[Is there a place for granulocytes transfusions in 2023 ?] / Y a-t-il une place pour les transfusions de granulocytes en 2023 ?

Despite modern antimicrobial treatments, bacterial and fungal infections remain major complications in neutropenic patients. Granulocyte transfusions appeared in the 1950s-60s but first clinical trials were limited by the difficulty of transfusing enough viable granulocytes. The refinement of apheresis techniques as well as donor pretreatment with corticosteroids and/or granulocyte colony-stimulating growth factor (G-CSF) have led to improved collection yield. Despite this, uncertainties remain regarding the real clinical usefulness of granulocyte transfusions. Few studies have been carried out since the G-CSF era and the quality of scientific evidence remains low, mainly because of small case series. The largest prospective randomized controlled study published so far failed to demonstrate any benefit of therapeutic granulocyte transfusions on mortality or infection control. However, the quality of this trial is limited due to its low statistical power (insufficient patient recruitment). Moreover, granulocyte transfusions are complex procedures, burdensome for the donor, expensive and associated with a significant risk of adverse effects. Therefore, the current place of granulocyte transfusion in clinical practice is guided by the experience of each center. With the increasing emergence of multi-resistant germs, it is likely that granulocyte transfusion will become interesting in the coming years. Standardization of collection and administration procedures and the final proof of their (in)effectiveness will remain the challenges for the future.

En dépit des traitements antimicrobiens modernes, les infections bactériennes et fongiques restent des complications majeures chez les patients neutropéniques. Les transfusions de granulocytes (TG) sont apparues dans les années 1950-1960, mais les premiers essais cliniques ont été limités par la difficulté de transfuser un nombre suffisant de granulocytes viables. Le perfectionnement des techniques d'aphérèse ainsi que la stimulation pharmacologique du donneur par corticostéroïdes et/ou facteur de croissance granulocytaire (G-CSF) ont permis d'améliorer le rendement des collectes. Malgré cela, des incertitudes subsistent quant à la réelle utilité clinique des TG. Peu d'études ont été réalisées depuis l'ère du G-CSF et la qualité des preuves scientifiques reste faible. La plus large étude prospective contrôlée randomisée publiée à ce jour n'a pas pu démontrer de bénéfice des TG sur la mortalité ou le contrôle des infections. Cependant, la valeur de cet essai est limitée en raison de sa faible puissance statistique (recrutement de patients insuffisant). De plus, les TG sont des procédures complexes, lourdes pour le donneur, coûteuses et associées à un risque non négligeable d'effets indésirables. Par conséquent, la place actuelle des TG dans la pratique clinique est principalement guidée par l'expérience de chaque centre. Avec l'émergence croissante de germes multirésistants, il est probable que les TG suscitent à nouveau l'intérêt dans les années à venir. Les défis seront de parvenir à une détermination définitive de leur (in)efficacité et d'uniformiser les procédures de collecte et d'administration.

Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft-versus-host disease prophylaxis.

Graft-versus-host disease (GVHD) is a major cause of toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). While rapamycin (RAPA) is commonly used in GVHD prophylaxis in combination with a calcineurin inhibitor (CNI), the understanding of its mechanism of action on human T cells is still incomplete. Here, we performed an extensive analysis of RAPA effects on human T cells in a humanized mouse model of GVHD, in ex-vivo T cell cultures and in patients given RAPA plus tacrolimus as GVHD prophylaxis after nonmyeloablative allo-HCT. We demonstrate that RAPA mitigates GVHD by decreasing T cell engraftment and differentiation, inhibiting CD8+ T cell activation and increasing the long-term IL-2 secretion, thereby supporting regulatory T cell (Treg) proliferation. In contrast, graft-versus-leukemia effects were not abrogated, as RAPA-treated T cells had increased resistance to apoptosis and retained their effector function and proliferative capacity upon re-stimulation. Importantly, we found that RAPA impact on Treg and CD8+ T cells was closely dependent upon IL-2 signaling and that therapeutic options interfering with IL-2, such as calcineurin inhibitors, antagonize the IL-2-dependent promotion of Treg mediated by RAPA. Our results suggest that RAPA immunological efficacy could be improved in combination with drugs having possible synergistic effects such as the hypomethylating agent 5-azacytidine.

In Vitro Th17-Polarized Human CD4+ T Cells Exacerbate Xenogeneic Graft-versus-Host Disease.

Acute graft-versus-host disease (aGVHD) is a severe complication of allogeneic hematopoietic stem cell transplantation. The role of Th17 cells in its pathophysiology remains a matter of debate. In this study, we assessed whether enrichment of human peripheral blood mononuclear cells (PBMCs) with in vitro Th17-polarized CD4+ T cells would exacerbate xenogeneic GVHD (xGVHD) into NOD-scid IL-2Rγ null (NSG) mice. Naive human CD4+ T cells were stimulated under Th17-skewing conditions for 8 to 10 days and then coinjected in NSG mice with fresh PBMCs from the same donor. We observed that Th17-polarized cells engrafted and migrated toward xGVHD target organs. They also acquired a double-expressing IL-17A+IFNγ+ profile in vivo. Importantly, cotransfer of Th17-polarized cells (1 × 106) with PBMCs (1 × 106) exacerbated xGVHD compared with transplantation of PBMCs alone (2 × 106). Furthermore, PBMC cotransfer with Th17-polarized cells was more potent for xGVHD induction than cotransfer with naive CD4+ T cells stimulated in nonpolarizing conditions (Th0 cells, 1 × 106 + 1 × 106 PBMCs) or with Th1-polarized cells (1 × 106 + 1 × 106 PBMCs). In summary, our results suggest that human Th17-polarized cells can cooperate with PBMCs and be pathogenic in the NSG xGVHD model.

[What is new in the management of multiple myeloma]. / Nouveautés dans la prise en charge du myélome.

Multiple myeloma is the second most frequent hematological malignancy. Unfortunately, it is still incurable. A better understanding of the myeloma pathophysiology favored the development of new therapeutic molecules that improved both survival and quality of life of patients. Diagnostic and prognostic criteria for myeloma have been reviewed and help to detect multiple myeloma more early and further help to define the best therapeutic strategy. These new regimens are associated with side effects that differ from those of classic molecules and that we have to be able to recognize and to treat appropriately.

Le myélome multiple est le second cancer hématologique le plus fréquent. Il reste malheureusement incurable à l'heure actuelle. Pourtant, ces deux dernières décennies ont été marquées par des progrès dans la compréhension de la physiopathologie du myélome, ce qui a permis le développement de nouvelles molécules thérapeutiques, améliorant la survie et la qualité de vie des patients. Les critères diagnostiques et pronostiques du myélome ont été revus et sont maintenant plus performants pour détecter des stades précoces et déterminer ainsi la stratégie thérapeutique à entreprendre. Les nouveaux régimes de traitement sont grevés d'un profil d'effets secondaires différent qu'il faut pouvoir reconnaître et traiter.

Long-term immune reconstitution and infection burden after mismatched hematopoietic stem cell transplantation.

Mismatched unrelated donor (MMUD) or umbilical cord blood (UCB) can be chosen as alternative donors for allogeneic stem cell transplantation but might be associated with long-lasting immune deficiency. Sixty-six patients who underwent a first transplantation from either UCB (n = 30) or 9/10 MMUD (n = 36) and who survived beyond 3 months were evaluated. Immune reconstitution was prospectively assessed at sequential time points after transplantation. NK, B, CD4(+), and CD8(+) T cells and their naïve and memory subsets, as well as regulatory T cells (Treg), were studied. Detailed analyses on infections occurring after 3 months were also assessed. The 18-month cumulative incidences of infection-related death were 8% and 3%, and of infections were 72% and 57% after MMUD and UCB transplantation, respectively. Rates of infection per 12 patient-month were roughly 2 overall (1 for bacterial, .9 for viral, and .3 for fungal infections). Memory, naïve CD4(+) and CD8(+)T cells, naïve B cells, and Treg cells reconstitution between the 2 sources were roughly similar. Absolute CD4(+)T cells hardly reached 500 per µL by 1 year after transplantation and most B cells were of naïve phenotype. Correlations between immune reconstitution and infection were then performed by multivariate analyses. Low CD4(+) and high CD8(+)T cells absolute counts at 3 months were linked to increased risks of overall and viral (but not bacterial) infections. When assessing for the naïve/memory phenotypes at 3 months among the CD4(+) T cell compartment, higher percentages of memory subsets were protective against late infections. Central memory CD4(+)T cells protected against overall and bacterial infections; late effector memory CD4(+)T cells protected against overall, bacterial, and viral infections. To the contrary, high percentage of effector- and late effector-memory subsets at 3 months among the CD8(+) T cell compartment predicted higher risks for viral infections. Patients who underwent transplantation from alternative donors represent a population with very high risk of infection. Detailed phenotypic analysis of immune reconstitution may help to evaluate infection risk and to adjust infection prophylaxis.

Pre-transplant prognostic factors of long-term survival after allogeneic peripheral blood stem cell transplantation with matched related/unrelated donors.

Mobilized peripheral blood has become the predominant stem cell source for allogeneic hematopoietic cell transplantation. In this retrospective single center study of 442 patients with hematologic malignancies, we analyzed prognostic factors for long-term survival after peripheral blood stem cell transplantation from HLA-matched related or unrelated donors. To account for disease/status heterogeneity, patients were risk-stratified according to the Disease Risk Index. Five-year overall survival was similar after transplants with matched related and unrelated donors (45% and 46%, respectively; P=0.49). Because donor age ≥60 years impacted outcome during model building, we further considered 3 groups of donors: matched unrelated (aged <60 years by definition), matched related aged <60 years and matched related aged ≥60 years. In multivariate analysis, the donor type/age group and the graft CD34(+) and CD3(+) cell doses impacted long-term survival. Compared with matched unrelated donor transplant, transplant from matched related donor <60 years resulted in similar long-term survival (P=0.67) while transplant from matched related donor ≥60 years was associated with higher risks for late mortality (hazard ratio (HR) 4.41; P=0.006) and treatment failure (HR: 6.33; P=0.009). Lower mortality risks were observed after transplant with CD34(+) cell dose more than 4.5×10(6)/kg (HR: 0.56; P=0.002) and CD3(+) cell dose more than 3×10(8)/kg (HR: 0.61; P=0.01). The Disease Risk Index failed to predict survival. We built an "adapted Disease Risk Index" by modifying risks for myeloproliferative neoplasms and multiple myeloma that improved stratification ability for progression-free survival (P=0.04) but not for overall survival (P=0.82).

Allogeneic stem cell transplantation for advanced cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and French Study Group on Cutaneous Lymphomas.

The treatment of advanced stage primary cutaneous T-cell lymphomas remains challenging. In particular, large-cell transformation of mycosis fungoides is associated with a median overall survival of two years for all stages taken together. Little is known regarding allogeneic hematopoietic stem cell transplantation in this context. We performed a multicenter retrospective analysis of 37 cases of advanced stage primary cutaneous T-cell lymphomas treated with allogeneic stem cell transplantation, including 20 (54%) transformed mycosis fungoides. Twenty-four patients (65%) had stage IV disease (for mycosis fungoides and Sézary syndrome) or disseminated nodal or visceral involvement (for non-epidermotropic primary cutaneous T-cell lymphomas). After a median follow up of 29 months, 19 patients experienced a relapse, leading to a 2-year cumulative incidence of relapse of 56% (95%CI: 0.38-0.74). Estimated 2-year overall survival was 57% (95%CI: 0.41-0.77) and progression-free survival 31% (95%CI: 0.19-0.53). Six of 19 patients with a post-transplant relapse achieved a subsequent complete remission after salvage therapy, with a median duration of 41 months. A weak residual tumor burden before transplantation was associated with increased progression-free survival (HR=0.3, 95%CI: 0.1-0.8; P=0.01). The use of antithymocyte globulin significantly reduced progression-free survival (HR=2.9, 95%CI: 1.3-6.2; P=0.01) but also transplant-related mortality (HR=10(-7), 95%CI: 4.10(-8)-2.10(-7); P<0.001) in univariate analysis. In multivariate analysis, the use of antithymocyte globulin was the only factor significantly associated with decreased progression-free survival (P=0.04). Allogeneic stem cell transplantation should be considered in advanced stage primary cutaneous T-cell lymphomas, including transformed mycosis fungoides.

Oral minocycline as systemic therapy for uncomplicated venous access device-related bloodstream infection with coagulase-negative staphylococci after allogeneic hematopoietic cell transplantation.

BACKGROUND: Venous access device-related bloodstream infection (VAD-BSI) with coagulase-negative staphylococci (CoNS) is a common complication after allogeneic hematopoietic cell transplantation (alloHCT). Standard systemic antimicrobial therapy for uncomplicated VAD-BSI with methicillin-resistant CoNS consists of intravenous (IV) vancomycin (vanco). This requires hospitalization, needs new competent venous access, exposes patients to potential toxicity (mainly renal) and increases the risk of commensal flora dysbiosis with selection of vanco-resistant enterococci. Combined with VAD management (removal or antibiotic locks), oral minocycline (mino) has been evaluated as an alternative systemic therapy for the treatment of uncomplicated VAD-BSIs with CoNS at our center, primarily when the reference treatment with IV vanco was not possible (renal failure or allergy) or when hospitalization was refused by patients. Here, we retrospectively report our single center experience with this mino-based approach. PATIENTS AND METHODS: From January 2012 to December 2020, 24 uncomplicated VAD-BSIs with CoNS in 23 alloHCT patients were treated with oral mino as systemic antibiotic therapy in combination with VAD management. VAD were implantable ports (n = 17), tunneled catheter (n = 1) or PIC-lines (n = 6). Staphylococci were S. epidermidis (n = 21) or S. haemolyticus (n = 3). Mino was administered with a loading dose of 200 mg followed by 100 mg BID for 7-14 days. For 8 VAD-BSIs, patients were initially treated with IV vanco for the first 1-3 days followed by oral mino, while 16 VAD-BSIs were treated with oral mino as the sole antimicrobial agent for systemic therapy. VAD management consisted of catheter removal (for tunneled catheters and PIC-lines, n = 7) or antibiotic locks with vanco (n = 15) or gentamicin (n = 2) administered at least 3 times a week for 14 days (for ports). RESULTS: Overall, clearance of bacteremia (as assessed by negativity for the same CoNS of surveillance peripheral blood cultures drawn between day+ 3 and +30 after initiation of systemic therapy) was achieved in all but 1 patient (with port) who had persistent bacteremia at day +9. No complication such as suppurative thrombophlebitis, endocarditis, distant foci of infection or BSI-related death was observed in any patient during the 3-month period after initiation of treatment. Regarding the 17 port-BSI cases for which VAD conservative strategy was attempted, failure of 3-month VAD preservation was documented in 7/17 cases and 3-month recurrence of VAD-BSI was observed in 3/17 cases (with 1 patient with cellulitis). Treatment with mino was well tolerated except for a mild skin rash in one patient. CONCLUSION: Further prospective studies are needed to evaluate efficacy and safety of this approach.

[Haematopoietic stem cell donation from minor donor: Respecting laws, assessing fitness, delivering information and good care (SFGM-TC)]. / Don de cellules souches hématopoïétiques à partir d'un donneur mineur : cadre réglementaire, information, évaluation de l'aptitude au don et parcours (SFGM-TC).

Haematopoietic stem cell collection from paediatric donors is a common and life-saving practice, as evidenced by the fact that there is a growing annual number of cases of transplants from minor donors among SFGM-TC centers over the last decade. Still, medical use of human tissue from a healthy and underage donor requires proper regulations and medical management. The guidelines below aim at underlining the importance of pondering the legal, medical and ethical aspects of using stem cells from healthy paediatric donors and stress out the importance of obtaining informed consent at the time of assessing HLA compatibility. Combined medical and psychological assessments are required before the donation, as well as one month later and one year later to ensure of the child's physical and mental wellbeing. Bone marrow harvest under general anaesthetics remains the preferred method of collection for children. Peripheral blood stem cell collection should only be considered for children who will not require a central venous access for collection. We aim at offering guidelines centered on the healthy child donating stem cells and his/her wellbeing, and these should be regularly reviewed as medical practices evolve.

Transplantation for myelofibrosis patients in the ruxolitinib era: a registry study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

In this SFGM-TC registry study, we report the results after stem cell transplantation (HSCT) in 305 myelofibrosis patients, in order to determine potential risk factors associated with outcomes, especially regarding previous treatment with ruxolitinib. A total of 102 patients were transplanted from an HLA-matched-sibling donor (MSD), and 143 patients received ruxolitinib. In contrast with previous studies, our results showed significantly worse outcomes for ruxolitinib patients regarding overall survival (OS) and non-relapse mortality (NRM), especially in the context of unrelated donors (URD). When exploring reasons for potential confounders regarding the ruxolitinib effect, an interaction between the type of donor and the use of ATG was found, therefore subsequent analyses were performed separately for each type of donor. Multivariable analyses did not confirm a significant negative impact of ruxolitinib in transplantation outcomes. In the setting of URD, only age and Fludarabine-Melphalan (FM) conditioning were associated with increased NRM. For MSD, only Karnoksfy <70% was associated with reduced OS. However, a propensity score analysis showed that ruxolitinib had a negative impact on OS but only in non-responding patients, consistent with previous data. To conclude, with all the precautions due to confounders and bias, ruxolitinib itself does not appear to increase mortality after HSCT.

Emerging drugs for prevention of graft failure after allogeneic hematopoietic stem cell transplantation.

INTRODUCTION: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the treatment of choice for many patients suffering from hematological malignancies, severe hemoglobinopathies, bone marrow failures or severe primary immunodeficiencies. Graft rejection/failure (GF) is a life-threatening complication following allo-HSCT that is most commonly caused by the reactivity of recipient T cells, natural killer (NK) cells or antibodies against donor grafted hematopoietic cells. The increasing use of allo-HSCT following reduced-intensity conditioning (RIC) and the increasing use of alternative donors (unrelated cord blood and human leukocyte antigen (HLA)-mismatched donor) have resulted in higher frequency of GF. AREAS COVERED: This review describes the pathogenesis and current prevention and treatment of GF as well as agents in development for GF prevention or treatment. EXPERT OPINION: The risk of GF may be reduced in the future by optimizing the conditioning regimens and post-grafting immunosuppression, increasing the number of hematopoietic stem cells (HSCs) and/or immune cells transplanted, optimizing HSC homing and better detecting patients at high risk of GF by searching for pre-transplant donor-specific anti-HLA antibodies in patients given grafts from HLA-mismatched donors, or by closely monitoring donor T- and/or NK-cell chimerism after allo-HSCT following RIC.

Darbepoetin-alfa and intravenous iron administration after autologous hematopoietic stem cell transplantation: a prospective multicenter randomized trial.

We conducted a randomized study analyzing the impact of darbepoetin alfa (DA) administration with or without intravenous (i.v.) iron on erythroid recovery after autologous hematopoietic cell transplantation (HCT). Patients were randomized between no DA (Arm 1), DA 300 µg every 2 weeks starting on Day 28 after HCT (Arm 2), or DA plus i.v. iron 200 mg on Days 28, 42, and 56 (Arm 3). The proportion achieving complete hemoglobin (Hb) response within 18 weeks (primary end point) was 21% in Arm 1 (n = 24), 79% in Arm 2 (n = 25), and 100% in Arm 3 (n = 23; P < 0.0001). Erythropoietic response was shown to be significantly higher in Arm 3 (n = 46) than in Arm 2 (n = 50; P = 0.008), resulting in lower DA use, reduced drug costs, and improved quality of life scores, but the effect on transfusions was not significant. In multivariate analysis, DA administration (P < 0.0001), i.v. iron administration (P = 0.0010), high baseline Hb (P < 0.0001), and low baseline creatinine (P = 0.0458) were independently associated with faster achievement of complete Hb response. In conclusion, DA is highly effective to ensure full erythroid reconstitution after autologous HCT when started on Day 28 post-transplant. I.v. iron sucrose further improves erythroid recovery.

Endovesical instillation of Cidofovir in the treatment of BK polyomavirus hemorrhagic cystitis after allogeneic hematopoietic cell transplantation.

BACKGROUND: Hemorrhagic cystitis (HC) with BK polyomavirus (BKPyV) is a common complication after allogeneic hematopoietic cell transplantation (alloHCT) that may lead to severe discomfort for the patient and significant morbidity (urinary obstruction, increased transfusion requirements and prolonged hospitalization). So far, there is no clear consensus on how to manage this complication. PATIENTS AND METHODS: Here, we report a single-center case series of 9 patients (4 children and 5 adults) treated with cidofovir endovesical (EV) instillation(s) for BKPyV-HC after alloHCT. EV Cidofovir was administered at a dose of 5 mg/kg, for 1 to 3 instillations (with a minimum delay between 2 successive doses of 5 days). RESULTS: Eight out of the 9 treated patients with EV Cidofovir achieved a complete resolution of HC after 1-3 instillation(s), without recurrence of symptomatic infection within the next 3 months. Only 1 adult patient did not improve after treatment and developed severe morbidity (emphysematous cystitis). CONCLUSION: Although this single-center case series of EV cidofovir for BKPyV HC after alloHCT shows encouraging results, only large prospective studies will definitively establish the effectiveness of this therapy.

[Graft failure, poor graft function erythroblastopenia: Actualization of definitions, diagnosis and treatment: Guidelines from the SFGM-TC]. / Non-prise de greffe, dysfonctionnement du greffon et érythroblastopénie : mise à jour des définitions, outils diagnostiques et prise en charge : recommandation de la SFGM-TC.

In this article, we discuss again the definition, the risk factor and guideline to treat the graft failure, the poor graft function and erythrobalstopenia. Graft failure is a severe but rare complication after hematopoietic cell transplantation (HCT). Despite disparity in the literature, we defined this complication and discussed the factor risks and recommendation for treatment based on new studies. Poor graft function is also a more frequent complication after HCT. New studies will soon be available to prove or not the current recommendation suggested in this article based on therapeutics medicine or cellular therapy. Erythroblastopenia, is a rarer complication post HCT. Despite anticipation for a better choice of compatibility donor/recipient, some patients still suffer from this complication.

Post-transplant cyclophosphamide prevents xenogeneic graft-versus-host disease while depleting proliferating regulatory T cells.

Graft-versus-host disease (GVHD) remains a serious limitation of allogeneic hematopoietic cell transplantation (allo-HCT). While post-transplant administration of cyclophosphamide (PTCy) is increasingly used as GVHD prophylaxis, its precise mechanisms of action and its impact on graft-versus-leukemia effects have remained debated. Here, we studied the mechanisms of xenogeneic GVHD (xGVHD) prevention by PTCy in different humanized mouse models. We observed that PTCy attenuated xGVHD. Using flow cytometry and single-cell RNA-sequencing, we demonstrated that PTCy depleted proliferative CD8+ and conventional CD4+ T cells but also proliferative regulatory T cells (Treg). Further, T-cell receptor ß variable region sequencing (TCRVB) analyses demonstrated that highly xenoreactive T-cell clones were depleted by PTCy. Although Treg frequencies were significantly higher in PTCy-treated than in control mice on day 21, xGVHD attenuation by PTCy was not abrogated by Treg depletion. Finally, we observed that PTCy did not abrogate graft-versus-leukemia effects.

Multipotent mesenchymal stromal cells as treatment for poor graft function after allogeneic hematopoietic cell transplantation: A multicenter prospective analysis.

Introduction: Poor graft function (PGF) is a rare but serious complication of allogeneic hematopoietic cell transplantation (alloHCT). Due to their hematopoietic supporting properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help to restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after alloHCT. Methods: We prospectively assessed the efficacy and safety of ex-vivo expanded BM-derived MSC from third-party donor in a series of 30 patients with prolonged severe cytopenia and PGF after alloHCT. This multicenter trial was registered at www.clinicaltrials.gov (#NTC00603330). Results: Within 90 days post-MSC infusion, 53% (95% CI, 35 - 71%) of patients improved at least one cytopenia (overall response, OR) and 37% (95% CI, 19 - 54%) achieved a complete hematological response (CR: absolute neutrophil count, ANC >0.5 x 109/L, Hb > 80g/L and platelet count > 20 x 109/L with transfusion independence). Corresponding response rates increased to 67% (95% CI, 50 - 84%) OR and 53% (95% CI, 35 - 71%) CR within 180 days after MSC infusion. A significant decrease in red blood cells and platelets transfusion requirement was observed after MSC (median of 30-days transfusion requirement of 0.5 and 0 from d90-120 post-MSC versus 5 and 6.5 before MSC, respectively, p ≤0.001). An increase in ANC was also noted by day +90 and +180, with 3/5 patients with severe neutropenia having recovered an ANC > 1 x 109/L within the 90-120 days after MSC infusion. Overall survival at 1 year post-MSC was 70% (95% CI, 55.4 - 88.5), with all but one of the patients who achieved CR being alive. A single infusion of third-party MSC appeared to be safe, with the exception of one deep vein thrombotic event possibly related to the intervention. Discussion: In conclusion, a single i.v. infusion of BM-derived MSC from third party donor seemed to improve hematological function after alloHCT, although spontaneous amelioration cannot be excluded. Comparative studies are warranted to confirm these encouraging results.

Overall Survival Rate in Allogeneic Stem Cell Transplanted Patients Requiring Intensive Care Can Be Predicted by the Prognostic Index for Critically Ill Allogeneic Transplantation Patients (PICAT) and the Sequential Organ Failure Assessment (SOFA) Scores.

Background. Allogeneic hematopoietic stem cell transplantation (allo-HCT) recipients requiring intensive care unit (ICU) have high mortality rates. Methods. In the current study, we retrospectively assessed whether the Prognostic Index for Critically Ill Allogeneic Transplantation patients (PICAT) score predicted overall survival in a cohort of 111 consecutive allo-HCT recipients requiring ICU. Results. Survival rates at 30 days and 1 year after ICU admission were 57.7% and 31.5%, respectively, and were significantly associated with PICAT scores (p = 0.036). Specifically, survival at 30-day for low, intermediate, and high PICAT scores was 64.1%, 58.1%, and 31.3%, respectively. At one-year, the figures were 37.5%, 29%, and 12.5%, respectively. In multivariate analyses, high PICAT score (HR = 2.23, p = 0.008) and relapse prior to ICU admission (HR = 2.98, p = 0.0001) predicted higher mortality. We next compared the ability of the PICAT and the Sequential Organ Failure Assessment (SOFA) scores to predict mortality in our patients using c-statistics. C statistics for the PICAT and the SOFA scores were 0.5687 and 0.6777, respectively. Conclusions. This study shows that while the PICAT score is associated with early and late mortality in allo-HCT recipients requiring ICU, it is outperformed by the SOFA score to predict their risk of mortality.

Allogeneic hematopoietic stem cell transplantation (HSCT) after reduced intensity conditioning.

Allogeneic hematopoietic stem cell transplantation (HSCT) following myeloablative (conventional) conditioning regimen is associated with a high incidence of transplant-related morbidity and mortality, limiting its use to younger patients without medical co-morbidities. Over the past few years, it has become more evident that the alloreactivity of transplanted donor immunocompetent cells against host tumor cells (graft-versus-tumor effects, GVT effects) plays a major role in eradicating malignancies after allogeneic HSCT. Based on these observations, several groups of investigators have developed reduced intensity conditioning (RIC) regimens allowing patients who are ineligible for conventional HSCT to benefit from the potentially curative GVT effects of allogeneic transplantation. Retrospective studies have suggested that, in comparison with myeloablative allogeneic HSCT, in patients aged 40-60 years, RIC HSCT was associated with a higher risk of relapse but a lower incidence of transplant-related mortality leading to similar progression-free and overall survivals. Prospective studies are ongoing to define which patients might most benefit from RIC HSCT, and to increase the anti-tumoral activity of the procedure while reducing the incidence and the severity of acute graft-versus-host disease (GVHD). In this article, we review the current status and perspectives of RIC HSCT.

High proportion of terminally differentiated regulatory T cells after allogeneic hematopoietic stem cell transplantation.

It is now well-established that regulatory T cells (Treg) represent a heterogeneous group of CD4+ T cells. Previous studies have demonstrated that Treg homeostasis was impacted by allogeneic hematopoietic cell transplantation (allo-HCT) and particularly so in patients with chronic graft-versus-host disease (GVHD). Here, we first assessed the ability of various Treg subsets to phosphorylate STAT5 in response to IL-2 or IL-7 stimulation in vitro. We then compared the frequencies of different Treg subtypes in healthy controls as well as in allo-HCT patients with or without chronic GVHD. The highest phosphorylated STAT5 (pSTAT5) signal in response to IL-2 was observed in the CD45RO+CD26-CD39+HLA-DR+ Treg fraction. In contrast, naive Treg were mostly less susceptible to IL-2 stimulation in vitro. Following IL-7 stimulation, most Treg subpopulations upregulated pSTAT5 expression but to a lesser extent than conventional T cells. Compared to healthy controls, allo-HCT patients had lower frequencies of the naive CD45RAbrightCD26+ Treg subpopulation but higher frequencies of the most differentiated memory CD45RO+CD26-CD39+ Treg subpopulations. Further, unbiased analysis revealed that six Treg clusters characterized by high expression of CD25, HLA-DR, and ICOS were significantly more frequent in patients with no or with limited chronic GVHD than in those with moderate/severe chronic GVHD.

Itacitinib prevents xenogeneic GVHD in humanized mice.

We assessed the impact of the Janus Kinase (JAK) 1 inhibitor itacitinib on xenogeneic graft-versus-host disease (xGVHD). XGVHD was induced by i.v. injection 20 × 106 human peripheral blood mononuclear cells (hPBMC) in NSG mice on day 0. Itacitinib (3 mg, ≈120 mg/kg) or methylcellulose was administered by force-feeding twice a day from day 3 to day 28. Mice were followed for xGVHD score and survival. In addition, human T-cell engraftment and as well as human T-cell subtypes were monitored in blood on days 14, 21, and 28 after transplantation. We observed that itacitinib-treated mice had significantly longer survival than control mice (median 45 versus 33 days; P < 0.001). Further, they also had lower absolute numbers of human CD4+ T cells on days 21 and 28 after transplantation as well as of human CD8+ T cells on days 14, 21, and 28 after transplantation. In addition, itacitinib-treated mice had higher frequencies of human regulatory T cells (Treg) on days 21 and 28 after transplantation. In summary, our data indicate that itacitinib decreases human T-cell engraftment, increases Treg frequencies and attenuates xGVHD in NSG mice transplanted with hPBMC.