Keywords

Acute lymphoblastic leukemia; Hematopoietic stem cell transplantation; Risk stratification; Conditioning therapy; Immunotherapies; Monoclonal antibodies

Introduction

Acute lymphoblastic leukemia (ALL), a clonal expansion or malignant transformation and proliferation of lymphoid progenitor cells in the bone marrow, blood and extramedullary sites, is a highly heterogeneous disease comprising several entities that have distinct clinical manifestations, therapeutic strategies and prognostic implications [1,2].

Worldwide, different induction chemotherapeutic regimens are utilized in the treatment of adult patients with ALL [3-6]. However, the main constituents of these chemotherapeutic regimens are almost similar with different dosing and treatment schedules and they include: anthracyclines such as daunorubicin, doxorubicin or idarubicin; corticosteroids such as prednisolone or dexamethasone; vincristine; L-asparaginase; cyclophosphamide; 6-mercaptopurine; and intrathecal (IT), oral as well as intravenous (IV) methotrexate [3-7].

Recently, the more intensified pediatric ALL chemotherapeutic regimens have been adopted in adolescents and young adults (AYAs), 15-40 years of age, having ALL and their use has been associated with superior response rates compared with the traditional adult regimens of chemotherapy [3,5,8].

Genetics, prognosis and risk stratification in ALL

Cytogenetic abnormalities occur in up to 85% of ALL patients. Also, numerical chromosomal abnormalities, alone or in association with structural changes, occur in 50% of patients with ALL [2,9,10]. The most common chromosomal abnormalities that are encountered in patients with ALL include: (1) Philadelphia chromosome (t 9,22), (2) chromosomal abnormalities that are associated with higher risk of central nervous system involvement such as: t 4,11; t 8,14 and t 14q+, (3 ) chromosomal abnormalities that are associated with high white cell and blast cell counts at presentation and high risk of relapse such as: t 9,22 and t 4,11, and (4) other common cytogenetic abnormalities that are encountered in patients with ALL include: t 10,14; t 1,14; deletion 11q22; deletion 11q23; hypodiploidy and hyperdiploidy [2,9-12]. Examples of the main molecular abnormalities that occur in ALL patients include: BCR-ABL1, ATM, MLL, TCRα, TCRβ, HOX11, HOX11L2, CDKN2A, CDKN2B, TAL1, TAL2, C-MYC, CRLF2, IKZF1, JAK2, CASP8AP2, IgH/BCL11B, NUP214-ABL, miR15, miR16, TCF3-PBX1, E2A-HLF, ETV6-RUNX1, EBF1, RB1, CREBBP1, SETD2, FOXO3A, KMT2A (MLL), EPHA7, GRIK2, BLIMP1 and FYN [11-13].

Studies have shown that the factors associated with prognosis and risk stratification in patients with ALL include: (1) age, (2) white blood count (WBC) count at presentation and proportion of circulating blasts, (3) presence or absence of extramedullary disease, (4) immunophenotyping profile and ALL subtype, (5) cytogenetic abnormalities and genetic mutations, (6) molecular and gene expression profiles, (7) rapidity and degree of cytoreduction, and (8) presence or absence of measurable residual disease at any stage of treatment [13-16]. ALL patients are stratified into the following 4 risk groups according to their cytogenetic profiles and other risk factors such as: age, WBC count at presentation, response or resistance to induction therapy: (1) low-risk with favorable cytogenetics, (2) standardrisk (SR) with intermediate cytogenetic risk, (3) high-risk (HR) with HR cytogenetics and (4) very HR with very HR cytogenetics [16,17].

High risk features that predict poor long-term outcome even with intensive chemotherapy in patients with ALL include: (1) age >35 years, (2) WBC count at presentation >30,000 in B-lineage and >100,000 in T-lineage, (3) pro-B; early and mature T cell types, (4) CD 20 positivity and CD 10 negative pre-B ALL on immunophenotyping, (5) poor performance status, (6) poor response to prednisolone, (7) peripheral blood blasts ≥ 5% on day15, (8) failure to achieve remission ˃4 weeks of induction chemotherapy, (9) involvement of central nervous system, (10) clinical relapse, and (11) presence of MRD (minimal residual disease: detectable molecular and immunophenotypic evidence of disease whilst in morphologic remission), (12) HR cytogenetic and molecular abnormalities including: + 8, - 7, deletion 6q, low hypodiloidy, near triploidy, immunoglobulin H gene rearrangement, intrachromosomal amplification of chromosome 21; t 8,14; t 4,11; t 1,19; t 9,22; Philadelphia-like (Ph-like) ALL and complex cytogenetics, and (13) HR genetic mutations including: IKZF1 deletion, unmutated NOTCH1, MLL (mixed lineage leukemia gene rearrangement, 11q23), RAS-PTEN altered, JAK 2 mutation, KMT2A rearrangement, CREBBP, CRLF2,ETP, PBXE2A+, and BAALC+ [2,18-24].

HSCT in Adults with ALL

GVL effect and MRD

Several studies in patients with ALL have shown: (1) high incidence of relapse following cytotoxic chemotherapy or even allogeneic hematopietic stem cell transplantation (HSCT) thus contributing to treatment failure, and (2) graft versus host disease (GVHD) encountered in the post-HSCT period has a protective effect against disease relapse by providing potent graft versus leukemia (GVL) effect [25-29]. Other studies have shown the prognostic relevance of detection of MRD in patients with ALL subjected to HSCT as MRD identified prior to allogeneic HSCT has been found to be the strongest predictor of post-HSCT relapse in ALL patients [30,31]. Evaluation or monitoring of MRD in ALL patients can be performed by: (1) flow cytometry, (2) real-time quantitative polymerase chain reaction, and (3) next generation sequencing [30,32].

Autologous HSCT in ALL

Complete remission (CR) can be achieved in approximately 80% of adults with ALL, but relapse occurs frequently leading to poor long-term disease-free survival (DFS) [33,34]. After achieving CR, patients with ALL can receive either consolidation followed by maintenance chemotherapy or allogeneic HSCT for HR patients or autologous HSCT for SR patients or HR patients who do not have an HLA identical sibling donor [34,35].

Autologous HSCT in patients with ALL was first introduced nearly 60 years ago [34]. Once performed in patients with ALL in CR1, autologous HSCT can produce leukemia-free survival in up to 65% of patients [34]. Autologous HSCT combined with post-transplantation maintenance therapy in the form of 6-mercaptopurine, methotrexate, vincristine and prednisolone or TKIs for Philadelphia chromosome (Ph+) ALL that could be valid therapeutic options in adult patients with ALL [35-37]. In patients with ALL, relapse rates can be reduced and outcomes can be improved by using adoptive immunotherapy and maintenance therapy after autologous HSCT [37,38]. Also, novel therapies such as blinatumomab may reduce the burden of MRD prior to autologous HSCT, thus making the combination of autologous HSCT and novel therapies a real alternative to allogeneic HSCT and prolonged maintenance therapy for ALL patients [36].

Conditioning therapies for allogeneic HSCT

Allogeneic HSCT cures hematologic malignancies by the pretransplantation conditioning therapy that kills leukemic cells directly and graft versus tumor (GVT) effect [39]. Recently, the outcome of HSCT has been steadily improving due to improvements in: conditioning therapies, GVHD prophylaxis and therapy, supportive care facilities, new antimicrobial agents, advanced diagnostic tools, availability of novel agents and targeted therapies such as TKIs, and donor selection by improvement of human leukocyte antigen (HLA) typing methods and the increased utilization of matched unrelated donors (MUDs) [25,40,41].

For the last 40 years, the standard myeloablative conditioning (MAC) regimen for ALL has been the combination of total body irradiation (TBI) and IV cyclophosphamide [42,43]. Alternative MAC regimens, with comparable efficacy and favorable toxicity profiles, include various combinations of: etoposide, fractionated TBI, cyclophosphamide, busulfan, melphalan, treosulfan, fludarabine, anti-thymocyte globulin, clofarabine and cytosine arabinoside [39,41,44-48].

Reduced intensity conditioning (RIC) regimens, which provide relapse protection by means of GVL effect, have been used extensively in adults with hematologic malignancies including ALL [49,50]. RIC-allogeneic HSCT is indicated in the presence of: old age, poor performance status, concurrent infection, significant organ dysfunction, and comorbid medical conditions [49,50]. RIC regimens have been associated with acceptable rates of donor engraftment and lower rates of treatment related mortality in comparison with MAC regimens [50].

The new therapeutic strategies that have been adopted in adults with ALL include: various TKIs for Ph+ ALL, pediatric inspired chemotherapeutic regimens for Philadelphia chromosome negative (Ph-) ALL, and HLA-haploidentical HSCT [49]. However, these strategies should be selected based on: age of the patient, Philadelphia chromosome positivity, donor availability, disease risk stratification and safety as well as efficacy of the therapeutic intervention [49].

Allogeneic HSCT in ALL

ALL patients having HR features are less likely to respond well to chemotherapy and are more likely to relapse. Thus, in order to have optimal control of their leukemia, these patients may require more intensified chemotherapeutic regimens, novel therapies in addition to HSCT [2,37-40]. Indications of allogeneic HSCT in adults with ALL include: (1) Ph+ ALL in CR1, (2) ALL with Ph-like molecular signature, (3) HR or very HR ALL in CR1, (4) relapsed ALL (ALL in CR2 or beyond), (5) primary refractory disease (ALL refractory to induction or first-line chemotherapy), after achievement of CR following salvage therapy, (6) presence of MRD at any stage during the course of the disease, regardless their initial risk group (SR or HR), and (7) MLL (mixed lineage leukemia) gene rearrangement [51-62].

In adult patients with ALL, post-remission therapies include: consolidation chemotherapy followed by maintenance therapy and autologous or allogeneic HSCT [60,61]. The role of frontline allogeneic HSCT for patients with ALL in CR1 is still controversial [63]. However, three meta-analyses that included 41 studies showed potential benefit of allogeneic HSCT in CR1 and they came to the following conclusions: (1) compared to chemotherapy alone or chemotherapy followed by autologous HSCT, myeloablative matched sibling donor (MSD) allografts had absolute survival benefit of up to 15% at 5 years, (2) MSD allografts improve survival in patients <35 years of age and constitute the optimal post-remission therapy in ALL patients ≥ 15 years old, (3) compared to chemotherapy, there was no beneficial effect of autologous HSCT, and (4) MSD allografts not only offered superior overall survival (OS) and DFS but also reduced the risk of relapse significantly although they were associated with increased risk of non-relapse mortality (NRM) [61,62,64].

In adults with ALL who are eligible for HSCT, either MAC therapies or RIC regimens can be offered according to the age and comorbid medical conditions of the recipient [47,65,66]. Also, the following stem cell sources can be utilized in recipients of allogeneic HSCT: MSD, MUD and umbilical cord blood (UCB) [23,65,67].

Focus on haploidentical HSCT

Haploidentical HSCT evolved several decades ago and over the years it has undergone several modifications in order to improve the: conditioning therapy, graft manipulation as well as posttransplantation immunosuppression [56,57,68]. Techniques that have been used to improve the outcome of this form of HSCT include: CD3/CD19 depletion so as to reduce GVHD; KIR B haplotype donors to lower relapse rates due to GVL effect; and infusion of high numbers of CD34+ cells in order to improve immune reconstitution [69]. Recently, unmanipulated allografts and post-transplantation cyclophosphamide yielded excellent outcomes that are comparable to those of unrelated UCB transplantation and MUD allografts [65,66,70].

In patients with Ph-ALL in CR1, haploidentical HSCT represents a valuable alternative for patients who lack MSDs [71,72]. Also, in adults with HR-ALL in CR1, haploidentical HSCT performed with post-transplantation cyclophosphamide has produced 52% DFS at 3 years, thus providing a suitable alternative to HLA-matched HSCT [63].

HSCT in T-cell ALL

T-cell ALL, which is common in adolescents and older patients, is an aggressive neoplasm derived from malignant transformation of lymphoblasts committed to T-cell lineage. Compared to B-cell ALL, it carries poorer prognosis due to: (1) more extensive involvement of bone marrow and extramedullary sites, (2) higher relapse rates even after allogeneic HSCT, and (3) higher incidence of drug resistance which is attributed to aberrant signaling pathways [73-78].

In the treatment of T-cell ALL, there is synergism between JAK 3 inhibitors and MEK/BCL2 inhibitors [76]. Allogeneic HSCT is a potentially curative therapeutic option for patients with T-cell ALL, but its use has been associated with high rates of relapse thus contributing to treatment failure [75]. Nelarabine which has selective cytotoxicity against T-cell lymphoblasts is usually used in relapsed and refractory T-cell ALL [73,79]. It is indicated in treating relapses post-allogeneic HSCT and in maintenance therapy following transplantation in HR patients [79]. In patients with T-cell ALL relapsing after allogeneic HSCT, the combination of nelarabine and donor lymphocyte infusions (DLIs) may provide long-term disease control and survival [77].

HSCT in Ph+ ALL

Philadelphia chromosome positivity is the commonest recurrent cytogenetic abnormality observed in adults with ALL as it has been reported in up to 25% of patients [80-84]. The introduction of TKIs into the therapeutic regimens of Ph+ ALL has been the most significant therapeutic advancement in recent years [81].

In adolescents with Ph+ALL, allogeneic HSCT is a controversial issue and there is increasing reluctance to offer allogeneic HSCT to this group of patients in the era of TKIs [80,84,85]. Studies have shown that in adolescents with Ph+ALL: excellent outcomes of the combination of TKI and chemotherapy with OS of 88% at 3 years, achievement of complete hematological remission in approximately 95% of patients, and no advantage of subjecting patients to allogeneic HSCT [86,87]. In young adults with Ph+ ALL studies have shown that: results of allogeneic HSCT are superior to chemotherapy alone; MSD and MUD allografts have yielded equivalent outcomes; in patients subjected to allogeneic HSCT: age, WBC count at presentation and early response to treatment have been found to be independent prognostic indicators; and advantage of early performance of allogeneic HSCT once morphologic remission is achieved [88-91].

The choice of TKI in the treatment of Ph+ALL is influenced by: toxicity profile, administration schedule, comorbid medical conditions, cost and patient preference [5]. Allogeneic HSCT is a potentially curative therapeutic modality, but it requires availability of a healthy HLA matching donor and it is associated with high rates of relapse and NRM [68]. However, haploidentical allogeneic HSCT is an alternative option for patients with Ph+ ALL who lack an HLA matching donor and its use is associated with lower relapse rate [92].

Philadelphia-like ALL

Ph-like ALL was adopted as a provisional entity in the recent world health organization classification [93]. It shares a similar gene expression profile with Ph+ ALL but lacks the BCR-ABL fusion or the t 9,22 by routine cytogenetics, FISH or molecular analysis [94,95]. Ph-like ALL occurs in up to 25% of adolescents and young adults with B-cell ALL and it is associated with: (1) deletion mutation involving IKZF1 gene that codes for the transcription factor IKAROS, (2) resistance to chemotherapy, and (3) poorer prognosis compared to other pre-B ALL subtypes [95].

Examples of molecular targets in Ph-like ALL include: ABL1, ABL2, CSF1R1, PDGFRB, EPOR, JAK2, CRLF2, JAK1, JAK3, FLT3, IL2RB, IL7R, TYK2, SH2B3, NRAS, KRAS, NF1, PTPN1, NTRK3 and PTK2B [96-101]. Examples of the targeted therapies that are currently used in the treatment of Ph-like ALL are: imatinib, dasatinib, nilotinib, poatinib, JAK2 inhibitors, JAK1 inhibitors, JAK3 inhibitors, FLT3 inhibitors, TYK 2 inhibitors, crizotinib and FAK inhibitors [96-101]. Examples of the investigational targeted therapies that can be used in the future treatment of Ph-like ALL include: givinostat, JQ1, luminespib and selumetinib targeting CRLF2; rapamycin that targets m-TOR activated pathway; gedatolisib targeting PI3K and m-TOR activated pathway; and birinapant which targets tumor necrosis factor-α-dependent pathway [93,102].

Relapse of ALL before and after HSCT

Despite receiving the standard chemotherapeutic regimens, up to 25% of ALL patients experience relapses of their disease at 5 years from diagnosis and initial therapy [103,104]. However, the prognosis of patients with relapsed ALL is poor as only a minority of adults with ALL who relapse after first line therapy can be rescued [103-105]. Salvage chemotherapeutic regimens in patients with relapsed ALL include: mitoxantrone, etoposide and cytarabine and the combination of fludarabine, cytarabine, pegylated-asparaginase and granulocyte colony stimulating factor [105]. Unfortunately, salvage chemotherapy alone is not curative in the setting of relapsed ALL [104]. However, allogeneic HSCT offers the best and may be the only chance for cure in adult patients with relapsed ALL [103-105]. GVHD, MRD, intrinsic factors of the disease and transplantation characteristics affect the occurrence as well as the outcome of ALL relapse after HSCT [106]. Unfortunately, the prognosis of patients with ALL who relapse after HSCT and those who are refractory to chemotherapy is extremely poor with ˂ 10% long-term survival [23,78,107].

Management of ALL relapse post-HSCT includes: tapering of immunosuppressive therapy; salvage chemotherapy followed by second allogeneic HSCT; pre-emptive immunotherapy in the form of DLI with frequent MRD monitoring; post-transplantation maintenance therapy; the use of novel and targeted therapies in post-HSCT to prevent further relapses; and enrollment in clinical trials [106-108].

Novel and targeted therapies in ALL

ALL is a malignancy that has genetic basis and it is influenced by epigenetics [109,110]. Examples of the main molecular markers and the important genetic targets in ALL include: BCR-ABL1; BCRABL1- like; ETV6-RUNX1; IKZF1; CDKN2A; CDKN2B and NOTCH1 [109]. Examples of the novel agents and targeted therapies that are currently used or under development are included in Table 1 [1,2,51,54,109,111-116].

Table 1 Novel agents and targeted therapies that are either currently used or under development for the treatment of acute lymphoblastic leukemia.

TKIs

The introduction of TKIs has revolutionized the therapy of patients with Ph+ ALL [81,90]. In patients with Ph+ ALL, the incorporation of TKIs into the treatment regimens at various stages of the disease has significantly improved the outcomes of patients. Imatinib, dasatinib and nilotinib have been incorporated in: the induction phase in combination with cytotoxic chemotherapy, in the consolidation and maintenance phases in conjunction with cytotoxic chemotherapy in patients who are not candidates for allogeneic HSCT, and in the post-transplantation maintenance therapy in recipients of allogeneic HSCT [80,117-120].

Ponatinib, a pan-bcr/abl TKI, is capable of inhibiting T315I kinase domain mutation that confers resistance to other TKIs and dismal prognosis [82,121]. It can be given prior to HSCT as bridging therapy to control disease and following HSCT to prevent disease relapse [82,122,123].

Nelarabine

Nelarabine, a purine nucleoside analogue and a soluble prodrug of Ara-G with specific cytotoxicity against T-lymphocytes, has significant activity in patients with T-cell ALL [124-132]. It is recommended for the treatment of adult patients with T-cell ALL who are in relapse or refractory to at least 2 chemotherapeutic regimens [124-131]. Its use in the treatment of patients having T-cell ALL relapsing after allogeneic HSCT has been associated with 90% OS at one year [130].

Blinatumomab

Blinatumomab, a bispecific T-cell engager monoclonal antibody construct, is designed to direct cytotoxic T-cells to CD19- expressing B-cells [133,134]. It is indicated in the treatment of patients with: Ph- relapsed/refractory pre-B ALL, pre-B ALL relapsing post-allogeneic HSCT, and HR Ph+ ALL [133,134]. The adverse effects of blimatumomab include: fever, neutropenia, neurotoxicity and cytokine release syndrome (CRS) [126].

CAR T-cells

Chimeric antigen receptors (CAR) consist of an extracellular antigen recognition domain linked to an intracellular signaling domain [135,136]. T-cells of the patient may be genetically modified to express an artificial T-cell receptor termed CAR designed to be specific to a tumor associated antigen [137]. The most extensively investigated CAR in clinical setting targets CD19 which is expressed in most B-cell malignancies as well as on normal B-cells, so CAR-mediated destruction of normal B-cells may cause B-cell aplasia [135].

CAR T-cell therapy involves several laboratory, technical and clinical procedures that include: obtaining peripheral blood mononuclear cells by leukapheresis, CD3 (T-cell) separation, engineering of T-cells to express CAR, lymphodepletion, CAR T-cell infusion, and finally cell death or apoptosis of CD19+ lymphoblasts [135-138]. Indication for CAR T-cell therapy include: relapsed and refractory B-cell ALL, B-cell lymphoid malignancies as well as other types of malignant hematological diseases, in addition to treatment of relapse post-allogeneic HSCT [135,139,140].

Studies have shown that treatment options in relapse after allogeneic HSCT for lymphoid malignancies including ALL include: DLI, salvage chemotherapy followed by a second allogeneic HSCT, and CAR T-cell infusions, [135,139,140].

CAR T-cells have been shown to be effective in treating in patients with relapsed/refractory ALL even among patients who have failed to respond to allogeneic HSCT [141]. Durable remissions lasting for 20-24 months or even longer have been achieved [142,143]. Patients with low disease burden have experienced lower incidence of adverse effects including CRS and neurotoxicity than patients with higher disease burden [143]. Second generation CD19-directed CAR T-cells have shown promising results in treating B-cell ALL [144]. Although the traditional doses of CAR T-cells infused range between 2 × 10⁵ and 2 × 10⁷/kg, trials using doses as low as 1 × 10⁵ have been shown to be safe and effective in the treatment of relapsed/ refractory B-cell ALL [144]. The 4 initial clinical trials on the use of CAR T-cells in the treatment of R/R ALL in the United States included 71 patients. Retrovirus or lentivirus transduction or sleeping beauty trasposon electroporation was used. Either no conditioning therapy or conditioning with cyclophosphamide was given. The incidence of CRS was about 27% and CR rate was approximately 88% [135,138].

Adverse effects or complications of CAR T-cell therapy in relapsed and refractory ALL include: CRS, neurotoxicity, macrophage activation syndrome, aplasia of normal B-lymphocytes, and death [111,112,145-150]. Management of CRS includes: supportive care, corticosteroids, vasopressors, ventilatory support and antiinterleukin- 6 receptor antibody (tocilizumab) therapy [150]. Novel and targeted therapies that can be used in the treatment of patients with ALL are shown in Table 1 [1,2,54,109,111-116].

Precision medicine and drug repurposing

Recently, knowledge concerning ALL has advanced to the extent that precision medicine may become a reality in the near future [116]. The following have attributed to the adaptation of precision medicine: better understanding of the biology of the disease, risk stratification and obtaining important information by using advanced technology such as molecular assays, next generation sequencing, epigenetic tests and gene expression profiling [109,147,148,151]. Drug repurposing or repositioning is a potential alternative to new drug discovery that takes plenty of time, cost and effort [152,153]. Drugs that have been repositioned for the treatment of ALL include: dasatinib, niclosamide, telmisartan, nelfinavir, triptolide, neprilisin and artesunate (ART 838) [153-158].

Conclusions and Future Directions

The recent advances in the diagnostics mainly in cytogenetic and molecular assays as well as genomic and epigenetic techniques have led to tremendous progress in: knowledge of the biology of ALL, the diagnosis and classification of ALL, risk stratification, prognosis, development of novel and targeted therapies, monitoring of response to treatment in addition to the introduction of precision medicine. The recent improvements in the management of patients with ALL are attributed to several reasons including: improvements in our understanding of the biology of the disease; advancements in the diagnostic techniques; improvements in supportive care; adoption of dose-intense pediatric-inspired chemotherapeutic regimens in AYAs; progress in HSCT procedures; monitoring of MRD; and the availability of several novel agents, targeted therapies as well as cellular and immunotherapies.

Prior to the introduction of targeted therapies such as TKIs, certain ALL subtypes were associated with poor outcome. With the recent availability of several novel therapies, some aggressive ALL subtypes are potentially curable even without HSCT. The incorporation of novel therapies at various stages in the therapeutic paradigm of ALL will further improve the outcome of patients. So, the availability of the modern therapeutic interventions has translated into improved response rates and outcomes. The integration of novel and targeted therapies before and after transplantation has further improved the outcomes of patients with ALL. Nevertheless, the different therapeutic interventions that are available for adults with ALL should be considered complementary to each other.

Despite the use of the intensified pediatric chemotherapeutic regimens, the outcome of ALL is poorer in adults than in children particularly in patients with HR features or disease relapse. Thus, allogeneic HSCT has more indications in adults than in children. However, sequencing of therapies and the incorporation of other therapeutic interventions into the management of ALL, before and after transplantation, is likely to improve the outcome of patients further.

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