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Stem Cell Transplantation in Cancer Treatment

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

Deadline for manuscript submissions: closed (10 April 2021) | Viewed by 40621

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Dr. Riccardo Masetti

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Pediatric Oncology and Hematology, University of Bologna, 40138 Bologna, Italy
Interests: hematopoietic stem cell transplantation; pediatric AML; pediatric MDS; cancer predisposing syndromes; gut microbiome; cellular therapies; pediatric hematology/oncology
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Dr. Luisa Strocchio

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Department of Pediatric Hematology/Oncology and Cell and Gene Therapy, IRCCS Bambino Gesù Children's Hospital, Rome, Italy
Interests: Hematopoietic stem cell transplantation; Acute lymphoblastic leukemia; Acute myeloid leukemia; Acute promyelocytic leukemia; Inherited bone marrow failure syndromes; Hemoglobinopathies

Special Issue Information

Dear Colleagues,

Stem cell transplantation (SCT) is currently universally established as a curative treatment option for many hematologic malignancies, as well as other neoplastic disorders.

Although this procedure was originally conceived more than 60 years ago as a treatment to rescue victims of accidental irradiation exposure, over the years the immunotherapeutic potential of SCT has been progressively discovered and exploited, marking a progressive transition of this technique from an experimental strategy to an ideal platform to explore a cellular-based anti-cancer approach.

The dramatic progress achieved over the last three decades in the field of HLA-matching techniques, conditioning regimens, graft manipulation, graft-versus-host disease prophylaxis, supportive care, and modulation of immunological complications led to a broad expansion of the clinical use of SCT, and indications for this procedure are becoming transversal and rapidly evolving. Moreover, research on the use of stem cells and mature reactive T-cells, which is now revolutionizing the scenario of cancer treatment, sinks its roots and moved its development starting from SCT.

This Special Issue will highlight the role of SCT in the challenging scenario of cancer treatment, covering both basic research and more clinical aspects that may advance our understanding of this intriguing procedure.

Dr. Riccardo Masetti
Dr. Luisa Strocchio
Guest Editors

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Keywords

Hematopoietic stem cell transplantation
Cancer
Hematological malignancies
Leukemia
Lymphoma
Immunotherapy

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Published Papers (11 papers)

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Research

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17 pages, 988 KiB

Open AccessArticle

The Expression of Genes Related to Lipid Metabolism and Metabolic Disorders in Children before and after Hematopoietic Stem Cell Transplantation—A Prospective Observational Study

by Wojciech Czogała, Małgorzata Czogała, Kinga Kwiecińska, Mirosław Bik-Multanowski, Przemysław Tomasik, Przemysław Hałubiec, Agnieszka Łazarczyk, Karol Miklusiak and Szymon Skoczeń

Cancers 2021, 13(14), 3614; https://doi.org/10.3390/cancers13143614 - 19 Jul 2021

Cited by 4 | Viewed by 2366

Abstract

Metabolic disorders in children after hematopoietic stem cell transplantation (HSCT) are poorly characterized. However, it is known that dyslipidemia and insulin resistance are particularly common in these patients. We conducted a prospective study of 27 patients treated with HSCT to assess the possibility of predicting these abnormalities. We measured gene expressions using a microarray technique to identify differences in expression of genes associated with lipid metabolism before and after HSCT. In patients treated with HSCT, total cholesterol levels were significantly higher after the procedure compared with the values before HSCT. Microarray analysis revealed statistically significant differences in expressions of three genes, DPP4, PLAG1, and SCD, after applying the Benjamini–Hochberg procedure (p^BH < 0.05). In multiple logistic regression, the increase of DPP4 gene expression before HCST (as well as its change between pre- and post-HSCT status) was associated with dyslipidemia. In children treated with HSCT, the burden of lipid disorders in short-term follow-up seems to be lower than before the procedure. The expression pattern of DPP4 is linked with dyslipidemia after the transplantation. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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10 pages, 438 KiB

Open AccessArticle

Clonal Hematopoiesis after Autologous Stem Cell Transplantation Does Not Confer Adverse Prognosis in Patients with AML

by Alexander D. Heini, Naomi Porret, Reinhard Zenhaeusern, Annette Winkler, Ulrike Bacher and Thomas Pabst

Cancers 2021, 13(13), 3190; https://doi.org/10.3390/cancers13133190 - 25 Jun 2021

Cited by 6 | Viewed by 2083

Abstract

Introduction: Despite a 50% cure rate, relapse remains the main cause of death in patients with acute myeloid leukemia (AML) consolidated with autologous stem cell transplantation (ASCT) in first remission (CR1). Clonal hematopoiesis of indeterminate potential (CH) increases the risk for hematological and cardiovascular disorders and death. The impact of CH persisting after ASCT in AML patients is unclear. Materials and Methods: We retrospectively investigated the prognostic value of persisting DNMT3A, TET2, or ASXL1 (DTA) mutations after ASCT. Patients underwent stratification depending on the presence of DTA mutations. Results: We investigated 110 consecutive AML patients receiving ASCT in CR1 after two induction cycles at our center between 2007 and 2020. CH-related mutations were present in 31 patients (28.2%) after ASCT. The baseline characteristics were similar between patients with or without persisting DTA mutations after ASCT. The median progression free survival was 26.9 months in patients without DTA mutations and 16.7 months in patients with DTA mutations (HR 0.75 (0.42–1.33), p = 0.287), and the median overall survival was 80.9 and 54.4 months (HR 0.79 (0.41–1.51), p = 0.440), respectively. Conclusion: We suggest that DTA-CH after ASCT is not associated with an increased risk of relapse or death. The persistence of DTA mutations after induction should not prevent AML patients in CR1 from ASCT consolidation. Independent studies should confirm these data. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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19 pages, 2217 KiB

Open AccessArticle

Cytokine-Induced Memory-Like NK Cells with High Reactivity against Acute Leukemia Blasts and Solid Tumor Cells Suitable for Adoptive Immunotherapy Approaches

by Matteo Tanzi, Michela Consonni, Michela Falco, Federica Ferulli, Enrica Montini, Annamaria Pasi, Rosalia Cacciatore, Silvia Brugnatelli, Paolo Pedrazzoli, Marco Zecca, Stella Boghen, Paolo Dellabona, Giulia Casorati and Daniela Montagna

Cancers 2021, 13(7), 1577; https://doi.org/10.3390/cancers13071577 - 30 Mar 2021

Cited by 7 | Viewed by 3397

Abstract

The limited efficacy of Natural Killer (NK) cell-based immunotherapy results in part from the suboptimal expansion and persistence of the infused cells. Recent reports suggest that the generation of NK cells with memory-like properties upon in vitro activation with defined cytokines might be an effective way of ensuring long-lasting NK cell function in vivo. Here, we demonstrate that activation with IL-12, IL-15 and IL-18 followed by a one-week culture with optimal doses of Interleukin (IL-2) and IL-15 generates substantial numbers of memory-like NK cells able to persist for at least three weeks when injected into NOD scid gamma (NSG) mice. This approach induces haploidentical donor-derived memory-like NK cells that are highly lytic against patients’ myeloid or lymphoid leukemia blasts, independent of the presence of alloreactive cell populations in the donor and with negligible reactivity against patients’ non-malignant cells. Memory-like NK cells able to lyse autologous tumor cells can also be generated from patients with solid malignancies. The anti-tumor activity of allogenic and autologous memory-like NK cells is significantly greater than that displayed by NK cells stimulated overnight with IL-2, supporting their potential therapeutic value both in patients affected by high-risk acute leukemia after haploidentical hematopoietic stem cell transplantation and in patients with advanced solid malignancies. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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16 pages, 450 KiB

Open AccessArticle

Melphalan, Etoposide, and Carboplatin Megatherapy with Autologous Stem Cell Transplantation in Children with Relapsing or Therapy-Resistant Extracranial Germ-Cell Tumors—A Retrospective Analysis

by Marek Ussowicz, Monika Mielcarek-Siedziuk, Jakub Musiał, Mateusz Stachowiak, Jadwiga Węcławek-Tompol, Dorota Sęga-Pondel, Jowita Frączkiewicz, Joanna Trelińska and Anna Raciborska

Cancers 2020, 12(12), 3841; https://doi.org/10.3390/cancers12123841 - 19 Dec 2020

Cited by 6 | Viewed by 2691

Abstract

Pediatric germ cell tumors (GCTs) are a group of chemosensitive malignancies with a 90% curability rate. We report a series of children with relapsing or therapy-resistant GCT treated with melphalan–etoposide–carboplatin high-dose chemotherapy (HDCT) and autologous stem cell transplantation. This consisted of 18 children, either with GCTs after relapse (nine patients) or with an unsatisfactory response to first-line chemotherapy (nine patients), who underwent HDCT. The HDCT regimens MEC1 (carboplatin 1500 mg/m², etoposide 1800 mg/m², and melphalan 140 mg/m²) and MEC2 (carboplatin 800 mg/m², etoposide 800 mg/m², and melphalan 140 mg/m²) were each used in nine patients. The median observation time was 81 months, the 5-year overall survival (OS) was 76%, and the event-free survival (EFS) was 70.8%. Non-relapse mortality was 0%, and four patients died after HDCT due to progression of the malignancy. No difference in OS or EFS was noted between the MEC1 and MEC2 protocols. The 5-year OS and 5-year EFS were higher in children treated with autologous stem cell transplantation before the age of four years. The presence of metastatic disease or time of HDCT consolidation during first/subsequent line chemotherapy did not affect patient survival. The melphalan–etoposide–carboplatin protocol is feasible in pediatric GCT, but is associated with potentially life-threatening complications. In conclusion, the use of HDCT must be examined in well-designed clinical trials, and the identification of patients who can benefit from this approach is critical to avoid overtreatment. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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15 pages, 824 KiB

Open AccessArticle

Prediction of Response and Survival Following Treatment with Azacitidine for Relapse of Acute Myeloid Leukemia and Myelodysplastic Syndromes after Allogeneic Hematopoietic Stem Cell Transplantation

by Christina Rautenberg, Anika Bergmann, Ulrich Germing, Caroline Fischermanns, Sabrina Pechtel, Jennifer Kaivers, Paul Jäger, Esther Schuler, Rainer Haas, Guido Kobbe and Thomas Schroeder

Cancers 2020, 12(8), 2255; https://doi.org/10.3390/cancers12082255 - 12 Aug 2020

Cited by 21 | Viewed by 3049

Abstract

To provide long-term outcome data and predictors for response and survival, we retrospectively analyzed all 151 patients with relapse of myeloid neoplasms after allogeneic hematopoietic stem cell transplantation (allo-HSCT) who were uniformly treated with first-line azacitidine (Aza) salvage therapy at our center. Patients were treated for molecular (39%) or hematologic relapse (61%), with a median of 5 cycles of Aza and at least one donor lymphocyte infusion in 70% of patients. Overall response was 46%, with 41% achieving complete (CR) and 5% achieving partial remission. CR was achieved after a median of 4 cycles and lasted for a median of 11 months (range 0.9 to 120 months). With a median follow-up of 22 months (range: 1 to 122 months), the 2-year survival rate was 38% ± 9%, including 17 patients with ongoing remission for >5 years. Based on results from multivariate analyses, molecular relapse and time to relapse were integrated into a score, clearly dividing patients into 3 subgroups with CR rates of 71%, 39%, and 29%; and 2-year survival rates of 64%, 38%, and 27%, respectively. In the subgroup of MDS and secondary AML, receiving upfront transplantation was associated with superior response and survival, and therefore pretransplant strategy was integrated together with relapse type into a MDS–sAML-specific score. Overall, Aza enables meaningful responses and long-term survival, which is a predictable with a simple-to-use scoring system. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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10 pages, 811 KiB

Open AccessArticle

HLA Evolutionary Divergence as a Prognostic Marker for AML Patients Undergoing Allogeneic Stem Cell Transplantation

by Malte Roerden, Annika Nelde, Jonas S. Heitmann, Reinhild Klein, Hans-Georg Rammensee, Wolfgang A. Bethge and Juliane S. Walz

Cancers 2020, 12(7), 1835; https://doi.org/10.3390/cancers12071835 - 8 Jul 2020

Cited by 20 | Viewed by 3369

Abstract

The diversity of human leukocyte antigens (HLAs) enables the presentation of immense repertoires of peptides, including tumor-associated antigens (TAAs). As a surrogate for immunopeptidome diversity, the HLA evolutionary divergence (HED) between individual HLA alleles might directly define the ability to present TAAs, a prerequisite for graft-versus-leukemia effects. We therefore analyzed the impact of HED on survival within a cohort of 171 acute myeloid leukemia (AML) patients after matched donor allogeneic hematopoietic stem cell transplantation (HSCT). Low HED (<25th percentile) of HLA class I (HED^{class I}) or HLA-DR antigens (HED^DR) was a strong determinant for adverse overall survival after allogeneic HSCT (OS), with a hazard ratio for death of 1.9 (95% CI 1.2–3.2) and 2.1 (95% CI 1.3–3.4), respectively. Defining a cutoff value for the combined HED^total (HED^{class I} and HED^DR), the respective 5 year OS was 29.7% and 64.9% in patients with low and high HED^total (p < 0.001), respectively. Furthermore, the risk of relapse was significantly higher in patients with low HED^total (hazard ratio (HR) 2.2, 95% CI 1.3–3.6) and event-free survival (EFS) was significantly reduced (5 year EFS 25.7% versus 54.4%, p < 0.001). We here introduce HED, a fundamental metric of immunopeptidome diversity, as a novel prognostic factor for AML patients undergoing allogeneic HSCT. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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Review

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19 pages, 345 KiB

Open AccessReview

Role of Stem Cell Transplantation in Multiple Myeloma

by Srinivas Devarakonda, Yvonne Efebera and Nidhi Sharma

Cancers 2021, 13(4), 863; https://doi.org/10.3390/cancers13040863 - 18 Feb 2021

Cited by 22 | Viewed by 5163

Abstract

Autologous stem cell transplantation (auto-SCT) has been the standard of care in eligible newly diagnosed multiple myeloma (MM) patients. Outcomes of patients with MM have improved significantly due to the advent of several novel drugs. Upfront use of these drugs in induction therapy has significantly increased the rate and depth of responses that have translated into longer remission and survival. This has now raised a debate regarding the role and relevance of auto-SCT in the management of myeloma. However, clinical trials have confirmed the utility of auto-SCT even in the era of novel drugs. Tandem auto-SCT followed by maintenance has shown a progression-free survival (PFS) benefit in high-risk MM, and hence can be considered in young and fit patients with high-risk disease. Auto-SCT has the advantages of resetting the bone marrow microenvironment, short-lived toxicity compared to the long-term physical and financial toxicities of continued chemotherapy in the absence of SCT, very low transplant-related mortality (TRM) in high volume centers, and providing longer disease-free survival when followed by maintenance therapy. Allogeneic SCT is one potentially curative option for MM, albeit with an increased risk of death due to high TRM. Strategies to modulate the graft-versus-host disease (GVHD) while maintaining or improving the graft-versus-myeloma (GVM) effect could place allogeneic SCT back in the treatment armamentarium of MM. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

17 pages, 304 KiB

Open AccessReview

Complications after CD19+ CAR T-Cell Therapy

by Olaf Penack and Christian Koenecke

Cancers 2020, 12(11), 3445; https://doi.org/10.3390/cancers12113445 - 19 Nov 2020

Cited by 35 | Viewed by 5962

Abstract

Clinical trials demonstrated that CD19+ chimeric antigen receptor (CAR) T-cells can be highly effective against a number of malignancies. However, the complete risk profile of CAR T-cells could not be defined in the initial trials. Currently, there is emerging evidence derived from post approval studies in CD19+ CAR T-cells demonstrating both short-term and medium-term effects, which were unknown at the time of regulatory approval. Here, we review the incidence and the current management of CD19+ CAR T-cell complications. We highlight frequently occurring events, such as cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, cardiotoxicity, pulmonary toxicity, metabolic complications, secondary macrophage-activation syndrome, and prolonged cytopenia. Furthermore, we present evidence supporting the hypothesis that CAR T-cell-mediated toxicities can involve any other organ system and we discuss the potential risk of long-term complications. Finally, we discuss recent pre-clinical and clinical data shedding new light on the pathophysiology of CAR T-cell-related complications. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

24 pages, 641 KiB

Open AccessReview

Role of Haematopoietic Stem Cell Transplantation in Peripheral T-Cell Lymphoma

by Chathuri Abeyakoon, Carrie van der Weyden, Sean Harrop, Amit Khot, Michael Dickinson, Costas K. Yannakou and H. Miles Prince

Cancers 2020, 12(11), 3125; https://doi.org/10.3390/cancers12113125 - 26 Oct 2020

Cited by 6 | Viewed by 2854

Abstract

Peripheral T-cell lymphomas (PTCLs) are distinct pathological entities with clinical advancements lagging behind their B-cell lymphoma counterpart. Frequently aggressive in their clinical behaviour, clinicians are constantly challenged with low complete remission rates, early relapses and failure to achieve long-term responses despite aggressive first-line chemotherapy, resulting in poor overall survival in the majority of patients. There is currently no consensus regarding the optimal therapy for PTCL and treatment approaches are mainly derived from prospective phase II studies, registry data and retrospective studies. Despite its biological heterogeneity, a less than satisfactory “one-size-fits-all” approach has been adopted to date. Although its role remains controversial, for many years, haematopoietic stem cell transplantation has been adopted by clinicians with the aim of overcoming poor outcomes by consolidating responses. In this review, we aim to define the role of both autologous and allogeneic stem cell transplantation in PTCL in both frontline and salvage settings, especially in the context of recent advancements in this field. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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15 pages, 796 KiB

Open AccessReview

Allogeneic Hematopoietic Stem Cell Transplantation in Cutaneous T-Cell Lymphomas

by Maëlle Dumont, Régis Peffault de Latour, Caroline Ram-Wolff, Martine Bagot and Adèle de Masson

Cancers 2020, 12(10), 2856; https://doi.org/10.3390/cancers12102856 - 3 Oct 2020

Cited by 12 | Viewed by 4244

Abstract

Cutaneous T-cell lymphomas (CTCLs) are non-Hodgkin lymphomas that develop primarily in the skin. They account for almost 80% of primary cutaneous lymphomas. Epidermotropic CTCLs (mycosis fungoides (MF) and Sézary syndrome (SS)) are the most common form of CTCL. The course of the disease ranges from an indolent clinical behavior in early-stage disease to an aggressive evolution in the advanced stages. Advanced-stage disease is defined by the presence of tumors, erythroderma, or significant blood, nodal or visceral involvement. Advanced-stage disease is characterized by frequent disease relapses, refractory disease, a severely impaired quality of life and reduced overall survival. In the last twenty-five years, allogeneic hematopoietic stem cell transplantation (HSCT) has led to prolonged remissions in advanced CTCL, presumably linked to a graft-versus-lymphoma effect and is thus emerging as a potential cure of the disease. However, the high post-transplant relapse rate and severe morbidity and mortality associated with graft-versus-host disease and infections are important issues. Allogeneic HSCT is thus mostly considered in young patients with no comorbidities and an aggressive, advanced-stage CTCL. Allogeneic HSCT gives the best results in patients with a pre-transplant complete remission of the lymphoma. For this reason, one of the challenges is to define the best time to consider allogeneic HSCT in the disease course. Early identification of patients at high risk for progression is important to identify candidates who may benefit from allogeneic HSCT before their disease becomes treatment-refractory. This review describes the role of allogeneic HSCT in CTCL, summarizes the published data and future perspectives in this area. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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18 pages, 458 KiB

Open AccessReview

Components of the Lectin Pathway of Complement in Haematologic Malignancies

by Maciej Cedzyński and Anna S. Świerzko

Cancers 2020, 12(7), 1792; https://doi.org/10.3390/cancers12071792 - 4 Jul 2020

Cited by 13 | Viewed by 4384

Abstract

The complement system is activated cascadically via three distinct major routes: classical pathway (CP), alternative pathway (AP) or lectin pathway (LP). The unique factors associated with the latter are collectins (mannose-binding lectin, collectin-10, collectin-11), ficolins (ficolin-1, ficolin-2, ficolin-3) and proteins of the mannose-binding lectin-associated serine protease (MASP) family (MASP-1, MASP-2, MASP-3, MAp19, MAp44). Collectins and ficolins are both pattern-recognising molecules (PRM), reactive against pathogen-associated molecular patterns (PAMP) or danger-associated molecular patterns (DAMP). The MASP family proteins were first discovered as complexes with mannose-binding lectin (MBL) and therefore named MBL-associated serine proteases, but later, they were found to interact with ficolins, and later still, collectin-10 and collectin-11. As well as proteolytic enzymes (MASP-1, MASP-2, MASP-3), the group includes non-enzymatic factors (MAp19, MAp44). In this review, the association-specific factors of the lectin pathway with haematologic malignancies and related infections are discussed. Full article

(This article belongs to the Special Issue Stem Cell Transplantation in Cancer Treatment)

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