[Second allogeneic (update). Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Deuxième allogreffe (mise à jour). Recommandations de la Société francophone de greffe de moelle osseuse et de thérapie cellulaire (SFGM-TC).

Relapse after allogeneic hematopoietic cell transplantation (allo-HCT) remains a major concern because it is associated with poor survival. A second allo-HCT is a valid option in this situation. During the 13th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to update the second allo-HCT recommendations elaborated during the previous workshop (2016). The main indication for a second allo-HCT remains relapse of initial hematologic malignancy. Disease status; complete remission (CR), and relapse time after the first allo-HCT>6 months impact positively the overall survival of patients after the second allo-HCT. Donor change is a valid option, particularly if there is HLA loss on leukemic cells after a first haploidentical or following a mismatched allo-HCT is documented. Reduced intensity conditioning is recommended, while a sequential protocol is a reasonable option in patients with proliferative disease. A post-transplant maintenance strategy after hematological recovery is recommended as soon as day 60, even if the immunosuppressive treatment has not yet been stopped. Hypomethylating agents, and targeted therapies such as anti FLT3, anti BCL2, anti-IDH1/2, TKI, anti-TP53, anti-CD33, anti-CD19, anti-CD22, anti-CD30, check point inhibitors, and CAR-T cells can be used as a bridge to transplant or as an alternative treatment to the second allo-HCT.

A deep dive into future therapies for microcytic anemias and clinical considerations.

INTRODUCTION: Microcytic anemias (MA) have frequent or rare etiologies. New discoveries in understanding and treatment of microcytic anemias need to be reviewed. AREAS COVERED: Microcytic anemias with a focus on the most frequent causes and on monogenic diseases that are relevant for understanding biocellular mechanisms of MA. All treatments except gene therapy, with a focus on recent advances. PubMed search with references selected by expert opinion. EXPERT OPINION: As the genetic and cellular backgrounds of dyserythropoiesis will continue to be clarified, collaboration with bioengineering of treatments acting specifically at the protein domain level will continue to provide new therapies in hematology as well as oncology and neurology.

A 16-month-long experience of COVID-19 in allogeneic haematopoietic stem cell transplantation recipients: An SFGM-TC multicentre cohort study.

This 16-month-long multicentre retrospective study of 225 allogeneic haematopoietic stem cell transplantation (alloHSCT) recipients with COVID-19 examines risk factors for severity and mortality, describing the successive waves of infections (from March to June 2020 and from August 2020 to June 2021). We confirm the negative role of low respiratory tract disease and immunosuppressive treatment. We highlight significantly lower percentages of severe forms and COVID-19-related mortality during the second wave. Monthly comparative evolution of cases in alloHSCT recipients and in the French population shows a higher number of cases in alloHSCT recipients during the first wave and a decrease from February 2021.

Targeting Serotonin With Common Antidepressants Induces Rapid Recovery From Cytopenia.

The hematopoietic system uses several, yet undiscovered, factors to adapt to stresses such as chemotherapy, infections, or bleeding. Serotonin is commonly known as a neurotransmitter but is also produced and used in peripheral organs. In particular, we have shown that serotonin synthesized in the bone marrow is necessary for erythroid progenitors' survival and proliferation. Serotonin levels can be increased by FDA approved antidepressants called selective serotonin reuptake inhibitors (SSRI). In this work, we report a previously unknown role of SSRI in the recovery of cytopenia, after autologous hematopoietic stem cell transplantation in patients and after sub-lethal irradiation in mice. We also observed an unexpected cooperation between SSRI and G-CSF on the improvement of the 3 hematopoietic lineages. Of note, SSRI do not seem to affect blood cells production in the absence of stress-induced hematopoiesis. We propose that the serotonergic system could be a valuable therapeutic target in stress-induced cytopenia, especially as a rescue after radiation or chemotherapy.

Neuropilin-1 cooperates with PD-1 in CD8+ T cells predicting outcomes in melanoma patients treated with anti-PD1.

Targeting immune checkpoints, such as Programmed cell Death 1 (PD1), has improved survival in cancer patients by restoring antitumor immune responses. Most patients, however, relapse or are refractory to immune checkpoint blocking therapies. Neuropilin-1 (NRP1) is a transmembrane glycoprotein required for nervous system and angiogenesis embryonic development, also expressed in immune cells. We hypothesized that NRP1 could be an immune checkpoint co-receptor modulating CD8+ T cells activity in the context of the antitumor immune response. Here, we show that NRP1 is recruited in the cytolytic synapse of PD1+CD8+ T cells, cooperates and enhances PD-1 activity. In mice, CD8+ T cells specific deletion of Nrp1 improves anti-PD1 antibody antitumor immune responses. Likewise, in human metastatic melanoma, the expression of NRP1 in tumor infiltrating CD8+ T cells predicts poor outcome of patients treated with anti-PD1. NRP1 is a promising target to overcome resistance to anti-PD1 therapies.

Evaluation of prognostic scores for respiratory syncytial virus infection in a French multicentre cohort of allogeneic haematopoietic stem cell transplantation recipients.

Haematopoietic stem cell transplantation (HSCT) recipients are at risk for severe respiratory syncytial virus (RSV) infection. Two prognostic scores have been proposed to predict the risk of progression from upper respiratory tract infection (URTI) to lower respiratory tract infection (LRTI) and death. This was a multicentre study of allogeneic HSCT recipients diagnosed with an RSV infection between 2010 and 2019 who were retrospectively stratified by the immunodeficiency scoring index (ISI) and the severe immunodeficiency (SID) score. Endpoints were overall survival, RSV-attributable mortality and progression to LRTI after URTI. Prognostic analyses were performed using Cox regression models. We included 147 consecutive patients, including 94 (63.9%) initially diagnosed with URTI and 53 (36.1%) with LRTI. At 90 days, 14 patients had died (survival rate, 90.5%; 95% CI: 85.9-95.3), and nine deaths were attributable to RSV (attributable mortality rate, 5.4%; 95% CI: 2.5-10.0). The cumulative 90-day incidence of LRTI after URTI was 13.8% (95% CI: 7.8-21.6). Neither score showed prognostic value for mortality, while the ISI allowed the prediction of progression to LRTI (p = 0.0008). Our results do not fully replicate the results previously reported in cohorts of HSCT recipients. This may reflect the recent epidemiology of RSV infections in this HSCT cohort.

[Establishment of Hematopoietic cell transplantation program in developing countries : Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Mise en place d'un programme de greffe de cellules souches hématopoïétiques dans les pays en voie de développement. Recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Hematopoietic cell transplantation (HCT) is the curative treatment for many malignant and non-malignant blood disorders and some solid cancers. However, transplant procedures are considered tertiary level care requiring a high degree of technicality and expertise and generating very high costs for hospital structures in developing countries as well as for patients without health insurance. During the 11th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines, for developing the transplant activity in emerging countries. Access to infrastructure must comply with international standards and therefore requires a hospital system already in place, capable of accommodating and supporting the HCT activity. In addition, the commitment of the state and the establishment for the financing of the project seems essential.

Treatment for pure red cell aplasia after major ABO-incompatible allogeneic stem cell transplantation: a multicentre study.

Pure red cell aplasia (PRCA) following allogeneic haematopoietic stem cell transplantation (aHSCT) with major ABO incompatibility is responsible for transfusion dependent anaemia, impaired quality of life and iron overload. We conducted a retrospective study, over a 10-year period, which included all consecutive patients who received a major ABO mismatched aHSCT, to assess the impact of specific treatment on PRCA. We did not observe any PRCA in the 57 aHSCT issued from cord blood. Among the remaining 631 patients, cumulative incidence of PRCA was 10·5% [range 8·2-13.0]. The median duration of resolved PRCA was 171 days [IQR 116; 261]. Pre-transplant high isohaemagglutinins titre was associated with an increased risk of PRCA (P < 10-4 ). PRCA did not affect overall survival (P = 0·95). Twenty-two patients (33·3%) received at least one specific treatment. The most commonly used treatments were rituximab (17 patients) and donor lymphocyte infusion (DLI; seven patients). Regarding PRCA resolution, we did not observe a significant difference between treated or untreated subjects (HR = 0·93, 95% confidence interval (CI) 0·48- 1·80; P = 0·82). Similar results were observed with erythropoietin treatment (22 patients, HR = 0·86 95% CI: [0·47-1·57] P = 0·62). Our data do not support the use of erythropoietin, rituximab or DLI for the treatment of PRCA.

Donor Lymphocyte Infusions After Allogeneic Transplantation: A Single-Center Experience.

Allogeneic hematopoietic cell transplantation (AHCT) represents the only curative therapy for many hematological malignancies. The graft versus leukemia effect, driven by donor T cells, plays a major role in its curative potential. This effect is sometimes very evident when patients with acute myeloid leukemia and myelodysplasia relapse after AHCT and are treated with donor lymphocyte infusions (DLIs). We retrospectively reviewed the charts of 64 patients who received DLI between 2012 and 2017 in our center. The mean age of the patients was 59 years (range, 34-79). Fifty percent were male (n = 32). The mean follow-up time after AHCT was 50.17 months (range, 8-174). The indication for DLI were disease progression, mixed chimerism, minimal residual disease, and other etiologies in 43.8%, 40.7%, 14%, and 1.5% of patients, respectively. The most common diagnosis was acute leukemia, followed by multiple myeloma. Of all patients, 59.4% received a transplant from a related donor, 39% received a transplant from an unrelated donor, and 1.6% received a transplant from a haploidentical donor. Reduced-intensity conditioning AHCT was the most frequent regimen used (53%). DLI was given alone in 79.7% of patients. Prophylactic DLI was given at 30 days after transplantation in patients who received human leukocyte antigen (HLA)-matched related human stem cell transplantation (HSCT) or 45 to 60 days post-transplant in patients receiving haploidentical HSCT or HLA-matched unrelated HSCT. Patients were treated without graft versus host disease (GVHD) prophylaxis. The use of DLI after transplantation remains a feasible procedure with rates of response >60%. Moreover, DLIs are well tolerated with a GVHD rate <10% in our series. We can hypothesize that in our experience the efficacy of this strategy does not rely on the induction of GVHD.

A monocentric study of steroid-refractory acute graft-versus-host disease treatment with tacrolimus and mTOR inhibitor.

Acute graft-versus-host disease (aGVHD) remains one of the leading causes of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. No consensus exists on the best second-line treatment of steroid-refractory acute GVHD (SR-aGVHD). Previously published smaller studies on the use of sirolimus in SR-aGVHD treatment report a response rate of 57 to 86%, with 40% overall survival. The association of tacrolimus and mTOR inhibitor is supported by pre-clinical data and has been used as GVHD prophylaxis. We report 42 patients who received tacrolimus and mTOR inhibitor as a second- or third-line treatment of SR-aGVHD. Thirty-one patients were treated in second-line, with an overall response rate of 48.5% (complete response: 42%). Eleven patients were treated in third-line, with an overall response rate of 27%. Thirty-eight patients had at least one episode of infection, due to bacteria, viruses, fungi and parasites in 61, 42, 12 and two episodes, respectively. For patients treated in second-line, six-month and one-year survival were 61% and 42%, respectively. None of the patients treated in third-line survived. These results were not promising enough to initiate a phase three randomized clinical trial, but tacrolimus and mTOR inhibitor can be discussed among other options for patients with SR-aGVHD.

Serotonin and orthodontic tooth movement.

Peripheral serotonin continuously reveals its unexpected involvements in many organ functions. In bone tissue, there is an increasing evidence for a local serotonergic system affecting the cellular and molecular actors involved in bone turnover. During orthodontic treatment, tooth movement relies on bone remodeling, itself a result of the inflammatory process triggered by application of orthodontic forces to the teeth. Nowadays, many adults proceed to an orthodontic treatment, it therefore seems important to consider physiological growth-related factors and external factors as medications that may influence adverse effects and efficacy of orthodontic treatment techniques. In this review, we focus on peripheral serotonin mechanism of regulation of bone remodeling during orthodontic movement. We discuss the differential effect of serotonin on alveolar bone inflammation that may open new strategies in orthodontics.

Enhanced Renewal of Erythroid Progenitors in Myelodysplastic Anemia by Peripheral Serotonin.

Tryptophan as the precursor of several active compounds, including kynurenine and serotonin, is critical for numerous important metabolic functions. Enhanced tryptophan metabolism toward the kynurenine pathway has been associated with myelodysplastic syndromes (MDSs), which are preleukemic clonal diseases characterized by dysplastic bone marrow and cytopenias. Here, we reveal a fundamental role for tryptophan metabolized along the serotonin pathway in normal erythropoiesis and in the physiopathology of MDS-related anemia. We identify, both in human and murine erythroid progenitors, a functional cell-autonomous serotonergic network with pro-survival and proliferative functions. In vivo studies demonstrate that pharmacological increase of serotonin levels using fluoxetine, a common antidepressant, has the potential to become an important therapeutic strategy in low-risk MDS anemia refractory to erythropoietin.

Serotonin, hematopoiesis and stem cells.

A large number of studies have focused on the role of serotonin as a neurotransmitter in the central nervous system, although only a small percentage of the body's serotonin (∼5%) can be found in the mature brain of mammals. In the gut, the enterochromaffin cells are scattered in the enteric epithelium from the stomach through the colon and produce over 95% of the body's serotonin. Since the generation of tryptophan hydroxylase (Tph1 and Tph2) knockout mice, unsuspected roles have been identified for serotonin synthesized outside the brain. Moreover, the murine model deficient in peripheral serotonin (Tph1-/-) is a unique experimental tool for exploring the molecular and cellular mechanisms involving serotonin's local effects through microserotonergic systems. In this review, we focus on peripheral serotonin and its role on progenitor or stem cells as well as on hematopoietic progenitors. We discuss the possible role of serotonin in hematopoietic diseases, and whether targeting the serotonergic system could be of therapeutic value for the regulation of normal and pathological hematopoiesis.

Human CD4- invariant NKT lymphocytes regulate graft versus host disease.

Despite increasing evidence for a protective role of invariant (i) NKT cells in the control of graft-versus-host disease (GVHD), the mechanisms underpinning regulation of the allogeneic immune response in humans are not known. In this study, we evaluated the distinct effects of human in vitro expanded and flow-sorted human CD4+ and CD4- iNKT subsets on human T cell activation in a pre-clinical humanized NSG mouse model of xenogeneic GVHD. We demonstrate that human CD4- but not CD4+ iNKT cells could control xenogeneic GVHD, allowing significantly prolonged overall survival and reduced pathological GVHD scores without impairing human T cell engraftment. Human CD4- iNKT cells reduced the activation of human T cells and their Th1 and Th17 differentiation in vivo. CD4- and CD4+ iNKT cells had distinct effects upon DC maturation and survival. Compared to their CD4+ counterparts, in co-culture experiments in vitro, human CD4- iNKT cells had a higher ability to make contacts and degranulate in the presence of mouse bone marrow-derived DCs, inducing their apoptosis. In vivo we observed that infusion of PBMC and CD4- iNKT cells was associated with decreased numbers of splenic mouse CD11c+ DCs. Similar differential effects of the iNKT cell subsets were observed on the maturation and in the induction of apoptosis of human monocyte-derived dendritic cells in vitro. These results highlight the increased immunosuppressive functions of CD4-versus CD4+ human iNKT cells in the context of alloreactivity, and provide a rationale for CD4- iNKT selective expansion or transfer to prevent GVHD in clinical trials.

[Hodgkin lymphoma: Current and future therapeutic strategies]. / Le lymphome de Hodgkin : stratégies thérapeutiques actuelles et futures.

Hodgkin lymphoma (HL) is a cancer that mostly affects young people, in which modern therapeutic strategies using chemotherapy and radiotherapy result in a cure rate exceeding 80%. Survivors are exposed to long-term consequences of treatments, such as secondary malignancies and cardiovascular diseases, whose mortality exceeds the one of the disease itself, with long-term follow-up. The current therapeutic strategy in HL, based on the assessment of initial risk factors, is the result of large clinical trials led by the main international cooperating groups. More recently, several groups have tried to develop treatment strategies adapted to the response to chemotherapy, evaluated by interim PET/CT scan. However to date, the combined treatment with chemotherapy followed by radiation therapy remains a standard in most of the above-diaphragmatic localized forms. Immune checkpoint inhibitors, and especially anti-PD1 antibodies, have shown dramatic results in some serious forms of relapsed or refractory HL, with limited toxicity, and may contribute in the future to reduce the toxicities of treatments.