Review Article - Journal of Cancer Immunology (2020) Volume 2, Issue 4
Immunotherapy in Pediatric Acute Lymphoblastic Leukemia
Julie M. Asare1,2, Cara A. Rabik1,2, Stacy Cooper1,2, Patrick A. Brown1,2*
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
- *Corresponding Author:
- Patrick Brown
Received date: September 13, 2020; Accepted date: October 02, 2020
Citation: Asare JM, Rabik CA, Cooper S, Brown PA. Immunotherapy in Pediatric Acute Lymphoblastic Leukemia. J Cancer Immunol. 2020; 2(4): 159-184.
Copyright: © 2020 Asare JM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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 . 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 . 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 . Despite these successes, about 2% of patients are refractory to chemotherapy and another 10% to 15% of patients will relapse . 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 . However, survival after relapse is about 30% due to a lack of effective salvage therapies .
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.
Table 1: B-ALL Targets.
|CD3||CD3 NK CART-T (Preclinical)|
TruUcar GC027 (Preclinical)
|CD38||Daratumab Isatuximab Mogalizumab|
|CD194||Mogamulizumab CD194/30 CAR-T|
|Interleukin-2receptor alpha||Basiliximab (Preclinical)|
|Interleukin-7 receptor alpha||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 . Calichaemicin is cleaved and binds to minor DNA grooves causing doublestranded DNA breaks and apoptosis of the leukemia cell . Clinical trials of InO in B-ALL are highlighted in Table 3.
|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)
|Adult R/R CD22+, Ph+/- B-ALL ||Phase III|
chemotherapy vs. Inotuzumab ozogamicin)
|1.8mg/m2/cycle Days 1, 8, 21||CR/CRh: (73.8% vs.|
35%), p<0.001 |
MRD negative: 78.4% (95%
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; 0.34-0.61), p<0.001)
7.7 mo vs. 6.2 mo (95%CI, 4.7-8.3)
2-year OS: 22.8% vs.
|Patients who proceed to transplant and developed SOS|
|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: 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:|
CR: 19 (40%)
CRh: 9 (19%)
MRD negative: 17 (65%)
Progressive disease: 8
|4 (30.7%)|| 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) . At the two-year follow-up, overall survival (OS) rates were superior with InO 22.8% and 10.0% .
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 . 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 . Twenty-one patients underwent a hematopoietic stem cell transplant (HSCT) after achieving CR . 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 .
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).
|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 . Risk factors for SOS included conditioning with dual alkylators, hyperbilirubinemia before HSCT, and prior HSCT (OR 6.02; p=0.032) . In the pediatric experience, 4 of the 13 patients (30.7%) who went on to HSCT developed grade 3 SOS in AALL1621 study  at 11 of the 21 (52%) patients in compassionate use study . 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 . 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 . CD38 expression has been seen on T-ALL blasts and remains stable after treatment with chemotherapy . Daratumumab is a human monoclonal antibody directed against CD38 . 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 . Unlike CARTs, BiTEs do not require manufacturing and infusion of T-cells .
Mechanism of action: CD19 is expressed on approximately 90% of B-ALL cells . Blinatumomab is a BiTE that binds to CD19 on leukemic cells and CD3- subunit of the TCR on T-cells . Clinical trials of Blinatumomab for B-ALL are highlighted in Table 5.
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.
|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)
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)
-271 in the blina arm
-134 in the SOC
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,
CRh: 24 (44%) vs.
6 (25%) (p<0.001
MRD negative: 76% vs. 48%
[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
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%
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,
HR 0.7 (95% CI,
6 mo estimated EFS (2nd or later relapse): 24.0%
(95% CI, 17.4-
31.3%); 1.6% (95%
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
|9 μ/day days 1-7|
and 28 μ/day
days 8-28 for
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%
CRh: 1 (4%) (95%
(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
Median OS (MRD responders vs nonresponsers): (38.9 vs 12.5
Pediatric and AYA R/R B-ALL after re-induction
Multicenter, randomized phase III trial
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 ±
2-year OS: 79.4
± 4.5% vs. 59.2 ±
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
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 . Eightyone patients (43%) had a CR/CRh within two cycles of blinatumomab . Median overall survival was 6.1 months . This was superior to historical controls who received SOC, salvage chemotherapy . Efficacy was confirmed in the TOWER trial, a multicentered, randomized, phase III trial comparing blinatumomab to chemotherapy in adult relapsed/refractory Ph- ALL . 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 .
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 . 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 . Twelvemonth OS and DFS are 96.2% and 91.6% respectively . There are several ongoing studies examining the efficacy of TKIs with blinatumomab (Table 6).
|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|
AIEOP-BFM ALL 2017
|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|
|NCT03541083 HOVON146ALL ||Blinatumomab in the prephase and consolidation in newly diagnoses B-ALL||Phase II Multicenter||18 y.o. to|
|NCT02807883||Blinatumomab maintenance following allo HSCT in|
Single center-MD Anderson
|NCT03114865||Blinatumomab in B-ALL post allo HSCT as remission maintenance||Phase I|
Single Center- SKCC
|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
|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|
|NCT02997761 ||Ibrutinib and Blinatumomab in R/R B-ALL||Phase II Single group- University of|
|NCT03263572 ||Blinatumomab, Methotrexate, cytarabine and ponatinib in Ph+ R/R ALL||Phase II|
Single center-MD Anderson
|NCT03147612 ||Low-intensity chemotherapy, ponatinib and blinatumomab in newly diagnosed and R/R Ph+ ALL||Phase II|
Single center- MD Anderson
|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 . Eighty-eight of 113 patients (78%) achieved a complete MRD response after one cycle of blinatumomab . 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) .
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) . 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 .
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 . Duration of response was 4.4 months . 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 . 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 . 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).
Pediatric and adult R/R ALL
(CTL119) (4-1BBz CAR)
|CR: 27 (90%)|
MRD negative: 22/27 (81%)
6-mo EFS: 67% (95% CI, 51-88)
6-mo OS: 78% (95% CI, 65-95)
|Pediatric and AYA R/R B-ALL |
(CTL119) (4-BBz CAR)
|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)
Children and AYA CD19+ ALL
|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)
MRD negative CR: 4
| (NCT02625480) ZUMA-4|
|Pediatric and AYA with R/R B-ALL or NHL |
(TCR zeta and CD28 signaling domain)
CR: 14/21 (66.7%) (95% CI, 43.0–85.4)
MRD negative: 12/20 (60%) (95% CI,
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)
[43, 47] NCT02435849
Adult R/R ALL
KTE-C19 (CD28 CAR)
|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-
R/R B-ALL treated with CD22 BBz CAR,
|21 Children and adults|
17-previously treated with CD19
CR: 12 (57%) CR
MRD negative 9 (75%)
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)
|Pediatric R/R B-ALL |
AUTO3-Bicistronic CD19 and CD22 CAR
Ox40 co-stim for CD19 CAR
41BB co-stim for CD22
CR and MRD: 7/10 1 year follow up:
-4 patients in ongoing CR/CRh with B-Cell
bispeciftc CAR-T in children and AYA patients with B-ALL
Lentiviral transduction bivalent CAR
fmc63 CD19 m971 CD22
41BB costimulatory endo-domain
CR: 4/4 (100%)
MRD negative: 3/4 (75%)
CD19 and CD22
CART cocktail for R/RB-ALL
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  and day 15 MRD have a better response . In addition, superior response was correlated with greater T-cell expansion of effector memory T-cells  and a higher percentage of regulatory T-cells . Identifying additional biomarkers to determine response is actively being studied.
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 . 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) . Third generation CARs further enhanced T-cell signaling by containing tandem cytoplasmic signaling from two co-stimulator receptors (CD28-4-1BB or CD28-OX40) . Fourth generation CARs have pro-proliferative T-cell costimulatory ligands (4-1BBL) or proinflammatory cytokines (IL-12) . 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 . Six- and 12-month relapse-free survival rates were 80% and 59% respectively .
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 . 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 . 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).
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|| |
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|
CD19 CAR-T in B-ALL
|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)
Single Center- Loyola University
18 y.o. and older
|NCT04404660 AUTO1|| |
CD19 CAR-T in R/R B-ALL
Phase I/II Multicenter
18 y.o. and older
|Efficacy and safety of reinfusion of Tisagenlecleucel in pediatric and AYA patients with B-ALL|| |
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|
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|
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
CARCIK-CD19 in R/R ALL post HSCT
|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
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.
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
*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 . 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) . 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 .
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.
CAR-T for T-ALL
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 . 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 . 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  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 .
Persistence of CAR
There have been several mechanisms proposed explaining why certain patients do not respond or&
- Hunger SP, Mullighan CG. Acute lymphoblastic leukemia in children. New England Journal of Medicine. 2015 Oct 15;373(16):1541-52.
- Siegel RL, Miller KD, Jemal A. Cancer statistics, 2020. CA: a Cancer Journal for Clinicians. 2020 Jan;70(1):7-30.
- Kantarjian HM, Keating MJ, Freireich EJ. Toward the potential cure of leukemias in the next decade. Cancer. 2018 Nov 15;124(22):4301-13.
- 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.
- 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.
- 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.
- 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-.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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-.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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-.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- Mehta RS, Rezvani K. Chimeric antigen receptor expressing natural killer cells for the immunotherapy of cancer. Frontiers in Immunology. 2018 Feb 15;9:283.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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).
- 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.
- 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.
- 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.
- 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.
- ClinicalTrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). Accessed April, 2020.