Review Article Open Access
Volume 2 | Issue 4 | DOI: https://doi.org/10.33696/cancerimmunol.2.028

Immunotherapy in Pediatric Acute Lymphoblastic Leukemia

  • 1The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA
  • 2Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
+ Affiliations - Affiliations

*Corresponding Author

Patrick Brown, pbrown2@jhmi.edu

Received Date: September 13, 2020

Accepted Date: October 02, 2020


Leukemia is the most common childhood malignancy and cause of pediatric cancer death. Significant advances in the cure rates of B-cell acute lymphoblastic leukemia (B-ALL) and T-cell acute lymphoblastic leukemia (T-ALL) have been achieved; however, patients with refractory or relapsed B-ALL or T-ALL continue to have poor outcomes. Immunotherapy is a revolutionary treatment aimed to improve survival and reduce the toxicity of chemotherapy by harnessing the patient’s own immune system to target cancer cells. Several immunotherapies have been developed including monoclonal antibodies, antibody drug conjugates, Bispecific T-cell engagers (BiTEs), and chimeric antigen receptor T-cell (CAR-T) therapy. Immunotherapy has been shown to have efficacy in relapsed acute leukemia; however, antigen escape relapse remains a challenge and the duration of effect is unknown. Nevertheless, immunotherapy holds the potential to significantly improve outcomes in relapsed pediatric acute B-ALL and T-ALL and is actively being studied in upfront therapy.


B-ALL, T-ALL, Immunotherapy, Monoclonal Antibodies, Antibody-drug Conjugates Bispecific T-Cell Engager (BiTE), Chimeric Antigen Receptor (CAR) T-Cells


ASMT: American Society for Transplantation and Cellular Therapy; B-ALL: B-cell Acute Lymphoblastic Leukemia; BiTE: Bispecific T-cell Engagers; CAR-T: Chimeric Antigen Receptor T-cell; COG: Children’s Oncology Group; CR: Complete Remission; CRh: Complete Remission with partial hematologic recovery; CRS: Cytokine Release Syndrome; FDA: U.S. Food and Drug Administration; HSCT: Hematopoietic Stem Cell Transplant; InO: Inotuzumab Ozogamicin; NK: Natural Killer; MRD: Minimal Residual Disease; OS: Overall Survival; OR: Odds Ratio; PFS: Progression-free Survival; scFv: Single-chain variable fragment; SOC: Standard of Care; SOS: Sinusoidal Obstructive Syndrome; T-All: T-cell acute lymphoblastic leukemia; TCR: T-cell Receptor; VHR: Very High-risk


Leukemia is the most common childhood malignancy and is the most common cause of cancer death before the age of 20 [1]. Pediatric leukemia can be subdivided into acute versus chronic and lymphoid versus myeloid leukemia. Acute lymphoid leukemia (ALL) can be further divided into B-cell precursor ALL (B-ALL) and T-cell ALL (T-ALL). The focus of this paper will be pediatric B-ALL and T-ALL.


Approximately 85% of ALL cases are B-ALL [2]. Cure rates for B-ALL significantly rose over the past five decades from 10% to 90% [1-3] due to multi-agent chemotherapy regiments, CNS prophylaxis and better risk stratification [3]. Despite these successes, about 2% of patients are refractory to chemotherapy and another 10% to 15% of patients will relapse [4]. Treatment for these patients remains a therapeutic challenge. Event free survival for patients with relapsed or refractory ranges from 13% to 40% [4-7]. Attempts to intensify chemotherapy in high risk patients resulted in excessive toxicity [8,9].


T-ALL accounts for approximately 15% of pediatric ALL cases [1,10]; and historically these patients have inferior outcomes to patients with B-ALL with event-free and overall survival around 70% and 80% respectively [11-13]. Survival has improved with intensification of therapy and T-cell focused regimens, such as the addition of nelarabine to treatment paradigms [14]. However, survival after relapse is about 30% due to a lack of effective salvage therapies [15].


Immunotherapy is a revolutionary treatment aimed to improve survival and reduce the toxicity of chemotherapy by harnessing the patient’s own immune system to target cancer cells. Several different approaches have been developed. Antibody therapy utilizes antigens present on the surface of leukemia cell to aid in the immune system’s attack of the cancer cell. Therapies include monoclonal antibodies, antibody drug conjugates and Bispecific T-cell engagers (BiTES). Adaptive therapies manipulate patient’s cytolytic immune cells to recognize tumor cells and elicit an anti-tumor response. These therapies include chimeric antigen receptor T-cell (CAR-T) therapy. This review will focus on immunotherapeutic options approved and under investigation for pediatric ALL. Common targets are highlighted in Tables 1 and 2.

Target Drug
CD19 Antibody-drug conjugates
CD20 Antibody
BiTE: Preclinical
•CD20/CD19 CAR-T
CD22 Antibody
•Moxetumomab pasudotox
Antibody-drug conjugates
•Inotuzumab Ozogamicin
•CD19/CD22 CAR-T

Table 1: B-ALL Targets.

Target Drug
CD1a CAR-T (Preclinical)
CD3 CD3 NK CART-T (Preclinical)
UCART7 (Preclinical)
TruUcar GC027 (Preclinical)
CD38 Daratumab Isatuximab Mogalizumab
CD52 Alemtuzumab
CD194 Mogamulizumab CD194/30 CAR-T
Interleukin-2receptor alpha Basiliximab (Preclinical)
Interleukin-7 receptor alpha Preclinical
TALLA-1 Preclinical
Hedgehog interacting proteins Preclinical
Human telomerase reverse transcriptase Preclinical

Table 2: T-ALL targets.

Monoclonal Antibodies/Antibody-drug Conjugates

Antibody therapy is engineered to attack specific antigens on tumor cells. Monoclonal antibodies stimulate antibody-dependent cytotoxicity; whereas, drug-antibody conjugates deliver a cytotoxic drug to the tumor cell when it binds and is phagocytosed by the target cell. In pediatric leukemia, both monoclonal antibody and antibody-drug conjugates have shown promise.

Inotuzumab ozogamicin (InO)

Mechanism of action: CD22 is expressed on 80% to 90% of B-ALL cells. Inotuzumab ozogamicin (InO) is a humanized anti-CD22 monoclonal antibody conjugated to the cytotoxic drug, calicheamicin [16]. Calichaemicin is cleaved and binds to minor DNA grooves causing doublestranded DNA breaks and apoptosis of the leukemia cell [16]. Clinical trials of InO in B-ALL are highlighted in Table 3.


Patients Phase N Dosing Response SOS Group/ study
Adult CD22+ R/R ALL Ph+/- Phase I/II Multicenter Open Label N=72 Phase 1 n=-24 Expansion n=13 Phase II n=35 1.2mg/m2/cycle (n=3) 1.6mg/m2/cycle (n=12) 1.8mg/m2/cycle (n=9) Days 1, 8, 15 over 28 day cycle Expansion (n=13) Recommended does 1.8mg/m2/cycle CR/CRh: 49(68%) MRD negative: 41(84%) Median DOR: 4.6 mo (95%CI; 3.8- 6.6) Median PFS: 3.9 mo (95%CI; 2.9- 5.4) Median OS: 7.4 mo (95%CI; 5.7- 9.2) N=4 [78] NCT01363297
Adult and pediatric CD22+ R/R B-ALL  Phase II Single center N=49 1.8mg/m2/cycle every 3-4 weeks CR/CRh: 28
MRD negative: 19 (39%)
Median OS: 5.1 mo (95%CI; 3.8–6.4)
N=22 [79] NCT01134575
Adult R/R CD22+, Ph+/- B-ALL  Phase III

Randomized (SOC
chemotherapy vs. Inotuzumab ozogamicin)
Ino n=164
SOC n=162
1.8mg/m2/cycle Days 1, 8, 21 CR/CRh: (73.8% vs.
35%), p<0.001 |

MRD negative: 78.4% (95%
CI; 68.4-86.5]
vs. 28.1% (95%
CI; 13.7-46.7), p<0.001

DOR: 4.6 mo
(95% CI; 3.9-
5.4) vs. 3.1 mo
(95% CI; 1.4-
4.9, p = 0.03

Median PFS: 5.0 mo (95%
CI; 3.9-5.8) vs.
1.7 mo (95%
CI; 0.34-
0.60); HR,
0.45 (97.5%
CI; 0.34-0.61), p<0.001)

Median OS:
7.7 mo vs. 6.2 mo (95%CI, 4.7-8.3)

2-year OS: 22.8% vs.
10.0% (HR
0.75; 97.5CI,
0.57-0.99), p=0.0105
Patients who proceed to transplant and developed SOS
InO-18/79 (22.8%)
SOC-3/35 (8.6%)
[17] NCT01564784
Pediatric R/R CD22+ B-ALL  Phase II N=5 1.3mg/m2 every 3 weeks (n=3)

Increased to 1.8mg/m2 every 3 weeks (n=1 of the 3)

Then weekly 0.8mg/m2 on Day 1 followed by 0.5mg/m2 on Days 8 & 15
CR: 1 (20%)

CRh: 2 (40%)

No response: 2
Pediatric R/R. CD22+ 
ALL compas- sionate use 
Retrospective analysis N=51 3 not evaluable for response Cycle one: three doses: 0.8mg/ m2 on week
1 followed by 0.5mg/m2 on weeks 2 and 3

One patient with MRD-only disease received 0.5mg/ m2/dose
for all three doses.

In second and subsequent cycles, assuming CR/CRh during cycle 1, patients received 0.5mg/m2/dose on days 1, 8, and
CR/CRh: 67%

CR: 15 (39%)

CRh: 13 (25%)

MRD negative: 20 (71%)

No response: 8

12-month EFS 23.4±7.5%

12-month OS 36.3±9.3%
Pediatric and AYA CD22+ 
B ALL in 2nd  relapse, refractory 
to two prior regimens, relapse after HSCT, or 1st relapse with DS 
Phase II Single arm N=48   CR/CRh:
28 (58.3%)
(95%CI, 43.2-

CR: 19 (40%)

CRh: 9 (19%)

MRD negative: 17 (65%)

Progressive disease: 8
4 (30.7%) [20] NCT02981628

Table 3: Inotuzumab ozogamicin studies.


Adult experience with InO: U.S. Food and Drug Administration (FDA) approval of InO for relapsed/ refractory CD22 positive ALL was based on the INOVATE trial. The study showed a superiority of InO compared to standard of care (SOC) chemotherapy with improved complete remission (CR)/remission with partial hematologic recovery (CRh) rates, 73.8% vs. 35% and progression-free survival (PFS) 5.0 months vs. 1.7 months. More patients proceed to transplant in the InO arm (48% vs. 22%, p<0.0001) [17]. At the two-year follow-up, overall survival (OS) rates were superior with InO 22.8% and 10.0% [17].

Pediatric experience with InO: Of five pediatric patients with relapsed CD22 positive B-ALL treated with InO as part of an adult phase 2 trial, three had a CR/CRh [18]. A retrospective analysis of compassionate use of InO in fifty-one pediatric patients with relapsed/refractory B-ALL showed a 12-month EFS and OS of 23% and 36% respectively [19]. Twenty-one patients underwent a hematopoietic stem cell transplant (HSCT) after achieving CR [19]. In the Children’s Oncology Group (COG) trial AALL1621 (NCT02981628) of InO in heavily pre-treated relapsed/refractory, CD22 positive B-ALL patients, 58.3% had a CR/CRh, with 65.4% of those having a minimal residual disease (MRD) response [20].

Ongoing Trials with InO in pediatrics: There are several ongoing pediatric trials investigating the timing and indications for InO. InO is being studied in upfront therapy, relapsed/refractory MRD positive ALL with chemotherapy, and as consolidation post-transplant (Table 4).

Study Aim Design Age Status
NCT03959085 AALL1732 InO added to post-induction chemotherapy in HR B-ALL Phase III Randomized Multicenter 1 y.o. to 24 y.o. Recruiting
NCT03150693 InO with frontline chemotherapy with young adults with newly diagnosed CD22 + B-ALL Phase III Randomized Multicenter 18 y.o. to 39 y.o Recruiting
NCT04307576 Addition of InO in chemotherapy for newly diagnosed B-ALL (IR/HR) Phase III Randomized 1 y.o. to 45 y.o. Not yet recruiting
NCT03739814 InO and Blinatumomab in newly diagnosed, or R/R CD22+ B-ALL Phase II Multicenter ≥ 18 y.o. Suspended-Request for amendment
NCT03962465 InO with augmented BFM Re-induction for AYA pa- tients with R/R B-ALL Phase I
Single Center-U. Virginia
18 y.o. to 55 y.o. Recruiting
NCT03991884 InO with chemotherapy in R/R CD22+  B-ALL (Ph+/-) Phase I
Single Center- U. Washington
≥ 18 y.o. Recruiting
NCT01925131S1312 InO with chemotherapy in R/R CD22+ B-ALL Phase I ≥ 18 y.o. Recruiting
NCT03677596 Study of a lower dose of InO in R/R, transplant eligible
B-ALL at risk of liver disease and plan for HSCT
Phase IV Randomized Multicenter 18 y.o. to 75 y.o. Recruiting
NCT03851081 InO and Vincristine sulfate liposome in R/R CD22+
Phase ib/II Single Center- Roswell Park Cancer Institute ≥ 18 y.o. Not yet recruiting
NCT02311998 Bosutinib with InO in R/R Ph+ B-ALL Phase I/II
Single Center-MD Anderson
≥ 18 y.o.  
NCT03856216 InO in CD22+ R/R B-ALL in patients who are not eligible for a myeloablative HSCT but eligible for a RIC HCST Phase II
Single Center-MD Anderson
18 y.o. to 70 y.o. Recruiting
NCT03610438 ALL2418 InO in B-ALL who have MRD+ disease after at least 3 months of any therapy
Phase IIa Exploratory Multicenter ≥ 18 y.o. Not yet recruiting
NCT03913559 InO for children with MRD+, CD22+ ALL with <5% blasts in BM Phase II Multicenter Up to 21 y.o. Recruiting
NCT03441061 InO in MRD+ B-ALL Phase II
Single Center- MD Anderson
≥ 18 y.o. Recruiting
NCT03104491 InO post-transplant in ALL who have a high risk of relapse Phase I/II Multicenter 16 y.o to 75 y.o. Recruiting
NCT03564678 Levocarnitine and Vitamin B Complex in treating InO and PEG-Asparaginase hyperbilirubinemia in ALL Phase II
Single Center-MD Anderson
12 y.o and older Recruiting

*Table is not comprehensive, please see clinicaltrials.gov for additional ongoing trials

Table 4: Ongoing trials with Inotuzumab ozogamicin in pediatric and AYA patients.

Sinusoidal obstructive syndrome (SOS): Sinusoidal obstructive syndrome (SOS) was seen more commonly in patients who are treated with InO than salvage chemotherapy, a serious concern in patients whom subsequent transplant is a consideration. In INOVATE trial, rates of SOS were 14.0% (5% fatal) in the InO arm vs. 2.1% in the SOC chemotherapy arm [17]. Risk factors for SOS included conditioning with dual alkylators, hyperbilirubinemia before HSCT, and prior HSCT (OR 6.02; p=0.032) [17]. In the pediatric experience, 4 of the 13 patients (30.7%) who went on to HSCT developed grade 3 SOS in AALL1621 study [20] at 11 of the 21 (52%) patients in compassionate use study [19]. Strategies to prevent SOS include avoiding dual alkylating agents and/or thiotepa and hepatoxic agents, prophylactic ursodiol, proceeding to HCT after two cycles of InO, and close monitoring for SOS [21]. Ongoing trials include Levocarnitine and Vitamin B to reduce hyperbilirubinemia with InO treatment (NCT03564678), lowering the dose of InO pre-transplant (NCT03677596) and reduced intensity transplant (NCT03856216).


Mechanism of action: CD38 is a type II transmembrane glycoprotein on the surface of thymocytes, activated T-cells and terminally differentiated B cells, with low level expression on other normal lymphoid and myeloid cells [22]. CD38 expression has been seen on T-ALL blasts and remains stable after treatment with chemotherapy [22]. Daratumumab is a human monoclonal antibody directed against CD38 [22]. It is FDA approved for multiple myeloma both as monotherapy and in combination [23,24]. Preclinical data has shown efficacy of Daratumumab in T-ALL models [22,25], and case series have shown efficacy as salvage therapy in relapsed T-ALL [26,27]. There are ongoing clinical trials of Daratumumab in pediatric T-ALL and B-ALL in combination with cytotoxic chemotherapy (NCT03384654). Other monoclonal antibodies being tested in T-ALL are listed in Table 2.


Bispecific T-cell-Engaging (BiTE) antibodies are antibodybased molecules that bind to distinct surface markers on T-cells and tumor cells to form the immunological synapse [28,29]. BiTEs bind the invariant signaling component of the T-cell receptor (TCR), CD3, and a surface target antigen on tumor cells, resulting in T-cell activation, expansion and tumor cell lysis [28,29]. BiTEs are independent of T-cell receptor specificity and do not require MHC presentation of the antigen; thus, bypassing T-cell regulation [29]. Unlike CARTs, BiTEs do not require manufacturing and infusion of T-cells [29].


Mechanism of action: CD19 is expressed on approximately 90% of B-ALL cells [30]. Blinatumomab is a BiTE that binds to CD19 on leukemic cells and CD3- subunit of the TCR on T-cells [29]. Clinical trials of Blinatumomab for B-ALL are highlighted in Table 5.

Patients Phase N Dosing Response Group/study
Adults with Ph- R/R B- ALL 
Multicenter, single -arm, open-label, phase II,
(185- received blina)
Continuous infusion over 4 wks of a 6 wk cycle
Two cycles for induction and 3 for consolidation
Cycle 1 initial dose 9μ/day  for 7 days then 28μ/day for the
remaining 3 wks.
cycles 28μ/day
CR or CRh 81 (43%) (95%CI;
CR 63 (33%)
CRh 18 (10%)
MRD negative: 60
Median RFS (MRD responders vs. non- responders) 6.9
mo (95% CI, 5.5-
10.1) vs 2.3 (95% CI 1.2-NE)
Median OS: (MRD responders vs. non-responders
11.5 mo (95% CI, 8.5-NE) vs. 6.7 mo (95% CI 2.0-NE)
MT103-211 (NCT01466179)
Ph- R/R ALL 
Blinatumomab vs standard 
of care (SOC) chemotherapy 
Phase III, randomized, open-label, multi- center trial comparing
Blinatumomab with conventional chemotherapy (2:1 ratio)
405 pts
-271 in the blina arm
-134 in the SOC
Intent-to treat
Blina 9μ/day
days 1-7 and 28
μ/day days 8-28
Cycles 2-5  days 1-28 in a 42 day cycles (consolidation)
Cycles 6-9 in
84 day cycles (maintenance)
CR : 91 (34%)
(95%CI, 28-40) vs
21 (16%) (95%CI,
10-23; p<0.001)
CRh: 24 (44%) vs.
6 (25%)  (p<0.001
MRD negative: 76% vs. 48%
(95%CI, 9-47)
[32, 36] TOWER (NCT02013167)
Ph- or + R/R Pediatric 
<18 (2 to 17) 
>25% BM blasts 
Phase I/II open label, multicenter
40 pts- phase I 44 phase II
recommended dosage
phase I (n =
26) or phase II (n = 44)
Phase I: dosages of 5, 15, and 30 μ/m2/d and a stepwise dosage of 15/30 μg/ m2/d (15 μ/ m2/d for the first 7 days and 30 μ/m2/d thereafter).
Recommended dosage of 5/15 μ/m2/d
Of the 70 pts that received the recommended dosage:
CR: 27 (39%)
(95% CI, 27-51%)
MRD negative: 14/27 (52%) (95%
CI, 32-71)
Median RFS: 4.4
mo (95% CI, 2.3-
7.6) (for patients who achieved CR_
Median OS: 7.5
mo (95%CI, 4.0-
6 mo estimated EFS (1st relapse): 40.8% (95%CI,
30.1-50.) vs.
25.9% (95%CI;
HR 0.7 (95% CI,
0.47-1.03; p=0.11)
6 mo estimated EFS (2nd or later relapse): 24.0%
(95% CI, 17.4-
31.3%); 1.6% (95%
CI, 0.1-7.5%):
HR 0.49 (95%
CI, 0.29-0.57; p<0.001)
MT103-205 (NCT01471782) AALL1121
R/R Ph+ B ALL, 
previously treated with at least one 2nd generation TKI or intolerant to 2nd generation TKI and refractory to imatinib 
>5% bone marrow blasts 
Phase II, multicenter, single arm trial of blina
45 patients
9 μ/day days 1-7
and 28 μ/day
days 8-28 for
cycle 1.
28 μ/day days
1-28 subsequent cycles
IF CR achieved could receive up to 3 cycles of consolidation unless a HSCT was scheduled
CR/CRh; 16 (36%)
(95% CI, 22- 51)
CR: 14 (31%) (95%
CI, 18-47)
CRh: 1 (4%) (95%
CI, 1-15)
MRD-negative: 14
(88%) (95% CI,
Median OS: 7.1 mo (95% CI, 5.6-NE)
Median RFS: 6.7
mo (95% CI, 4.4- NE)
(Martinelli, JCO, 2017)
Adult R/R B- ALL in 
ftrst or later hematologic CR but MRD positive 
Multicenter, open label, single arm trial
113 evaluable patients
Excluded no central MRD assay results or a test sensitivity that did not reach 10−4
15 μ/m2/day for
28 days followed by 2-2wk tx free period
Up to 4 cycles
(remained in CR
MRD negative: 88/113 (78%)
(95% CI, 69-85)
Median OS: 36.5mo (95% CI,
Median RFS (MRD responders vs nonresponsers): (23.6 vs 5.7
months; p=0.002)
Median OS (MRD responders vs nonresponsers): (38.9 vs 12.5
months; p=0.002
[35] BLAST
MT103-203 NCT01207388
Pediatric and AYA R/R B-ALL after re-induction 
Multicenter, randomized phase III trial
208 HR/IR
patients were randomized
Chemotherapy arm- Blocks
2 and 3 of UKALLR3
Two cycles at 15 μ/m2/day for 28 day
2-year DFS: 59.3
± 5.4% vs. 41.0 ±
6.2% (p=0.05)
2-year OS: 79.4
± 4.5% vs. 59.2 ±
6.0% (p=0.005)
[38] NCT02101853
Pts with B-ALL 0 to 21 y.o 
who were transplanted with CR but MRD + 
Retrospective analysis, multicenter
10/15 CR1 with EOC+
Singe 12 day
course 15μ/m2/d
2 had course shortened to go to HCT (18 and 20 days of blina)
1 received 2 cycles of blina
MRD negative: 14/15 (93%)
1-yr post HCT relapse incidence 27.8%
1-yr OS: 93.2%

Table 5: Blinatumomab studies.

Role in relapsed/refractory B-ALL: In 2014, the FDA granted accelerated approval of blinatumomab for adult Philadelphia chromosome negative (Ph-) relapsed/ refractory B-ALL based on a single-arm study of 189 adults that showed efficacy and manageable toxicity [31]. Eightyone patients (43%) had a CR/CRh within two cycles of blinatumomab [31]. Median overall survival was 6.1 months [31]. This was superior to historical controls who received SOC, salvage chemotherapy [31]. Efficacy was confirmed in the TOWER trial, a multicentered, randomized, phase III trial comparing blinatumomab to chemotherapy in adult relapsed/refractory Ph- ALL [32]. CR was achieved in 91 patients (34%) in the blinatumomab arm compared to 21 patients (16%) in the SOC arm. The median overall survival was significantly longer for the blinatumomab arm (7.7 months versus (4.0 months) in the SOC arm [32].

Role in Philadelphia chromosome-positive (Ph+) ALL: The approval of blinatumomab was extend to Ph+ relapsed/refractory B-ALL based on the ALCANTARA trial showing a 36% CR/CRh, with 88% complete MRD response in patients with relapsed/refractory Ph+ ALL, previously treated with TKI treatment [33]. Blinatumomab as consolidation to treatment with TKI has also been studied in a multicenter phase II trial of Ph+ ALL, patients were treated with dasatinib, followed by post-induction consolidation with blinatumomab. At the end of two cycles of blinatumomab 19/35 (54%) had a molecular response that further increased after subsequent cycles [34]. Twelvemonth OS and DFS are 96.2% and 91.6% respectively [34]. There are several ongoing studies examining the efficacy of TKIs with blinatumomab (Table 6).

Study Aim Design Age Status
NCT02101853 AALL1331 Blinatumomab compared to SOC chemotherapy in pediatric and AYA patients as a bridge
to transplant in relapsed ALL after re-induction with block 1 of UKALLR3/mitoxantrone arm
Phase III trial Multicenter Randomized 1 y.o. to 30 y.o. Active, not recruiting
HR/IR arm closed early due to trend to superiority
NCT02393859  Blinatumomab vs. SOC in pediatric patient with
Ph-, HR, first relapsed B-ALL
Phase III Multicenter Randomized >28 days
to <18 y.o.
Active, not recruit- ing
NCT03914625 AALL1731  Blinatumomab in combination with chemotherapy in newly diagnosed SR B-ALL
Role of immunotherapy in patients with Down Syndrome and B-ALL
Phase III Randomized Multicenter 1 y.o. to 21 y.o. Recruiting
St. Jude Total Therapy XVII 
Blinatumomab for Newly diagnosed SR ALL
Blinatumomab for patients with HR ALL (and MRD of 0.01 to 1% at the end of induction)
Phase II/III Randomized Multicenter 1 y.o. to 18 y.o. Recruiting
Incorporating Blinatumomab with standard chemotherapy regimens in newly diagnosed HR/IR B-ALL Phase III Randomized Multicenter[ed] <18 y.o. Recruiting
NCT02877303  Blinatumomab and chemotherapy (Hyper-CVAD) in newly diagnosed B-ALL Phase II
Single center-MD Anderson
14 y.o and older Recruiting
NCT03367299  Chemotherapy and blinatumomab in newly diagnosed Ph- ALL Phase II Multicenter 18 y.o. to
65 y.o
NCT03541083 HOVON146ALL  Blinatumomab in the prephase and consolidation in newly diagnoses B-ALL Phase II Multicenter 18 y.o. to
70 y.o.
NCT02807883 Blinatumomab maintenance following allo HSCT in
Phase II
Single center-MD Anderson
1-70 y.o. Recruiting
NCT03114865 Blinatumomab in B-ALL post allo HSCT as remission maintenance Phase I
Single Center- SKCC
≥18 y.o. Recruiting
NCT04044560 (OZM-097)  Blinatumomab for MRD in Pre-B ALL following stem cell transplant Phase II Single arm Open label Multicenter 1 y.o and older Active, not yet recruiting
NCT03982992 DLI-TARGET  Allogeneic donor lymphocyte infusions combined with Blinatumomab in B-ALL who have mixed chimerism (MC) or are MRD after allo HSCT and are refractory to at least one
MRD-or MC targeted therapy (i.e blinatumomab, DLI, TKI, etc)
Phase II Single center- Klinikum der Universität München ≥18 y.o. Recruiting
NCT02790515 NCT03849651  Blinatumomab in naïve T-cell depleted haploidentical donor HCT for R/R ALL Phase II
Single center-St. Jude
Up to 21 y.o. Recruiting
NCT02879695  Blinatumomab and Nivolumab with or without ipilimumab in patients with poor risk relapsed or refractory CD19+ precursor B-ALL Phase I Multicenter 16 y.o. and older Recruiting
NCT03605589 Pembrolizumab Blinatumomab in pediatric and AYA R/R ALL Phase I Pilot
Single Center- Cincinnati Children’s Hospital
1 y.o. to 40 y.o. Recruiting
NCT03512405 Pembrolizumab and blinatumomab in R/R ALL Phase I/II
Single center-City of Hope Medical Center
≥18 y.o. Recruiting
NCT03160079 Pembrolizumab and Blinatumomab in R/R B-ALL with high marrow lymphoblasts (>50% blasts) Phase i/II Multicenter ≥18 y.o. Recruiting
NCT02744768  Dasatinib and Blinatumomab in newly diagnosed Ph+ ALL Phase II Multicenter ≥18 y.o. Recruiting
NCT03318770 GIMEMA 2116  Dasatinib and blinatumomab following chemotherapy in Ph+ ALL Observational Case-Control Prospective ≥18 y.o. Not yet recruiting
NCT04329325  Blinatumomab and TKI (Dasatinib) in patients with Ph+ ALL Phase II Single
≥18 y.o. Recruiting
NCT02997761  Ibrutinib and Blinatumomab in R/R B-ALL Phase II Single group- University of
California Davis
≥18 y.o. Recruiting
NCT03263572  Blinatumomab, Methotrexate, cytarabine and ponatinib in Ph+ R/R ALL Phase II
Single center-MD Anderson
≥18 y.o. Recruiting
NCT03147612  Low-intensity chemotherapy, ponatinib and blinatumomab in newly diagnosed and R/R Ph+ ALL Phase II
Single center- MD Anderson
≥18 y.o. Recruiting
NCT03628053 OBERON  Tisagenlecleucel vs Blinatumomab or Inotuzumab for patients with R/R B-ALL Phase III Randomized Multicenter ≥18 y.o. Not yet recruiting
NCT03739814 Inotuzumab ozogamicin and blinatumomab in patients with newly diagnosed or R/R  CD22+ B-ALL Phase II Multicenter ≥18 y.o. Suspended-Request for amendment

*Table is not comprehensive, please see clinicaltrials.gov for additional ongoing trials.

Table 6: Ongoing trials with Blinatumomab in pediatric and AYA patients.

Role in MRD positive disease: In 2018 the FDA granted approval for blinatumomab for the treatment of adults and children with B-ALL in a morphological first or second CR with MRD [35]. Eighty-eight of 113 patients (78%) achieved a complete MRD response after one cycle of blinatumomab [35]. Patients who achieved a complete MRD response had a prolonged OS (38.9 vs 12.5 months; p=0.002) and RFS (23.6 vs 5.7 months; p=0.002) [35].

Role in first vs. later relapse: Blinatumomab appears to be a more effective salvage therapy in first versus second or later relapse. In the TOWER study, blinatumomab’s effect on overall survival was greater for first salvage therapy (HR 0.59; p=0.016) than second or greater salvage therapy (HR 0.72; p=0.055) [36]. Similarly, in the BLAST MRD trial, patients who had previously relapsed had inferior RFS and OS compared with those treated in first remission (HR 2.02 for CR2 vs CR1 relapse and HR 3.34 for CR3 vs. CR1 relapse, -p=0.001), suggesting the importance of MRD clearance early in the treatment course [35].

Role in pediatrics: Efficacy and safety of blinatumomab was shown in the pediatric population in the Study MT103- 205 a phase I/II study, of the 70 patients. Twenty-seven (39%) achieved a CR with 14 (52%) of the responders having a completed MRD response [37]. Duration of response was 4.4 months [37]. There are several pediatric trials studying the role of blinatumomab in relapsed/ refractory B-ALL and as consolidation for transplant (Tables 6 and 7). The COG trial AALL1331 (NCT02101853) is a phase III randomized trial for relapsed B-ALL testing blinatumomab as post-reinduction consolidation, with high risk (HR) and intermediate risk (IR) patients proceeding to HSCT, and low risk (LR) patients receiving maintenance chemotherapy. The HR/IR randomization was terminated early due to evidence of superiority and decrease toxicity of the blinatumomab arm [38]. In these groups blinatumomab arm had an improved 2-year DFS (59.3% vs. 41.0% p=0.05), 2-year OS (79.4% vs. 59.2% p=0.005) and MRD clearance (21% vs. 79% p<0.0001) with fewer and less severe toxicities compared to SOC chemotherapy [38]. Data for the low risk (LR) randomization is pending. There are ongoing studies investigating the role of blinatumomab in upfront therapy including the COG trial AALL1731 (NCT03914625) that is studying the addition of blinatumomab to standard chemotherapy in patients with NCI SR B-ALL at high risk for relapse. Blinatumomab is also being studied in HR/IR newly diagnosed B-ALL in the European Studies AIEOP-BFM ALL 2017 (NCT03643276) and PETHEMABLIN- 01 (NCT03523429). Lastly, blinatumomab is also being studied as maintenance after allogenic HSCT (NCT02807883 & NCT03114865) (Table 6). Combining blinatumomab with other immunotherapies is also being investigated. There is an ongoing adult trial combining treatment with inotuzumab ozogamicin with mini-HCVD with or without blinatumomab in previously untreated acute lymphoblastic leukemia, (NCT01371630). In AYA patients, blinatumomab and inotuzumab ozogamicin are being studied in newly diagnosed and relapsed/refractory CD22+ B-ALL (NCT03739814). The ability of checkpoint inhibitors to further enhance the efficacy of blinatumomab is also actively being studied (NCT03605589, NCT03512405, NCT03160079, NCT02879695).

Patients Phase N Response Group/study
Pediatric and adult R/R ALL 
(CTL119) (4-1BBz CAR) 
Phase I/IIa
25 pediatric
5 adult
CR: 27 (90%)
MRD negative: 22/27 (81%)
6-mo EFS: 67% (95% CI, 51-88)
6-mo OS: 78% (95% CI, 65-95)
[60] NCT01626495
Pediatric and AYA R/R B-ALL 
(CTL119) (4-BBz CAR) 
Phase I/II
ITT MRD: (40/45) 89%
12-mo EFS: 50.8% (95% CI, 36.9-69.9)
12-mo OS: 69.5% (95% CI, 55.8-86.5)
[46] NCT02028455
Children and AYA CD19+ ALL 
(CTL119) (4-1BBz) 
Pilot protocol
CR: 50 (94%)
MRD negative: 45 (90%)
6-mo EFS: 70% (95% CI, 58-85)
6-mo RFS: is 72% (95% CI, 59-87%)
12-mo EFS: 45% (95% CI, 31-66)
12-mo RFS: 44% (95% CI, 30-65)
12-mo OS: 78% (95% CI, 67-91)
Pediatric and AYA R/R B-ALL 
KTE-C19 (CD28 CAR) 
Phase 1
4 treated
MRD negative CR: 4
[82] (NCT02625480) ZUMA-4
Pediatric and AYA with R/R B-ALL or NHL 
(TCR zeta and CD28 signaling domain) 
Phase 1
CR: 14/21 (66.7%) (95% CI, 43.0–85.4)
MRD negative: 12/20 (60%) (95% CI,
OS: 51.6%
[45] NCT01593696
Pediatric and AYA R/R B-ALL CD19+ 
Tisagenlecleucel (CD3-zeta: 4-1BB) 
5% blasts in BM 
Phase II Multicenter
screened N=97 enrolled N=75 infused
RR: 65 (81%) (95% CI, 71-89)
CR: 45 (60%)
CRh: 16 (12%)
MRD negative: 64 (98%)
6-mo RFS: 80% (95% CI, 65-89)
12-mo RFS: 59% (95% CI, 41-73)
18 mo RFS: 66% (95% CI, 52-77)
6-mo EFS: 73% (95% CI; 60-82)
6-mo OS: 90% (95% CI 63-86)
12-mo EFS: 50% (95%CI, 35-64)
12-mo OS: 76% (95% CI, 63-86)
18 mo OS: 70% (95% CI, 58-79)
[4347] NCT02435849
Adult R/R ALL 
KTE-C19 (CD28 CAR) 
Phase 1
CR: 44/53 (83%) (95% CI, 70-92)
MRD: 32 (67%; 95% CI, 52-80)
Median EFS: 6.1 months (95% CI, 5.0-
Median OS: 12.9 months (95% CI, 8.7-
[44] NCT01044069
R/R B-ALL treated with CD22 BBz CAR, 
(4-1BB domain) 
Phase I
21 Children and adults
17-previously treated with CD19
CR: 12 (57%) CR
MRD negative 9 (75%)
[48] NCT02315612
R/R B-Cell malignances, sequential infusion of  CD19 and CD22 3rd generation CAR-T 
N=89 N=51- ALL
MRD Negative: 96% (95% CI, 86.3-
Median PFS: 13.6 mo (95% CI, 6.5 to NE)
Median OS: 31.0 mo (95% CI, 10.6-NE)
[83] ChiCTR-
Pediatric R/R B-ALL 
AUTO3-Bicistronic CD19 and CD22 CAR 
Ox40 co-stim for CD19 CAR 
41BB co-stim for CD22 
Phase I
CR and MRD: 7/10 1 year follow up:
-3 relapses
-4 patients in ongoing CR/CRh with B-Cell
Amelia Study
bispeciftc CAR-T in children and AYA patients with B-ALL 
Lentiviral transduction bivalent CAR 
fmc63 CD19 m971 CD22 
41BB costimulatory endo-domain 
Phase I
CR: 4/4 (100%)
MRD negative: 3/4 (75%)
CD19 and CD22 
CART cocktail for R/RB-ALL 
Phase I
CR/CRh: 15/15 (100%)
MRD negative: 14/15 (93.3%)

Table 7: B-cell CART studies.

Biomarkers to predict response: Predictive biomarkers of response to blinatumomab are emerging. Patients who have a lower baseline disease burden [31] and day 15 MRD have a better response [39]. In addition, superior response was correlated with greater T-cell expansion of effector memory T-cells [40] and a higher percentage of regulatory T-cells [41]. Identifying additional biomarkers to determine response is actively being studied.

CAR-T Therapy

Chimeric antigen receptors (CARs) are T-cells that are engineered to recognize tumor associated antigens. CARs are composed of T-cell signaling moiety and a tumor specific antigen binding domain, commonly a single-chain variable-fragment monoclonal antibody that is fused to a transmembrane domain [42]. Various generations of CARs have been developed to heighten function based on the knowledge that T-cells require two signals to be activated, T-cell receptor (TCR) engagement and co-stimulation. First generation CARs consisted of T-cell receptor complex domain and antigen recognition domains, only providing signal 1; whereas, second generation CARs were constructed to contain co-stimulatory signaling domains including CD28, 4-1BB (CD137), and OX40 (CD134) [42]. Third generation CARs further enhanced T-cell signaling by containing tandem cytoplasmic signaling from two co-stimulator receptors (CD28-4-1BB or CD28-OX40) [42]. Fourth generation CARs have pro-proliferative T-cell costimulatory ligands (4-1BBL) or proinflammatory cytokines (IL-12) [42]. Advantages of CAR-T therapy include HLA-independent recognition of tumor antigen; allowing T-cells to recognize the antigen as foreign and activity is unaffected by HLA down regulation in tumor cells. In addition, both CD4+ and CD8+ T-cell subsets are transduced, allowing for both helper and cytotoxic activity.


Commercial approval: There are two FDA approved CD19 directed CAR-T products, tisagenlecleucel (CTL019) and axicabtagene ciloleucel. Both are second generation CAR-T-cells. Tisagenlecleucel uses a 41BB costimulatory domain and is transduced by lentivirus, whereas axicabtagene ciloleucel uses the CD28 costimulatory domain and is produced by retroviral transduction. Tisagenlecleucel is FDA approved for relapsed/refractory B-ALL in pediatric and young adult patients. Axicabtagene ciloleucel is approved for relapsed/refractory B-cell lymphoma in adults and is being studied for the treatment of pediatric B-ALL.

The FDA approval of tisagenlecleucel was based on a pivotal, global multicenter trial of tisagenlecleucel in pediatric relapsed/refractory, CD19+, B-ALL that showed an overall remission rate of 81%, all with MRD response [43]. Six- and 12-month relapse-free survival rates were 80% and 59% respectively [43].

Clinical trials: Trials have shown second generation CD19-CAR-T therapy induced remission in heavily pre-treated patients with multiple relapsed/refractory B-ALL [43-46]. Axicabtagene ciloleucel is currently being studied in pediatric patients with relapsed/refractory B-ALL previously treated with salvage therapy or HSCT (NCT02625480). In adult relapsed/refractory B-ALL, 44 of the 53 patients (83%) had a CR and 32 patients (67%) had a MRD response [44]. In a Phase 1 trial of 21 pediatric patients with relapsed/refractory B-ALL or Non-Hodgkin’s Lymphoma, CR was seen in 66.7% (14 of 21) of patients with a MRD response occurring in 60% of patients [45]. CD19-CAR-T therapy is being studied in newly diagnosed very high-risk (VHR) B-ALL patients in the COG trial AALL1721 (NCT03876769) and St Jude Total Therapy XVII (NCT03117751). In addition, CD19- CAR-T is being studied in combination with checkpoint inhibitors to enhance efficacy for the CAR-Ts and decrease T-cell exhaustion (Table 8).

Study Aim Design Age Status
St. Jude Total Therapy XVII
19-BBzCART for MRD positive B-ALL or isolated CNS relapse
Randomized Single Center
1 y.o. to 18 y.o.
Tisagenlecleucel in newly diagnosed HR B-ALL with EOC MRD positive disease
Phase II Multicenter
1 y.o. to 25 y.o.
KTE-C19 in Pediatric and adolescents with R/R B-ALL Phase I/II Multicenter  
Up to 21
UCART19 in R/R pediatric B-ALL
Phase I Multicenter  
Upt 17 y.o.
CTA101 UCAR-T for R/R CD19+ B-ALL  
Phase I
3 y.o. to 70 y.o.
Tisagenlecleucel in HR B-ALL with EOC + disease Phase II Multicenter  
1 y.o. to 25 y.o.
CTL019 in R/R or relapse <6 mot after allo-HSCT Phase II Multicenter  
Up to 25 y.o.
Active not Recruiting
NCT03263208 CD19 CAR-T for R/R CD19 B-ALL Phase I/II 2 y.o. to 70 y.o. Unknown
Phase I Single center- China  
4 y.o. to 70 y.o.
CD19 autologous CAR-T Cohort A- hypodiloid Cohort B- t(17; 19)
Cohort C- infants with very high risk KMT2A B-ALL
Cohort D- CNS relapse who did not receive XRT or BMT
CART19 cells transduced with a lentiviral vector to express anti-CD19 scFv:41-BB:TCRζ
Phase II Single Center- UPenn
Up to 29 y.o.
NCT03768310 CARMA CD19 multivirus-specific CAR-for CD19+ B-ALL of NHL undergoing related allo HSCT Phase I
Single Center- Baylor
1 y.o. to 75 y.o.
Not yet recruiting
CD19 CAR-T for R/R B-cell malignancies
(CD19-CD34 CAR transduced T cells)
Phase I
Single Center- Loyola University
18 y.o. and older
NCT04404660 AUTO1  
Phase I/II Multicenter
18 y.o. and older
Efficacy and safety of reinfusion of Tisagenlecleucel in pediatric and AYA patients with B-ALL  
Phase II
Up to 25 y.o.
Not yet recruiting
Study of out of specification for release as commercial product for Tisagenlecleucel in pediatric and AYA R/R B-ALL and B-NHL
Phase III
Child, AYA, adult
JCAR017 in R/R B-ALL or B-NHL
Phase I/II Multicenter
Up to 25 y.o.
huJCAR014 for R/R B-Cell ALL and NHL
EGFRt-expressing CD4+/CD8+
Phase I
Single Center- University of Washington
18 y.o. and older
Anti-CD19 U-CAR-T for B cell hema- tologic malignancies
Early Phase I Single Center- China  
2 to 70 y.o.
Not yet recruiting
NCT03389035 CARCIK
Phase I/II Multicenter- Italy  
1 y.o. to 75 y.o.
PBCAR0191 for patients with R/R NHL and R/R B-ALL
Phase I/IIa Multicenter
18 y.o. and older
Autologous CD22 CAR-T in R/R B-ALL
Phase I
Single Center- Stanford University
18 y.o. and older
CD19/CD22 CAR-T for R/R B-cell malignancies
Phase I Single center-
Lucile Packard Children’s Hospital, Stanford
1 y.o. to 30 y.o.
NCT03289455 AMELIA
CD19/22 CART (AUTO3) for R/ALL
Phase I/II Multicenter-UK
1 y.o. to 24 y.o.
Active, not recruiting
CD19/CD22 CAR-T in R/R B-ALL
Phase I Single center- NCI  
3 y.o. to 30 y.o.
CD19/CD22 CAR-T in R/R B-cell malignancies
Phase I Single center- Stanford University  
18 y.o. and older
CD19/CD22 CAR for R/R B-ALL
Phase I Single center- Seattle
Up to 30 y.o.
CD20/19 CAR-T for R/R B-ALL
Phase I Single center-
Medical College Wisconsin
1 y.o. to 39 y.o.
Not yet recruiting
Optimization of Tocilizumab timing for CD19 CAR-T associated CRS
Pilot study Single Center- CHOP
1 y.o. to 24 y.o.
Active, not recruiting
Long term follow-up of CAR-T.
Patients are followed for 15 years following their last CAR-T infusion
Not applicable Multicenter
All ages

*Table is not comprehensive, please see clinicaltrials.gov for additional ongoing trials.

Table 8: Ongoing CAR-T trials for B-ALL.

Unanswered questions: Several unanswered questions remain including the role of CD19-CAR-T in upfront therapy and if it should be used as monotherapy versus a bridge to HSCT. Historically, patients at high risk of relapse, myeloablative transplant is recommended. In the Park et al. study, subsequent transplant did not influence EFS or OS for the patients who had a MRD response after CD19-CAR-T [44]. In the Eliana study, the 18-month EFS was 66% with a median persistence of CAR-T of 168 days [43,47]. Eight patients underwent allogeneic hematopoietic stem-cell transplantation while in remission [43,47]. Conversely, 29 (45%) patients had an ongoing response without additional treatment, and 19 patients (29%) relapsed without receiving additional therapy [43,47]. An association has been seen between early loss of B-cell aplasia with relapse. In patients with early loss of B-cell aplasia, if there is an available donor and the patient is in good functional status, early transplant is recommended. Long term follow-up is needed to better assess which patient’s CAR-T can be used as monotherapy.


Studies of CD22 showed a similar anti-leukemic effect and safety profile to CD19-CARs. In a phase I trial of CD22 BB.z CART in heavily pretreated relapsed/refractory patients, 12/21 (57%) of patients had a CR, with nine patients having a MRD response (NCT02315612) [48]. To further potentate the efficacy of CD22, CAR-T Bryostatin 1 has been seen to upregulate CD22 on leukemia cell lines and improve CART function and persistence [49].

Dual targeting CAR-T

Antigen-escape relapse after CD19 directed therapies is a major challenge, thus dual targeting of CD19 and CD22 is being developed. Bi-cistronic CAR-T that express CD19 and CD22 scFv simultaneously on every cell and mono- CARs that express CD19 and CD22 scFv separately have been developed as dual-target CAR-T cells. Phase 1 trials of different dual targeting CAR-T therapies are highlighted in Table 8.


Several challenges have been encountered in the development of CAR-T including disease heterogeneity, T-cell aplasia, fratricide, and increased side effects in T-ALL. There is a large amount of disease heterogeneity in T-ALL due to distinct stages when T-cell differentiation arrest occurs, making identifying a target difficult [50]. Furthermore, targets on T-lymphoblasts are likely to be on normal T-cells leading to a severe immunocompromised state and fratricide of CAR-T. Fratricide of the CAR-T product or the destruction of the CAR-T due to the target being on both the malignant T-cells and on the CAR-T, leads to decreased CAR-T expansion and persistence. CD3 and CD7 CAR-Ts are more prone to fratricide compared to other targets such as CD1a and CD5 [51,52]. Gene editing to decrease expression of the target antigen on the CAR-T is being studied [53,54] in addition to “off-the-shelf” CAR-T without the target antigen [55]. Preclinical efficacy has been shown in NK-CARs [56,57].

Challenges in CAR-T manufacturing

One of the challenges of CAR-T is manufacturing the product. For adequate collection of T-cells, it requires an absolute lymphocyte count ≥ 500 cells/μL or an absolute CD3 count ≥ 150 cells/μL. This is particularly challenging in heavily pre-treated patients due to poor bone marrow in patients with a higher cumulative dose of chemotherapy [58] and in younger patients due to their size. In the phase II study of tisagenlecleucel, eight patients did not receive the CAR-T infusion due to manufacturing related issues and another seven died before infusion [43,47]. Early collection is suggested for high risk patients; and gene-edited, universal CAR-T-cells are in development. Allogeneic CD19-CAR-T-cells successfully treated two infants with B-ALL using non–HLA-matched, universal, CAR19 (UCART19) T-cells manufactured from a healthy female donor [59].

Persistence of CAR

There have been several mechanisms proposed explaining why certain patients do not respond or have a durable remission following treatment with CD19-CART-cells. One mechanism of relapse is poor persistence of the CAR-T-cell [46,60]; however, the length of CAR persistence required to induce a durable response or cure is unknown. There is no commercially available test to detect CAR-T persistence. B-cell aplasia has been used as a marker with early emergence of CD19-positive B-cells, within six months of CAR-T infusion, being associated with early relapse [46,60]. The presence of hematogones in the bone marrow has also been suggested as an earlier marker of loss of persistence and can occur while B-cell aplasia is still present [61]. Persistence may also be influenced by the CAR-T construct. The 19-BBz CAR are more persistent (168 days) than 19-28zCAR (~28 days), and 19-BBz CAR-T are associated with longer remission without HSCT [43,45]. Another contributor to decreased persistence is the development of T-cell mediated antiCAR immune response related to the murine CD19 scFV [45]. Re-infusion with humanized anti-CD19 CAR T-cells has induced remissions in children and young adults with relapsed/refractory B-ALL previously treated with murineCD19-CAR-T [62]. Lastly, expansion and persistence are improved with CAR-T generated from early linage T-cells (naïve T-cells and stem central memory T-cells) versus more differentiated T-cells (effector memory and terminal effector cells) [63,64]. Similar to studies in blinatumomab, T-cell exhaustion and high levels of T- regulatory cells have also been thought to contribute to treatment failure due to poor CAR-T persistence [65,66]. Most CAR-T protocols include lymphodepletion prior to CAR-T infusion, which leads to depletion of regulatory T-cells and greater engraftment. In addition, it is felt checkpoint inhibition may mitigate T-cell exhaustion. Re-expansion of CART-cells has been seen in patients who are treated PD-1 inhibitors after early loss of CAR-T-cells or relapse [67].

Antigen escape

In antigen directed therapy, escape, or loss of the therapy directed antigen on tumor cells is commonly seen in relapse [37,43]. Mechanisms of CD19 escape seen with blinatumomab and CD19-CAR-T include: selecting for pre-existing antigen negative leukemia, trogocytosis, the development of mutations or alternate splice variants of CD19, or lineage switching [68-74]. There are ongoing trials using two immunotherapies targeting different antigens and bispecific CAR-T-cells (Table 8) to mitigate this effect.

Side effects of immunotherapy

Cytokine release syndrome (CRS): Cytokine release syndrome (CRS) is a systemic inflammatory response due to a rise in cytokine levels during T-cell activation and expansion. Symptoms range from mild and self-limiting to severe and life- threatening and consists of fever, myalgia, capillary leak, hemodynamic instability, coagulopathy and multi-organ failure [75]. Higher disease burden has been associated with higher grade CRS [60]. Varying grading symptoms have been developed, and ASBMT consensus grading system was developed last year [76]. Tocilizumab, an IL-6 receptor antagonist, has been shown to be effective in treating CRS [76]. Other medications that have been considered include infliximab, etanercept, and anakinra [75]. There are ongoing studies regarding the optimal timing of Tocilizumab administration where patients with a higher disease burden will receive early Tocilizumab (NCT0290637).

Neurotoxicity: Neurotoxicity has also been seen with immunotherapy. Symptoms include delirium, encephalopathy, aphasia, lethargy, seizures and cerebral edema [76]. Symptoms typically occur either during or more commonly after CRS. The ASBMT similarly recently created an Immune effector-cell associated encephalopathy (ICE) score [76]. Corticosteroids are recommended for severe neurotoxicity.

B-cell aplasia:

B-cell aplasia is an on-target, off tumor adverse effect of immunotherapy directed to antigens on normal B-cells including CD19, CD20 and CD22. B-cell aplasia occurred in all patients who responded to Tisagenlecleucel, and 83% experienced B-cell aplasia for at least 6 months [43,47]. Immunoglobulin replacement is recommended following treatment while there are signs of B-cell aplasia.

Future Directions

The development of immunotherapy is a major advancement in treating pediatric ALL. Particularly in relapsed and refractory B-ALL, immunotherapy has been able to induce remission in chemotherapy refractory patients who had limited treatment options. The timing of immunotherapy in treatment paradigms is being investigated including the role in upfront, salvage, consolidation, and maintenance therapy. Furthermore, checkpoint inhibitors are being studied to further enhance the efficacy of many immunotherapies (Table 9). The role of immunotherapy in T-ALL has remained a challenge, and further research into optimal targets to limit effects on normal T-cells and maximize the efficacy of the therapy is ongoing. Preclinical and clinical research has shown significant promise in improving survival for these patients.

Conflicts of Interest

Brown: Scientific Advisory Boards – Novartis, Servier,
Jazz, Janssen.

Author Contribution Statement

All authors wrote manuscript.


1. Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. New England Journal of Medicine. 2015 Oct 15;373(16):1541-52.

2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a Cancer Journal for Clinicians. 2020 Jan;70(1):7-30.

3. Kantarjian HM, Keating MJ, Freireich EJ. Toward the potential cure of leukemias in the next decade. Cancer. 2018 Nov 15;124(22):4301-13.

4. Sun W, Malvar J, Sposto R, Verma A, Wilkes JJ, Dennis R, et al. Outcome of children with multiply relapsed B-cell acute lymphoblastic leukemia: a therapeutic advances in childhood leukemia & lymphoma study. Leukemia. 2018 Nov;32(11):2316-25.

5. Borowitz MJ, Wood BL, Devidas M, Loh ML, Raetz EA, Salzer WL, et al. Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232. Blood. 2015 Aug 20;126(8):964-71.

6. Nguyen K, Devidas M, Cheng SC, La M, Raetz EA, Carroll WL, et al. Factors influencing survival after relapse from acute lymphoblastic leukemia: a Children’s Oncology Group study. Leukemia. 2008 Dec;22(12):2142-50.

7. Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis. JAMA Oncology.2017 Jul 1;3(7):e170580-.

8. Rodriguez V, Kairalla J, Salzer W, Raetz E, Loh ML, Carroll Aet al. A Pilot Study of Intensified PEGAsparaginase in High Risk Acute Lymphoblastic Leukemia: Children’s Oncology Group Study AALL08P1. Journal of Pediatric Hematology/Oncology. 2016 Aug;38(6):409.

9. Salzer WL, Burke MJ, Devidas M, Chen S, Gore L, Larsen EC, et al. Toxicity associated with intensive postinduction therapy incorporating clofarabine in the very high-risk stratum of patients with newly diagnosed high-risk B-lymphoblastic leukemia: A report from the Children’s Oncology Group study AALL1131. Cancer. 2018 Mar 15;124(6):1150-9.

10. Howlader N, Noone AM, Krapcho M, Miller D, Brest A, Yu M, et al. SEER Cancer Statistics Review. 2019; Available at: https://seer.cancer.gov/csr/1975_2017. Accessed April, 2020.

11. Winter SS, Dunsmore KP, Devidas M, Wood BL, Esiashvili N, Chen Z, et al. Improved survival for children and young adults with T-lineage acute lymphoblastic leukemia: results from the Children’s Oncology Group AALL0434 methotrexate randomization. Journal of Clinical Oncology. 2018 Oct 10;36(29):2926.

12. D’Angiò M, Valsecchi MG, Testi AM, Conter V, Nunes V, Parasole R, et al. Clinical features and outcome of SIL/TAL1-positive T-cell acute lymphoblastic leukemia in children and adolescents: a 10-year experience of the AIEOP group. Haematologica. 2015 Jan;100(1):e10.

13. Patrick K, Wade R, Goulden N, Mitchell C, Moorman AV, Rowntree C, et al. Outcome for children and young people with Early T-cell precursor acute lymphoblastic leukaemia treated on a contemporary protocol, UKALL 2003. British Journal of Haematology. 2014 Aug;166(3):421-4.

14. Dunsmore KP, Winter S, Devidas M, Wood BL, Esiashvili N, Eisenberg N, et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy. Journal of Clinical Oncology. 2018 Jun 01;36(15_Suppl):10500-10500.

15. Freyer DR, Devidas M, La M, Carroll WL, Gaynon PS, Hunger SP, et al. Postrelapse survival in childhood acute lymphoblastic leukemia is independent of initial treatment intensity: a report from the Children’s Oncology Group. Blood, The Journal of the American Society of Hematology. 2011 Mar 17;117(11):3010-5.

16. DiJoseph JF, Armellino DC, Boghaert ER, Khandke K, Dougher MM, Sridharan L, et al. Antibody-targeted chemotherapy with CMC-544: a CD22-targeted immunoconjugate of calicheamicin for the treatment of B-lymphoid malignancies. Blood. 2004 Mar 1;103(5):1807- 14.

17. Kantarjian HM, DeAngelo DJ, Stelljes M, Liedtke M, Stock W, Gökbuget N, et al. Inotuzumab ozogamicin versus standard of care in relapsed or refractory acute lymphoblastic leukemia: Final report and long-term survival follow-up from the randomized, phase 3 INOVATE study. Cancer. 2019 Jul 15;125(14):2474-87.

18. Rytting M, Triche L, Thomas D, O’Brien S, Kantarjian H. Initial experience with CMC-544 (inotuzumab ozogamicin) in pediatric patients with relapsed B-cell acute lymphoblastic leukemia. Pediatric Blood & Cancer. 2014 Feb;61(2):369-72.

19. Bhojwani D, Sposto R, Shah NN, Rodriguez V, Yuan C, Stetler-Stevenson M, et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia. 2019 Apr;33(4):884- 92.

20. O’Brien MM, Ji L, Shah NN, Rheingold SR, Bhojwani D, Yi JS, et al. A Phase 2 Trial of Inotuzumab Ozogamicin (InO) in Children and Young Adults with Relapsed or Refractory (R/R) CD22+ B-Acute Lymphoblastic Leukemia (B-ALL): Results from Children’s Oncology Group Protocol AALL1621.

21. Kebriaei P, Cutler C, De Lima M, Giralt S, Lee SJ, Marks D, et al. Management of important adverse events associated with inotuzumab ozogamicin: expert panel review. Bone Marrow Transplantation. 2018 Apr;53(4):449-56.

22. Bride KL, Vincent TL, Im SY, Aplenc R, Barrett DM, Carroll WL, et al. Preclinical efficacy of daratumumab in T-cell acute lymphoblastic leukemia. Blood. 2018 Mar 1;131(9):995-9.

23. Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. New England Journal of Medicine. 2015 Sep 24;373(13):1207-19.

24. Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. New England Journal of Medicine. 2016 Oct 6;375(14):1319-31.

25. Doshi P, Sasser AK, Axel A, van Bueren JL. Daratumumab treatment alone or in combination with vincristine results in the inhibition of tumor growth and long term survival in preclinical models of acute lymphocytic leukemia. Haematologica 2014 Jun 1;99:109.

26. Ofran Y, Ganzel C, Harlev S, Slouzkey I, Beyar Katz O, Hayun M, et al. Daratumumab in combination with vincristine or nelarabine as effective salvage therapy for patients with acute lymphoblastic leukemia at high risk of relapse. Blood. 2018 Nov 29;132(Supplement 1):5206-.

27. Bonda A, Punatar S, Gokarn A, Mohite A, Shanmugam K, Nayak L, et al. Daratumumab at the frontiers of posttransplant refractory T-acute lymphoblastic leukemia—a worthwhile strategy?. Bone Marrow Transplantation. 2018 Nov;53(11):1487-9.

28. Al-Hussaini M, Rettig MP, Ritchey JK, Karpova D, Uy GL, Eissenberg LG, et al. Targeting CD123 in acute myeloid leukemia using a T-cell–directed dual-affinity retargeting platform. Blood. 2016 Jan 7;127(1):122-31. Frankel SR, Baeuerle PA. Targeting T cells to tumor cells using bispecific antibodies. Current Opinion in Chemical Biology. 2013 Jun 1;17(3):385-92.

29. Frankel SR, Baeuerle PA. Targeting T cells to tumor cells using bispecific antibodies. Current Opinion in Chemical Biology. 2013 Jun 1;17(3):385-92.

30. Raponi S, Stefania De Propris M, Intoppa S, Laura Milani M, Vitale A, et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibodybased immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leukemia & Lymphoma. 2011 Jun 1;52(6):1098-107.

31. Topp MS, Gökbuget N, Stein AS, Zugmaier G, O’Brien S, Bargou RC, et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. The Lancet Oncology. 2015 Jan 1;16(1):57- 66.

32. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera JM, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. New England Journal of Medicine. 2017 Mar 2;376(9):836-47.

33. Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, et al. Complete hematologic and molecular response in adult patients with relapsed/ refractory Philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, singlearm, multicenter study. Journal of Clinical Oncology. 2017;35(16):1795-802.

34. Chiaretti S, Bassan R, Vitale A, Elia L, Piciocchi A, Ferrara F, et al. A Dasatinib-Blinatumomab Asatinib- Blinatumomab Combination for the Front-Line: Preliminary Results of the GIMEMA LAL2116 D-ALBA Trial: On Behalf of the GIMEMA Acute Leukemia Working Party. HemaSphere. 2019 Jun 1;3(S1):746.

35. Gökbuget N, Dombret H, Bonifacio M, Reichle A, Graux C, Faul C, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018 Apr 5;131(14):1522-31.

36. Dombret H, Topp MS, Schuh AC, Wei AH, Durrant S, Bacon CL, et al. Blinatumomab versus chemotherapy in first salvage or in later salvage for B-cell precursor acute lymphoblastic leukemia. Leukemia & Lymphoma. 2019 Jul 29;60(9):2214-22.

37. von Stackelberg A, Locatelli F, Zugmaier G, Handgretinger R, Trippett TM, Rizzari C, et al. Phase I/ phase II study of blinatumomab in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Journal of Clinical Oncology. 2016 Dec 20;34(36):4381-9.

38. Brown PA, Ji L, Xu X, Devidas M, Hogan L, Borowitz MJ, et al. A Randomized Phase 3 Trial of Blinatumomab Vs. Chemotherapy As Post-Reinduction Therapy in High and Intermediate Risk (HR/IR) First Relapse of B-Acute Lymphoblastic Leukemia (B-ALL) in Children and Adolescents/Young Adults (AYAs) Demonstrates Superior Efficacy and Tolerability of Blinatumomab: A Report from Children’s Oncology Group Study AALL1331. Blood. 2019 Nov 21;134(Supplement 2).

39. Brown P, Zugmaier G, Gore L, Tuglus CA, von Stackelberg A. Day 15 bone marrow minimal residual disease predicts response to blinatumomab in relapsed/ refractory paediatric B-ALL. British Journal of Haematology. 2020 Feb;188(4):e36-9.

40. Zugmaier G, Gökbuget N, Klinger M, Viardot A, Stelljes M, Neumann S, et al. Long-term survival and T-cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood. 2015 Dec 10;126(24):2578-84.

41. Duell J, Dittrich M, Bedke T, Mueller T, Eisele F, Rosenwald A, et al. Frequency of regulatory T cells determines the outcome of the T-cell-engaging antibody blinatumomab in patients with B-precursor ALL. Leukemia. 2017 Oct;31(10):2181-90.

42. Park JH, Brentjens RJ. Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells. Discovery Medicine. 2010 Apr;9(47):277.

43. Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. New England Journal of Medicine. 2018 Feb 1;378(5):439-48.

44. Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. New England Journal of Medicine. 2018 Feb 1;378(5):449-59.

45. Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 doseescalation trial. The Lancet. 2015 Feb 7;385(9967):517-28.

46. Gardner RA, Finney O, Annesley C, Brakke H, Summers C, Leger K, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017 Jun 22;129(25):3322-31.

47. Grupp SA, Maude SL, Rives S, Baruchel A, Boyer MW, Bittencourt H, et al. Updated analysis of the efficacy and safety of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory (r/r) acute lymphoblastic leukemia. Blood. 2018 Nov 29;132(Supplement 1):895-.

48. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nature Medicine. 2018 Jan;24(1):20.

49. Ramakrishna S, Highfill SL, Walsh Z, Nguyen SM, Lei H, Shern JF, et al. Modulation of target antigen density improves CAR T-cell functionality and persistence. Clinical Cancer Research. 2019 Sep 1;25(17):5329-41.

50. Noronha EP, Marques LV, Andrade FG, Thuler LC, Terra-Granado E, Pombo-de-Oliveira MS, et al. The profile of immunophenotype and genotype aberrations in subsets of pediatric T-cell acute lymphoblastic leukemia. Frontiers in Oncology. 2019 Apr 30;9:316.

51. Cooper ML, Choi J, Staser K, Ritchey JK, Devenport JM, Eckardt K, et al. An “off-the-shelf” fratricideresistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia. 2018 Sep;32(9):1970-83.

52. Mamonkin M, Rouce RH, Tashiro H, Brenner MK. A T-cell–directed chimeric antigen receptor for the selective treatment of T-cell malignancies. Blood, The Journal of the American Society of Hematology. 2015 Aug 20;126(8):983-92.

53. Gomes-Silva D, Srinivasan M, Sharma S, Lee CM, Wagner DL, Davis TH, et al. CD7-edited T cells expressing a CD7-specific CAR for the therapy of T-cell malignancies. Blood, The Journal of the American Society of Hematology. 2017 Jul 20;130(3):285-96.

54. Png YT, Vinanica N, Kamiya T, Shimasaki N, Coustan- Smith E, Campana D. Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies. Blood Advances. 2017 Nov 28;1(25):2348- 60.

55. Rasaiyaah J, Georgiadis C, Preece R, Mock U, Qasim W. TCRaß/CD3 disruption enables CD3-specific antileukemic T cell immunotherapy. JCI Insight. 2018 Jul 12;3(13).

56. Mehta RS, Rezvani K. Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Frontiers in Immunology. 2018 Feb 15;9:283.

57. You F, Wang Y, Jiang L, Zhu X, Chen D, Yuan L, et al. A novel CD7 chimeric antigen receptor-modified NK-92MI cell line targeting T-cell acute lymphoblastic leukemia. American Journal of Cancer Research. 2019;9(1):64.

58. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor–modified T cells for acute lymphoid leukemia. New England Journal of Medicine. 2013 Apr 18;368(16):1509-18.

59. Qasim W, Zhan H, Samarasinghe S, Adams S, Amrolia P, Stafford S, et al. Molecular remission of infant B-ALL after infusion of universal TALEN gene-edited CAR T cells. Science Translational Medicine. 2017 Jan 25;9(374).

60. Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. New England Journal of Medicine. 2014 Oct 16;371(16):1507-17.

61. Hucks G, Rheingold SR. The journey to CAR T cell therapy: the pediatric and young adult experience with relapsed or refractory B-ALL. Blood Cancer Journal. 2019 Jan 22;9(2):1-9.

62. Maude SL, Barrett DM, Rheingold SR, Aplenc R, Teachey DT, Callahan C, et al. Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children and young adults with relapsed/ refractory acute lymphoblastic leukemia. Blood. 2016 Dec 2;128(22):217.

63. Singh N, Perazzelli J, Grupp SA, Barrett DM. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Science Translational Medicine. 2016 Jan 6;8(320):320ra3.

64. Sabatino M, Hu J, Sommariva M, Gautam S, Fellowes V, Hocker JD, et al. Generation of clinical-grade CD19- specific CAR-modified CD8+ memory stem cells for the treatment of human B-cell malignancies. Blood. 2016 Jul 28;128(4):519-28.

65. Yao X, Ahmadzadeh M, Lu YC, Liewehr DJ, Dudley ME, Liu F, et al. Levels of peripheral CD4+ FoxP3+ regulatory T cells are negatively associated with clinical response to adoptive immunotherapy of human cancer. Blood. 2012 Jun 14;119(24):5688-96.

66. Cui Y, Zhang H, Meadors J, Poon R, Guimond M, Mackall CL. Harnessing the physiology of lymphopenia to support adoptive immunotherapy in lymphoreplete hosts. Blood, The Journal of the American Society of Hematology. 2009 Oct 29;114(18):3831-40.

67. Li AM, Hucks GE, Dinofia AM, Seif AE, Teachey DT, Baniewicz D, et al. Checkpoint inhibitors augment CD19- directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia. Blood. 2018 Nov 29;132(Supplement 1):556.

68. Nagel I, Bartels M, Duell J, Oberg HH, Ussat S, Bruckmueller H, et al. Hematopoietic stem cell involvement in BCR-ABL1–positive ALL as a potential mechanism of resistance to blinatumomab therapy. Blood, The Journal of the American Society of Hematology. 2017 Nov 2;130(18):2027-31.

69. Hamieh M, Dobrin A, Cabriolu A, van der Stegen SJ, Giavridis T, Mansilla-Soto J, et al. CAR T cell trogocytosis and cooperative killing regulate tumour antigen escape. Nature. 2019 Apr;568(7750):112-6.

70. Orlando EJ, Han X, Tribouley C, Wood PA, Leary RJ, Riester M, et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nature Medicine. 2018 Oct;24(10):1504-6.

71. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discovery. 2015 Dec 1;5(12):1282- 95.

72. Oberley MJ, Gaynon PS, Bhojwani D, Pulsipher MA, Gardner RA, Hiemenz MC, et al. Myeloid lineage switch following chimeric antigen receptor T-cell therapy in a patient with TCF3-ZNF384 fusion-positive B-lymphoblastic leukemia. Pediatric Blood & Cancer. 2018 Sep;65(9):e27265.

73. Jacoby E, Nguyen SM, Fountaine TJ, Welp K, Gryder B, Qin H, et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nature Communications. 2016 Jul 27;7(1):1-0.

74. Gardner R, Wu D, Cherian S, Fang M, Hanafi LA, Finney O, et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T-cell therapy. Blood. 2016 May 19;127(20):2406-10.

75. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014 Jul 10;124(2):188-95.

76. Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, et al. ASTCT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biology of Blood and Marrow Transplantation. 2019 Apr 1;25(4):625-38.

77. Shah NN, Stevenson MS, Yuan CM, Richards K, Delbrook C, Kreitman RJ, et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatric Blood & Cancer. 2015 Jun;62(6):964-9.

78. DeAngelo DJ, Stock W, Stein AS, Shustov A, Liedtke M, Schiffer CA, et al. Inotuzumab ozogamicin in adults with relapsed or refractory CD22-positive acute lymphoblastic leukemia: a phase 1/2 study. Blood Advances. 2017 Jun 27;1(15):1167-80.

79. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, et al. Inotuzumab ozogamicin, an anti-CD22–calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. The Lancet Oncology. 2012 Apr 1;13(4):403-11.

80. Keating AK, Gossai N, Phillips CL, Maloney K, Campbell K, Doan A, et al. Reducing minimal residual disease with blinatumomab prior to HCT for pediatric patients with acute lymphoblastic leukemia. Blood Advances. 2019 Jul 9;3(13):1926.

81. Grupp SA, Maude SL, Shaw PA, Aplenc R, Barrett DM, Callahan C, et al. Durable remissions in children with relapsed/refractory ALL treated with T cells engineered with a CD19-targeted chimeric antigen receptor (CTL019). Blood. 2015 Dec 3;126(23):681.

82. Lee DW, Wayne AS, Huynh V, Handgretinger R, Pieters R, Michele G, et al. 1008PDZUMA-4 preliminary results: phase 1 study of KTE-C19 chimeric antigen receptor T cell therapy in pediatric and adolescent patients (pts) with relapsed/refractory acute lymphoblastic leukemia (R/R ALL). Annals of Oncology. 2017 Sep 1;28(suppl_5).

83. Wang N, Hu X, Cao W, Li C, Xiao Y, Cao Y, et al. Efficacy and safety of CAR19/22 T-cell cocktail therapy in patients with refractory/relapsed B-cell malignancies. Blood, The Journal of the American Society of Hematology. 2020 Jan 2;135(1):17-27.

84. Amrolia PJ, Wynn R, Hough RE, Vora A, Bonney D, Veys P, et al. Phase I study of AUTO3, a bicistronic chimeric antigen receptor (CAR) T-cell therapy targeting CD19 and CD22, in pediatric patients with relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL): Amelia Study. Blood. 2019 Nov 13;134(Supplement 1):2620.

85. Schultz LM, Davis KL, Baggott C, Chaudry C, Marcy AC, Mavroukakis S, et al. Phase 1 study of CD19/CD22 bispecific chimeric antigen receptor (CAR) therapy in children and young adults with B cell acute lymphoblastic leukemia (ALL). Blood. 2018 Nov 29;132(Supplement 1):898.

86. Yang J, Li J, Zhang X, Lv F, Guo X, Wang Q, et al. A feasibility and safety study of CD19 and CD22 chimeric antigen receptors-modified T cell cocktail for therapy of B cell acute lymphoblastic leukemia. Blood. 2018 Nov 29;132(Supplement 1):277.

87. ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Accessed April, 2020.

Author Information X