We are delighted to present the Rising Stars: Cell and Stem Cell Transplantation 2022 article collection. This collection showcases the high-quality work of internationally recognized researchers in the early stages of their independent careers. All Rising Star researchers were individually nominated by the Frontiers in Transplantation editors in recognition of their potential to influence the future directions in their respective fields. The work presented here highlights the diversity of research performed across the entire breadth of Cell and Stem Cell Transplantation and presents advances in theory, experiment and methodology with applications to compelling problems. New articles will be added to this collection as they are published.

San Raffaele Hospital (IRCCS)

Frontiers in Transplantation

Cell and Stem Cell Transplantation

Rising Stars: Cell and Stem Cell Transplantation 2022

Editorial on the Research Topic <a href="https://www.frontiersin.org/research-topics/38267/rising-stars-cell-and-stem-cell-transplantation-2022">Rising stars: cell and stem cell transplantation 2022</a>The Research Topic &#x201c;Rising Stars in Cell and Stem Cell Transplantation&#x201d; includes authors from different countries and serves as a forum for new directions and emerging trends in the field of hematopoietic stem cell transplantation (HSCT) and cellular therapies.This Research Topic includes a heterogeneous set of topics, spanning from allogeneic HSCT to chimeric antigen receptor (CAR) T cells, and potential complications such as graft versus host disease (GvHD), infections and hepatic veno-occlusive disease (VOD).The Research Topic starts with the brief research report from <a href="https://doi.org/10.3389/frtra.2023.1149393">El Cheikh et al.</a>, describing the experience of a transplant center in Lebanon with haploidentical HSCT for hematological malignancies in adult patients.Numbers of HSCT in Europe and globally is rising, thanks to the massive expansion of transplant technology, including the notable developments in haploidentical HSCT with rapid donor availability (<a href="#B1">1</a>). Moreover, the use of post-transplant cyclophosphamide (PT-Cy) (<a href="#B2">2</a>) and reduced intensity conditioning (RIC) regimens (<a href="#B3">3</a>) improved outcomes, expanded transplant procedure to frail/older candidates and decreased toxicities. In this paper, they reported encouraging results with haploidentical HSCT and PT-Cy as GvHD prophylaxis, confirming the feasibility of such approaches also in the Middle East and encouraging its implementation to centers across different countries.The next manuscript reported the successful use of CAR-T cell therapy despite bacterial, fungal and Coronavirus disease 2019 (COVID-19) infections. Patients undergoing CAR-T cell therapy are often profoundly immunosuppressed from prior treatments and by concomitant hypogammaglobulinemia. These factors may increase the overall infection risk following cell infusion (<a href="#B4">4</a>). <a href="https://doi.org/10.3389/frtra.2023.1238494">Radici et al.</a> reported the case report of a patient affected by refractory mantle cell lymphoma achieving complete metabolic remission after Brexucel. During the treatment course, the patient experienced multiple infectious complications, including pulmonary aspergillosis, co-infections by Stenotrophomonas maltophilia and COVID-19. Early initiation of supportive therapies and dexamethasone contributed to the control and resolution of these infections. This case reflects the importance of personalized decision-making and the potential benefits of CAR-T cell therapy in high-risk patients. Importantly, the advances made in the management of unforeseeable emergency conditions—such as the COVID-19 pandemic- now make it possible to ensure an adequate course of care for patients who are candidates for cell therapies (CAR-T/HSCT) where the time factor does not allow for postponement.Finally, the Research Topic approached the impact of major complications on transplant outcomes, driving the reader into a manuscript able to provide a detailed and updated insight on GvHD and VOD.Transplant outcome has progressively improved over time (<a href="#B5">5</a>). However, GvHD remains one of the major life-threatening complications after allogeneic HSCT, mainly in case of severe and refractory forms (<a href="#B6">6</a>, <a href="#B7">7</a>). The focus of the review by <a href="https://doi.org/10.3389/frtra.2023.1251112">Gottardi et al.</a> is the treatment of steroid refractory GvHD in children. In the pediatric setting, consolidated evidence regarding GvHD treatments is still lacking, and results are mainly derived from experiences on adult patients. Furthermore, the number of treated patients is limited, and the incidence of acute and chronic GvHD is lower, contributing to a very heterogeneous approach of this complication in this peculiar setting. Some therapies adopted in the adult setting have been evaluated also in children. Moreover, recently the increasing understanding of GvHD pathogenesis encouraged the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive side effects. This Review critically explores the current experience on novel approaches to treat refractory GvHD within a pediatric setting.Furthermore, the last article showcases a new screening approach to early identify patients at risk for hepatic VOD, also known as sinusoidal obstructive syndrome (SOS), a potentially life-threatening complication following HSCT procedure. During the decade, VOD/SOS was associated to decreased mortality rates, thanks to early intensive and multidisciplinary approaches (<a href="#B8">8</a>). The brief research report from <a href="https://doi.org/10.3389/frtra.2022.996003">Avenoso et al.</a> explores a new approach based on a focused VOD/SOS ward round, aiming to provide an early diagnosis of VOD/SOS, with prompt identification of patients at risk. In their experience they reported a rapid identification of patients with multiple risk factors for VOD/SOS, allowing an earlier diagnosis and the administration of specific treatment with defibrotide on the same day of diagnosis. Moreover, this approach may have high educational value for the health care professionals working within transplant services.In conclusion, we hope that the readers appreciate the varied research included in this Research Topic, &#x201c;Rising Stars in Cell and Stem Cell Transplantation&#x201d;. The editorial team put substantial effort into screening and evaluating the high-quality manuscripts produced by researchers and their groups. We hope that this Research Topic will aid in the efforts to foster collaboration among researchers, as this is crucial element in the progression of research and science.RG: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing. ML: Writing &#x2013; original draft, Writing &#x2013; review &amp; editing.The topic editors would like to acknowledge all the authors who participated in this Research Topic.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

Editorial: Rising stars: cell and stem cell transplantation 2022

BackgroundThe COVID-19 pandemic has had a significant impact on the management and care of onco-hematological patients, particularly those with lymphoproliferative disorders who are at higher risk for COVID-19 associated bacterial and fungal superinfections.</sec>Case presentationWe present the successful treatment of a 44-year-old male patient with refractory mantle cell lymphoma treated with chimeric antigen receptor T (CAR-T) cell therapy, despite concurrent COVID-19 infection. The patient developed grade II cytokine release syndrome, requiring admission to the intensive care unit. The CAR-T cells expanded effectively, and the patient achieved complete metabolic remission. During the treatment course, the patient experienced complications including COVID-19-associated pulmonary aspergillosis and a co-infection with Stenotrophomonas maltophilia and the SARS-CoV-2 omicron variant. Prompt antifungal and antibacterial therapy, along with appropriate COVID-19 treatment, led to the resolution of these infections. Dexamethasone was also administered to reduce inflammation and aid hematologic recovery. Despite the presence of multiple infections, the patient achieved complete remission of lymphoma, highlighting the effectiveness of CAR-T cell therapy in this high-risk patient.</sec>ConclusionDespite the challenges posed by concurrent infections, the decision to proceed with CAR-T cell therapy in this patient proved to be successful, resulting in complete remission of lymphoma. Early initiation of supportive therapies and the use of dexamethasone contributed to the resolution of complications. This case underscores the importance of individualized decision-making and the potential benefits of CAR-T cell therapy in similar high-risk patients.</sec>

Background: The COVID-19 pandemic has had a significant impact on the management and care of onco-hematological patients, particularly those with lymphoproliferative disorders who are at higher risk for COVID-19 associated bacterial and fungal superinfections.Case presentation: We present the successful treatment of a 44-year-old male patient with refractory mantle cell lymphoma treated with chimeric antigen receptor T (CAR-T) cell therapy, despite concurrent COVID-19 infection. The patient developed grade II cytokine release syndrome, requiring admission to the intensive care unit. The CAR-T cells expanded effectively, and the patient achieved complete metabolic remission. During the treatment course, the patient experienced complications including COVID-19-associated pulmonary aspergillosis and a co-infection with Stenotrophomonas maltophilia and the SARS-CoV-2 omicron variant. Prompt antifungal and antibacterial therapy, along with appropriate COVID-19 treatment, led to the resolution of these infections. Dexamethasone was also administered to reduce inflammation and aid hematologic recovery. Despite the presence of multiple infections, the patient achieved complete remission of lymphoma, highlighting the effectiveness of CAR-T cell therapy in this high-risk patient.Conclusion: Despite the challenges posed by concurrent infections, the decision to proceed with CAR-T cell therapy in this patient proved to be successful, resulting in complete remission of lymphoma. Early initiation of supportive therapies and the use of dexamethasone contributed to the resolution of complications. This case underscores the importance of individualized decision-making and the potential benefits of CAR-T cell therapy in similar high-risk patients.

Successful CAR-T cell therapy in a refractory MCL patient with bacterial, fungal and COVID-19 infection: a case report

Systemic steroids are still the first-line approach in acute graft-versus-host disease (aGvHD), and the backbone of chronic GvHD management. Refractoriness to steroid represent a major cause of morbidity and non-relapse mortality after hematopoietic stem cell transplantation (HSCT). In both backgrounds, several second-line immunosuppressive agents have been tested with variable results in terms of efficacy and toxicity. Solid evidence regarding these approaches is still lacking in the pediatric setting where results are mainly derived from adult experiences. Furthermore, the number of treated patients is limited and the incidence of acute and chronic GvHD is lower, resulting in a very heterogeneous approach to this complication by pediatric hematologists. Some conventional therapies and anti-cytokine monoclonal antibodies used in the adult setting have been evaluated in children. In recent years, the increasing understanding of the biological mechanisms underpinning the pathogenesis of GvHD justified the efforts toward the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive effects. Moreover, many questions regarding the precise timing and setting in which to integrate these new approaches remain unanswered. This Review aims to critically explore the current evidence regarding novel approaches to treat SR-GvHD in pediatric HSCT recipients.

Systemic steroids are still the first-line approach in acute graft-versus-host disease (aGvHD), and the backbone of chronic GvHD management. Refractoriness to steroid represent a major cause of morbidity and non-relapse mortality after hematopoietic stem cell transplantation (HSCT). In both backgrounds, several second-line immunosuppressive agents have been tested with variable results in terms of efficacy and toxicity. Solid evidence regarding these approaches is still lacking in the pediatric setting where results are mainly derived from adult experiences. Furthermore, the number of treated patients is limited and the incidence of acute and chronic GvHD is lower, resulting in a very heterogeneous approach to this complication by pediatric hematologists. Some conventional therapies and anti-cytokine monoclonal antibodies used in the adult setting have been evaluated in children. In recent years, the increasing understanding of the biological mechanisms underpinning the pathogenesis of GvHD justified the efforts toward the adoption of targeted therapies and non-pharmacologic approaches, with higher response rates and lower immunosuppressive effects. Moreover, many questions regarding the precise timing and setting in which to integrate these new approaches remain unanswered. This Review aims to critically explore the current evidence regarding novel approaches to treat SR-GvHD in pediatric HSCT recipients.

Treatment of steroid-refractory graft versus host disease in children

This letter describes the experience of the American University of Beirut Medical Center in Lebanon with haploidentical stem cell transplant (haplo-SCT) for hematological malignancies in adult patients. Haplo-SCT made it possible through universal and rapid donor availability for most of the adult patients with leukemia or lymphoma not only in the Middle East but also globally. Moreover, the use of post-transplant cyclophosphamide (PTCy) and reduced intensity conditioning (RIC) regimens when indicated improved the outcome and decreased the toxicity of haploidentical stem cell transplant.RIC regimens also allowed its use in the elderly population. Patients from throughout the Middle East come to our center, the American university of Beirut Medical Center, to receive this transformative type of stem cell transplant. In this paper, we discuss the results of haplo-SCT with PTCy done on adult patients with hematological malignancies in our center from 2015 to 2021. The results are encouraging and show that haplo-SCT should be considered more often in the Middle Eastern countries. The subgroup analysis showed the importance of achieving complete remission of the disease prior to transplant to improve outcomes in our center. There is a paucity of literature on the outcomes of haplo-SCT in the Middle East which may contribute to the limited number of centers that offer this type of SCT. Herein, we aim to fill this gap in the hopes of encouraging the implementation of this potentially curative modality of treatment to a larger extent in the Middle East.

This letter describes the experience of the American University of Beirut Medical Center in Lebanon with haploidentical stem cell transplant (haplo-SCT) for hematological malignancies in adult patients. Haplo-SCT made it possible through universal and rapid donor availability for most of the adult patients with leukemia or lymphoma not only in the Middle East but also globally. Moreover, the use of post-transplant cyclophosphamide (PTCy) and reduced intensity conditioning (RIC) regimens when indicated improved the outcome and decreased the toxicity of haploidentical stem cell transplant.RIC regimens also allowed its use in the elderly population. Patients from throughout the Middle East come to our center, the American university of Beirut Medical Center, to receive this transformative type of stem cell transplant. In this paper, we discuss the results of haplo-SCT with PTCy done on adult patients with hematological malignancies in our center from 2015 to 2021. The results are encouraging and show that haplo-SCT should be considered more often in the Middle Eastern countries. The subgroup analysis showed the importance of achieving complete remission of the disease prior to transplant to improve outcomes in our center. There is a paucity of literature on the outcomes of haplo-SCT in the Middle East which may contribute to the limited number of centers that offer this type of SCT. Herein, we aim to fill this gap in the hopes of encouraging the implementation of this potentially curative modality of treatment to a larger extent in the Middle East.

Haploidentical stem cell transplantation with post-transplant cyclophosphamide challenges and outcome from a tertiary care center in Lebanon

Sinusoidal obstructive syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a potentially life-threatening complication following haemopoietic stem cell transplantation (HSCT). The availability of new drugs for malignant hematological conditions has allowed more patients to be eligible for allogeneic haematopoietic stem cell transplants, which has translated into a significant proportion of transplant patients having multiple risk factors for VOD/SOS. Based on these considerations, we undertook a dedicated weekly VOD/SOS ward round, aiming to facilitate early diagnosis of VOD/SOS and pre-emptively identify patients at risk, where a careful evaluation of differential diagnosis is essential. Herein, we present the results of our VOD/SOS ward round; between September 2020 and April 2022, 110 consecutive patients were evaluated in a focused VOD/SOS ward round. From the 110 patients, 108 had undergone HSCT and had at least one known risk factor for developing VOD/SOS. The median number of risk factors present in the VOD/SOS group and non-VOD/SOS group was five (range: three to six) and three (range: zero to seven), respectively. Late-onset VOD/SOS was diagnosed in 45% of our patients. The early identification of patients with multiple risk factors for VOD/SOS allowed an earlier diagnosis and the administration of defibrotide on the same day of diagnosis, which was two days earlier than our previous experience prior to the implementation of this protocol.

Sinusoidal obstructive syndrome (SOS), also known as hepatic veno-occlusive disease (VOD), is a potentially life-threatening complication following haemopoietic stem cell transplantation (HSCT). The availability of new drugs for malignant hematological conditions has allowed more patients to be eligible for allogeneic haematopoietic stem cell transplants, which has translated into a significant proportion of transplant patients having multiple risk factors for VOD/SOS. Based on these considerations, we undertook a dedicated weekly VOD/SOS ward round, aiming to facilitate early diagnosis of VOD/SOS and pre-emptively identify patients at risk, where a careful evaluation of differential diagnosis is essential. Herein, we present the results of our VOD/SOS ward round; between September 2020 and April 2022, 110 consecutive patients were evaluated in a focused VOD/SOS ward round. From the 110 patients, 108 had undergone HSCT and had at least one known risk factor for developing VOD/SOS. The median number of risk factors present in the VOD/SOS group and non-VOD/SOS group was five (range: three to six) and three (range: zero to seven), respectively. Late-onset VOD/SOS was diagnosed in 45% of our patients. The early identification of patients with multiple risk factors for VOD/SOS allowed an earlier diagnosis and the administration of defibrotide on the same day of diagnosis, which was two days earlier than our previous experience prior to the implementation of this protocol.

Systematic screening and focused evaluation for veno-occlusive disease/sinusoidal obstructive syndrome (VOD/SOS) following allogeneic stem cell transplant is associated with earlier diagnosis and prompt institution of defibrotide treatment