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Hematology
Acute lymphoblastic leukemia (ALL) is a blood cancer that primarily affects children but also adults. It is due to the malignant proliferation of lymphoid precursor cells that invade the bone marrow and can spread to extramedullary sites. ALL is divided into B cell (85%) and T cell lineages (10 to 15%); rare cases are associated with the natural killer (NK) cell lineage (<1%). To date, the survival rate in children with ALL is excellent while in adults continues to be poor. Despite the therapeutic progress, there are subsets of patients that still have high relapse rates after chemotherapy or hematopoietic stem cell transplantation (HSCT) and an unsatisfactory cure rate. Hence, the identification of more effective and safer therapy choices represents a primary issue.
- immunotherapy
- antibody–drug conjugate
- CAR-based therapies
1. Introduction
ALL is a hematologic malignancy characterized by the uncontrolled proliferation of early lymphoid precursors that infiltrate bone marrow [1,2,3].
The central nervous system (CNS) and testes are the most common sites of precursors’ extra-medullary spread [4], although theoretically, any organ or tissue could be infiltrated. The involvement of skin, kidneys, and ovaries has also been extensively described [5,6].
ALL is divided into tumors of B-lineage, T-lineage, and uncommon variants of NK cell lineage which are morphologically indistinguishable. According to the 2022 revisions to the World Health Organization (WHO) and International Consensus Classification (ICC), the classification of major subtypes of ALL includes four distinct entities: B-ALL/LBL not otherwise specified (NOS), B-ALL/LBL with recurrent genetic abnormalities, T-ALL/LBL, and NK-ALL/LBL [7,8], as shown in Table 1.
Table 1. WHO classification of acute lymphoblastic leukemia.
| B-lymphoblasticleukemia/lymphoma |
| B-lymphoblasticleukemia/lymphoma, NOS |
| B-lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities |
| B-lymphoblastic leukemia/lymphoma with t(9;22)(q34.1;q11.2);BCR-ABL1 |
| B-lymphoblastic leukemia/lymphoma with t(v;11q23.3);KMT2A rearranged |
| B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1);ETV6-RUNX1 |
| B-lymphoblastic leukemia/lymphoma with hyperdiploidy |
| B-lymphoblastic leukemia/lymphoma with hypodiploidy |
| B-lymphoblastic leukemia/lymphoma with t(5;14)(q31.1;q32.3)IL3-IGH |
| B-lymphoblastic leukemia/lymphoma with t(1;19)(q23;p13.3);TCF3-PBX1 |
| Provisional entity:B-lymphoblastic leukemia/lymphoma with translocations involving tyrosine kinases or cytokine receptors (“BCR-ABL1–like”) |
| Provisional entity:B-lymphoblastic leukemia/lymphoma with intrachromosomal amplification of chromosome 21 (iAMP21) |
| T-lymphoblastic leukemia/lymphoma (can only be differentiated from B-ALL/LBL based on IHC and/or flow cytometry). |
| Provisional entity: Early T-cell precursor lymphoblastic leukemia |
| Provisional entity: NK cell lymphoblastic leukemia/lymphoma |
Few environmental and/or genetic factors have been associated with an increased risk of ALL. Among these, ionizing radiation, pesticide exposure, childhood infections [9,10,11], and genetic conditions such as Down syndrome or ataxia telangiectasia are included [12,13,14,15].
Its incidence varies among people of different ages, sex, and race [16,17,18]. The age-specific incidence curve for ALL has a bimodal distribution with peak incidences in children aged between 1 and 4, and adults aged 55 or above [19]. Males develop it more than females with a ratio of 1.2:1 [20].
Globally, the estimated annual incidence of ALL is 1 to 5 cases/100,000 population, and more than two-thirds of cases of ALL are of the B-cell phenotype [17,21,22,23]. Italy, the USA, Switzerland, and Costa Rica are the countries with the highest ALL incidence [17]. In the USA, about 6660 new cases and 1560 deaths (including both children and adults) were estimated in 2022 [20].
The outcome is more disappointing in adults (5-year overall survival (OS) < 45%) than in children (5-year survival rate of over 90%) [24,25,26], and this is related to multiple factors such as a higher incidence of poor prognostic markers, a lower incidence of favorable subtypes, and traditional chemotherapy regimens [27].
Although there has been a substantial improvement in OS over time, there is still a gap in the availability of leukemia treatments between countries. This is partly due to the different socioeconomic status; low-income countries are less likely to use available treatments and this may contribute to poor survival [28].
Therefore, there is a joint effort to find more accessible solutions and to develop promising therapeutic strategies aiming to maintain remission, improve survival, and control the toxicities associated with chemotherapy regimens.
2. Different Biological Characteristics in Pediatric and Adults ALL Patients
Childhood and adult ALL are biologically distinct and diverge in their molecular landscape but also their cellular origin [1]. Even if the exact causes of ALL are not yet understood, it has been demonstrated that in children, it is the result of a multistep process associated with the acquisition of genetic alterations in lymphoid progenitors during inutero development [29,30]. Chromosome aneuploidy, structural alterations, rearrangements, copy number variations (CNVs), and sequence mutations all contribute to leukemogenesis [31].
Disease cytogenetic abnormalities have a different prognostic impact between age categories. Usually, adult patients have a higher white blood cell count, an increased frequency of T-lineage ALL, and a decreased incidence of hyperdiploidy than children [32,33]. Also demonstrated was an increase in the presence of unfavorable genetic anomalies with increasing age (incidence up to 53% over 55 years), such as the Philadelphia chromosome [34]. In contrast, genetic alterations, such as hyperdiploid karyotype, frequently seen in pediatric ALL patients, are related to a favorable outcome [35].
The gap in outcome between children and adults is due to the differences in disease biology and treatment tolerance and also to the intensified chemotherapy regimens used in children that permit improved response rates and prolonged survival [36]. Fortunately, the management of ALL in adult patients has significantly improved thanks to the administration of pediatric-inspired regimens or even unmodified pediatric protocols (adults up to 60 years old), so chemotherapy intensity has increased [37].
3. Evolution of ALL Treatment Applications
Treatment for ALL is divided into four different phases: remission induction, consolidation, intensification, and long-term maintenance. CNS prophylaxis is given at the proper intervals during the treatment. Allogeneic HCT is optional after consolidation.
Standard frontline chemotherapy is used for induction therapy, while targeted drug therapy, alone or combined with chemotherapy, is employed for all phases.
The achievement of the current treatment modalities is the result of changes that happened in a temporal space that started in the 1970s when the older strategies were applied [38].At that time, cranial radiotherapy (CRT) to prevent CNS relapse was used for all patients [39,40]. However, intensive and prolonged therapy for ALL was considered responsible for detrimental effects on intellectual and learning abilities [41,42,43]. As a result, some years later, CRT intensity has been reduced and intrathecal therapy and high doses of systemic chemotherapy substituted the previous method [44,45,46,47,48].
Then, conventional chemotherapy was optimized, raising the chance of cure in the highest-risk patients while minimizing long-term adverse events in those with the lowest risk [49,50,51,52].
However, in childhood ALL, CNS-directed prophylaxis remains an obliged choice. Indeed, the high possibility of infiltration of the CNS, by massive numbers of leukemic cells, puts patients at a higher chance of CNS relapse leading to severe morbidity and mortality [53,54].
Until now, little information is known about where leukemia cells reside in the CNS and about their interactions with cellular components of the CNS microenvironment, which could induce their quiescence and survival. Certain studies suggested that some B-Cell Precursor (BCP)-ALL cells would be able to survive in particular CNS niches for a very long time as extramedullary minimal residue disease and could be responsible for CNS relapse [55,56,57].
Fernandez-Sevilla et al. proposed that the choroid plexus (CP), secretory tissue responsible for producing cerebrospinal fluid, constitutes a sanctuary for pediatric BCP-ALL cells. Inside it, interactions between BCP-ALL cells and microenvironment cell components promote their survival and chemoresistance [58].
Allo-HCT used as a consolidation therapy contributes to the considerable improvement in the prognosis of patients with ALL, but not without complications(complexity and graft vs. host disease (GVHD)). Access to allo-HCT is usually reserved for patients with high-risk characteristics or relapsing disease [59,60,61,62]. Until recently, for those patients as well as for older adults, the treatment options were extremely limited.
4. Immunotherapy for ALL
Finding the best treatment for ALL is an ongoing challenge leading to the continuous development of new therapeutic approaches. Among these, immunotherapy stands out, exploiting the patient’s immune system to target cancer cells, improving survival, and reducing the toxicity of chemotherapy. Major immunotherapies include the use of bispecific antibodies, CART or CARNK cells, and antibody–drug conjugates, which are showing important results primarily in the treatment of B-ALL. CART or CARNK cells and antibody therapy also hold promise for the treatment of T-ALL.
5. New Treatments under Investigation
Future research directions aim to minimize chemotherapy and HSCT and to improve the life expectancy of patients with ALL, especially older patients and those with ALL resistant to available treatments. The question is what real advances in ALL therapy can we expect in the next future? The answer will come from the use of combination therapies capable of reducing drug resistance and improving drug efficacy to obtain a better and longer outcome. Therefore, several studies are currently ongoing to evaluate different drug combination uses in relapse and frontline treatment settings.
In Ph+ ALL, the combination of blinatumomab with TKI, particularly the third-generation ponatinib, is showing promising efficacy, with a deep and durable response and less need for both chemotherapy and HCST in the first remission [189].
The results of a phase 2 monocentric study presented at ASH 2021 by Short et al. evidenced that the combination of these two agents had synergistic effects on apoptosis. While ponatinib inhibits BCR-ABL kinases, blinatumomab promotes an antitumor response against CD19-expressing B cells [190].
This chemotherapy-free combination of ponatinib and blinatumomab was safe and effective in both newly diagnosed(ND) and R/R Ph+ ALL patients. Particularly favorable outcomes (estimated 2-year event-free survival (EFS) and OS 95%) were reported for the ND cohort that was not transplanted in first remission, suggesting that this regimen may serve as an effective transplant-sparing therapy in these patients [190]. Good results were also obtained by combining ponatinib with lower-intensity chemotherapy (hyper-CVAD) as an initial treatment for adult patients (age ≥ 18–75 years) with ND-Ph+ ALL (NCT01424982). Stable, long-term remission has been shown in 70% of patients [191]. Other encouraging data were presented by a Spanish group (PETHEMA) that carried out a phase 2 PONALFIL trial, in which ponatinib (30 mg/d) was combined with an induction/consolidation chemotherapy followed by HSCT to treat adults with ND-Ph+ ALL [192]. In comparison to a more conventional therapeutic approach, this combination therapy showed good clinical activity and a favorable toxicity profile. CR was achieved in 100% of patients (30/30), 14 (47%) of whom obtained CMR and 5 (17%) MMR.
Induction with TKIs is showing promising results also in the phase 3 PhALLCON study(NCT03589326), where a comparison of first-line ponatinib (PON) vs. imatinib (IM) with reduced-intensity chemotherapy (CT) has been carried out in patients with newly diagnosed Ph+ ALL. The first report of PhALLCON demonstrates that PON resulted in more durable and deeper responses, with a trend toward improved EFS and comparable safety vs. IM.
With regard to CART cell therapy, given the success of tisagenlecleucel (Kymriah), approved for use in children and young adults up to the age of 25, and more recently of brexucabtagene autoleucel (Tecartus), approved for all adult patients with R/R B-ALL, future works are focusing on designing new CAR structures with improved anti-tumor efficacy and a better safety profile.
Among multiple strategies, there is one in the phase 1 ALLCAR19 study (NCT02935257), which evaluated the effectiveness of a novel CD19 CAR that uses non-mobilized autologous leukapheresis (CAT-41BBzCAR, also known as AUTO1, another name: obecabtagene autoleucel, obe-cel) in adult patients with R/R B-ALL. Updated data showed a tolerable safety profile of AUTO1 in adult patients with R/R B-ALL despite the high disease burden [193,194].Furthermore, another phase 1b/2 trial (FELIX trial—NCT04404660) aims to find the best balance between the safety and efficacy of this CAR construct. Obe-cel has a lower affinity for CD19 than similar CART cell products and this helps to avoid CART cell over-activation and exhaustion so the T cells can stay active for a longer period [195].The first results by Roddie et al. demonstrated that this therapy has a good safety profile and high remission rates and it might offer a durable treatment option for these patients [194].
To overcome frequent relapses (10–20% of patients) following CD19 CART therapy, a CD22 CART cell therapy has been developed. Pan et al. demonstrated that CD22 CART cell therapy was highly effective in inducing remission in R/R B-ALL patients who failed from previous CD19 CART cell therapy and can be also considered a good bridge for subsequent transplantation to achieve durable remission [196]. Another useful strategy seems to be the development of dual-target CARs by simultaneously targeting CD19 and a second antigen (CD22 or CD20). As shown by Dai et al., this approach is feasible, safe, and able to induce remission in adult patients with R/R B-ALL [197].
Progress in targeted immunotherapies for B-ALL also generated big expectations for T-ALL therapy. Glucocorticoids (GCs) represent central components of T-ALL therapy, and the early response to GC-based therapy is an important predictor of long-term outcomes [198]. Nevertheless, relapse continues to represent a challenge in the clinical management of T-ALL. At the moment, nelarabine, a purine deoxyguanosine analog that inhibits DNA synthesis, remains the only drug for treating the relapse of T-ALL (response rates of over 50% in children and 36% in adults) [199,200,201]. Therefore, there is a need to develop efficient methods of augmenting the response to GC and overcoming resistance to steroid treatment. Most of the ongoing preclinical studies involve novel drugs able to enhance the results of glucocorticoid therapy and that could potentially be included in the induction phase in newly diagnosed ALL patients to prevent relapse and provide better outcomes.
This entry is adapted from the peer-reviewed paper 10.3390/cancers15133346
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