 0 2 (6) 2 (3)
5 0 1 (8) 1 (11) 1 (8) 1 (3) 4 (6)
.5 0 0 0 0 3 (9) 3 (4)

Median (range) duration since primary diagnosis, y 1.5 (0.5-4.9) 2.1 (0.2-6.6) 1.1 (0.4-20.4) 1.6 (0.2-4.9) 2.5 (0.4-16.0) 1.7 (0.2-20.4)
Response to last induction therapy, n (%)

Relapsed 1 (33) 5 (42) 5 (56) 7 (54) 12 (34) 30 (42)

Refractory 2 (67) 5 (42) 4 (44) 5 (38) 19 (54) 35 (49)

Unknown 0 2 (17) 0 1 (8) 4 (11) 7 (10)

Prior SCT, n (%) 1 (33) 1 (8) 3 (33) 3 (23) 15 (43) 23 (32)

27 JUNE 2017 x VOLUME 1, NUMBER 15

WBC, white blood cells.

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*Two patients enrolled in the phase 2 part were undergoing first salvage (protocol deviations).
†Patients had $5 chromosomal aberrations.
‡Based on a minimum of 20 metaphases.
§Two patients had missing data (phase 1 [1.6 mg/m2], n 5 1; phase 1 dose expansion, n 5 1).
‖Based on central laboratory analysis; the results for 2 patients were based on peripheral blood analysis (aspirate not collected).
{Three patients had missing data (phase 1 dose expansion, n 5 1; phase 2, n 5 2).
 Table 2. (continued)
Phase 1 part
Dose escalation
Characteristic 1.2 mg/m2 (n 5 3) 1.6 mg/m2 (n 5 12) 1.8 mg/m2 (n 5 9) Dose expansion 1.8 mg/m2 (n 5 13) Phase 2 part (n 5 35) All treated (n 5 72)

Cytogenetics, n (%)

Ph1 2 (67) 1 (8) 1 (11) 3 (23) 9 (26) 16 (22)

Complex† 0 1 (8) 2 (22) 1 (8) 11 (31) 15 (21)

Normal‡ 0 6 (50) 4 (44) 1 (8) 4 (11) 15 (21)

Unknown§ 0 1 (8) 0 0 3 (9) 4 (6)

Other 1 (33) 2 (17) 2 (22) 7 (54) 8 (23) 20 (28)

27 JUNE 2017 x VOLUME 1, NUMBER 15

t(4;11) 0 0 0 2 (15) 0 2 (15)

Median (range) CD221,‖ % blasts 99.6 (96-100) 98.7 (31-100) 98.4 (97-100) 95.1 (52-100) 99.2 (78-100) 99.0 (31-100)
BM blasts, n (%){
,50% 0 4 (33) 1 (11) 1 (8) 5 (14) 11 (15)

$50% 3 (100) 8 (67) 8 (89) 11 (85) 28 (80) 58 (81)

Peripheral blasts, cells/mm3, n (%)

0 0 7 (58) 5 (56) 2 (15) 13 (37) 27 (38)

.0-1000 3 (100) 4 (33) 0 1 (8) 6 (17) 14 (19)

.1000-5000 0 0 2 (22) 5 (38) 7 (20) 14 (19)

.5000-10 000 0 1 (8) 1 (11) 1 (8) 3 (9) 6 (8)

.10 000 0 0 1 (11) 4 (31) 6 (17) 11 (15)

Median (range) WBC, 3 109/L 1.2 (0.6-1.4) 2.6 (0.5-27.8) 5.4 (2.5-29.1) 17.9 (0.5-67.2) 3.3 (0.5-57.1) 4.4 (0.5-67.2)

WBC, white blood cells.

*Two patients enrolled in the phase 2 part were undergoing first salvage (protocol deviations).
†Patients had $5 chromosomal aberrations.
‡Based on a minimum of 20 metaphases.
§Two patients had missing data (phase 1 [1.6 mg/m2], n 5 1; phase 1 dose expansion, n 5 1).
‖Based on central laboratory analysis; the results for 2 patients were based on peripheral blood analysis (aspirate not collected).
{Three patients had missing data (phase 1 dose expansion, n 5 1; phase 2, n 5 2).

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INOTUZUMAB OZOGAMICIN FOR CD22-POSITIVE ALL
1171
Table 3. Treatment-related TEAEs (‡10% of all treated population)
Phase 1 part
Dose escalation
Dose expansion
1.2 mg/m2 (n 5 3) 1.6 mg/m2 (n 5 12) 1.8 mg/m2 (n 5 9) 1.8 mg/m2 (n 5 13) Phase 2 part (n 5 35) All treated (n 5 72)
TEAEs, n (%) Any grade Grade ‡3 Any grade Grade ‡3 Any grade Grade ‡3 Any grade Grade ‡3 Any grade Grade ‡3 Any grade Grade ‡3

Thrombocytopenia* 2 (67) 1 (33) 4 (33) 3 (25) 4 (44) 4 (44) 4 (31) 4 (31) 12 (34) 12 (34) 26 (36) 24 (33)

Neutropenia†,‡ 1 (33) 1 (33) 2 (17) 2 (17) 5 (56) 5 (56) 3 (23) 3 (23) 9 (26) 7 (20) 20 (28) 18 (25)
AST increased 0 0 3 (25) 0 5 (56) 0 3 (23) 0 8 (23) 2 (6) 19 (26) 2 (3)

Nausea 0 0 2 (17) 0 2 (22) 0 3 (23) 0 8 (23) 0 15 (21) 0

Vomiting 0 0 2 (17) 0 2 (22) 1 (11) 2 (15) 0 6 (17) 0 12 (17) 1 (1)

Fatigue 0 0 5 (42) 0 1 (11) 0 1 (8) 0 4 (11) 0 11 (15) 0

Febrile neutropenia 0 0 0 0 0 0 2 (15) 2 (15) 9 (26) 7 (20) 11 (15) 9 (13)

AP increased 0 0 0 0 4 (44) 1 (11) 1 (8) 0 5 (14) 0 10 (14) 1 (1)

Anemia§ 0 0 1 (8) 1 (8) 2 (22) 1 (11) 2 (15) 2 (15) 5 (14) 4 (11) 10 (14) 8 (11)
GGT increased 1 (33) 0 0 0 5 (56) 1 (11) 0 0 3 (9) 0 9 (13) 1 (1)

ALT increased 0 0 1 (8) 1 (8) 1 (11) 1 (11) 1 (8) 0 5 (14) 0 8 (11) 2 (3)
Pyrexia 0 0 0 0 1 (11) 0 2 (15) 0 5 (14) 0 8 (11) 0

Hyperbilirubinemia 0 0 0 0 1 (11) 0 0 0 6 (17) 0 7 (10) 0

*Includes entries under the preferred term “platelets decreased.”

†Includes entries under the preferred term “neutrophil count decreased.”
‡One patient with grade 3 neutropenia had a prior event of treatment-related grade 4 neutropenia recorded after the data snapshot and was not included in this table.
§Includes entries under the preferred term “hemoglobin count decreased.”

In a futility IA of 10 evaluable patients receiving the RP2D in 1 had VOD/SOS ongoing at the time of death due to PD). Of 24
the phase 1 dose-escalation part (see supplemental Materials), $1 patients who proceeded to HSCT, 2 experienced VOD/SOS after
achieved CR/CRi (n 5 7). Per protocol, 13 additional patients were poststudy HSCT. These 2 patients received pretransplant condition-
enrolled in the dose-expansion cohort to confirm the RP2D, among ing with cyclophosphamide plus total body irradiation (TBI) and
whom no DLTs were observed. Six (46% [95% CI, 19% to 75%]) of etoposide plus fractionated TBI.
these patients achieved CR/CRi, of whom 5 (83%) achieved MRD Of all treated patients, 12 (17%) permanently discontinued treatment
negativity. In a futility IA of the first 12 evaluable patients receiving due to TEAEs, including ascites (n 5 2) and liver-related TEAEs
the RP2D in stage 1 of phase 2, $2 achieved CR/CRi; per protocol, (elevated ALT, AST, alkaline phosphatase [AP], GGT, and VOD [n 5 1
23 patients were enrolled in stage 2 without interruption, for a total each]; supplemental Table 2). Seven patients (10%) reduced dose due
of 35 patients in phase 2 of the study. to TEAEs, most commonly thrombocytopenia (n 5 3) and neutropenia
Safety and tolerability (n 5 3); 37 had dose delays due to TEAEs, most commonly thrombo-
Among all treated patients (n 5 72), the most frequent treatment- cytopenia (n 5 10), AST increased (n 5 9), neutropenia (n 5 10), and
related treatment-emergent AEs (TEAEs; $15% of patients) were ALT increased (n 5 6; supplemental Table 2).
thrombocytopenia (any grade, 36%; grade $3, 33%), neutropenia Fifty-four deaths (75%) occurred, including 12 during treatment and
(28%; 25%), aspartate aminotransferase (AST) increased (26%; up to 42 days after last dose and 42 during follow-up. Causes
3%), nausea (21%; 0%), vomiting (17%; 1%), fatigue (15%; 0%), of death during treatment included PD (n 5 9), septic shock,
and febrile neutropenia (15%; 13%; Table 3). The incidence of all- pneumonia, and subdural hematoma (n 5 1 each).
causality TEAEs followed a similar pattern (supplemental Table 1).
The most common serious TEAE was febrile neutropenia (22%). Efficacy

Treatment-related hepatic TEAEs included elevated AST (any Of the 35 patients receiving the RP2D in phase 2, 24 (69%)
grade, 26%; grade $3, 3%), g-glutamyltransferase (GGT: 13%; achieved CR/CRi (1-sided P , .0001 for the null hypothesis: CR/
1%), alanine aminotransferase (ALT; 11%; 3%), and hyperbilirubine- CRi rate #20%); therefore, the primary phase 2 endpoint (CR/CRi)
was met (Table 4). Potential prognostic factors (supplemental
mia (10%; 0%). Four VOD/SOS cases were reported (1 during phase
1 dose expansion [1.8 mg/m2] and 3 during phase 2), 2 confirmed by Table 3) were also assessed.
biopsy; all were considered treatment related and 1 was fatal. One Among all patients treated (n 5 72), 49 (68%) achieved CR/CRi
VOD/SOS event occurred during treatment (patient recovered with (CR, n 5 23; CRi, n 5 26; Table 4), with a median time to CR/CRi
sequelae of ascites and was able to proceed to allogeneic HSCT of 27.0 (range, 15-91) days. The median DOR was 4.6 (95% CI,
without further liver toxicity); another occurred during follow-up 3.8-6.6) months (Figure 1A). Ten patients who initially had CRi later
without intervening HSCT, shortly after starting maintenance therapy achieved CR during treatment. Of the 49 patients with CR/CRi,
with ponatinib and continued until death due to pneumonia. Three of 41 (84%) achieved MRD negativity (median time to MRD negativity,
the 4 patients with VOD/SOS had received defibrotide (2 recovered; 29.0 [range, 21-141] days); 18 (37%) relapsed during treatment or

1172 DeANGELO et al 27 JUNE 2017 x VOLUME 1, NUMBER 15

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 Table 4. Efficacy endpoints
Phase 1 part
Dose escalation
Dose expansion
Endpoint 1.2 mg/m2 (n 5 3) 1.6 mg/m2 (n 5 12) 1.8 mg/m2 (n 5 9) 1.8 mg/m2 (n 5 13) Phase 2 part (n 5 35) All treated (n 5 72)

Hematologic remission,
n (%) (95% CI)*

CR/CRi 2 (67) (9-99) 9 (75) (43-95) 8 (89) (52-100) 6 (46) (19-75) 24 (69) (51-83)† 49 (68) (56-79)
CR 1 (33) 7 (58) 3 (33) 2 (15) 10 (29) 23 (32)

CRi 1 (33) 2 (17) 5 (56) 4 (31) 14 (40) 26 (36)

Median (range) time to 39 (22-56) 29 (22-59) 38 (22-78) 27 (21-85) 25.5 (15-91) 27 (15-91)
CR/CRi, d
Median (95% CI) DOR
among responders,‡ mo
CR/CRi 4.7 (4.6-4.8) NR (0.7-NR) 10.8 (1.2-NR) 7.2 (2.1-NR) 3.8 (2.2-5.8)§ 4.6 (3.8-6.6)‖

CR 4.6 NR (0.7-NR) 15.2 (1.2-15.2) 6.1 (2.1-10.0) 2.8 (0.9-5.5) 4.6 (2.2-15.2)
CRi 4.8 NR (NR-NR) 7.0 (1.7-NR) NR (2.8-NR) 4.0 (1.2-6.6) 4.8 (3.8-9.0)
MRD negativity among
responders,{ n (%) (95% CI)

27 JUNE 2017 x VOLUME 1, NUMBER 15

CR/CRi 2/2 (100) (16-100) 8/9 (89) (52-100) 8/8 (100) (63-100) 5/6 (83) (36-100) 18/24 (75) (53-90) 41/49 (84) (70-93)
CR 1/1 (100) (3-100) 6/7 (86) (42-100) 3/3 (100) (29-100) 2/2 (100) (16-100) 7/10 (70) (35-93) 19/23 (83) (61-95)
CRi 1/1 (100) (3-100) 2/2 (100) (16-100) 5/5 (100) (48-100) 3/4 (75) (19-99) 11/14 (79) (49-95) 22/26 (85) (65-96)

Median (range) time to 98.5 (98-99) 32.0 (22-64) 30.0 (22-141) 25.0 (21-134) 25.5 (21-80) 29.0 (21-141)
MRD negativity, d

HSCT rate
Patients proceeding to 0 9 (75) 4 (44) 3 (23) 8 (23) 24 (33)
poststudy HSCT, n (%)
Median (range) time to — 36 (20-60) 61.5 (41-84) 77 (55-90) 40 (27-148) 45.5 (20-148)
HSCT, d
PFS‡

Events, n (%) 3 (100) 6 (50) 7 (78) 11 (85) 31 (89) 58 (81)

Median (95% CI), mo 5.5 (2.1-6.4) 6.5 (1.4-NR) 8.8 (1.3-16.7) 1.9 (1.0-5.0) 3.7 (2.6-4.7) 3.9 (2.9-5.4)

Probability of PFS at 0 0.46 (0.20-0.70) 0.44 (0.10-0.70) 0.15 (0-0.40) 0.08 (0-0.20) 0.20 (0.10-0.30)
12 mo (95% CI)

OS‡
Events, n (%) 3 (100) 6 (50) 6 (67) 10 (77) 29 (83) 54 (75)

Median (95% CI), mo 9.2 (2.1-11.3) NR (2.6-NR) 16.5 (2.6-NR) 5.8 (3.5-10.8) 6.4 (4.5-7.9) 7.4 (5.7-9.2)

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Probability of OS at 0 0.50 (0.20-0.70) 0.67 (0.30-0.90) 0.23 (0.10-0.50) 0.18 (0.10-0.30) 0.30 (0.20-0.40)
12 mo (95% CI)

NR, not reached.

*95% CI is the exact CI for a binomial proportion.
†One-sided P , .0001 for the null hypothesis (H0): CR 1 CRi rate #20% using binomial distribution.
‡Uncensored for HSCT.

INOTUZUMAB OZOGAMICIN FOR CD22-POSITIVE ALL

§Median DOR was similar upon inclusion of 4 additional patients censored for HSCT (3.8 [95% CI, 2.2-4.2] mo).
‖Median DOR was 4.3 (95% CI, 3.8-5.6) mo with 9 additional patients censored for HSCT.
{MRD negativity was defined as ,0.01% leukemic blasts/total nucleated mononuclear cells in BM; 95% CI is the exact CI for a binomial proportion.

1173
within 30 days of the last dose. Median DOR and MRD-negativity decreased with time on treatment (;50% at C4D1 compared with
rates among patients achieving CRi, CR, and CR/CRi were similar C1D1 [data not shown]); this decrease tended to be less in patients
(Table 4). who had relatively higher proportions of leukemic BM blasts,
suggesting a direct relationship between the extent of InO elimination
For all treated patients, median PFS and OS were 3.9 (95% CI, 2.9-
and BM blast level.
5.4) and 7.4 (95% CI, 5.7-9.2) months; the Kaplan-Meier estimated
probabilities of PFS and OS at 12 months were 0.20 (95% CI, 0.10- BM blasts and MRD negativity
0.30) and 0.30 (95% CI, 0.20-0.40), respectively (Figure 1B-C).
The effect of BM blast count or salvage status on PFS is shown in An analysis of dose-normalized Cmax and Cmin by MRD-negativity
supplemental Table 4. status indicated that patients achieving MRD negativity tended to
have higher peak and trough InO concentrations throughout treatment
In all treated patients, 24 (33%) proceeded to poststudy HSCT vs those who did not (Figure 3A). In contrast, achievement of MRD
(median time to HSCT, 45.5 [range, 20-148] days), nearly all of negativity appeared to be unrelated to baseline disease burden
whom (n 5 22/24 [92%]) had achieved CR/CRi before HSCT. Of (percentage baseline BM blasts). Evidence supporting this is provided
the 2 patients who proceeded to HSCT without achieving CR/CRi, by plots of baseline BM blast percentages determined for individual
1 had a partial response and 1 had disease resistant to InO treatment patients at each protocol-specified BM aspirate collection time
and initiated new (non-InO) induction therapy before HSCT. Before (Figure 3B), which show that line profiles for patients achieving
HSCT, most patients (n 5 15/24 [63%]) had received fludarabine- MRD negativity (green lines) originated across a range of baseline
and/or TBI-based conditioning regimens (n 5 17/24 [71%]); only 1 BM blast percentages. This lack of a relationship between the
had received dual alkylator conditioning (cyclophosphamide, thiotepa, percentage of BM blasts at baseline and achievement of MRD
and fludarabine). Of the 24 patients who had poststudy HSCT, 12 negativity was also apparent from the serum InO concentration time
subsequently died (2 died due to relapse/PD). Seven of the 12 course during cycles 1 through 4 (Figure 3C).
patients died #100 days after poststudy HSCT (1 died due to
relapse/PD). Other causes of death after poststudy HSCT were Baseline mRNA levels in peripheral whole blood and
sepsis (n 5 4), complications of HSCT, gut graft-versus-host relationship with clinical outcome
disease/liver dysfunction, hepatic failure/SOS, respiratory failure, Baseline levels of several mRNAs were significantly higher in patients
Klebsiella pneumoniae/liver graft-versus-host disease, and un- who subsequently achieved CR/CRi and MRD negativity vs those
known (each n 5 1). During the study, 4 patients had extramedullary who did not achieve CR/CRi, including mRNAs encoded by genes
disease that regressed, and 4 of the patients had extramedullary implicated in stress response/drug resistance (ABCG2, median sev-
disease that remained stable or increased in size. The 27 patients enfold higher [P 5 .0071]; BCL2L1, median 11-fold higher [P 5 .0055];
who achieved CR/CRi and did not have poststudy HSCT received FASLG, median fourfold higher [P 5 .036]). No relationship was
median 4 (range, 1-6) treatment cycles; 5 (19%) of these patients apparent between baseline peripheral blood CD22 mRNA levels
were aged $65 years; 15 (56%) received prestudy SCT; 21 (78%) and achieving CR/CRi and MRD negativity.
received $2 salvage treatments; 16 (59%) experienced PD/relapse
,1 month of discontinuing treatment; 3 (11%) died ,1 month of Peripheral blood CD22 mRNA levels were decreased by day 15
discontinuing treatment (1 due to relapse/PD); and 11 (41%) relative to baseline (median, 97% decrease; P , .0001), consistent
initiated a new induction systemic therapy during follow-up. with selective ablation of CD22-positive leukemic blasts by InO
(supplemental Figure 2). CD22 mRNA levels in patients who
Pharmacokinetics subsequently achieved CR/CRi and MRD negativity were lower by
day 15 vs those who did not achieve CR/CRi (P 5 .01). Comparable
Mean peak serum InO concentrations were observed at or near the
reductions and trends were evident for several other mRNAs
end of infusion; these generally increased with cycle number
encoding B-cell lineage markers, including PAX5, VPREB1, and
(supplemental Table 5). Unconjugated calicheamicin concentra-
EBF1 (data not shown). Conversely, mRNA levels for several genes
tions were below the LLOQ for most patients and time points.
implicated in stress response, drug resistance, and apoptotic
regulation were two- to fivefold higher by day 15 relative to baseline
Peripheral blood B-lymphocyte depletion
(ABCG2, BCL2L1, FASLG; all P , .0001). P values for these PG
and regeneration analyses were not adjusted for the potential for false discovery due
For all treated patients (n 5 72), InO treatment was accompanied to the large number of samples assessed; hence, these findings are
by a consistently rapid depletion followed by a slow regeneration of considered preliminary.
B-lymphocytes in peripheral blood during follow-up, with substantial
interpatient differences in regeneration rate (Figure 2A). A similar Discussion
rapid depletion followed by slow regeneration of B-lymphocytes was In this phase 1/2 trial of single-agent InO for relapsed/refractory
apparent regardless of InO dose, although few patients received the
CD22-positive ALL, the RP2D was 1.8 mg/m2 per cycle (0.8 mg/m2
lower doses (Figure 2B). [day 1]; 0.5 mg/m2 [days 8 and 15]) as a starting dose, with
InO elimination according to percentage of leukemic blasts in BM subsequent dose reduction to 1.6 mg/m2 per cycle upon achievement
(relative to total leukocytes) separated by dosing events is shown of CR/CRi. Toxicities associated with treatment were primarily
for individual patients in Figure 2C. As shown by the color gradient cytopenias and liver-related toxicities. Encouraging clinical activity
of the points (darker 5 higher percent blasts; lighter 5 lower was observed, with 68% of all treated patients achieving CR/CRi and
percent blasts), the percentage of leukemic blasts in BM decreased 33% of patients able to proceed to poststudy HSCT. Nevertheless,
over time and with each cycle, with very low percentages observed at remission was often transitory with 18 (37%) patients relapsing during
later time points. In general, the InO serum elimination rate constant treatment or within 30 days of the last dose; consolidation with HSCT

1174 DeANGELO et al 27 JUNE 2017 x VOLUME 1, NUMBER 15

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Figure 1. Kaplan-Meier distributions. (A) DOR. (B) PFS. (C) OS.
See supplemental Materials for DOR, PFS, and OS definitions. A
PR, partial response. 1.0 n Median DOR (95% CI), mo
0.9
All treated 49 4.6 (3.8–6.6)
0.8 Phase 2 part 24 3.8 (2.2–5.8)
0.7

DOR probability
0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30
Months
Patients at risk, n
All Treated 49 31 18 13 10 9 7 7 1 1 0
Phase 2 part 24 13 5 2 0

B
1.0
n Median PFS (95% CI), mo
0.9
All treated 72 3.9 (2.9–5.4)
0.8 Phase 2 part 35 3.7 (2.6–4.7)
0.7
Probability of PFS

0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30
Months
Patients at risk, n
All Treated 72 43 24 17 11 10 7 7 3 1 0
Phase 2 part 35 21 9 5 1 0

C
1.0 n Median OS (95% CI), mo
0.9
All treated 72 7.4 (5.7–9.2)
0.8 Phase 2 part 35 6.4 (4.5–7.9)
0.7
Probability of OS

0.6
0.5
0.4
0.3
0.2
0.1
0.0
0 3 6 9 12 15 18 21 24 27 30
Months
Patients at risk, n
All Treated 72 58 42 28 19 14 12 12 7 2 0
Phase 2 part 35 28 19 9 4 0

27 JUNE 2017 x VOLUME 1, NUMBER 15 INOTUZUMAB OZOGAMICIN FOR CD22-POSITIVE ALL 1175

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 Figure 2. Peripheral blood B-lymphocyte depletion and
A 5 regeneration. (A) B-lymphocyte concentration in blood was
determined vs time for individual patients during InO treatment
Lymphocytes in peripheral blood, 109/L

(red circles; n 5 72) and during follow-up (triangles; n 5 24). Data

4 were fitted to a linear mixed-effects model (green dashed lines 5
individual model predictions; solid black line 5 best fit line for
overall mean effect of time on B-lymphocyte depletion and
3
regeneration). (B) B-lymphocyte concentration profiles vs time by
InO dose (1.2, 1.6, and 1.8 mg/m2 per cycle) for individual
2 patients. (C) InO elimination vs time by percent of BM blasts for
individual patients. The 4 panels show serum InO concentration
vs time data for InO dosing at cycle 1 day 1 and 15 and cycle 2
1 days 1 and 15. BM aspirates were collected at screening
(circles), cycle 1 day 28 (triangles), and cycle 2 day 28 (squares).
Symbol colors are scaled by percent leukemic blasts in BM.
0

0 250 500 750 1000

Time post first dose, d
Best Fit Line Individual Predictions On–Drug Follow-Up

B 20

1.2 mg/m2
15
10
Lymphocytes in peripheral blood, 109/L

5
0
20
1.6 mg/m2

15
10
5
0
20
1.8 mg/m2

15
10
5
0
0 250 500 750
Days
InO treatment (n=72) Follow–up (n=24)

C 7.5
Cycle 1
Day 1

5.0
2.5
0.0
7.5
Cycle 1
Day 15
Log [InO], ng/mL

5.0
2.5
0.0
7.5
Cycle 2
Day 1

5.0
2.5
0.0
7.5
Cycle 2
Day 15

5.0
2.5
0.0
10 1000
Time postdose, h
Percent leukemic
BM aspirate at Screening Cycle1 Day 28 Cycle 2 Day 28 BM blasts 0 25 50 75

1176 DeANGELO et al 27 JUNE 2017 x VOLUME 1, NUMBER 15

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Figure 3. Relationship between InO PK parameters and
MRD status. (A) Box plots of dose normalized (dn) values of A
median Cmax and Cmin by cycle (1 to 4) and by achievement of Cmin, dn Cmax, dn
MRD negativity (yes vs no). Boxes correspond to the 25% and
75% percentiles; whiskers extend to the most extreme data point
1000
that is no more than 1.5 times the length of the box away from the
box. Red points represent potential outliers and correspond to
individual values .1.5 times the interquartile range above or below

Log [InO], ng/mL

the respective quartile. (B) Relationship between percentage BM
blasts at baseline and achieving MRD negativity for individual
patients. Green and blue plots correspond to patients achieving
and not achieving MRD negativity, respectively. (C) The 5 panels 10
show serum InO concentration vs time by MRD-negativity status
for dosing at cycle 1 day 1 and 15, cycle 2 days 1 and 15,
and cycle 4 day 1. Symbol sizes represent percent leukemic
blasts in BM.

Cycle 1 Cycle 2 Cycle 4 Cycle 1 Cycle 2 Cycle 4

Achievement of MRD Negativity Yes No

B
100

75
Baseline BM blasts, %

50

25

0
Screening Cycle 1 Cycle 2
Day 28 Day 28
Achievement of MRD Negativity Yes No

C
Cycle 1 Day 1 Cycle 1 Day 15 Cycle 2 Day 1 Cycle 2 Day 15 Cycle 4 Day 1
n=59 n=55 n=56 n=52 n=23

1000
Log [InO], ng/mL

10
e

e
st

st

st

st

st
h

h
Pr

Pr

Pr

Pr

Pr
Po

Po

Po

Po

Po
+2

+2

+2

+2

+2

Achievement of MRD negativity Yes No Percent BM blasts at baseline 25 50 75

27 JUNE 2017 x VOLUME 1, NUMBER 15 INOTUZUMAB OZOGAMICIN FOR CD22-POSITIVE ALL 1177

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for suitable patients with readily available donors may extend the DOR. risk of VOD/SOS.52 Lower doses of InO combined with chemo-
The short-lived remission might appear at odds with the observed high therapy are also being examined in patients with relapsed/refractory
MRD-negativity rate (84%) among responders, which has been ALL (Southwestern Oncology Group S1312 trial [NCT01925131])
shown to be prognostic of prolonged remission following induction to assess whether this regimen will be associated with increased
therapy for de novo ALL.44 However, the distribution of MRD markers efficacy and/or decreased toxicity.
used at initial diagnosis can change at relapse due to clonal evolution,45 InO treatment was accompanied by a rapid decrease in B-lymphocyte
suggesting that MRD-negativity rate in second or subsequent remission count, followed by slow and variable regeneration. Although CD22
may have decreased prognostic value in DOR compared with that in the expression is not a significant determinant of InO exposure, separate
de novo ALL setting. analyses (not shown) demonstrated that the number of doses
The observation that .50% of patients with CR/CRi achieved a administered did influence elimination rate, an effect thought to be
CRi as opposed to a CR raises the question whether the CR rate associated in part with target-mediated drug clearance. Notably,
may have been improved by extending the time allowed for platelet patients achieving MRD negativity tended to have higher serum InO
recovery; notably, 10 patients who initially achieved CRi later concentrations. Changes in mRNA profiles in blood consistent with
achieved CR during treatment. However, the extent to which the mechanism of action of InO were evident, including decreased
platelets would have recovered given more time is unclear because CD22 mRNA. By day 15, CD22 mRNA levels in patients who
most patients achieving CR/CRi proceeded to additional therapies subsequently achieved CR/CRi and MRD negativity were lower vs
such as HSCT to consolidate the response to InO. those who did not achieve CR/CRi (P 5 .01). The results corroborate
the proposed mechanism of action of InO, although these exploratory
The reported CR/CRi rate is higher compared with that observed in exposure and pharmacodynamic/PG analyses require confirmation by
a previous phase 1/2 study (68% vs 58%)18 and compared with further studies. Moreover, measurement of CD22 mRNA in peripheral
conventional chemotherapy (ranging from 30% to 40% after first whole blood may warrant further exploration as a simple and
salvage and 10% to 20% after later salvage).3,13,30 Other novel sensitive way to assess circulating disease burden.
therapies have also yielded higher response rates compared
with standard chemotherapy. Blinatumomab, a bispecific CD19- In conclusion, single-agent InO administered in a weekly regimen at
directed CD3 T-cell engager,30 has demonstrated relatively high an initial cumulative dose of 1.8 mg/m2 per cycle is associated with
remission rates, with 69% and 43% of patients with early and manageable toxicities and encouraging clinical activity in this
refractory relapses achieving CR or CR with partial hematologic multiple relapsed/refractory population. Patients achieving MRD
recovery in 2 phase 2 trials.46,47 The median OS in these 2 negativity tended to have higher peak and trough InO concentra-
blinatumomab trials were 9.8 (95% CI, 8.5-14.9) and 6.1 (95% CI, tions throughout treatment. In contrast, no correlation was observed
4.2-7.5) months (median follow-up, 12.1 and 9.8 months) vs 7.4 (95% between achievement of MRD negativity and baseline disease
CI, 5.7-9.2) months reported here for InO.46,47 Chimeric antigen burden, suggesting that InO treatment might be effective regardless
receptor–modified T cells targeting CD19 have also demonstrated of baseline disease severity. Further exploration of InO for the
high remission rates (60% to 90%) and MRD-negativity rates among treatment of CD22-positive relapsed/refractory ALL in patients
having undergone 1 and 2 salvage treatments is currently ongoing.
responders (80% to 100%) in pediatric and young adult patients
with relapsed/refractory ALL.48-50 InO can be administered in the
outpatient setting as a short (1 hour) weekly infusion, which is a particular
Acknowledgments
advantage over other therapies that require hospital admission The authors thank Craig Davis, Sherry Li, and Jean-Claude Marshall
(eg, intensive chemotherapy) or infusion over prolonged durations (employees of Pfizer Inc) for their contributions to pharmacoge-
(eg, 4 weeks of continuous infusion for blinatumomab).51 nomics assay planning, design, execution, and data analysis, and Hui
Zhang (employee of Pfizer Inc) for her statistical contributions to the
The safety profile of single-agent InO in this study is consistent with
study.
that reported previously, and no new unexpected toxicities were
This study was sponsored by Pfizer Inc. Editorial support was
observed.18 Four patients developed VOD/SOS, none of whom
provided by Simon J. Slater and Kevin O’Regan, of Complete
had received prestudy HSCT. Two patients experienced VOD/SOS
Healthcare Communications, LLC, and was funded by Pfizer Inc.
during therapy or follow-up but without an intervening HSCT and 2
K.L. was employed as a clinician through inVentiv Health, who were
developed VOD/SOS after poststudy HSCT. In a previous study,
paid contractors to Pfizer Inc for the development of this manuscript.
36 of 90 patients receiving single-agent InO (40%) proceeded to
allogeneic SCT, of whom 6 (17%) experienced VOD/SOS after Authorship
transplantation.18 The VOD/SOS rate was higher in patients who
had undergone SCT after receiving a dual alkylator conditioning Contribution: R.A., J.B., A.S.A., D.J.D., E.V., and H.M.K. designed the
regimen compared with those who had received a single alkylator study; C.A.S., M.L., A.S.A., W.S., D.J.D., A.S.S., A.S., and H.M.K.
regimen (n 5 5/13 vs 1/21). In another study of 79 patients executed the study; A.D.L., M.L., A.S.A., W.S., D.J.D., A.S.S., A.S.,
receiving single-agent InO for relapsed/refractory non-Hodgkin and H.M.K. supervised the data acquisition; R.A., A.D.L., C.A.S., M.L.,
lymphoma, which excluded patients with prior allogeneic SCT, 1 J.B., A.S.A., W.S., D.J.D., A.S.S., A.S., E.V., K.L., H.M.K., and L.F.
developed VOD/SOS.43 Taken together, these data suggest that oversaw the data analysis or the data interpretation; and R.A., A.D.L.,
patients receiving InO without transplantation may be at a lower risk C.A.S., M.L., J.B., A.S.A., W.S., D.J.D., A.S.S., A.S., E.V., K.L., H.M.K.,
for developing VOD/SOS and that the risk of VOD/SOS may and L.F. prepared the manuscript.
be higher in patients subsequently proceeding to SCT. In particular, Conflict-of-interest disclosure: D.J.D. served as a consultant for
patients who received conditioning with double-alkylating agents (eg, Pfizer, Novartis, Baxalta, BMS, and Amgen. W.S. received honoraria
high-dose busulfan and cyclophosphamide) may be at especially higher from ADC Therapeutics, Amgen, Gilead Sciences, Sigma-Tau and

1178 DeANGELO et al 27 JUNE 2017 x VOLUME 1, NUMBER 15

From www.bloodadvances.org by guest on June 7, 2019. For personal use only.

received royalties for a chapter in Up to Date; A.S.S. received hon- of Pfizer. H.M.K. has received research funding from Pfizer, Amgen,
oraria, research funding, travel, accommodations, and expenses, Astex, Novartis, and BMS. A.S.A. has received research funding and
served as a consultant for Amgen and Stemline Therapeutics, and served as a consultant for Pfizer. A.S. declares no competing fi-
received research funding, travel, accommodations, expenses, and nancial interests.
served as a consultant for Amgen, Pharmacyclics, Seattle Genetics,
and Stemline Therapeutics. M.L. has received research funding and Correspondence: Daniel J. DeAngelo, Department of Medical
served as a consultant for Pfizer. C.A.S. has received research Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave, Dana
funding from Pfizer and Amgen and served as a consultant for Pfizer. Building, Room 2050, Boston, MA 02215; e-mail: daniel_deangelo@
E.V., K.L., R.A., J.B., A.D.L., and L.F. are employees and stockholders dfci.harvard.edu.

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