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Aureli, A.; Marziani, B.; Venditti, A.; Sconocchia, T.; Sconocchia, G. Acute Lymphoblastic Leukemia Immunotherapy Treatment. Encyclopedia. Available online: (accessed on 24 June 2024).
Aureli A, Marziani B, Venditti A, Sconocchia T, Sconocchia G. Acute Lymphoblastic Leukemia Immunotherapy Treatment. Encyclopedia. Available at: Accessed June 24, 2024.
Aureli, Anna, Beatrice Marziani, Adriano Venditti, Tommaso Sconocchia, Giuseppe Sconocchia. "Acute Lymphoblastic Leukemia Immunotherapy Treatment" Encyclopedia, (accessed June 24, 2024).
Aureli, A., Marziani, B., Venditti, A., Sconocchia, T., & Sconocchia, G. (2023, July 06). Acute Lymphoblastic Leukemia Immunotherapy Treatment. In Encyclopedia.
Aureli, Anna, et al. "Acute Lymphoblastic Leukemia Immunotherapy Treatment." Encyclopedia. Web. 06 July, 2023.
Acute Lymphoblastic Leukemia Immunotherapy Treatment

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, 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 researchers 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 [63].
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 [64].
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 [64]. 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 [65]. 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 [66]. 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 [67][68].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 [69].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 [68].
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 [70]. 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 [71].
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 [72]. 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) [73][74][75]. 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.
Therapies targetingNOTCH1, such as the proteasome inhibitor (bortezomib) [76][77], JAK inhibitors (ruxolitinib) [78], BCL inhibitors (venetoclax) [79], and anti-CD38 therapy (daratumumab) [80], are showing promising results for better prognosis of patients with T-ALL.


  1. Malard, F.; Mohty, M. Acute Lymphoblastic Leukaemia. Lancet 2020, 395, 1146–1162.
  2. Terwilliger, T.; Abdul-Hay, M. Acute Lymphoblastic Leukemia: A Comprehensive Review and 2017 Update. Blood Cancer J. 2017, 7, e577.
  3. Berg, S.L.; Steuber, P.; Poplack, D.G. Clinical Manifestations of Acute Lymphoblastic Leukemia. In Hematology, Basic Principles and Practice; Churchill Livingstone: Philadelphia, PA, USA, 2000.
  4. Del Principe, M.I.; Buzzatti, E.; Piciocchi, A.; Forghieri, F.; Bonifacio, M.; Lessi, F.; Imbergamo, S.; Orciuolo, E.; Rossi, G.; Fracchiolla, N.; et al. Clinical Significance of Occult Central Nervous System Disease in Adult Acute Lymphoblastic Leukemia. A Multicenter Report from the Campus ALL Network. Haematologica 2021, 106, 39–45.
  5. Inaba, H.; Greaves, M.; Mullighan, C.G. Acute Lymphoblastic Leukaemia. Lancet 2013, 381, 1943–1955.
  6. Hunger, S.P.; Mullighan, C.G. Acute Lymphoblastic Leukemia in Children. N. Engl. J. Med. 2015, 373, 1541–1552.
  7. Alaggio, R.; Amador, C.; Anagnostopoulos, I.; Attygalle, A.D.; Araujo, I.B.d.O.; Berti, E.; Bhagat, G.; Borges, A.M.; Boyer, D.; Calaminici, M.; et al. The 5th Edition of the World Health Organization Classification of Haemato lymphoid Tumours: Lymphoid Neoplasms. Leukemia 2022, 36, 1720–1748.
  8. Arber, D.A.; Orazi, A.; Hasserjian, R.P.; Borowitz, M.J.; Calvo, K.R.; Kvasnicka, H.M.; Wang, S.A.; Bagg, A.; Barbui, T.; Branford, S.; et al. International Consensus Classification of Myeloid Neoplasms and Acute Leukemias: Integrating Morphologic, Clinical, and Genomic Data. Blood 2022, 140, 1200–1228.
  9. Spector, L.G.; Ross, J.A.; Robison, L.L.; Bhatia, S. Epidemiology and Etiology. In Childhood Leukemias, 2nd ed.; Cambridge University Press: Cambridge, UK, 2006; pp. 48–66.
  10. Sehgal, S.; Mujtaba, S.; Gupta, D.; Aggarwal, R.; Marwaha, R.K. High Incidence of Epstein Barr Virus Infection in Childhood Acute Lymphocytic Lukemia: A Preliminary Study. Indian J. Pathol. Microbiol. 2010, 53, 63.
  11. Geriniere, L.; Bastion, Y.; Dumontet, C.; Salles, G.; Espinouse, D.; Coiffier, B. Heterogeneity of Acute Lymphoblastic Leukemia in HFV-Seropositive Patients. Ann. Oncol. 1994, 5, 437–440.
  12. Chessells, J.M.; Harrison, G.; Richards, S.M.; Bailey, C.C.; Hill, F.G.H.; Gibson, B.E.; Hann, I.M.; Bailey, C.C.; Barton, C.; Broadbent, V.; et al. Down’s Syndrome and Acute Lymphoblastic Leukaemia: Clinical Features and Response to Treatment. Arch. Dis. Child. 2001, 85, 321–325.
  13. Dördelmann, M.; Schrappe, M.; Reiter, A.; Zimmermann, M.; Graf, N.; Schott, G.; Lampert, F.; Harbott, J.; Niemeyer, C.; Ritter, J.; et al. Down’s Syndrome in Childhood Acute Lymphoblastic Leukemia: Clinical Characteristics and Treatment Outcome in Four Consecutive BFM Trials. Leukemia 1998, 12, 645–651.
  14. Bielorai, B.; Fisher, T.; Waldman, D.; Lerenthal, Y.; Nissenkorn, A.; Tohami, T.; Marek, D.; Amariglio, N.; Toren, A. Acute Lymphoblastic Leukemia in Early Childhood as the Presenting Sign of Ataxia-Telangiectasia Variant. Pediatr. Hematol. Oncol. 2013, 30, 574–582.
  15. Toledano, S.R.; Lange, B.J. Ataxia-Telangiectasia and Acute Lymphoblastic Leukemia. Cancer 1980, 45, 1675–1678.
  16. Lim, J.Y.S.; Bhatia, S.; Robison, L.L.; Yang, J.J. Genomics of Racial and Ethnic Disparities in Childhood Acute Lymphoblastic Leukemia. Cancer 2014, 120, 955–962.
  17. Dores, G.M.; Devesa, S.S.; Curtis, R.E.; Linet, M.S.; Morton, L.M. Acute Leukemia Incidence and Patient Survival among Children and Adults in the United States, 2001–-2007. Blood 2012, 119, 34–43.
  18. Feng, Q.; De Smith, A.J.; Vergara-Lluri, M.; Muskens, I.S.; McKean-Cowdin, R.; Kogan, S.; Brynes, R.; Wiemels, J.L. Trends in Acute Lymphoblastic Leukemia Incidence in the United States by Race/Ethnicity From 2000 to 2016. Am. J. Epidemiol. 2021, 190, 519–527.
  19. Hallböök, H.; Gustafsson, G.; Smedmyr, B.; Söderhäll, S.; Heyman, M. Treatment Outcome in Young Adults and Children >10 Years of Age with Acute Lymphoblastic Leukemia in Sweden. Cancer 2006, 107, 1551–1561.
  20. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer Statistics, 2022. Cancer J. Clin. 2022, 72, 7–33.
  21. Redaelli, A.; Laskin, B.L.; Stephens, J.M.; Botteman, M.F.; Pashos, C.L. A Systematic Literature Review of the Clinical and Epidemiological Burden of Acute Lymphoblastic Leukaemia (ALL). Eur. J. Cancer Care 2005, 14, 53–62.
  22. Allemani, C.; Weir, H.K.; Carreira, H.; Harewood, R.; Spika, D.; Wang, X.S.; Bannon, F.; Ahn, J.V.; Johnson, C.J.; Bonaventure, A.; et al. Global Surveillance of Cancer Survival 1995–2009: Analysis of Individual Data for 25 676 887 Patients from 279 Population-Based Registries in 67 Countries (CONCORD-2). Lancet 2015, 385, 977–1010.
  23. Dong, Y.; Shi, O.; Zeng, Q.; Lu, X.; Wang, W.; Li, Y.; Wang, Q.; Wang, Q.; Wang, Q. Leukemia Incidence Trends at the Global, Regional, and National Level between 1990 and 2017. Exp. Hematol. Oncol. 2020, 9, 14.
  24. Bassan, R.; Hoelzer, D. Modern Therapy of Acute Lymphoblastic Leukemia. J. Clin. Oncol. 2011, 29, 532–543.
  25. Pulte, D.; Gondos, A.; Brenner, H. Improvement in Survival in Younger Patients with Acute Lymphoblastic Leukemia from the 1980s to the Early 21st Century. Blood 2009, 113, 1408–1411.
  26. Pui, C.H.; Pei, D.; Campana, D.; Bowman, W.P.; Sandlund, J.T.; Kaste, S.C.; Ribeiro, R.C.; Rubnitz, J.E.; Coustan-Smith, E.; Jeha, S.; et al. Improved Prognosis for Older Adolescents with Acute Lymphoblastic Leukemia. J. Clin. Oncol. 2011, 29, 386–391.
  27. Jabbour, E.; O’Brien, S.; Konopleva, M.; Kantarjian, H. New Insights into the Pathophysiology and Therapy of Adult Acute Lymphoblastic Leukemia. Cancer 2015, 121, 2517–2528.
  28. Bonaventure, A.; Harewood, R.; Stiller, C.A.; Gatta, G.; Clavel, J.; Stefan, D.C.; Carreira, H.; Spika, D.; Marcos-Gragera, R.; Peris-Bonet, R.; et al. Worldwide Comparison of Survival from Childhood Leukaemia for 1995–2009, by Subtype, Age, and Sex (CONCORD-2): A Population-Based Study of Individual Data for 89 828 Children from 198 Registries in 53 Countries. Lancet Haematol. 2017, 4, e202–e217.
  29. Ghosn, E.; Yoshimoto, M.; Nakauchi, H.; Weissman, I.L.; Herzenberg, L.A. Hematopoietic Stem Cell-Independent Hematopoiesis and the Origins of Innate-like B Lymphocytes. Development 2019, 146, dev170571.
  30. Greaves, M.F.; Maia, A.T.; Wiemels, J.L.; Ford, A.M. Leukemia in Twins: Lessons in Natural History. Blood 2003, 102, 2321–2333.
  31. Shin, S.Y.; Lee, H.; Lee, S.T.; Choi, J.R.; Jung, C.W.; Koo, H.H.; Kim, S.H. Recurrent Somatic Mutations and Low Germline Predisposition Mutations in Korean ALL Patients. Sci. Rep. 2021, 11, 8893.
  32. Mancini, M.; Scappaticci, D.; Cimino, G.; Nanni, M.; Derme, V.; Elia, L.; Tafuri, A.; Vignetti, M.; Vitale, A.; Cuneo, A.; et al. A Comprehensive Genetic Classification of Adult Acute Lymphoblastic Leukemia (ALL): Analysis of the GIMEMA 0496 Protocol. Blood 2005, 105, 3434–3441.
  33. Groupe Francais de Cytogenetique Hematologique. Cytogenetic Abnormalities in Adult Acute Lymphoblastic Leukemia: Correlations with Hematologic Findings and Outcome. A Collaborative Study of the Groupe Français de Cytogέnέtique Hέmatologique: By the Groupe FranGais de Cytogέnέtique Hέmatologique (Partic). Blood 1996, 87, 3135–3142.
  34. Advani, A.S.; Hunger, S.P.; Burnett, A.K. Acute Leukemia in Adolescents and Young Adults. Semin. Oncol. 2009, 36, 213–226.
  35. Litzow, M.R. Antigen-Based Immunotherapy for the Treatment of Acute Lymphoblastic Leukemia: The Emerging Role of Blinatumomab. Immunotargets Ther. 2014, 3, 79–89.
  36. Stary, J.; Zimmermann, M.; Campbell, M.; Castillo, L.; Dibar, E.; Donska, S.; Gonzalez, A.; Izraeli, S.; Janic, D.; Jazbec, J.; et al. Intensive Chemotherapy for Childhood Acute Lymphoblastic Leukemia: Results of the Randomized Intercontinental Trial ALL IC-BFM 2002. J. Clin. Oncol. 2014, 32, 174–184.
  37. Beldjord, K.; Chevret, S.; Asnafi, V.; Huguet, F.; Boulland, M.L.; Leguay, T.; Thomas, X.; Cayuela, J.M.; Grardel, N.; Chalandon, Y.; et al. Oncogenetics and Minimal Residual Disease Are Independent Outcome Predictors in Adult Patients with Acute Lymphoblastic Leukemia. Blood 2014, 123, 3739–3749.
  38. Pinkel, D. Five-Year Follow-Up of Total Therapy of Childhood Lymphocytic Leukemia. JAMA 1971, 216, 648–652.
  39. Aur, R.J.; Simone, J.; Hustu, H.O.; Walters, T.; Borella, L.; Pratt, C.; Pinkel, D. Central Nervous System Therapy and Combination Chemotherapy of Childhood Lymphocytic Leukemia. Blood 1971, 37, 272–281.
  40. Bleyer, W.A.; Poplack, D.G. Prophylaxis and Treatment of Leukemia in the Central Nervous System and Other Sanctuaries. Semin. Oncol. 1985, 12, 131–148.
  41. Anderson, F.S.; Kunin-Batson, A.S. Neurocognitive Late Effects of Chemotherapy in Children: The Past 10 Years of Research on Brain Structure and Function. Pediatr. Blood Cancer 2009, 52, 159–164.
  42. Kadan-Lottick, N.S.; Zeltzer, L.K.; Liu, Q.; Yasui, Y.; Ellenberg, L.; Gioia, G.; Robison, L.L.; Krull, K.R. Neurocognitive Functioning in Adult Survivors of Childhood Non-Central Nervous System Cancers. J. Natl. Cancer Inst. 2010, 102, 881–893.
  43. Bleyer, W.A. Neurologic Sequelae of Methotrexate and Ionizing Radiation: A New Classification. Cancer Treat. Rep. 1981, 65 (Suppl. 1), 89–98.
  44. Oeffinger, K.C.; Mertens, A.C.; Sklar, C.A.; Kawashima, T.; Hudson, M.M.; Meadows, A.T.; Friedman, D.L.; Marina, N.; Hobbie, W.; Kadan-Lottick, N.S.; et al. Chronic Health Conditions in Adult Survivors of Childhood Cancer. N. Engl. J. Med. 2006, 355, 1572–1582.
  45. Pui, C.-H.; Cheng, C.; Leung, W.; Rai, S.N.; Rivera, G.K.; Sandlund, J.T.; Ribeiro, R.C.; Relling, M.V.; Kun, L.E.; Evans, W.E.; et al. Extended Follow-up of Long-Term Survivors of Childhood Acute Lymphoblastic Leukemia. N. Engl. J. Med. 2003, 349, 640–649.
  46. Hijiya, N.; Hudson, M.M.; Lensing, S.; Zacher, M.; Onciu, M.; Behm, F.G.; Razzouk, B.I.; Ribeiro, R.C.; Rubnitz, J.E.; Sandlund, J.T.; et al. Cumulative Incidence of Secondary Neoplasms as a First Event After Childhood Acute Lymphoblastic Leukemia. JAMA 2007, 297, 1207–1215.
  47. Geenen, M.M.; Cardous-Ubbink, M.C.; Kremer, L.C.M.; Van Den Bos, C.; Van Der Pal, H.J.H.; Heinen, R.C.; Jaspers, M.W.M.; Koning, C.C.E.; Oldenburger, F.; Langeveld, N.E.; et al. Medical Assessment of Adverse Health Outcomes in Long-Term Survivors of Childhood Cancer. JAMA 2007, 297, 2705–2715.
  48. Waber, D.P.; Turek, J.; Catania, L.; Stevenson, K.; Robaey, P.; Romero, I.; Adams, H.; Alyman, C.; Jandet-Brunet, C.; Neuberg, D.S.; et al. Neuropsychological Outcomes from a Randomized Trial of Triple Intrathecal Chemotherapy Compared with 18 Gy Cranial Radiation as CNS Treatment in Acute Lymphoblastic Leukemia: Findings from Dana-Farber Cancer Institute ALL Consortium Protocol 95-01. J. Clin. Oncol. 2007, 25, 4914–4921.
  49. Schrappe, M.; Reiter, A.; Ludwig, W.-D.; Harbott, J.; Zimmermann, M.; Hiddemann, W.; Niemeyer, C.; Henze, G.; Feldges, A.; Zintl, F.; et al. Improved Outcome in Childhood Acute Lymphoblastic Leukemia despite Reduced Use of Anthracyclines and Cranial Radiotherapy: Results of Trial ALL-BFM 90. Blood 2000, 95, 3310–3322.
  50. Silverman, L.B.; Gelber, R.D.; Dalton, V.K.; Asselin, B.L.; Barr, R.D.; Clavell, L.A.; Hurwitz, C.A.; Moghrabi, A.; Samson, Y.; Schorin, M.A.; et al. Improved Outcome for Children with Acute Lymphoblastic Leukemia: Results of Dana-Farber Consortium Protocol 91-01. Blood 2001, 97, 1211–1218.
  51. Lukenbill, J.; Advani, A.S. The Treatment of Adolescents and Young Adults with Acute Lymphoblastic Leukemia. Curr. Hematol. Malig. Rep. 2013, 8, 91–97.
  52. Rowe, J.M.; Buck, G.; Burnett, A.K.; Chopra, R.; Wiernik, P.H.; Richards, S.M.; Lazarus, H.M.; Franklin, I.M.; Litzow, M.R.; Ciobanu, N.; et al. Induction Therapy for Adults with Acute Lymphoblastic Leukemia: Results of More than 1500 Patients from the International ALL Trial: MRC UKALL XII/ECOG E2993. Blood 2005, 106, 3760–3767.
  53. Williams, M.T.S.; Yousafzai, Y.M.; Elder, A.; Rehe, K.; Bomken, S.; Frishman-Levy, L.; Tavor, S.; Sinclair, P.; Dormon, K.; Masic, D.; et al. The Ability to Cross the Blood–Cerebrospinal Fluid Barrier Is a Generic Property of Acute Lymphoblastic Leukemia Blasts. Blood 2016, 127, 1998–2006.
  54. Krishnan, S.; Wade, R.; Moorman, A.V.; Mitchell, C.; Kinsey, S.E.; Eden, T.O.B.; Parker, C.; Vora, A.; Richards, S.; Saha, V. Temporal Changes in the Incidence and Pattern of Central Nervous System Relapses in Children with Acute Lymphoblastic Leukaemia Treated on Four Consecutive Medical Research Council Trials, 1985–2001. Leukemia 2009, 24, 450–459.
  55. Akers, S.M.; Rellick, S.L.; Fortney, J.E.; Gibson, L.F. Cellular Elements of the Subarachnoid Space Promote ALL Survival during Chemotherapy. Leuk. Res. 2011, 35, 705–711.
  56. Gaynes, J.S.; Jonart, L.M.; Zamora, E.A.; Naumann, J.A.; Gossai, N.P.; Gordon, P.M. The Central Nervous System Microenvironment Influences the Leukemia Transcriptome and Enhances Leukemia Chemo-Resistance. Haematologica 2017, 102, e136–e139.
  57. Jonart, L.M.; Ebadi, M.; Basile, P.; Johnson, K.; Makori, J.; Gordon, P.M. Disrupting the Leukemia Niche in the Central Nervous System Attenuates Leukemia Chemoresistance. Haematologica 2020, 105, 2130–2140.
  58. Fernández-Sevilla, L.M.; Valencia, J.; Flores-Villalobos, M.A.; Gonzalez-Murillo, Á.; Sacedón, R.; Jiménez, E.; Ramírez, M.; Varas, A.; Vicente, Á. The Choroid Plexus Stroma Constitutes a Sanctuary for Paediatric B-Cell Precursor Acute Lymphoblastic Leukaemia in the Central Nervous System. J. Pathol. 2020, 252, 189–200.
  59. Locatelli, F.; Schrappe, M.; Bernardo, M.E.; Rutella, S. How I Treat Relapsed Childhood Acute Lymphoblastic Leukemia. Blood 2012, 120, 2807–2816.
  60. Goldstone, A.H.; Richards, S.M.; Lazarus, H.M.; Tallman, M.S.; Buck, G.; Fielding, A.K.; Burnett, A.K.; Chopra, R.; Wiernik, P.H.; Foroni, L.; et al. In Adults with Standard-Risk Acute Lymphoblastic Leukemia, the Greatest Benefit Is Achieved from a Matched Sibling Allogeneic Transplantation in First Complete Remission, and an Autologous Transplantation Is Less Effective than Conventional Consolidation. Blood 2008, 111, 1827–1833.
  61. Cornelissen, J.J.; van der Holt, B.; Verhoef, G.E.; van’t Veer, M.B.; van Oers, M.H.; Schouten, H.C.; Ossenkoppele, G.; Sonneveld, P.; Maertens, J.; van Marwijk Kooy, M.; et al. Myeloablative Allogeneic versus Autologous Stem Cell Transplantation in Adult Patients with Acute Lymphoblastic Leukemia in First Remission: A Prospective Sibling Donor versus No-Donor Comparison. Blood 2009, 113, 1375–1382.
  62. Jamieson, C.H.M.; Amylon, M.D.; Wong, R.M.; Blume, K.G. Allogeneic Hematopoietic Cell Transplantation for Patients with High-Risk Acute Lymphoblastic Leukemia in First or Second Complete Remission Using Fractionated Total-Body Irradiation and High-Dose Etoposide: A 15-Year Experience. Exp. Hematol. 2003, 31, 981–986.
  63. Haddad, F.G.; Short, N.J. What Is the Optimal Tyrosine Kinase Inhibitor for Adults with Newly Diagnosed Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia? Hematology 2022, 2022, 213–217.
  64. Short, N.J.; Kantarjian, H.; Konopleva, M.; Desikan, S.P.P.; Jain, N.; Ravandi, F.; Huang, X.; Wierda, W.G.; Borthakur, G.; Sasaki, K.; et al. Updated Results of a Phase II Study of Ponatinib and Blinatumomab for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Blood 2021, 138, 2298.
  65. Jabbour, E.; Short, N.J.; Ravandi, F.; Huang, X.; Daver, N.; DiNardo, C.D.; Konopleva, M.; Pemmaraju, N.; Wierda, W.; Garcia-Manero, G.; et al. Combination of Hyper-CVAD with Ponatinib as First-Line Therapy for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia: Long-Term Follow-up of a Single-Centre, Phase 2 Study. Lancet Haematol. 2018, 5, e618–e627.
  66. Ribera, J.-M.; Garcia, O.; Ribera, J.; Montesinos, P.; Cano, I.; Martínez, P.; Esteve, J.; Esteban, D.; García-Fortes, M.; Alonso, N.; et al. Ponatinib and Chemotherapy in Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Final Results of Ponalfil Clinical Trial. Blood 2021, 138, 1230.
  67. Roddie, C.; O’Reilly, M.A.; Marzolini, M.A.V.; Wood, L.; Dias, J.; Cadinanos Garai, A.; Bosshard, L.; Abbasian, M.; Lowdell, M.W.; Wheeler, G.; et al. ALLCAR19: Updated Data Using AUTO1, a Novel Fast-Off Rate CD19 CAR in Relapsed/Refractory B-Cell Acute Lymphoblastic Leukaemia and Other B-Cell Malignancies. Blood 2020, 136, 3–4.
  68. Roddie, C.; Dias, J.; O’Reilly, M.A.; Abbasian, M.; Cadinanos-Garai, A.; Vispute, K.; Bosshard-Carter, L.; Mitsikakou, M.; Mehra, V.; Roddy, H.; et al. Durable Responses and Low Toxicity after Fast Off-Rate Cd19 Chimeric Antigen Receptor-t Therapy in Adults with Relapsed or Refractory b-Cell Acute Lymphoblastic Leukemia. J. Clin. Oncol. 2021, 39, 3352–3364.
  69. Ghorashian, S.; Kramer, A.M.; Onuoha, S.; Wright, G.; Bartram, J.; Richardson, R.; Albon, S.J.; Casanovas-Company, J.; Castro, F.; Popova, B.; et al. Enhanced CAR T Cell Expansion and Prolonged Persistence in Pediatric Patients with ALL Treated with a Low-Affinity CD19 CAR. Nat. Med. 2019, 25, 1408–1414.
  70. Pan, J.; Niu, Q.; Deng, B.; Liu, S.; Wu, T.; Gao, Z.; Liu, Z.; Zhang, Y.; Qu, X.; Zhang, Y.; et al. CD22 CAR T-Cell Therapy in Refractory or Relapsed B Acute Lymphoblastic Leukemia. Leukemia 2019, 33, 2854–2866.
  71. Dai, H.; Wu, Z.; Jia, H.; Tong, C.; Guo, Y.; Ti, D.; Han, X.; Liu, Y.; Zhang, W.; Wang, C.; et al. Bispecific CAR-T Cells Targeting Both CD19 and CD22 for Therapy of Adults with Relapsed or Refractory B Cell Acute Lymphoblastic Leukemia. J. Hematol. Oncol. 2020, 13, 30.
  72. Gao, J.; Liu, W.J. Prognostic Value of the Response to Prednisone for Children with Acute Lymphoblastic Leukemia: A Meta-Analysis. Eur. Rev. Med. Pharmacol. Sci. 2018, 22, 7858–7866.
  73. Berg, S.L.; Blaney, S.M.; Devidas, M.; Lampkin, T.A.; Murgo, A.; Bernstein, M.; Billett, A.; Kurtzberg, J.; Reaman, G.; Gaynon, P.; et al. Phase II Study of Nelarabine (Compound 506U78) in Children and Young Adults with Refractory T-Cell Malignancies: A Report from the Children’s Oncology Group. J. Clin. Oncol. 2005, 23, 3376–3382.
  74. Dunsmore, K.P.; Winter, S.S.; Devidas, M.; Wood, B.L.; Esiashvili, N.; Chen, Z.; Eisenberg, N.; Briegel, N.; Hayashi, R.J.; Gastier-Foster, J.M.; et al. Children’s Oncology Group AALL0434: A Phase III Randomized Clinical Trial Testing Nelarabine in Newly Diagnosed t-Cell Acute Lymphoblastic Leukemia. J. Clin. Oncol. 2020, 38, 3282–3293.
  75. Gökbuget, N.; Basara, N.; Baurmann, H.; Beck, J.; Brüggemann, M.; Diedrich, H.; Güldenzoph, B.; Hartung, G.; Horst, H.A.; Hüttmann, A.; et al. High Single-Drug Activity of Nelarabine in Relapsed T-Lymphoblastic Leukemia/Lymphoma Offers Curative Option with Subsequent Stem Cell Transplantation. Blood 2011, 118, 3504–3511.
  76. Chun-fung, S.; Wan, T.M.; Mohan, A.A.M.; Qiu, Y.; Jiao, A. Bortezomib Is Effective in Treating T-ALL, Inducting G2/M Cell Cycle Arrest and WEE1 Downregulation. Blood 2021, 138, 4360.
  77. Zheng, R.; Li, M.; Wang, S.; Liu, Y. Advances of Target Therapy on NOTCH1 Signaling Pathway in T-Cell Acute Lymphoblastic Leukemia. Exp. Hematol. Oncol. 2020, 9, 31.
  78. Jaramillo, S.; Hennemann, H.; Horak, P.; Teleanu, V.; Heilig, C.E.; Hutter, B.; Stenzinger, A.; Glimm, H.; Goeppert, B.; Müller-Tidow, C.; et al. Ruxolitinib Is Effective in the Treatment of a Patient with Refractory T-ALL. EJHaem 2021, 2, 139–142.
  79. Richard-Carpentier, G.; Jabbour, E.; Short, N.J.; Rausch, C.R.; Savoy, J.M.; Bose, P.; Yilmaz, M.; Jain, N.; Borthakur, G.; Ohanian, M.; et al. Clinical Experience with Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia. Clin. Lymphoma Myeloma Leuk. 2020, 20, 212–218.
  80. Bride, K.L.; Vincent, T.L.; Im, S.Y.; Aplenc, R.; Barrett, D.M.; Carroll, W.L.; Carson, R.; Dai, Y.; Devidas, M.; Dunsmore, K.P.; et al. Preclinical Efficacy of Daratumumab in T-Cell Acute Lymphoblastic Leukemia. Blood 2018, 131, 995–999.
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