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REVIEW ARTICLE
Year : 2022  |  Volume : 59  |  Issue : 1  |  Page : 4-11
 

Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies


1 Department of Hematology and Blood Bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
2 Department of Hematology and Blood Bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences; Pediatric Cell and Gene Therapy Research Center, Gene, Cell and Tissue Research Institute, Tehran University of Medical Science, Tehran, Iran

Date of Submission23-Jun-2019
Date of Decision14-Jan-2020
Date of Acceptance29-Oct-2020
Date of Web Publication19-May-2022

Correspondence Address:
Ahmad Gharehbaghian
Department of Hematology and Blood Bank, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_567_19

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 » Abstract 


Acute lymphoblastic leukemia (ALL) is the malignant transformation of lymphoid progenitors that affects both children and adults. Although the outcome of pediatric patients has been improved dramatically, there are still many challenges in the treatment of adults. Patients with primary resistant or relapsed disease have the worst outcome and despite the administration of intensified multi-agents chemotherapies, the outcome of this group remains very poor. Accordingly, the development of novel therapeutic options is considered necessary. Having a comprehensive insight into the pathophysiology of ALL and aberrant signaling pathways is crucial for introducing effective targeted therapies. Combination therapies with new drugs and innovative targeted therapies with the aim of affecting the main aberrant signaling pathways in the disease are considered as new approaches. Here we tried to have a comprehensive review on the potential molecular targets in the treatment of refractory/relapsed ALL and the current therapeutic agents.


Keywords: Acute lymphoblastic leukemia, refractory/relapsed, targeted therapy


How to cite this article:
Hosseini MS, Jafari L, Yami A, Gharehbaghian A. Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies. Indian J Cancer 2022;59:4-11

How to cite this URL:
Hosseini MS, Jafari L, Yami A, Gharehbaghian A. Therapeutic approaches for relapsed/refractory adult acute lymphoblastic leukemia (ALL), a review on monoclonal antibodies and targeted therapies. Indian J Cancer [serial online] 2022 [cited 2022 Jul 4];59:4-11. Available from: https://www.indianjcancer.com/text.asp?2022/59/1/4/345484





 » Introduction Top


Acute lymphoblastic leukemia (ALL) is the malignancy of lymphoid progenitors from B-cell (B-ALL) or T-cell (T-ALL) lineages. It is the most common malignancy of childhood[1] and the second most prevalent acute leukemia in adults.[2] Most cases are affected by B-ALL which comprises 85% and 75% of pediatric and adult ALL, respectively.[3] Unlike the ALL of B-cell lineage which generally represents with good prognosis especially in children, the prognosis of T-ALL is not favorable. In comparison with B-ALL, patients with T-ALL are at higher risk of remission induction failure and would experience early relapse and isolated central nervous system (CNS) relapse. However, with the advances in the chemotherapeutic regimens the outcome of patients has been improved, as pediatric and adult patients with T-ALL show a cure rate of about 75% and 50%, respectively.[4]

Standard protocol for ALL treatment comprises three main phases including remission induction, consolidation, and maintenance. A prophase stage has been also recommended in most cases of ALL especially for patients with a high disease burden. It utilizes oral steroids for 5–7 days prior to induction therapy to diminish disease burden. The patient's response to steroids is an indicative marker for predicting the overall outcome of treatment.[5] Induction therapy with the duration of 4 weeks is generally based on corticosteroids, vincristine, and anthracyclines. Although standard protocols of pediatric ALL contain L-asparaginase, but its administration in adults is controversial because of high toxicity and adverse events. The consolidation phase typically takes advantage of the same drugs of induction. Throughout treatment, intrathecal methotrexate in various intervals is also included to prevent CNS relapse. Long-term maintenance mainly includes 6-mercaptopurine, methotrexate, vincristine, and corticosteroids and is continued for 2-3 years.[2],[5]

The main challenge is about cases with primary resistant or relapsed disease. The outcome of these patients is very poor even with the administration of intensified multi-agents chemotherapies. In case of intensified cytotoxic chemotherapy, the toxicity of drugs is also a major concern. Currently, salvage therapy to gain a second complete remission (CR) is the only therapeutic choice, while more than 50% of cases do not achieve it.[6] In eligible patients, allogeneic hematopoietic stem cell transplantation (HSCT) is recommended following second CR.[6] To date, many efforts have been devoted to finding novel agents and new protocols for treatment of patients with refractory/relapsed ALL. Intensified multi-agent chemotherapy and the use of completely novel agents like monoclonal antibodies (MoAbs) are considered as therapeutic options for these patients. Combination therapies enhance the efficacy of each agent and allow for using lower doses which in turn lead to lower toxicity.


 » Targeted Therapies Top


Monoclonal antibodies (MoAbs)

MoAbs are mainly established for B-ALL. The common molecular targets of these antibodies are cluster of differentiation (CD)22, CD20, CD19, and CD52. Traditionally, MoAbs were simple and unconjugated, but advances in biotechnology resulted in the development of more effective antibodies that are conjugated to cytotoxic agents.[7] A list of MoAbs for treatment of B-ALL is provided in [Table 1], among which some antibodies have received United States Food and Drug Administration (US FDA) approval for different conditions [Table 2].[8] The mechanisms by which unconjugated MoAbs exert their effects are usually antibody-dependent cell-mediated cytotoxicity (ADCC) or complement-mediated cytotoxicity [Figure 1]a.[7]
Table 1: Monoclonal antibodies for treatment of B-ALL

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Table 2: Monoclonal antibodies with FDA approval

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Figure 1: Mechanisms of action of monoclonal antibodies. (a) Unconjugated antibodies, (b) conjugated antibodies, (c) Bi-specific T-cell engagers

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Anti CD22 MoAbs

CD22 is a differentiation marker specific to B-cell lineage with no expression on hematopoietic stem cells. Besides normal B-cells, it is also frequently expressed on B-ALL cells (more than 90%).[6] CD22 is rapidly internalized following MoAb linkage and thereby is an appropriate target for transferring cytotoxic agents into the leukemic cells [Figure 1]b.[2] Several MoAbs using CD22 as a molecular target have been developed so far, such as inotuzumab ozogamicin, epratuzumab and Moxetumomab Pasudotox.

Anti CD20 MoAbs

CD20 is a specific antigen of B-cell lineage with expression on both normal and malignant B-cells in almost all stages of differentiation. The first generation of anti CD20 MoAb is rituximab which has improved the outcome of patients with CD-20 positive leukemia.[2] Rituximab is an unconjugated antibody and is the most frequently used MoAb in B-ALL.[7] Ofatumumab and obinutuzumab are two novel anti CD20 antibodies.

Anti-CD19 MoAbs

CD19 is another B-lineage specific antigen which is expressed in almost all stages of differentiation, but has no expression on plasma cells. Similar to CD22, CD19 is also rapidly internalized following antibody linkage, making it an attractive antigen for antibody-drug/toxin therapy.[2] Coltuximab ravtansine, denintuzumab mafodotin and ADCT-402 are conjugated MoAbs against CD19. Blinatumomab is a bi-specific T-cell engager (BiTE) antibody which targets both CD3 and CD19 and thereby recruits cytotoxic T-cells against malignant B-cells [Figure 1]c.[6] Thirty-six patients who suffered from relapsed or refractory B-precursor ALL were subject to a study in which treatment with blinatumomab was applied in cycles of 4 weeks of continuous infusion and subsequently 2 weeks of interval as treatment-free (in a uniformed study consisting of a dose-finding phase and an extension phase). Sixty-nine percent which would include 25 patients successfully reached CR or CR with partial hematologic recovery, among them 88% reached a minimal residual disease (MRD) response. Median overall survival (OS) was 9.8 months (95% [CI]: 8.5-14.9), and median relapse-free survival (RFS) was 7.6 months (95% [CI]: 4.5-9.5).[9] Another study was conducted on 405 patients, among whom 271 patients were treated with blinatumomab and the remaining 134 patients underwent chemotherapy. Median OS in a group who received blinatumomab was remarkably higher than the other one (7.7 month for blinatumomab and 4 month for chemotherapy). Within a post-treatment period of 12 weeks, remission rates were considerably higher in the blinatumomab-treated patients than in the chemotherapy group, both in terms of CR with full hematologic recovery (34% versus 16%, P < 0.001) and in terms of CR with full, partial, or incomplete hematologic recovery (44% versus 25%, P < 0.001).[10]

Anti CD52 MoAb

CD52 is expressed on both B and T lymphocytes and also in most patients with ALL.[6] Alemtuzumab which is also known as Campath-1H, is a humanized Immunoglobulin G1 (IgG1) kappa monoclonal antibody targeting CD52. As a single agent, alemtuzumab did not lead to the promising results, but it has been reported beneficial after intensive chemotherapy in B- and T-ALL patients who achieved CR.[6] Although alemtuzumab may be useful in CD52 positive cases of T-ALL, but in contrast to adult T-cell leukemia-lymphoma (ATLL), only a few cases of T-ALL are associated with CD52 expression.[11] In a study carried out by the Children's Oncology Group (COG), 13 children or young adults with relapsed or refractory B- (n = 10) or T-ALL (n = 3) in a phase II trial were treated with alemtuzumab.[12] Single-agent alemtuzumab was administrated initially for 28 days and receivers were subsequently permitted to continue treatment with alemtuzumab alongside chemotherapy. In this case, merely two patients responded with only one achieving a CR. This illustrates that as a single agent, alemtuzumab performs a modest activity.[12]

Proteasome inhibitors

Currently, proteasome inhibitors are considered as attractive therapeutic options in the treatment of refractory/relapsed ALL patients. Proteasome inhibitors are known to inhibit the Nuclear factor kappa B (NF-kB) pathway which is mainly via accumulation of IkB-α. It has been shown that inhibition of NF-kB pathway can enhance the sensitivity of resistant ALL cells to treatment. Several studies have shown that bortezomib and carfilzomib, the first and second generation of proteasome inhibitors respectively, can overcome resistance to specific agents including glucocorticoids, doxorubicin and melphalan.[13],[14] Takahashi et al. assessed the toxicity of bortezomib and carfilzomib on several B-ALL cell lines that can be considered as a model of refractory ALL. According to their results, cell lines with Ph+ chromosome, IKAROS family zinc finger 1 (IKZF1) deletion or homozygous loss of cyclin dependent kinase inhibitor 2A were associated with higher sensitivity to proteasome inhibitors. They also found that carfilzomib is a more effective and less toxic drug in combination chemotherapies, compared with bortezomib.[15]

NF–kB signaling pathway is also active in many cases of T-ALL.[16] Although NF–kB pathway is not sufficient for T-ALL transformation,[17] but significantly contributes in the survival of leukemia cells and leukemic stem cells.[13] Enhanced NF–kB signaling is also a potent cause of steroid resistance in ALL patients.[13]

It has been indicated that mutated Notch-1 leads to the activation of NF–kB signaling as its downstream targets.[17] It has been also shown that NF–kB pathway can be active in a manner independent of Notch-1 signaling. Therefore inhibition of this pathway has been suggested as an attractive therapeutic option for T-ALL therapy.[17] Koyama et al. showed that bortezomib can also attenuate the transcription of Notch-1 and its downstream targets including hairy and enhancer of split-1 (HES1), GATA binding protein 3 (GATA3) and Runt-related transcription factor 3 (RUNX3) in T-ALL cells.[18] Several studies tried to assess dual inhibition of Notch-1 and NF-kB pathways which lead to promising results. In a study by Yang et al. the synergistic effect of a γ-secretase inhibitor and bortezomib was demonstrated in T-cell lymphoproliferative neoplasms.[19]

Inhibitors of Notch-1 pathway

Notch-1 signaling pathway is a critical regulator of lymphopoiesis which triggers T-lineage commitment of the lymphoid precursors and is necessary for thymocyte development.[16] Following the linkage of ligands, the Notch receptors underwent proteolytic cleavage by γ-secretase which then leads to the secretion of Notch-1 intracellular domain (NICD). After translocation of NICD to nucleus it serves as a transcription factor for several genes which are involved in apoptosis blockade, cellular differentiation and cell cycle progress. Gain of function mutations of Notch-1 lead to the malignant transformation of T-cells.[16] Traditionally the well-known role of Notch-1 in T-ALL was restricted to the t(7;9) translocation which has a prevalence of about <1% among T-ALL cases.[4] However, now the main part of T-ALL pathogenesis is ascribed to the signaling of Notch-1 which is constitutively active in about 60% of cases with T-ALL, but no cases of B-ALL.[4] A schematic view of the main aberrant signaling pathways in the pathogenesis of T-ALL is illustrated in [Figure 2].
Figure 2: Schematic view of the main aberrant signaling pathways in T-ALL and the potential molecular targets for therapy

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A considerable number of studies tried to investigate the efficacy of agents which affect Notch-1 signaling pathways including Notch-1 inhibitory antibodies, γ-secretase inhibitors, and also inhibitors of downstream signaling components of the Notch pathway mainly HES and myelocytomatosis oncogene (MYC). MYC contributes in the development and maturation of lymphoid lineage and plays essential role in thymocyte development.[20] Although MYC alterations are only reported in <5% of T-ALL cases, but mutated Notch-1 and also other upstream deregulated pathways lead to the increased MYC signaling in many T-ALL cases and it has been indicated that MYC is one of the most prevalent active oncogenes in T-ALL.[21] Some part of this activation is ascribed to the mutations of F-box and WD repeat domain containing 7 (FBXW7), an E3 ubiquitin ligase which is responsible for the proteasomal degradation of both MYC and Notch-1. FBXW7 mutations are reported in about 10-20% of patients with T-ALL.[22] A comprehensive list of investigated targeted therapies for T-ALL is provided in [Table 3].
Table 3: Targeted therapies for T-ALL

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Inhibitors of PI3K/AKT/mTOR pathway

Sustained phosphatidylinositol 3-kinase(PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling is reported in 50-75% of T-ALL cases and is associated with poor prognosis. Dysregulated PI3K/AKT/mTOR pathway in T-ALL is mainly due to the inactivation of phosphatase and tension homolog (PTEN), the negative regulator of PI3K/AKT axis. PTEN inactivation may stem from PTEN gene mutations or abnormalities of other pathways leading to PTEN downregulation.[23] Loss of PTEN has been reported in about 20% of T-ALL cases.[24] Mutations in AKT1, PIK3CA, and PIK3R1 are also a direct mechanism of PI3K/AKT/mTOR defect in T-ALL. It has been also reported that mutations of Notch may lead to active PI3K/AKT/mTOR signaling, indirectly. For targeting this pathway, a wide variety of agents have been introduced. Rapalogs (mTOR inhibitors) are the first agents used for PI3K/AKT/mTOR inhibition, among which rapamycin is the most well-known drug. Currently, with the introduction of novel agents, PI3K/AKT/mTOR signaling axis can be inhibited at different levels. PI3K inhibitors are classified as pan PI3K inhibitors, selective inhibitors of PI3K isoforms (α, β, δ and γ) and dual inhibitors. According to a study by Lonetti et al. in which the efficacy of different PI3K inhibitors on T-ALL cell lines was evaluated, the pan PI3K inhibitor BKM-120 was the most cytotoxic agent in comparison with selective inhibitors.[23] Bressanin et al. compared the therapeutic potential of some of these inhibitors including GDC-0941 (pan class I PI3K inhibitor), NVP-BAG956 (dual PI3K/PDK1 inhibitor), MK-2206 (Akt inhibitor), RAD-001 (mTORC1 inhibitor) and KU-63794 (ATP competitive mTORC1/mTORC2 inhibitor). They demonstrated that NVP-BAG956 has the highest cytotoxicity against T-ALL cell lines and primary samples.[25]

Based on a study by Gomes et al. sustained activation of PI3K/AKT/mTOR pathway is also a common finding in adult B-ALL[26] and inhibitors of this pathway lead to promising results in treatment of B-ALL.[27],[28]


 » Chimeric Antigen Receptor T Cell Therapy Top


Chimeric antigen receptor (CAR) T cell immunotherapy has demonstrated promising results in refractory/relapsed ALL patients in the past few decades. CD19 is a pan B cell-specific antigen that is expressed on nearly all B cell leukemia and has been found as a potential approach in CAR T cell therapy for B-ALL. Studies by several groups indicated that autologous CD19 CAR T cells induced 70 to 90% CR rate in pediatric and adult B-ALL patients.[63] Therefore, after multicenter clinical trials, tisagenlecleucel, as an anti CD19 CAR T cell, was approved by the US FDA for these patients.[64] Newly, allogenic CD19 CAR T cell is under investigation in B-ALL patients which may lead to great revolution in immunotherapy.[65] CD22 is also expressed on B cell leukemia and is considered as an attractive antigen in CAR T cell therapies. It has been reported that CD22 CAR T cell not only has potent antitumor activity in denovo refractory/resistant B-ALL patients, but also is effective in patients resistant to CD19 CAR T cell therapy and is associated with high CR in these patients.[66] CARs specific for CD19 have led to high remission rates (over 80%) in patients with refractory ALL and diffuse large B-cell lymphoma (DLBCL). CTL019 is a reprogrammed cytotoxic T cell with an anti-CD19 CAR subjected as T cell therapy to eliminate target cells. Phase II study of CTL019 in children/young adults with refractory CD19+ B-ALL confirmed the efficacy of a single infusion of CTL019, without additional therapy. In this trial following lympho-depletion chemotherapy, 68 patients received a single dose of CTL019. The rate of CR or CR with incomplete blood recovery (CRi) was 83% within 3 months. Relapse-free probability and survival probability (at 6 months) were 75% (95% [CI]: 57%-87%) and 89% (95% [CI]: 77%-94%), respectively.[67] Also, the efficacy of anti-CD19 CAR T cell therapy (KTE-C19) in patients with refractory DLBCL has been discussed in a study conducted by Locke et al. which resulted in an overall response rate (ORR) of 71% and CR rate of 57%.[68]

It is very likely that these remission rates will also prolong OS for untreatable patients. These findings have prompted the FDA to approve anti-CD19 CAR T cells as the first T cell therapy even for refractory ALL and DLBCL.[69]

Despite of B-cell leukemia, studies about CAR T-cell therapy in T-cell leukemia is challenging and has limitations including CAR T-cell fratricide, T-cell aplasia, and contamination of CAR T-cell products with malignant T-cells. However preclinical data have shown advantages in utilizing CAR-T cell therapy for relapsed/refractory T-cell malignancies.[70] Different CD markers are under investigation for CAR-T cell therapy against T-ALL. Since CD7 is overexpressed on the surface of T-cell leukemia/lymphoma cells and also regulates TCR signaling in these cells, CD7 CAR-T cells could be a proper candidate for immunotherapy. Studies indicated that CD7 CAR-T cells eliminated malignant cells and had high protective and durable effect in a mouse xenograft model of T-ALL.[71] CD5 is another marker expressed in approximately 80% of T-ALL cases. It has been reported that transduction of CD5-CAR into NK-92 cell line (a human NK cell line) exerts potent anti-tumor activity and robust cytotoxicity against T-cell leukemia/lymphoma cell line and also have an inhibitory effect on leukemia progression in mouse models.[72],[73] As the result, CD5-CAR NK-92 cell is a new alternative therapeutic approach that could recognize and target malignant T-cells.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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