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Cancers
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Advances in Acute Lymphoblastic Leukemia Therapy
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Advances in Acute Lymphoblastic Leukemia Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (31 December 2021) | Viewed by 14664

Special Issue Editor

Dr. Luca Lo Nigro

E-Mail Website
Guest Editor
Cytogenetic-Cytofluorimetric-Molecular Biology Laboratory, Center of Pediatric Hematology Oncology, Azienda Policlinico "G. Rodolico" - San Marco Building 4, 95123 Catania, Italy
Interests: acute lymphoblastic leukemia; minimal residual disease; next-generation sequencing; genomic subgroups; chemotherapy; immunotherapy; targeted therapy; toxicity; quality of life
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Acute lymphoblastic leukemia (ALL) develops at any age, but it is most frequent in children, comprising 25% of their malignant tumors. The introduction of combined chemotherapy including CNS leukemia prophylaxis in the 1960s significantly improved the prognosis of this previously incurable disease. Progress in the understanding of biology together with the routinely implemented detection of minimal residual disease, a reflection of the early treatment response, allowed risk group assignment into different treatment arms. This optimized the treatment intensity by a careful identification of patients in whom the treatment intensity may be reduced, or must be intensified. Pediatric-inspired regimens are now being successfully administered in younger adults. Hematopoietic stem cell transplantation (HSCT) increases the chance of cure in very-high-risk patients. More than 90% of children and ≥50% of adults below 50 years, but only 25% older patients are currently cured of their disease. Further increase of the intensity of chemotherapy causes unacceptable toxicity. The contribution of HSCT is complicated by significant late sequelae in children and high acute toxicity in individual patients. The implementation of whole-genome methods into routine diagnostics helped to discover molecular pathways involved in leukemic cell proliferation. The combination of chemotherapy with tyrosine kinase inhibitors as an example of targeted therapy improved the prognosis of Philadelphia-positive ALL. Recent progress in the development of immunotherapy has an enormous impact on ALL treatment. The monoclonal antibodies blinatumomab and inotuzumab ozogamicin achieved high response rates in refractory B precursor ALL. So far, they have been evaluated in front-line regimens. Chimeric antigen receptor T cells have the potential to improve the prognosis of patients with very-high-risk disease and to substitute HSCT in some indications.

In the present Special Issue, we will discuss how all these advances in diagnostic methods and therapeutic modalities have been improving the outcome of ALL in children and adults, including the reduction of acute toxicity and late sequelae. 

Dr. Luca Lo Nigro
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • acute lymphoblastic leukemia
  • minimal residual disease
  • next-generation sequencing
  • chemotherapy
  • immunotherapy
  • targeted therapy
  • toxicity
  • quality of life

Published Papers (5 papers)

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Research

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9 pages, 1118 KiB  
Article
FLT3-ITD in Children with Early T-cell Precursor (ETP) Acute Lymphoblastic Leukemia: Incidence and Potential Target for Monitoring Minimal Residual Disease (MRD)
by Luca Lo Nigro, Nellina Andriano, Barbara Buldini, Daniela Silvestri, Tiziana Villa, Franco Locatelli, Rosanna Parasole, Elena Barisone, Anna Maria Testi, Andrea Biondi, Maria Grazia Valsecchi, Carmelo Rizzari, Valentino Conter, Giuseppe Basso and Giovanni Cazzaniga
Cancers 2022, 14(10), 2475; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14102475 - 17 May 2022
Cited by 3 | Viewed by 2099
Abstract
Early T-cell precursor (ETP) is an aggressive form of acute lymphoblastic leukemia (ALL), associated with high risk of relapse. This leukemia subtype shows a higher prevalence of mutations, typically associated with acute myeloid leukemia (AML), including RAS and FLT3 mutations. FLT3-ITD was identified [...] Read more.
Early T-cell precursor (ETP) is an aggressive form of acute lymphoblastic leukemia (ALL), associated with high risk of relapse. This leukemia subtype shows a higher prevalence of mutations, typically associated with acute myeloid leukemia (AML), including RAS and FLT3 mutations. FLT3-ITD was identified in 35% cases of adult ETP-ALL, but data in the pediatric counterpart are lacking. ETPs frequently lack immunoglobulin (IG) and T-cell receptor (TR) gene rearrangements, used for minimal residual disease (MRD) monitoring. Among 718 T-ALL enrolled in Italy into AIEOP-BFM-ALL2000, AIEOP-ALLR2006, and AIEOP-BFM-ALL2009 consecutive protocols, 86 patients (12%) were identified as ETP and 77 out of 86 children were studied for the presence of FLT3-ITD. A total of 10 out of 77 (13%) ETP cases were FLT3-ITD positive. IG/TR MRD monitoring was feasible only in four cases. FLT3-ITD MRD monitoring was performed using real-time PCR in all FLT3-ITD positive ETP cases. A comparison between IG/TR and FLT3-ITD resulted in comparable findings. Our study demonstrated that the FLT3-ITD prevalence in children was lower (13%) than that reported in adult ETP-ALL. FLT3-ITD can be used as a marker for sensitive molecular MRD monitoring in ETP-ALL when IG/TR markers are not available, potentially selecting those patients who should spare allogeneic hematopoietic stem cell transplantation (HSCT). Finally, the FLT3 pathway is a robust druggable target in this aggressive form of leukemia. Full article
(This article belongs to the Special Issue Advances in Acute Lymphoblastic Leukemia Therapy)
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17 pages, 1512 KiB  
Article
Characteristics and Outcome of Elderly Patients (>55 Years) with Acute Lymphoblastic Leukemia
by Daniela V. Wenge, Klaus Wethmar, Corinna A. Klar, Hedwig Kolve, Tim Sauer, Linus Angenendt, Georg Evers, Simon Call, Andrea Kerkhoff, Cyrus Khandanpour, Torsten Kessler, Rolf Mesters, Christoph Schliemann, Jan-Henrik Mikesch, Christian Reicherts, Monika Brüggemann, Wolfgang E. Berdel, Georg Lenz and Matthias Stelljes
Cancers 2022, 14(3), 565; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14030565 - 23 Jan 2022
Cited by 3 | Viewed by 3202
Abstract
Prognosis of elderly ALL patients remains dismal. Here, we retrospectively analyzed the course of 93 patients > 55 years with B-precursor (n = 88) or T-ALL (n = 5), who received age-adapted, pediatric-inspired chemotherapy regimens at our center between May 2003 [...] Read more.
Prognosis of elderly ALL patients remains dismal. Here, we retrospectively analyzed the course of 93 patients > 55 years with B-precursor (n = 88) or T-ALL (n = 5), who received age-adapted, pediatric-inspired chemotherapy regimens at our center between May 2003 and October 2020. The median age at diagnosis was 65.7 years, and surviving patients had a median follow-up of 3.7 years. CR after induction therapy was documented in 76.5%, while the rate of treatment-related death within 100 days was 6.4%. The OS of the entire cohort at 1 and 3 year(s) was 75.2% (95% CI: 66.4–84.0%) and 47.3% (95% CI: 36.8–57.7%), respectively, while the EFS at 1 and 3 years(s) was 59.0% (95% CI: 48.9–69.0%) and 32.9% (95% CI: 23.0–42.8%), respectively. At 3 years, the cumulative incidence (CI) of relapse was 48.3% (95% CI: 38.9–59.9%), and the CI rate of death in CR was 17.3% (95% CI: 10.9–27.5%). Older age and an ECOG > 2 represented risk factors for inferior OS, while BCR::ABL1 status, immunophenotype, and intensity of chemotherapy did not significantly affect OS. We conclude that intensive treatment is feasible in selected elderly ALL patients, but high rates of relapse and death in CR underline the need for novel therapeutic strategies. Full article
(This article belongs to the Special Issue Advances in Acute Lymphoblastic Leukemia Therapy)
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12 pages, 667 KiB  
Article
Blinatumomab as a Bridge Therapy for Hematopoietic Stem Cell Transplantation in Pediatric Refractory/Relapsed Acute Lymphoblastic Leukemia
by Katarzyna Pawinska-Wasikowska, Aleksandra Wieczorek, Walentyna Balwierz, Karolina Bukowska-Strakova, Marta Surman and Szymon Skoczen
Cancers 2022, 14(2), 458; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020458 - 17 Jan 2022
Cited by 9 | Viewed by 3152
Abstract
Despite the progress that has been made in recent decades in the treatment of pediatric acute leukemias, e.g., converting acute lymphoblastic leukemia (ALL) from a fatal to a highly curable disease, 15–20% of children still relapse. Blinatumomab, a bispecific CD3/CD19 antibody construct, has [...] Read more.
Despite the progress that has been made in recent decades in the treatment of pediatric acute leukemias, e.g., converting acute lymphoblastic leukemia (ALL) from a fatal to a highly curable disease, 15–20% of children still relapse. Blinatumomab, a bispecific CD3/CD19 antibody construct, has been successfully used in relapsed/refractory r/r B-cell precursor ALL (BCP-ALL) as a bridge to hematopoietic stem cell transplantation (HSCT). We retrospectively assessed the efficacy and toxicity of blinatumomab in 13 children with r/r BCP-ALL. Between 2017 and 2021, thirteen children, aged 1–18 years, with r/r BCP-ALL were treated with blinatumomab. Two patients were administered blinatumomab for refractory relapse without complete remission (CR), one due to primary refractory disease, and ten patients were in CR with minimal residual disease (MRD) ≥ 10−3. The response rate in our cohort of patients was 85%, with subsequent feasible HSCT in 11 out of 13 children. Ten children reached MRD negativity after the first blinatumomab administration. The three-year OS for the study patients was 85% (Mantel–Cox, p < 0.001) and median follow-up was 24.5 (range: 1–47). All responders proceeded to HSCT and are alive in CR, and MRD negative. Although our study had some limitations with regard to its retrospective design and limited patient population, it clearly showed blinatumomab as not only a feasible but also an effective therapeutic option in pretreated children with r/r BCP-ALL, with a tolerable toxicity profile, paving the way for an HSCT procedure. Full article
(This article belongs to the Special Issue Advances in Acute Lymphoblastic Leukemia Therapy)
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12 pages, 1783 KiB  
Article
Blinatumomab in Children and Adolescents with Relapsed/Refractory B Cell Precursor Acute Lymphoblastic Leukemia: A Real-Life Multicenter Retrospective Study in Seven AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica) Centers
by Giuliana Beneduce, Antonia De Matteo, Pio Stellato, Anna M. Testi, Nicoletta Bertorello, Antonella Colombini, Maria C. Putti, Carmelo Rizzari, Simone Cesaro, Monica Cellini, Elena Barisone, Fara Petruzziello, Giuseppe Menna and Rosanna Parasole
Cancers 2022, 14(2), 426; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020426 - 15 Jan 2022
Cited by 14 | Viewed by 2842
Abstract
Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab [...] Read more.
Five-year event-free survival in pediatric B-cell precursor acute lymphoblastic leukemia (BCP-ALL) currently exceeds 80–85%. However, 15–20% of patients still experience a relapsed/refractory disease. From 1 January 2015 to 31 December 2020, thirty-nine patients, 0–21 years old with r/r BCP-ALL were treated with blinatumomab with the aim of inducing remission (n = 13) or reducing MRD levels (n = 26) in the frame of different multiagent chemotherapy schedules, in seven AIEOP centers. Patients were treated in compassionate and/or off-label settings and were not enrolled in any controlled clinical trials. Treatment was well tolerated; 22 (56.4%) patients reported adverse events (AE) on a total of 46 events registered, of which 27 (58.7%) were ≤2 grade according to CTCAE. Neurological AEs were 18 (39.1%); only two patients required transient blinatumomab discontinuation. Complete remission (CR) rate was 46% for the 13 patients treated with ≥5% blasts and 81% PCR/FC MRD negativity in the 26 patients with blasts < 5%. Median relapse-free survival was 33.4 months (95% CI; 7.5–59.3); median overall survival was not reached over a mean follow-up of 16 months. In our study, as in other real-life experiences, blinatumomab proved to be effective and well-tolerated, able to induce a high rate of CR and MRD negativity. Full article
(This article belongs to the Special Issue Advances in Acute Lymphoblastic Leukemia Therapy)
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Review

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18 pages, 3720 KiB  
Review
Cardiac Relapse of Acute Lymphoblastic Leukemia Following Hematopoietic Stem Cell Transplantation: A Case Report and Review of Literature
by Irtiza N. Sheikh, Dristhi Ragoonanan, Anna Franklin, Chandra Srinivasan, Bhiong Zhao, Demetrios Petropoulos, Kris M. Mahadeo, Priti Tewari and Sajad J. Khazal
Cancers 2021, 13(22), 5814; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers13225814 - 19 Nov 2021
Cited by 3 | Viewed by 2442
Abstract
Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) occurs in soft tissues and various organs outside the testis and central nervous system. Treatments such as hematopoietic stem cell transplantation and more novel modalities such as immunotherapy have eradicated ALL at extramedullary sites. In [...] Read more.
Isolated extramedullary relapse of acute lymphoblastic leukemia (ALL) occurs in soft tissues and various organs outside the testis and central nervous system. Treatments such as hematopoietic stem cell transplantation and more novel modalities such as immunotherapy have eradicated ALL at extramedullary sites. In some instances, survival times for relapsed ALL at these sites are longer than those for relapsed disease involving only the bone marrow. Isolated relapse of ALL in the myocardium is rare, especially in children, making diagnosis and treatment of it difficult. More recent treatment options such as chimeric antigen receptor T-cell therapy carry a high risk of cytokine release syndrome and associated risk of worsening cardiac function. Herein we present the case of an 11-year-old boy who presented with relapsed symptomatic B-cell ALL in the myocardium following allogeneic hematopoietic stem cell transplantation. This is an unusual presentation of relapsed ALL and this case demonstrates the associated challenges in its diagnosis and treatment. The case report is followed by a literature review of the advances in treatment of pediatric leukemia and their application to extramedullary relapse of this disease in particular. Full article
(This article belongs to the Special Issue Advances in Acute Lymphoblastic Leukemia Therapy)
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