Regular Article

TRANSPLANTATION

Blinatumomab maintenance after allogeneic

hematopoietic cell transplantation for B-lineage acute
lymphoblastic leukemia
Mahmoud R. Gaballa,1,* Pinaki Banerjee,2,* Den

ai R. Milton,3 Xianli Jiang,4 Christina Ganesh,2 Sajad Khazal,5 Vandana Nandivada,2
Sanjida Islam,2 Mecit Kaplan,2 May Daher,2 Rafet Basar,2 Amin Alousi,2 Rohtesh Mehta,2 Gheath Alatrash,2 Issa Khouri,2 Betul Oran,2
David Marin,2 Uday Popat,2 Amanda Olson,2 Priti Tewari,5 Nitin Jain,6 Elias Jabbour,6 Farhad Ravandi,6 Hagop Kantarjian,6
Ken Chen,4 Richard Champlin,2 Elizabeth Shpall,2 Katayoun Rezvani,2,† and Partow Kebriaei2,†
1
Bone Marrow Transplant and Cellular Immunotherapy Program, Massachusetts General Hospital Cancer Center, Boston, MA, USA; 2Department of Stem Cell
Transplantation & Cellular Therapy, Houston; 3Department of Biostatistics; 4Department of Bioinformatics & Computational Biology; and 5Department of Pedi-
atric Stem Cell Transplantation & Cellular Therapy and 6Department of Leukemia, MD Anderson Cancer Center, University of Texas, Houston, Houston, TX, USA

KEY POINTS Patients with B-lineage acute lymphoblastic leukemia (ALL) are at high-risk for relapse after
allogeneic hematopoietic cell transplantation (HCT). We conducted a single-center phase 2
 Blinatumomab is safe
and feasible for use in study evaluating the feasibility of 4 cycles of blinatumomab administered every 3 months
B-ALL after allogeneic during the first year after HCT in an effort to mitigate relapse in high-risk ALL patients.
HCT.
Twenty-one of 23 enrolled patients received at least 1 cycle of blinatumomab and were
 The composition of a included in the analysis. The median time from HCT to the first cycle of blinatumomab was
patient’s T-cell subsets 78 days (range, 44 to 105). Twelve patients (57%) completed all 4 treatment cycles. Neutro-
at the time of treat- penia was the only grade 4 adverse event (19%). Rates of cytokine release (5% G1) and neu-
ment is indicative of
whether they will rotoxicity (5% G2) were minimal. The cumulative incidence of acute graft-versus-host disease
respond to (GVHD) grades 2 to 4 and 3 to 4 were 33% and 5%, respectively; 2 cases of mild (10%) and
blinatumomab. 1 case of moderate (5%) chronic GVHD were noted. With a median follow-up of 14.3
months, the 1-year overall survival (OS), progression-free survival (PFS), and nonrelapse mor-
tality (NRM) rates were 85%, 71%, and 0%, respectively. In a matched analysis with a contemporary cohort of 57
patients, we found no significant difference between groups regarding blinatumomab’s efficacy. Correlative studies of
baseline and posttreatment samples identified patients with specific T-cell profiles as “responders” or “nonresponders”
to therapy. Responders had higher proportions of effector memory CD8 T-cell subsets. Nonresponders were T-cell defi-
cient and expressed more inhibitory checkpoint molecules, including T-cell immunoglobulin and mucin domain 3 (TIM3).
We found that blinatumomab postallogeneic HCT is feasible, and its benefit is dependent on the immune milieu at time
of treatment. This paper is posted on ClinicalTrials.gov, study ID: NCT02807883.

Introduction maintenance strategies. Donor lymphocyte infusion (DLI) has

The therapeutic landscape of acute lymphoblastic leukemia been used preemptively in patients with signs of early relapse
(ALL) is rapidly evolving. Allogeneic hematopoietic cell trans- with some success,11-15 but is generally associated with remis-
plantation (HCT) is a potentially curative option for patients with sion rates below 10% and an elevated risk of graft-versus-host
high-risk ALL, with overall survival (OS) ranging from 30% to disease (GVHD).16 Hence, there continues to be an unmet need
60%, depending on disease characteristics and risk profile.1,2 for mitigation strategies to reduce the risk of relapse in high-risk
Measurable residual disease (MRD) and high-risk cytogenetics/ ALL patients.
molecular features are key determinants of relapse risk and out-
comes in patients.3-9 The management of ALL patients who Blinatumomab is a bispecific T-cell engager (BiTE), with one arm
relapse after allogeneic HCT is challenging with poor survival targeting CD19 on B-ALL blasts and the other arm binding to
outcomes, regardless of the treatment modality used.2,10 CD3z on T cells. Upon binding, T cells become activated and
Thus, it is critical to employ strategies to minimize the risk for exert perforin-dependent cytotoxicity against target cells
relapse, even after transplantation. However, other than tyrosine expressing CD19. Studies have shown a clinical benefit of blina-
kinase inhibitor (TKI) maintenance post-HCT in patients with Phil- tumomab in MRD-positive ALL patients in morphologic com-
adephia chromosome-positive (Ph1) ALL, there are limited plete response (CR), where 80% successfully converted into

1908 blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12

MRD negativity.17 Its clinical benefit was also investigated in the Board. Patients provided informed consent prior to enrollment
relapsed and refractory (R/R) setting. A phase 2 study of 189 in the clinical study in accordance with the Declaration of Hel-
patients with R/R ALL treated with blinatumomab showed an sinki. This phase 2 clinical trial was registered at ClinicalTrials.gov
overall response rate (ORR) of 43%, and with a median follow- (NCT02807883).
up of 8.9 to 9.8 months, the median progression-free survival
(PFS) and OS were 5.9 and 6.1 months, respectively.18 Similar Patient eligibility
findings were noted in children with R/R ALL.19 Its activity was The study was initially limited to adults only, but after safety was
confirmed in the phase 3 clinical trial (TOWER) by Kantarjian and confirmed following treatment in 8 adults, it was subsequently
colleagues with 405 patients with CD19-positive R/R B-ALL who amended to include children. The final eligibility age at time of
were randomized to either blinatumomab (n 5 271) or standard enrollment was 1 to 70 years. Other key eligibility criteria
chemotherapy (n 5 134).20 Compared with the chemotherapy- included receiving allogeneic HCT within the last 100 days for
treated cohort, the blinatumomab-treated cohort had superior B-ALL at high risk of relapse as determined by: (1) complete
outcomes, as shown by higher rates of ORR (44% vs 25%, P , hematologic remission beyond CR1 at the time of allogeneic
.001), superior 6-month EFS (31% vs 12%, HR 0.55; 95% CI HCT, (2) primary induction failure requiring more than 1 line of
0.43-0.71, P , .001), and superior median OS (7.7 months vs 4 therapy, (3) positive MRD by flow cytometry (threshold .0.01%)
months, HR 0.71; 95% CI 0.55-0.93, P 5 .01).20 Finally, the feasi- or molecular assays by PCR (sensitivity 1/10 000) before alloge-
bility of blinatumomab following allogeneic HCT was illustrated neic HCT, and/or (4) high-risk cytogenetic or molecular profile
in a study by Stein and colleagues; 64 patients received blinatu- defined as Ph1 ALL, Ph-like ALL, KMT2A gene rearrangement,
momab after relapse following prior allogeneic HCT.21 Grade 3 complex cytogenetics, or hypodiploid cytogenetics at diagnosis.
to 4 cytokine release syndrome (CRS) was noted in 3% of Additionally, patients with MRD positivity after HCT were eligi-
patients, and grade 3 to 4 neurotoxicity was noted in 16% of ble for the study.
patients. GVHD occurred in 11% of patients and did not require
blinatumomab discontinuation or hospitalization. Efficacy was Enrollment occurred within 30 to 100 days after allogeneic HCT
similar to what was observed in patients without prior HCT, and after adequate hematologic recovery, defined as an abso-
where 45% had CR/CRh within 2 cycles of blinatumomab, and lute neutrophil count $0.5 3 109/L and platelet count .20 3
34% had MRD response.21 109/L. Patients needed to have adequate performance status
(ECOG #2 or Karnofsky $50) and have adequate organ func-
Many mechanisms of immune evasion exist for relapse following tion, defined as creatinine clearance greater than 30 mL/min,
allogeneic HCT, including low levels of cytotoxic effector T cells ALT/AST ,5 3 upper limit of normal (ULN) and serum bilirubin
and upregulation of inhibitory checkpoint molecules soon after ,3 3 ULN. Patients were excluded from the study if they had
transplant.22 Based on the safety profile of blinatumomab, spe- relapsed disease, defined as .5% blasts in bone marrow (BM)
cifically its lack of hematopoietic cell cytotoxicity, and its mecha- or peripheral blood (PB) and/or active involvement of the central
nism of action of specifically directing cytotoxic T cells to nervous system (CNS) by ALL (defined as $5 leukocytes/mL with
leukemic blasts during the immediate posttransplant time period the presence of blast cells in the CNS or cranial-nerve palsy),
when there may be low levels of mature T cells present, we pos- active GVHD requiring systemic steroids, systemic steroids
tulated that blinatumomab would be an ideal agent to test in beyond physiologic replacement, and/or uncontrolled infection.
this setting. We conducted a phase 2 study to evaluate the fea-
sibility and clinical benefit of blinatumomab administered for 1 Treatment
year after allogeneic HCT in high-risk B-ALL patients. While the Patients received blinatumomab as continuous IV infusion on
benefit of blinatumomab use may be highest in MRD-positive days 1 through 28 of each cycle. Dosing and administration fol-
patients prior to allogeneic HCT, we included in our study other lowed the standard FDA guidelines for children and adults.
high-risk populations to see if they may benefit from this Briefly, patients $45 kg received 28 mg of blinatumomab daily
strategy. administered as a continuous infusion on days 1 through 28,
and patients ,45 kg (dose based on BSA) received 15 mg/m2
per day (maximum: 28 mg/day) as a continuous infusion on days
Methods 1 through 28.23 Patients were premedicated with dexametha-
Study design sone 16 to 20 mg IV prior to the start of each cycle. Patients
This was a prospective, open-label, single-arm, single-center were hospitalized for observation during the first 3 days of cycle
clinical trial evaluating the use of blinatumomab postallogeneic 1 and the first 2 days of cycle 2. The first cycle was given within
HCT in B-ALL patients at high risk of relapse after transplant. the first 3 months after allogeneic HCT and then at approxi-
The primary endpoint was feasibility, defined by the rate of mately 6, 9, and 12 months following transplant. The study did
treatment-related toxicities attributable to blinatumomab, acute not require patients to be off immunosuppression prior to initiat-
GVHD (aGVHD), and secondary graft failure. Secondary end- ing therapy with blinatumomab. The transplant preparative regi-
points were PFS, OS, impact of MRD status, and nonrelapse men, GVHD prophylaxis, graft source, and graft allotype were
mortality (NRM). Continuous monitoring of toxicity was con- determined by the treating physician and not prescribed by this
ducted for all patients starting with the first cohort of 5 patients. protocol. For patients with Ph1 ALL, the use of TKI therapy
The study followed a Bayesian model, and dose-limiting toxic- posttransplant was permitted.
ities were defined as grades 3 to 4 aGVHD .30%, secondary
graft failure .30%, or NRM within 1 cycle of blinatumomab. The Safety and evaluations
study was conducted after the protocol was reviewed and Disease assessments with PB studies (eg, flow cytometry and
approved by MD Anderson Cancer Center’s Institutional Review chimerisms) and BM examinations were done prior to each cycle

BLINATUMOMAB IN B-ALL POST–ALLOGENEIC HCT blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 1909
Table 1. Patient and treatment characteristics (BD Biosciences: Clone MH1), CD19 (BD Biosciences: Clone
HIB19), TIM-3 (BD Biosciences: Clone 7D3), and TIGIT (eBio-
Measure All patients, n 5 21, (%) science: Clone MBSA43). Cells were acquired using an X-20 For-
tessa (BD Biosciences). The analysis was implemented with the
Gender
cyt3 package in MATLAB (https://github.com/dpeerlab/cyt3).24
Male 17 (81) Raw data were first transformed using hyperbolic arcsin with a
Female 4 (19) cofactor of 150. Bh-SNE25 version of SNE was run against the
collection of all samples, with 8000 data points subsampled for
Age
each; viSNE reduced the high-dimensional flow cytometry data
Mean (SD) 37.9 (16.2) into 2 dimensions, and the result was visualized in the viSNE
Median (range) 29.9 (16.9-65.6) map (2D scatterplot). PhenoGraph clustering26 was then used to
identify subpopulations in the viSNE map. The number of near-
Race/ethnicity
est neighbors was set at 100. The annotation of subpopulations
White 13 (62) by PhenoGraph was directly shown in the viSNE map, where
Hispanic 8 (38) cells that belong to the same subpopulation were shown in the
same color.
High-risk cytogenetic/ 18 (90)
molecular risk at diagnosis
Response definitions and outcome
Ph1 2
CR was defined as having #5% malignant blasts in the BM, nor-
Ph-like 8
mal blood counts with ANC $0.5 3 109/L and platelet .20 3
KMT2A 4 109/L, normal karyotype, and absence of extramedullary disease.
Complex* 2 MRD was assessed using multiparameter flow cytometry with a
Hypodiploid 2 threshold of .0.01%. Myeloablative and reduced-intensity con-
ditioning regimens were defined according to the Center for
Days from HCT to International Blood and Marrow Transplant Research (CIBMTR)
blinatumomab start
criteria.27 aGVHD was staged and graded according to the crite-
Median (range) 78.0 (44.0-105.0) ria published by Przepiorka and colleagues.28 Chronic GVHD
MRD prior to blinatumomab
(cGVHD) was reported based on the 2014 NIH cGVHD Consen-
treatment sus Conference.29
Detected 2 (10)
Statistical methods
Not detected 19 (90)
OS time and NRM were computed from date of allogeneic HCT
Number of cycles to last known vital sign. Patients alive at the last follow-up date
1 21 were censored. PFS time was computed from date of allogeneic
HCT to date of disease progression or death (if he or she died
2 13
without disease progression) or the last evaluation date. Patients
3 12
who were alive and did not experience progression of disease
4 12 at the last follow-up date were censored. In addition, relapse
and GVHD were computed from date of allogeneic HCT to date
*Complex karyotype defined as 5 or more cytogenetic abnormalities. of event; patients who did not experience the event were cen-
sored at their last follow-up date. Patients who remained in
and at study completion. Patients who remained in remission remission were grouped as “responders,” and those that pro-
after blinatumomab therapy were labeled “Responders,” and gressed during therapy with blinatumomab were grouped as
patients with disease progression defined by recurrence of MRD “nonresponders.” OS and PFS were estimated using the
by flow cytometry or morphologic leukemic blasts were labeled Kaplan-Meier method. The cumulative incidences of relapse,
“Nonresponders.” The Common Terminology Criteria for NRM, and GVHD were evaluated using the competing risks
Adverse Events (CTCAE) version 4 was used to grade toxicities. method. The competing risk for relapse was death and for NRM
was relapse, while the competing risks for GVHD were relapse
Flow cytometry data analysis and death.
Samples were collected following informed consent from 15
consecutive patients (4 nonresponders, 11 responders), sepa- A contemporary cohort of patients with high-risk B-ALL who
rated using Ficoll density separation (Lymphoprep, STEMCELL received allogeneic HCT was identified retrospectively. To cor-
Technologies), and cryopreserved. PB mononuclear cells (PBMC) rect for potential bias in the HCT comparisons, treatment
were then thawed and immunostained with CD127 (BD Bio- patients were matched to controls (1:2 where possible) using
sciences: Clone HIL7RM21), CD25 (BioLegend: Clone BC96), the following steps: 1) patients were divided into groups based
LAG-3 (BD Biosciences: Clone T47-530), PD-1 (BioLegend: on disease status at allogeneic HCT, cytogenetic risk, and MRD
Clone EH12.2H7), CCR7 (BD Biosciences: Clone 3D12), CD3 prior to allogeneic HCT; we did not match for conditioning regi-
(BD Biosciences: Clone UCHT1), CD45RO (BD BioSciences: men intensity as a separate analysis comparing the 2 treatment
Clone UCHL1), CD8 (BioLegend: Clone SK1), 2B4 (BioLegend: groups by regimen intensity did not yield different results (data
Clone C1.7), CTLA-4 (BioLegend: Clone L3D10), CD160 (BioLe- not shown); 2) within each subgroup of completely matched
gend: Clone 341204), CD4 (BioLegend: Clone RPA-T4), PDL1 patients, a random number generator was employed from the

1910 blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 GABALLA et al

Table 2. Patient and transplant characteristics for study group and matched cohort

HCT patients

Blinatumomab
Measure All, n 5 57 (%) n 5 21 (%) Controls n 5 36 (%) P value*
Gender
Male 33 (58) 17 (81) 16 (44) .012
Female 24 (42) 4 (19) 20 (56)

Age in years, median 38.0 (16.0-66.0) 29.0 (16.0-65.0) 41.0 (19.0-66.0) .26†
(range)

Race/ethnicity
White 36 (65) 13 (62) 23 (68) .13
Hispanic 15 (27) 8 (38) 7 (21)
Other 4 (7) 0 (0) 4 (12)

High cytogenetic/ 49 (89) 18 (90) 31 (89) 1.00

molecular risk

Months from diagnosis

to HCT
Median (range) 7.8 (2.9-107.7) 8.8 (3.2-107.7) 7.0 (2.9-99.8) .25†

Disease status at HCT

CR 1 32 (56) 11 (52) 21 (58) .86
CR 2 18 (32) 7 (33) 11 (31)
CR 31 7 (12) 3 (14) 4 (11)

MRD at HCT
Detected 10 (18) 4 (20) 6 (17) .73
Not detected 46 (82) 16 (80) 30 (83)
Unknown 1 1 0

Karnofsky performance
status
#80 5 (11) 1 (6) 4 (13) .65
$80 42 (89) 15 (94) 27 (87)

HCT-CI
Median (Range) 3.0 (0.0-8.0) 3.0 (0.0-8.0) 3.0 (0.0-8.0) .91†

Donor type
MRD 22 (39) 7 (33) 15 (42) .48
MUD 21 (37) 10 (48) 11 (31)
Haplo 14 (25) 4 (19) 10 (28)

Conditioning regimen
MAC 25 (44) 4 (19) 21 (58) .010
MAC/TBI 8 (14) 5 (24) 3 (8)
RIC 24 (42) 12 (57) 12 (33)

*Fisher’s exact test.

†Wilcoxon rank-sum test.

uniform distribution on the interval (0,1) using a prime modulus while group differences in cumulative incidences were assessed
multiplicative generator; and 3) each treated patient was by stratified Gray’s test.30
matched with 1 or 2 (where possible) control patient(s) starting
from the lowest generated random number. Group differences All statistical analyses were performed using SAS 9.4 for Win-
in OS and PFS were evaluated using a stratified log-rank test dows (SAS Institute Inc., Cary, NC). All statistical tests used a

BLINATUMOMAB IN B-ALL POST–ALLOGENEIC HCT blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 1911
Table 3. Incidence of toxicities graded by CTCAE, V4

Maximum grade

Grade 1 Grade 2 Grade 3 Grade 4

Toxicity n (%) n (%) n (%) n (%)
Constitutional
Fatigue 3 (14) 0 (0) 1 (5) 0 (0)
Fever 1 (5) 2 (10) 0 (0) 0 (0)
Flu-like syndrome 1 (5) 0 (0) 0 (0) 0 (0)

Hematologic
Anemia 1 (5) 0 (0) 0 (0) 0 (0)
Leukopenia 2 (10) 6 (29) 4 (19) 0 (0)
Neutropenia 2 (10) 0 (0) 0 (0) 4 (19)
Thrombocytopenia 3 (14) 0 (0) 1 (5) 0 (0)

Cardiovascular
Chest pain 0 (0) 1 (5) 0 (0) 0 (0)
Hypotension 0 (0) 1 (5) 0 (0) 0 (0)
Arrythmias 1 (5) 0 (0) 0 (0) 0 (0)
Thromboembolic event 2 (10) 0 (0) 0 (0) 0 (0)

Pulmonary
Dyspnea 0 (0) 1 (5) 0 (0) 0 (0)
Cough 1 (5) 0 (0) 0 (0) 0 (0)
Gastrointestinal

Abdominal pain 0 (0) 1 (5) 0 (0) 0 (0)

Nausea 2 (10) 1 (5) 0 (0) 0 (0)
Vomiting 1 (5) 0 (0) 0 (0) 0 (0)
Oral mucositis 1 (5) 0 (0) 0 (0) 0 (0)
Diarrhea 5 (24) 1 (5) 1 (5) 0 (0)
Elevated liver enzymes 4 (19) 5 (24) 1 (5) 0 (0)

Infections
Viral 2 (10) 0 (0) 0 (0) 0 (0)
Bacterial 1 (5) 0 (0) 0 (0) 0 (0)

Electrolyte abnormalities
Hypokalemia 0 (0) 0 (0) 1 (5) 0 (0)
Hypomagnesemia 1 (5) 0 (0) 0 (0) 0 (0)

Neurologic
Headache 3 (14) 0 (0) 0 (0) 0 (0)
Dizziness 1 (5) 0 (0) 0 (0) 0 (0)
Confusion 0 (0) 1 (5) 0 (0) 0 (0)
Transient dysphasia 1 (5) 0 (0) 0 (0) 0 (0)
Tremors 1 (5) 0 (0) 0 (0) 0 (0)

Skin
Rash 4 (19) 1 (5) 2 (10) 0 (0)

Renal
Elevated creatinine 1 (5) 1 (5) 0 (0) 0 (0)

1912 blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 GABALLA et al

Table 3. (continued)

Maximum grade

Grade 1 Grade 2 Grade 3 Grade 4

Toxicity n (%) n (%) n (%) n (%)
Others
Dry eye 1 (5) 0 (0) 0 (0) 0 (0)
Alopecia 1 (5) 0 (0) 0 (0) 0 (0)
Anxiety 1 (5) 0 (0) 0 (0) 0 (0)
Arthralgia 1 (5) 0 (0) 0 (0) 0 (0)
Hiccups 1 (5) 0 (0) 0 (0) 0 (0)
Insomnia 3 (14) 0 (0) 0 (0) 0 (0)

significance level of 5%. No adjustments for multiple testing patients were in CR1, and 80% had no detectable MRD at the
were made. time of HCT. The Karnosky performance score was $80% in
94% of patients, and the median comorbidity index was 3
(range, 0 to 8). Regarding the source of allogeneic HCT graft,
Results 33% were matched siblings, 48% matched unrelated donors,
Patient and disease characteristics and 19% had haploidentical family donors. Approximately half
Twenty-three patients signed consent, and 21 patients who of the patients received a reduced-intensity conditioning regi-
received at least 1 dose of blinatumomab therapy postalloge- men. The median time from diagnosis to HCT was 8.8 months
neic HCT were included in the analysis. Two patients never (range, 3.2 to 107.7 months). The median number of blinatumo-
received therapy due to GVHD that required treatment. Table mab cycles received was 4 (range, 1 to 4). Except for gender, all
1 summarizes patient and treatment characteristics for the key characteristics were similar between the study and control
study cohort. Eighty-one percent of the patients were male, groups (Table 2).
62% were White, with a median age of 30 (17 to 66) years, and
90% (19 of 21) had a high-risk cytogenetic or molecular profile Safety and feasibility
at diagnosis. Two patients had .1 HCT prior to blinatumomab Blinatumomab was well-tolerated posttransplantation, with the
therapy. Seventy-six percent of patients were exposed to blina- most common severe adverse events being limited to hemato-
tumomab prior to allogeneic HCT. The median days from trans- logic cytopenias, including leukopenia (19% G3) and neutrope-
plant to the first day of cycle 1 of blinatumomab was 78 (range, nia (19% G4), as noted in Table 3. Diarrhea occurred in 7
44 to 105), and MRD was detected prior to the start of blinatu- patients (33%) and was mostly grade 1 (5 patients) and not
momab in 2 patients. Fifty-seven percent of patients (12 of 21) GVHD-related. Importantly, only 1 patient developed grade 1
completed all 4 cycles of therapy (Table 1). Three patients CRS, and 1 patient developed grade 2 neurotoxicity in the form
could not complete treatment due to GVHD, and the remain- of confusion that resolved with a temporary hold of the blinatu-
ing patients (n 5 6) relapsed before they could complete all 4 momab infusion (Table 3). Furthermore, rates of GVHD were
intended cycles. All patients were on tacrolimus during cycle 1 acceptable, with cumulative rates of aGVHD grades 2 to 4 and
of blinatumomab, with a mean tacrolimus level of 7.4 ng/mL 3 to 4 noted at 33% and 5%, respectively. Two patients (10%)
(range, 4.3 to 10.3 ng/mL). were noted to have NIH mild cGVHD (oral 1/3; oral 1/3, liver
1/3), and 1 patient (5%) had moderate cGVHD (skin 3/3, liver
Transplant characteristics for the study group and the matched 1/3). Finally, none of the patients developed secondary graft fail-
cohort are listed in Table 2. In the study group, about half of the ure. Study accrual was slow, and consequently, the study was

Baseline High
Mean arcsinh-transformed

Non-responder 1.5
fluorescent intensity

Responder
1
Posttreatment
Non-responder 0.5

Responder
0
Low
8

3
1
R7

CD D3

CD O
0
L1

4
IT

3
19

4
CD

2B

G
PD

16

CD

LA
R

G
PD

CD
CC

C
LA

45

TI
TI

CT

Figure 1. Heatmap of surface marker expression of T cells in nonresponders and responders. Hyperbolic arcsin transformed fluorochrome expression for 14
markers were averaged for baseline samples taken from nonresponders (n 5 3) and responders (n 5 10), and posttreatment samples from nonresponders (n 5 4) and
responders (n 5 11).

BLINATUMOMAB IN B-ALL POST–ALLOGENEIC HCT blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 1913
 A Non-responders Responders
15 15
10 10
5 5

bh-SNE2

bh-SNE2
Baseline
0 0
–5 –5
–10 –10
–15 –15
–15 –10 –5 0 5 10 15 –15 –10 –5 0 5 10 15
bh–SNE1 bh–SNE1
15 15
10 10
Posttreatment

5 5

bh-SNE2
bh-SNE2

0 0
–5 –5
–10 –10
–15 –15
–15 –10 –5 0 5 10 15 –15 –10 –5 0 5 10 15
bh–SNE1 bh–SNE1
CD8 T cells: 2 17 19 22
CD4 T cells: 5 12 16 25

1 4 7 10 13 16 19 22 25
2 5 8 11 14 17 20 23
3 6 9 12 15 18 21 24

B
Cluster
1 (10.32%)
High
2 (9.99%)
5
Mean arcsinh-transformed
3 (9.83%)
fluorescent intensity

4 (9.59%) 4
5 (7.80%)
3
6 (6.40%)
7 (6.25%) 2
8 (5.42%)
1
9 (5.04%)
10 (3.70%) 0
11 (3.67%) Low
12 (3.39%)
13 (3.20%)
14 (2.93%)
15 (2.93%)
16 (2.09%)
17 (1.69%)
18 (1.65%)
19 (1.23%)
20 (1.17%)
21 (0.93%)
22 (0.27%)
23 (0.26%)
24 (0.13%)
25 (0.13%)
8
LA B4
3
CC 1
CD CD7
45 3
CD RO
PD60
CD1
TI 4
TI IT
CD 3
CT 19
4
CD

G
PD
R

LA
G
1
2

Figure 2. Subpopulations identified via viSNE analysis of 14 surface markers in all 56 samples. (A) viSNE map for nonresponders and responders color-coded
according to PhenoGraph cluster annotation. viSNE maps were separated to baseline and posttreatment in both nonresponders and responders groups. (B) Heatmap
of mean surface marker expression in each cluster. Percentage in parentheses denotes the size of each cluster.

1914 blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 GABALLA et al

 stopped early due to the sponsor’s decision. Since none of the
A 21 patients enrolled met the toxicity criteria for stopping the
1.0
Blinatumomab trial, the feasibility of blinatumomab postallogeneic HCT as con-
solidation therapy in patients with B-lineage ALL was met.

0.8
Laboratory correlates
Cumulative incidence of relapse

To study the kinetics of T-cell response after blinatumomab ther-

apy, we studied the T-cell populations and expression of check-
0.6
point molecules in serial PBMCs for 15 patients with available
samples (11 responders and 4 nonresponders). Responders had
greater numbers of CD3, CD4, and CD160 T cells compared with
0.4
nonresponders, both at baseline and posttreatment (Figure 1). In
addition, responders had higher levels of CD8 T cells after therapy
0.2
(Figure 1). Detailed quantitative values for the heat map findings
are supplied in a box-plot diagram (supplemental Figure 1). viSNE
analysis confirmed increased numbers of effector memory and ter-
0.0 minally differentiated effector memory cells both within the CD8
and CD4 T-cell compartments in responders compared with non-
0 10 20 30 40 50
responders, pointing to their critical role in mediating cytotoxicity
Months post HCT
(Figure 2). Detailed quantitative values for the viSNE analysis are
21 13 5 4 1 1
supplied in a box-plot diagram (supplemental Figure 2).
B
1.0
We also examined the expression of checkpoint molecules on T
cells, including LAG3, PD1, PDL1, TIGIT, TIM3 (T-cell immuno-
Probability of progression-free survival

0.8 globulin and mucin domain 3), and CTLA4. Checkpoint mole-
cules LAG3, PD1, TIGIT, and TIM3 were expressed at high
++ ++
+
+ ++ + + ++ + +
levels both at baseline and after treatment in all patient samples
0.6 (Figure 1); however, TIM3 was the only checkpoint that was
expressed at statistically higher levels in nonresponders com-
pared with responders after blinatumomab treatment (P 5 .04)
0.4 (supplemental Figure 1). Finally, CD19 expression was lowest
after 1 cycle of blinatumomab in responders compared with
nonresponders (Figure 1), and the difference was statistically sig-
0.2 nificant after treatment (supplemental Figure 1).

Efficacy
Blinatumomab
Seventeen of the 21 (81%) patients were alive at the end of the
0.0
study, and the median follow-up time for all patients was 14.3
0 10 20 30 40 50 months (range, 7.5 to 52.4 months). Six patients progressed,
Months post HCT including the 2 patients who had MRD positivity prior to the
21 13 5 4 1 1 start of blinatumomab therapy, for a cumulative incidence of
C relapse of 29% (95% CI 11%-49%). The 1-year OS and PFS for
1.0
patients were 85% (95% CI 61%-95%) and 71% (95% CI 47%-
++ 86%), respectively (Figure 3). There were no regimen-related
0.8 +++
+ ++ + + ++ ++ + deaths. We compared our results to a contemporary cohort con-
trol that included information for 128 patients (Table 2). Using a
Probability of overall survival

2:1 (control:treated) ratio, the matched analysis dataset included

0.6 information for 57 (36:21) patients. The median follow-up time
for the control group was 24.6 months (range, 3.4 to 67.4). No
statistically significant differences in PFS and OS were observed
0.4 between groups (Figure 4).

0.2 Discussion
To our knowledge, this is the first study to investigate the use
Blinatumomab of prophylactic blinatumomab in the posttransplant setting to
0.0
0 10 20 30 40 50
Figure 3. Study outcomes for patients treated with blinatumomab. At 1 year,
Months post HCT the rate of relapse was 29% (95% CI, 11%-49%) (A), progression-free survival
21 16 6 5 2 1 (PFS) 71% (95% CI, 47%-86%) (B), and overall survival (OS) 85% (95% CI, 61%-
95%) (C).

BLINATUMOMAB IN B-ALL POST–ALLOGENEIC HCT blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 1915
 Notably, we were able to glean important mechanistic insights
A into why this type of cellular therapy had benefits in only a sub-
1.0
set of patients. Broadly, cluster analysis clearly identifies res-
+ ponders as having higher frequencies of CD4 and CD8 T cells
Probability of progression-free survival

0.8 with an effector memory phenotype compared with nonres-

++ ++
++++ + + ++ + + ponders (Figure 2; supplemental Figure 2). Furthermore, at
+ baseline, prior to the initiation of blinatumomab, the responder
0.6 +
+
++ group had relatively higher levels of CD160 which, while shown
++ ++
+
+ ++ +++ ++ to be inhibitory to CD4 T-cell function in some studies,31 has
been associated with CD81 T-cell effector function in other
0.4
studies (Figure 1; supplemental Figure 2).32 Interestingly, how-
ever, we did not find a difference in the CD4 Treg frequencies
0.2 at baseline33 between responders and nonresponders (P 5
.378, data not shown). Our findings are limited by both the small
Blinatumomab sample size included in the correlative analysis and the imbal-
Controls p=0.44
0.0 ance of a greater number of responders (73%) vs nonrespond-
0 10 20 30 40 50 60 70 ers. Thus, our exploratory findings require further investigation
Months post HCT in larger, prospective studies.

Blinatumomab 21 13 5 4 1 1 0 0 The in vivo modulation of blinatumomab has been recently

Controls 36 23 15 13 10 7 3 0
reported by Puzzolo and colleagues.34 Extensive in vivo monitor-
ing was performed in 43 patients treated on the GIMEMA
B LAL2216 study of upfront induction with dasatinib followed by 2
1.0 ++
to 5 cycles of consolidation with blinatumomab in adult patients
+
with Ph1 ALL. They noted a progressive increase in CD31 T
0.8 ++
+
+++ + + ++ ++ + cells after each cycle of blinatumomab that became significant
Probability of overall survival

++
+ ++ ++ after cycle 3, specifically with an increase in the CD3/CD8 T-cell
++
subset. Furthermore, they noted increases in CD4/CD45RO1
0.6 + +
+ ++ + ++ ++
T-NK and NK lymphocyte populations, while they noted a pro-
gressive reduction in T-regulatory (Tregs) CD41 T cells, which
0.4 have been shown in some studies to drive tumor evasion and
limit the efficacy of blinatumomab.33,35,36 In contrast to our
study, they did not find a correlation between immune modula-
0.2
tion and the degree of molecular response that was reached in
Blinatumomab about 80% of patients.34
p=0.23
0.0 Controls

0 10 20 30 40 50 60 70 The association of higher memory CD4 and CD8 T-cell subsets

Months post HCT in blinatumomab-responding patients has been noted before.37
One approach to address low levels of T cells would be to com-
Blinatumomab 21 16 6 5 2 1 0 0
bine DLI with blinatumomab. In fact, this strategy was investi-
Controls 36 27 19 16 12 8 3 0
gated by Ueda and colleagues in 4 patients with B-ALL who
relapsed following allogeneic HCT and subsequently received
Figure 4. Comparison of PFS and OS between patients treated with blinatu- DLI concurrently during the second or later cycles of blinatumo-
momab maintenance and no posttransplant maintenance (matched-case
cohort). At 1 year, the rates of PFS for the blinatumomab vs the control group
mab. Prolonged remission was noted in 2 of the patients.38 Vari-
were 71% vs 68%, P 5 .44 (A), and the rates for OS for the blinatumomab vs the able efficacy, along with the risk for GVHD, has limited the
control group were 85% vs 76%, P 5 .23 (B). enthusiasm for further investigating this approach. Another strat-
egy may be to use cytokines to restore T-cell activity. Interleukin-
7 (IL-7) is a common g-chain cytokine required for lymphocyte
mitigate the risk of relapse. Our study established the feasibility survival and expansion, specifically preventing lymphocyte apo-
of this approach, with 91% of enrolled patients able to receive ptosis and restoring CD41 and CD81 T-cell function.39 Although
at least 1 cycle of blinatumomab at a median of 78 days follow- not currently approved for clinical use, IL-7 is under investigation
ing the day of HCT and 57% completing all 4 intended cycles of in numerous clinical trials, including one in which it was used to
treatment. As expected, based on the previously published tox- promote T-cell recovery after T-cell-deplete allogeneic HCT.40
icity profile of blinatumomab, the drug was well tolerated, with
no significant toxicity noted. Importantly, treatment did not Upregulation of exhaustion markers PD1, TIM3, and LAG3 have
need to be stopped secondary to cytopenias, and there were been previously noted on ALL blast cells,41 and at lower levels
no cases of secondary graft failure. Furthermore, despite the of TIGIT.42 Furthermore, treatment with blinatumomab resulted
expectant hypogammaglobulinemia with blinatumomab, there in an increase in CTLA-4, PD1, TIM3, and LAG3 expression in
were no excess infections, as shown in Table 3, and the NRM cell assays.41 While we observed mildly elevated levels of these
rate was 0. Finally, GVHD rates were not in excess of what checkpoint molecules in our patient samples (Figure 1), critically,
would be expected, and in fact, grades 3 to 4 aGVHD were only TIM3 expression was found to be significantly higher in
quite low at 5%. nonresponders after treatment with blinatumomab (Figure 1;

1916 blood® 24 MARCH 2022 | VOLUME 139, NUMBER 12 GABALLA et al

supplemental Figure 1). TIM3 has been shown to regulate both Acknowledgments
innate and adaptive immune responses, potentially acting as a This work was supported by grants (1 R01 CA211044-01, 5
positive or negative regulator.43 Checkpoint blockade, including P01CA148600-03, and P50CA100632-16) from the National Institutes
against TIM3, is most actively investigated in solid tumors. How- of Health (NIH), the Specialized Program of Research Excellence
ever, there are several trials addressing this route of resistance (SPORE) in Leukemia grant (P50CA100632), grant (CA016672) to the
in ALL by combining blinatumomab with checkpoint inhibitors. Anderson Cancer Center from the NIH, the Cancer Center Support
Grant (NCI Grant P30 CA016672), and the clinical trial was supported
Inhibitors of PD1 in combination with blinatumomab are actively
by Amgen Pharmaceutical.
being investigated in the following ongoing clinical trials
for adults with relapsed B-ALL (ClinicalTrials.gov Identifier:
NCT03512405, NCT03168079, NCT04524455). Another ongo-
ing trial is investigating the combination of blinatumomab with Authorship
checkpoint inhibitors of PD1 and CTLA4 in patients with Contribution: M.R.G., P.B., X.J., K.R., and P.K. were involved in writing
relapsed B-ALL (ClinicalTrials.gov identifier: NCT02879695). Five the manuscript, study design, data collection, data analysis, data inter-
patients have been treated with blinatumomab combined with pretation, and reviewing and editing of manuscript; V.N., S.I., M.K., and
R.B. were involved in running the laboratory studies, data analysis, and
nivolumab, and 4 have achieved CR with MRD negativity.44
reviewing and editing of the manuscript; D.R.M. was involved in data
analysis, data interpretation, literature search, writing the manuscript, and
Efficacy for blinatumomab maintenance is difficult to determine creating the tables and figures; and C.G., S.K., M.D., A.A., R.M., G.A.,
since this was not a prospectively randomized study. In efforts to I.K., B.O., D.M., U.P., A.O., P.T., N.J., E.J., F.R., H.K., K.C., R.C., and E.S.
estimate possible activity, we compared outcomes with a were involved in data collection, data interpretation, and reviewing and
matched 2:1 cohort, and based on this analysis, saw no significant editing of the manuscript.
benefit for blinatumomab maintenance (Figure 4). In addition to
Conflict-of-interest disclosure: K.R., P.B., M.D., R.B., and The University
the inherent limitations of this type of analysis, we acknowledge
of Texas MD Anderson Cancer Center (MDACC) have an institutional
the short follow-up duration for the blinatumomab group, and we financial conflict of interest with Takeda Pharmaceutical for the licensing
will need to monitor outcomes with longer follow-up. In the non- of the technology related to CAR-NK cells. K.R., R.B., and The University
transplant setting, Rambaldi and colleagues recently reported on of Texas MD Anderson Cancer Center have an institutional financial con-
the outcomes for the subset of patients who received continued flict of interest with Affimed GmbH. K.R. participates on scientific advi-
blinatumomab for maintenance and consolidation45 from the sory boards for GemoAb, Avenge Bio, Kiadis, GSK, and Bayer. All other
authors declare no competing financial interests.
original randomized, phase 3 study of blinatumomab vs standard
chemotherapy in patients with Ph-negative, refractory, or relapsed
ORCID profiles: X.J., 0000-0003-1697-8575; S.K., 0000-0002-3731-
B-ALL20; 267 patients received blinatumomab induction, and 36
608X; M.K., 0000-0003-0079-8617; U.P., 0000-0002-7592-2224; A.O.,
(13%) received continued maintenance, defined as 6 or more 0000-0002-1669-0355; K.C., 0000-0003-4013-5279; R.C., 0000-0002-
cycles of blinatumomab. The maintenance cohort had longer OS 4314-5037.
(median unreached vs 15.5 months, OR 0.37, 95% CI 0.16-0.88)
and PFS (14.5 months [95% CI 7.1-21.9] vs 9.8 months [95% CI Correspondence: Partow Kebriaei, Department of Stem Cell Transplan-
8.5-11.1], OR 0.48, 95% CI 0.22-1.03) compared with those who tation & Cellular Therapy, The University of Texas, M.D. Anderson Can-
didn’t receive maintenance.45 cer Center, 1515 Holcombe Blvd, Houston, TX 77030; e-mail:
pkebriae@mdanderson.org.
In conclusion, we demonstrated that blinatumomab mainte-
nance therapy following transplant is feasible and has a very Footnotes
safe toxicity profile. While our study did not demonstrate a clear
Submitted 12 July 2021; accepted 29 November 2021; prepublished
clinical advantage of this approach in the entire cohort, we
online on Blood First Edition 16 December 2021. DOI 10.1182/
showed that response to blinatumomab therapy posttransplan- blood.2021013290.
tation is dependent on the immune profile of the patient post-
transplantation, with a distinct immune phenotype-predicting *M.R.G. and P.B. contributed equally to this study.
response. This may inform which patients will most likely benefit
from blinatumomab therapy posttransplantation. Larger- †K.R. and P.K. contributed equally to this study.
prospective studies are needed to confirm these findings. In
addition, we also found that overexpression of checkpoint The online version of this article contains a data supplement.
molecules, specifically TIM3, may be implicated as a mechanism
The publication costs of this article were defrayed in part by page
of resistance, and therefore combination therapies with blinatu- charge payment. Therefore, and solely to indicate this fact, this article
momab and immune checkpoint inhibitors may result in is hereby marked “advertisement” in accordance with 18 USC section
improved efficacy. 1734.

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