Monoclonal antibodies for the treatment of acute lymphocytic leukemia: A literature review

Abstract

BACKGROUND:

Acute lymphocytic leukemia (ALL) is a type of blood cancer that is more prevalent in children. Several treatment methods are available for ALL, including chemotherapy, upfront treatment regimens, and pediatric-inspired regimens for adults. Monoclonal antibodies (Mabs) are the novel Food and Drug Administration (FDA) approved remedies for the relapsed/refractory (R/R) adult ALL. In this article, we aimed to review studies that investigated the efficacy and safety of Mabs on ALL.

METHODS:

We gathered studies through a complete search with all proper related keywords in ISI Web of Science, SID, Scopus, Google Scholar, Science Direct, and PubMed for English language publications up to 2020.

RESULTS:

The most commonly studied Mabs for ALL therapies are CD-19, CD-20, CD-22, and CD-52. The best results have been reported in the administration of blinatumomab, rituximab, ofatumumab, and inotuzumab with acceptable low side effects.

CONCLUSION:

Appling personalized approach for achieving higher efficacy is one of the most important aspects of treatment. Moreover, we recommend that the wide use of these Mabs depends on designing further cost-effectiveness trials in this field.

Keywords

Monoclonal antibodies acute lymphocytic leukemia anti-cancer targeted therapy

1. Background

Acute lymphocytic leukemia (ALL) is a type of blood cancer more prevalent in children [1]. It more frequently affects the children under 5 years and adults over 50 years of age [2]. ALL is one of the most frequent types of cancer in children [3]. About 60% of ALL cases happen in children and people under 20 years old with cure rates near 90% [4]. ALL spreads out quickly in children’s bodies, therefore it can cause death within a few weeks [1]. Owing to the late diagnosis and expense of using devices for the determination of cancer cells, the mortality rate has strongly increased [2]. ALL is caused due to the proliferation abnormality in the production of premature white blood cells (WBC) in the bone marrow. It is characterized by the abnormal rate of immature WBC in the peripheral blood, bone marrow or other organs [2, 5, 6]. Although there are a variety of modalities available to treat ALL, there is no standard of care neither for the frontline nor relapsed/refractory (R/R) settings [7]. Several treatment methods are available for this disease, including chemotherapy, upfront treatment regimens and pediatric-inspired regimens for adults [8]. Unpredictable responses related to different combination chemotherapy regimens have been observed and rigorous chemotherapy usually doesn’t cause complete remission [7, 9]. This treatment method also can be accompanied by myelosuppression and other toxicities [7]. Moreover, Patients who are over 60 years old are an exclusively vulnerable population who may not be able to endure it well. The course of upfront treatment regimens is generally long and include multidrug combinations. Pediatric-inspired regimens are more efficient in comparison to traditional method for adults. Nevertheless, usage of this approach in one series of patients over 44 years of age has been associated with additional morbidity/mortality [8]. Though patients’ response to primary induction therapy is acceptable, at least half of them experience R/R disease. At this time, there is no standard treatment regimen and these patients typically have to reach a complete remission before receiving an allogeneic haemopoietic stem-cell transplantation (AHSCT), which is the only potential cure. Therefore, the main goal of salvage or frontline therapy is an efficient reduction in tumor burden until AHSCT can be accomplished [7, 8, 9].

Novel therapeutic interventions in ALL therapy are monoclonal antibodies (Mab), chimeric antigen receptor T cells (CAR-T), and immunomodulators. Furthermore, several new drugs affecting molecular directions involved in leukemic cell multiplication have been developed [10]. First-in-human trial of an anti-CD22 CAR T-cell therapy has proved that the immunotherapeutic approach is feasible, safe, and effective for the treatment of young patients with R/R ALL [11]. Besides, Protein-based biopharmaceuticals are usually highly exclusive and have a lower potential to cause unpleasant effects and immune reactions than small-molecule drugs. However, they also exhibit their challenges [12]. Mabs have been newly approved by the Food and Drug Administration (FDA) for the treatment of R/R adult ALL [10]. There are different targets for Mabs in the treatment of ALL, including CD-19, CD-20, CD-22 and CD-52 [11, 13, 14, 15]. Herein aimed to summarize the Mabs used to treat ALL.

2. Method

We carried out this study using several databases such as ISI Web of Science, SID, Scopus, Google Scholar, Science Direct, and PubMed to search for English language publications up to December 2020. We also reviewed references cited in these studies, and articles reporting phase 1 to 3 clinical trials evaluating Mab effects on acute lymphocytic leukemia were included as well. Our main keywords were acute lymphocytic leukemia, ALL, monoclonal antibodies, Mabs, blinatumomab, denintuzumab mafodotin, ADCT-402, rituximab, ofatumumab, obinutuzumab, inotuzumab ozogamicin, moxetumomab pasudotox, coltuximab ravtansine, epratuzumab, blinatumomab and, alemtuzumab.

3. Monoclonal antibodies

Antibodies, also called Immunoglobulins, are the product of B cells, consisting of five different isotypes including IgA, IgD, IgE, IgG, and IgM. The most abundant and famous type is IgG. IgG consists of four polypeptide chains including two similar, heavy chains named H chains and two similar, shorter chains named L chains, which together make a Y-shaped complex weighing about 150 kDa. Amino acid sequence variability is found in the N-terminal of each polypeptide [16, 17]. IgG, contains two antigen binding sites named V region and consists of two variable regions, one in heavy chain and the other one is a part of light chain. The constant or C regions of antibodies have much lower amino acid sequence diversity among different immunoglobulins. Purity of the immunizing antigen specifies the antibodies. Meanwhile, some antigens contain various antigen-binding sites or epitopes. There is a need for high amounts of immunoglobulins having similar specificities for an epitope in clinical setting. Regarding to the proliferation incapability of plasma cells achieving this purpose seemed infeasible. However, in 1970s, the problem has been solved, when Köhler and Milstein aimed to produce single fusion cell lines (hybridomas), by fusing B cells and myeloma cells of mice, capable of being cultivated extensively in vitro and producing limitless number of immunoglobulins with a particular specificity. And this led to the development of the Mab era [17, 18]. In recent years, Mab era has seen a great progress both in the field of knowledge and drug market due to the rapid development of molecular biology. In order to produce therapeutic antibodies and drugs with antibody-derived antigen binding region (such as Fab, Fc-fusion protein, scFv), several exploration platforms have emerged. These platforms can be categorized into three types including antibodies derived from rodent species or a display platform (e.g. phage, yeast, ribosomal, or mammalian cell antibody display), or humanized antibodies derived from human B cells or transgenic animals [17, 19]. Followed, the Mabs used in the treatment of ALL are reviewed. Table 1 summarizes the findings of the studies on Mabs for the treatment of ALL.

4. CD19

CD19 is a specific B cell antigen which is presented in more than 90% of precursor B-cell (PBC)-ALL blasts [20]. It is a key controller in B-cell development which makes CD19 a favorable target for the immunotherapy of B-cell malignancies [21]. Previous studies verified the potency of anti-CD19 immunotherapy by CAR T cells and bispecific T cell engager (BiTE) antibody, blinatumomab, in the treatment of B cell cancers [22, 23, 24, 25].

4.1 Blinatumomab

Blinatumomab is a BiTE that binds to CD3 positive cytotoxic T cells, allowing them to identify and eliminate CD19 positive ALL blasts [26]. Blinatumomab can induce polyclonal T cell response without requiring the specificity of T cell receptor, additional T cell co-stimuli, or the presence of class I MHC [27]. The FDA has approved blinatumomab for the treatment of patients with PBC-ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. In a randomized controlled phase 3 trial, Kantarjian et al. compared blinatumomab with conventional chemotherapy in patients with R/R PBC-ALL. They showed that treating these patients with blinatumomab was associated with a significantly higher complete remission (CR) rate and improved overall survival (OS). They also noted that Cytokine release syndrome (CRS) and neurological toxicity were seen more frequently in patients treated with blinatumomab [26]. A retrospective multicenter cohort analysis of 239 ALL patients (227 were R/R) showed a response rate of 65% in patients with R/R disease and stated that these patients’ median relapse-free survival and overall survival (OS) after blinatumomab were 32 and 12.7 months, respectively. They reported grade 3 or greater adverse events of cytokine release syndrome, neurological and liver adverse events in 3%, 7%, and 10% of patients [28].

In a single-arm phase 2 study of blinatumomab in patients with R/R Philadelphia-negative PBC-ALL, despite the overall complete remission rate of 43%, it was 29 and 73 in patients with more and less than 50% marrow involvement. In addition, after one cycle of blinatumomab treatment, the minimal residual disease (MRD) negativity rate was 80% in patients with detectable leukemia existing only as MRD. These data insinuate that blinatumomab, and other BiTE therapies, can be more effective when applied to cytoreduced and MRD $+$ patients [29].

4.2 Denintuzumab

Denintuzumab mafodotin is a humanized anti-CD-19 Mab conjugated with monomethyl auristatin F (MMAF). MMAF exhibits antimitotic activity through microtubule disruption and is attached to the Mab via a maleimidocaproyl linker. Fathi et al. reported that patients with R/R PBC-ALL, B-cell lymphoma, and Burkitt leukemia/lymphoma that received denintuzumab once every three weeks had a complete remission of 35% (including incomplete platelet/blood recovery). Also, they noted pyrexia, nausea, and fatigue as the most common adverse events, alongside headache, chills, vomiting, blurred vision, and anemia. They concluded that denintuzumab mafodotin has a tolerable safety profile and promising efficacy in highly pretreated adult cases of PBC-ALL and highly aggressive B-cell lymphomas [24].

Table 1
Monoclonal antibodies for the treatment of acute lymphocytic leukemia

Author (year)	Study name/ phase	Mab	Mechanism	Regimen	Outcomes
Badar et al. (2020)	Retrospective multicenter cohort analysis	Blinatumomab	Anti-CD19	Blinatumomab with or without tyrosine kinase inhibitor or chemotherapy	In patients with R/R disease:
CR with or without blood recovery: 65%
median relapse-free survival: 32 months
OS: 12.7 months
In patients received the drug for MRD:
MRD negativity achievement: 75%
OS: 34.7 months.	Grade 3 and more complications seen included: Toxicity of liver, neurotoxicity and CRS.	[28]
Kantarjian et al. (2017)	Phase 3	Blinatumomab	Anti-CD19	G1: blinatumomab and G2: standard of-care chemotherapy	Median OS: 7.7 months in G1 and 4.0 months in G2 (the difference was statistically significant)
Remission rates after 12 weeks of therapy:
Complete remission with blood recovery: 34% in G1 vs 16% in G2
Complete remission with/without blood recovery: 44% in G1 vs 25% in G2
Median duration of remission: 7.3 months in G1vs. 4.6 months in G2	Grade 3 or 4 toxicity were reported in 87% of the patients in G1 and in 92% of the patients in G2.	[26]
Assi et al. (2017)	–	Blinatumomab	Anti-CD19	Blinatumomab $+$ Tyrosine Kinase Inhibitor (ponatinib, $n=$ 8; dasatinib, $n=$ 3; bosutinib, $n=$ 1)	Complete hematologic response rate: 50%
Complete cytogenetic response rate: 71%
Complete molecular response rate: 75%
1-year OS rate: 73%	Grade 3 neurotoxicity was seen in 2 patients. Grade 1 or 2 neurotoxicity included tremor, blurry vision, and confusion. No cardiovascular disease or pancreatitis was observed.	[73]
Topp et al. (2015)	phase 2	Blinatumomab	Anti-CD19	Blinatumomab (9 $\mu$ g/day for the first 7 days and 28 $\mu$ g/day thereafter) by continuous intravenous infusion over 4 weeks every 6 weeks (up to five cycles)	After 2 cycles:
CR with complete or partial count recovery: 43%
CR with complete count recovery: 33%	The most common grade 3/4 AE: febrile neutropenia (25%), neutropenia (16%), and anaemia (14%)
Three grade 3 CRS and three treatment-related deaths, due to sepsis, Escherichia coli sepsis, and Candida infection, has been reported.
Neurologic grade 4 AE has been observed in 4 patients.	[29]

Table 1, continued
Author (year)	Study name/ phase	Mab	Mechanism	Regimen	Outcomes	Safety profile	Ref
Fathi et al. (2015)	Phase 1	Denintuzumab	Anti-CD20	Denintuzumab weekly (Days 1 and 8 of 21-day cycles) or once every 3 weeks (q3wk)	q3wk schedule had a CR with/without complete count recovery rate of 35% in R/R B-ALL	Similar AE between dosing schedules
Most common AE: were pyrexia (54%), nausea (52%), fatigue (51%), headache (44%), chills (38%), vomiting (37%), blurred vision (35%), and anemia (34%).
superficial microcystic keratopathy in 56%	[24]
Hoelzer et al. (2014)	GMALL	Rituximab	Anti-CD20	Rituximab $+$ chemotherapy	CRR: 88%
OSR: 80%
PFS: 71%	Side effects such as mucositis	[74]
Thomas et al. (2010)	Phase 2	Rituximab	Anti-CD20	Rituximab (375 mg/m ${}^{2}$ ) $+$ hyper-CVAD	CR: 95%
3-year CRD rate: 60%
3-year OS rate: 58%
In younger patients, modified hyper-CVAD showed better CRD and OS rates compared to standard hyper-CVAD.	Reasons for early treatment discontinuation included relapse (9 patients), deaths in CR (7 patients), infectious-related toxicity (2 patients).	[75]
Griffin et al. (2009)	ANHL0121 (phase 2)	Rituximab	Anti-CD20	Rituximab $+$ chemotherapy	CRR: 60%	Acceptable safety profile	[76]
Thomas et al. (2006)	Phase 2	Rituximab	Anti-CD20	Rituximab $+$ hyper-CVAD	EFS: 80%
DFS: 88%
OSR: 89%
CRR: 70%	One death in CR from infection	[38]
Jabbour et al. (2020)	Phase 2	Ofatumumab	Anti-CD20	Ofatumumab $+$ hyper-CVAD	ORR: 98%	Acceptable safety profile	[77]
Sasaki et al. (2015)	Phase 2	Ofatumumab	Anti-CD20	Ofatumumab $+$ hyper-CVAD	CRR: 79%
OSR: 87%
PFS: 68%	Safe and highly effective	[78]
Stock et al. (2020)	The phase 1/2 study 1010 and phase 3 study 1022		Anti-CD22	Study 1010: InO (0.8 mg/m ${}^{2}$ on day 1 and 0.5 mg/m ${}^{2}$ on days 8 and 15 of each 21-day cycle)
Study 1022: InO versus standard intensive chemotherapy (SC)	Study 1022: CR/CRi: 73% in InO group and 56% in SC group
MRD negativity among CR/CRi patients: 81% in InO group and 33% in SC group
12-months PFS rate: 20.1% in InO group and 4.8% in SC group.
Study 1010: CR/CRi: 56%
MRD negativity among CR/CRi patients: 100%
Median PFS: 4.4 months	The most common non-hematologic grade 3–5 AEs in InO groups were and gastrointestinal disorders (31%) in study 1010 and multiorgan abnormalities (41%) in study 1022. In study 1022, the increased grade 3 or higher gamma-glutamyl transferase was seen in 27.3% of patients in InO group and none of the patients in SC group.	[79]

Table 1, continued
Author (year)	Study name/ phase	Mab	Mechanism	Regimen	Outcomes	Safety profile	Ref
Jabbour et al. (2020)	INO-VATE	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab ozogamicin	MOS:14.1 months in MRD – and 702 months in MRD $+$
CRR: 76%
CRiR:52%
mPFS: 8.6 months in MRD– and 5.4 months in MRD $+$		[80]
Badar et al. (2020)	–	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab ozogamicin	ORR: 63%
CR:44%	The most common grade 3 or higher adverse events observed were transaminitis (16%), hyperbilirubinemia (5%), bleeding (4%), nonocclusive disease (2%), and hyperglycemia (2%)	[54]
Kantarjian et al. (2018)	Phase 2	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab (1.3 to 1.8 mg/m2 for the first cycle and 1.0 to 1.3 mg/m2 for the following cycles) $+$ mini-hyper CVD $+$ Maintenance therapy with dose-reduced POMP	2-year PFS rate: 59%
2-year OS rate: 66%
3-year PFS rate: 49%
3-year OS rate: 56%
Median PFS: 35 months
Median OS: not reached
ORR: 98%
CR: 85%	The treatment was well tolerated and most AEs were grade 1 or 2. The most common grade 3 or 4 AEs included prolonged thrombocytopenia (81%), Infections (52% during induction and 69% during consolidation chemotherapy), hyperglycemia (54%), hypokalemia (31%), increased aminotransferases (19%), hyperbilirubinemia (17%), and hemorrhage (15%).	[58]
Jabbour et al. (2018)	Phase 2	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab (1.8 to 1.3 mg/m2 for the first cycle and 1.3 to 1.0 mg/m2 for the following cycles) $+$ mini-hyper CVD	CR: 59%
ORR: 78%
1-year OS rate: 46%
1-RFS rate: 40%
MOS: 11 months
Median RFS: 8 months	The regimen was well-tolerated. Prolonged thrombocytopenia (longer than 6 weeks) was seen in 81% of the patients. 95% of the patients experienced hepatic AEs.	[59]
Kantarjian et al. (2016)	Phase 3	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab ozogamicin (G1) versus standard intensive chemotherapy (G2)	CRR:80.7% in G1 and 29.4% in G2
MRD: 78.4% in G1 and 28.1% in G2
Median PFS: 5 months in G1 and 1.8 months
MOS: 7.7 months in G1 and 6.7 months in G2	Veno-occlusive liver disease occurred in 15 patients in G1 and 1 patient in G2.	[81]
Betts et al. (2016)	Phase 3	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab ozogamicin	CR: 60 –79%
CRiR: 80.7%		[82]

Table 1, continued
Author (year)	Study name/ phase	Mab	Mechanism	Regimen	Outcomes	Safety profile	Ref
Jabbour et al. (2015)	–	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab ozogamicin	ORR: 58%
CRR: 19%
CRiR: 33%
MOS: 6.3 months	Five patients (6%) died within 4 weeks of starting therapy	[83]
Kantarjian et al. (2013)	Phase 2	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab ozogamicin	CRR: 19%
CRiR: 9% 30%CR ${}_{P}$
ORR: 58% MOS: 6.2 months
MS with the single-dose schedule: 5.0 months
MS with the weekly dose schedule: 7.3 months	Single-agent therapy was safe, highly active, and convenient/
A weekly dose schedule became clear to be equally efficient and less toxic than a single-dose schedule/single-dose
inotuzumab was related to continuing liver function abnormalities in 2 of 49 patients
Veno-occlusive disease was noted in 6 of 36 patients after stem cell transplantation	[84]
Kantarjian et al. (2012)	Phase 2	Inotuzumab ozogamicin (InO)	Anti-CD22	Inotuzumab ozogamicin (1 $\cdot$ 8 mg/m ${}^{2}$ , I.V, over 1 h every 3–4 weeks)	ORR: 57%
MOS: 5.1 months
CR: 18%
Marrow CR: 39%
Resistant disease: 39%	The most frequent AEs included fever (20 patients had grade 1–2, and 9 had grade 3–4), hypotension (12 grade 1–2, and 1 grade 3), Raised bilirubin concentration (12 grade 1–2, and 2 grade 3), and Raised aminotransferase concentration (27 grade 1–2, and 1 grade 3).	[85]
Chevallier et al. (2017)	Phase 2	Epratuzumab	Anti-CD22	Epratuzumab $+$ hyper-CVAD	ORR:50%
CRR:30%
CRiR:3%
PRR:17%
MOS: 3 months
LFS: 4.7 months	Well-tolerated	[86]
Raetz et al. (2015)	ADVL04P2	Epratuzumab	Anti-CD22	Epratuzumab (dose of 360 mg/m ${}^{2}$ ) $+$ chemotherapy (4 doses weekly (B1) and 8 doses weekly (B2))	Second complete remission (CR2): 65% in B1 and 66% in B2
MRD negative: 8/26 in B1 and 12/31 in B2
2-year EFS rate: 25.9% in B1 and 39.9% in B2
2-year OS rate: 34.2% in B1 and 49.3% in B2	The combination of epratuzumab and chemotherapy was well-tolerated. The most common treatment related AEs included infections (50%), fever and neutropenia (26.3%), hyperglycemia (24.6%) ALT elevation (9.6%), and pancreatitis (6.1%).	[87]

Table 1, continued
Author (year)	Study name/ phase	Mab	Mechanism	Regimen	Outcomes	Safety profile	Ref
Advani et al. (2014)	SWOG S0910 (phase 2)	Epratuzumab	Anti-CD22	Epratuzumab (360 mg/m ${}^{2}$ ) $+$ clofarabine (40 mg/m ${}^{2}$ ) $+$ cytarabine (1 g/m ${}^{2}$ )	CR/CRi: 52%
MOS: 5 months
MRD-negative: 1 patient	Twenty-four deaths occurred with three during treatment. The most common grade 3–5 treatment-related AEs were transaminase elevation ( $n=$ 11), febrile neutropenia ( $n=$ 17), lung infection ( $n=$ 4), and sepsis ( $n=$ 3).	[88]
Raetz et al. (2008)	A Children’s Oncology Group Pilot Study	Epratuzumab	Anti-CD22	Epratuzumab (360 mg/m2, I.V, twice weekly)	SD: 11 patients
PD: 3 patients
CR: 9 patients	The treatment was well-tolerated. One patient experienced a grade 4 seizure and another patient had a grade 3 ALT elevation. Two patients died due to infections.	[89]
Gorin et al. (2013)	Phase 2	Alemtuzumab	Anti-CD52	Alemtuzumab (doses of 3, 10, and 30 mg) $+$ granulocyte-colony stimulating factor (G-CSF, 5 $\mu$ g/kg)	CR: 4 patients
One patient had clearance of blast cells in in peripheral blood but not in the marrow.	AEs included fever and chills ( $n=$ 3), skin rash ( $n=$ 3), bronchospasm ( $n=$ 2), tumor lysis syndrome ( $n=$ 1), pulmonary aspergillosis ( $n=$ 1), Cytomegalovirus (CMV) reactivations ( $n=$ 2) and CMV pulmonary infection ( $n=$ 1).	[66]
Stock et al. (2009)	CALGB 10102 (phase 1)	Alemtuzumab	Anti-CD52	Alemtuzumab 30 mg 3 times a week for 4 weeks	MOS: 55 months	Mild non-hematologic toxicities	[90]
Liedtke et al. (2012)	Phase 1	mAb216	Binding to lactosamine antigen	MAb216 (from 1 mg/kg/h to 200 mg/h I.V.)	Peripheral blasts reduction: 6–65% in the first infusion and 81% after the addition of vincristine	MAb216 was well-tolerated. Grade 1–2 AEs were seen in 3 of 13 patients. One patient developed grade 3 epistaxis and experienced dose limiting-toxicity (DLT).	[72]

Abbreviations: CRiR: CR with incomplete platelets recovery rate; CRR: complete response rate; CRp: CR with no platelet recovery; ORR: overall response rate; PRR: partial responses rate; MOS: Median overall survival; MS: Median survival; LFS: leukemia-free survival; mPFS: Median progression-free survival; RFS: relapse-free survival; EFS: Event-free survival; CR: complete remission; CRi: CR with incomplete hematologic recovery; CRD: complete response duration; AHSCT: allogeneic haemopoietic stem-cell transplantation; CRS: cytokine release syndrome; AE: adverse events; OS: overall survival; CVAD: cyclophosphamide, vincristine, doxorubicin, dexamethasone; POMP: purinethol, oncovin, methotrexate, prednisone; MRD: minimal residual disease; SD: stable disease; PD: Progressive disease.

4.3 Coltuximab

Coltuximab ravtansine (SAR3419) is an anti-CD19 humanized Mab conjugated to Ravtansine (DM4), a cytotoxic maytansinoid. DM4 inhibits tubulin polymerization, resulting in cell cycle stoppage. Coltuximab ravtansine was studied in several trials for non-Hodgkin lymphoma (NCT01472887, NCT01440179, NCT00796731, NCT00549185). However, its phase II trial for R/R ALL was terminated early due to lack of clinical response [4].

5. CD20

Most B-cells express CD20, whereas only up to half of the PBC-ALL blasts express it [30]. CD20 plays a role in regulating B-cell proliferation and differentiation, and inhibits early-stage B lymphocyte activation [31, 32]. Several pathways are involved in the function of Mabs to CD20, such as apoptosis induction by CD20 cross-linking and complement and Antibody-dependent cellular cytotoxicity [33]. Besides, CD20 does not internalize nor shed following Mab infusion, providing a sustained immunological attack [34].

5.1 Rituximab

Rituximab is an anti-CD-20 Mab used for non-Hodgkin’s lymphoma (B-NHL), intravascular large B-cell lymphoma (IVLBCL), and Burkitt’s lymphoma. Given that there is a 30–40% chance of survival in patients with ALL, and traditional chemotherapy kills all of the the cycling cells, the goal is to develop more specific therapies. Because 30% of ALL cases are CD20 positive, rituximab is a viable option for ALL therapy [35, 36]. Rituximab has shown promising results when added to hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in CD-20 positive ALL patients [30, 37, 38]. Thomas et al. reported a significant benefit of adding rituximab to standard hyper-CVAD chemotherapy regarding three-year complete remission duration rate and overall survival in young CD20-positive PBC-ALL [37]. Maury et al. reported a 32% rate of CD20 positive cases among Ph- PBC-ALL patients. Also, they reported that Ph-ALL patients treated with chemotherapy in combination with rituximab had a significantly longer Event-free survival (ESS) than the chemotherapy alone group [30].

5.2 Obinutuzumab

Obinutuzumab, a type 2 anti-CD20, induces higher antibody-dependent cell-mediated cytotoxicity (ADCC) and direct cytotoxicity than rituximab (type 1), while having lower complement-dependent cytotoxicity (CDC) activity [39]. FDA recently approved obinutuzumab to be used as a combination with chlorambucil for the first-line treatment of chronic lymphocytic leukemia (CLL) [40]. In a preclinical study, 30 mg/kg of obinutuzumab was prescribed to patients sensitive to rituximab, resistant Burkitt lymphoma, and PBC-ALL in xenograft mice. They showed the Superiority of obinutuzumab inoverall survival (OS) compared to rituximab [41, 42]. Tumor lysis syndrome is a life-threatening complication that can occur during the treatment of lymphoma or leukemia. In a study, five percent of patients with B-cell lymphoma treated with obinutuzumab experienced the condition [43].

5.3 Ofatumumab

Ofatumumab is a fully human Mab against CD20, used as the first line of treatment for CLL because it has shown a considerable effect on overall survival and one-year progression in CLL [44, 45]. In patients unsuitable for fludarabine, ofatumumab is administered in combination with chlorambucil [46]. Compared to Rituximab, Ofatumumab binds to CD20with more affinity, which may be responsible for its superior ADCC [47, 48, 49]. Ofatumumab is highly active in patients who are resistant to rituximab and patients who are not resistant to rituximab [50]. In a study on 63 patients with Ph-negative CD20 $+$ ALL treated with ofatumumab and hyper-CVAD, the response rate was 97%, and 92% of the patients achieved MRD negativity. They also reported infections, raised transaminases, and hyperbilirubinemia as the most frequent grade 3 or more non-hematological adverse effects [51]. In addition, no cases of Tumor lysis syndrome with ofatumumab were reported in a systematic review [43].

6. CD22

CD22 is another B cell-specific antigen expressed on mature and some immature B-cells and most PBC-ALL blasts. When antigen cross-links the B cell antigen receptor (BCR), CD22 is phosphorylated and changes the B cell activation and function, leading to apoptosis in that subgroup of B cells. It is a negative controller of BCR signaling and is the presumable determinant of the threshold of signals transduced through BCRs. It may also control autoimmunity by regulating B-cell responses to foreign and self-antigens. In a study carried out early on a clinical trial of a chimeric antigen receptor (CAR) against CD22, it has been found that T-cell therapy can lead to remission of ALL in most children and young adults with R/R ALL, it has been also demonstrated that immunologic therapy is practical and safe [52].

6.1 Inotuzumab

Inotuzumab ozogamicin (InO) is an anti-CD22 Mab conjugated with calicheamicin. It is noted to be more effective than chemotherapy in treating R/R precursor PBC-ALL patients [53], and FDA has approved it for the treatment of adults with R/R PBC-ALL. Several studies reported favorable results in the treatment of patients with R/R CD22 positive ALL with inotuzumab ozogamicin, regarding response rate and survival improvement [52, 54, 55, 56, 57]. The combination of inotuzumab ozogamicin and mini-hyper-CVD showed promising activity in newly diagnosed [58] and R/R patients with Philadelphia chromosome-negative ALL [59]. McDonald et al. have observed a high incidence of sinusoidal obstruction syndrome (SOS) and Drug-induced liver injury (DILI) after treatment with InO [57].

6.2 Moxetumomab

Moxetumomab pasudotox (MP) is constructed from the variable domain of an anti-CD22 Mab conjugated to a fragment of Pseudomonas exotoxin A. Following the binding of MP to CD22, the exotoxin gets internalized into the cell and activates the apoptosis cascade. Using MP assists the toxin in passing through the cell membrane and destroying cells. Moxetumomab (moxe) can be selected for patients with relapsed or resistant Hairy cell leukemia (HCL) and HCL variant (HCLv). Moxe has a unique capability to achieve MRD negativity and complete remission (CR) in chemo-resistantconditions without chemotherapy-type toxicities. Moxe is a suitable choice to use before chemotherapy or nonchemotherapy agents that are incapable ofclear MRD. It may also be combined with rituximab to increase MRD-negativeCRs [60].

6.3 Epratuzumab

Epratuzumab is an anti-CD22 Mab and works mainly by removing BCR complex components from the surface of B-cells, thus resulting in reduced B-cell activation and signaling [61]. In a phase 2 trial in children, epratuzumab was for the initial relapse of PBC-ALL alongside standard chemotherapy protocol. By adding epratuzumab, historical results of chemotherapy mono treatment were not improved, although it was well tolerated [4, 62]. However, in another study, in 50% of patients with R/R CD22 $+$ PBC-ALL, hyper-CVAD plus epratuzumab produced an objective response [63].

7. CD52

CD52 is found both as a soluble molecule and a cell surface antigen expressed by various immune cells. Both forms have shown modulating effect on T-cell activation [64].

Alemtuzumab is an anti-CD52 antibody that suppresses the bone marrow and prevents T-cell production. The best dose of IV injection is 30 mg, 3 times/week for 1–3 months. Suppressing B and T-cells increases the risk of infectious diseases like cytomegalovirus and viremia [65]. Consequently, further observation is essential while the drug is in use. Treating R/R adult ALL cases with the combination of alemtuzumab and granulocyte-colony stimulating factor is suitable for a short duration to achieve complete remission, but it is associated with an increased risk of complications such as bronchospasm and skin rash [66]. Furthermore, a study showed that alemtuzumab-induced T-cell reduction increases the risk of hematologic malignancies (such as ALL) relapse after AHSCT [67].

8. Lactosamine antigen

The i-antigen is a linear chain consisting of repetitious N-acetyllactosamine units. It is primarily expressed in fetal and neonatal cells [68]. An i-like molecule, linear poly-N-acetyl-lactosamine, is expressed in B-cells [69]. Human mAb216 is a member of IgM antibodies classified as cold agglutinins (CAs) because they can bind to red blood cells (RBCs) and result in agglutination at 4 ${}^{\circ}$ C. The variable heavy chain of mAb216 is encoded by the VH4-34 gene, which binds with high affinity to linear poly-N-acetyl-lactosamine and results in killing normal B lymphocytes, B-cell lymphomas, and B-progenitor lymphoblasts [70, 71]. In a phase 1 study on 13 patients with R/R B-cell ALL, mAb216 monotherapy and in combination with vincristine was well-tolerated. The addition of vincristine to mAb216 resulted in better response and greater reduction of the peripheral blasts [72]. Further studies are required to evaluate the efficacy and safety of mAb216 alone and in combination with other therapeutic agents.

9. Conclusion

Various Mabs have been investigated in treating ALL, and new Mabs are being developed and tested. The most effective and studied ones are Mabs against CD19, CD20, CD22, and CD52. This review showed that Mabs fight ALL by different mechanisms and result in different outcomes, with varying side effects. The most promising results of ALL therapy with Mabs were associated with blinatumomab, rituximab, ofatumumab, and inotuzumab. Moxetumumab and blinatumomab are favorable choices for achieving MRD negativity, and inotuzumab, epratuzumab, and alemtuzumab may improve treatment outcomes in R/R ALL cases. FDA approved blinatumomab for MRD positive PBC-ALL and Inotuzumab ozogamicin for R/R PBC-ALL. Applying a personalized approach for achieving higher efficacy is one of the most critical aspects of treatment with Mabs that can happen in the future with more investigation of predictors of response and studying Mabs in patients with special ALL blasts phenotype. Greater efficacy of Mab therapy in comparison to chemotherapy in the treatment of ALL, either for induction of complete remission or achieving MRD negativity, along with acceptable safety, makes them an appealing treatment option. So, they may be used more widely in the future. Finally, we recommend more cost-effectiveness research in this field.

Abbreviations

CRiR: CR with incomplete platelets recovery rate; CRR: complete response rate; CRp: CR with no platelet recovery; ORR: overall response rate; PRR: partial responses rate; MOS: Median overall survival; MS: Median survival; LFS: leukemia-free survival; mPFS: Median progression-free survival; RFS: relapse-free survival; EFS: Event-free survival; CR: complete remission; CRi: CR with incomplete hematologic recovery; CRD: complete response duration; AHSCT: allogeneic haemopoietic stem-cell transplantation; CRS: cytokine release syndrome; AE: adverse events; OS: overall survival; CVAD: cyclophosphamide, vincristine, doxorubicin, dexamethasone; POMP: purinethol, oncovin, methotrexate, prednisone; MRD: minimal residual disease; SD: stable disease; PD: Progressive disease.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Pending journal policy.

Availability of data and material

The datasets generated and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Competing interests

None.

Funding

None.

Authors’ contributions

Study concept and design: Niloofar Deravi

Acquisition of data: Hossein Pourmontaseri, Niloofar Habibzadeh, Sarina Entezari, Fatemeh samadian, Drafting of the Manuscript: Niloofar Deravi, Sarina Entezari, Fatemeh samadian, Shamim Kiyani, Mina Taheri

Critical revision of the manuscript for important intellectual content: Niloofar Deravi, Ali Ahmadi, Mohammad Sadegh Fallahi, Amirhossein Tamimi, Study supervision: Niloofar Deravi

Footnotes

Acknowledgments

The authors would like to thank the researchers whose articles were included in this study.

Conflict of interest

None.

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M.J.

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90.

Stock

Sanford

Lozanski

Vij

Byrd

J.C.

Powell

B.L.

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Monoclonal antibodies for the treatment of acute lymphocytic leukemia: A literature review

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSION:

Keywords

1. Background

2. Method

3. Monoclonal antibodies

4. CD19

4.1 Blinatumomab

4.2 Denintuzumab

Table 1 Monoclonal antibodies for the treatment of acute lymphocytic leukemia

5. CD20

5.1 Rituximab

5.2 Obinutuzumab

5.3 Ofatumumab

6. CD22

6.1 Inotuzumab

6.2 Moxetumomab

6.3 Epratuzumab

7. CD52

8. Lactosamine antigen

9. Conclusion

Abbreviations

Ethics approval and consent to participate

Consent for publication

Availability of data and material

Competing interests

Funding

Authors’ contributions

Footnotes

Acknowledgments

Conflict of interest

References

Table 1
Monoclonal antibodies for the treatment of acute lymphocytic leukemia