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CAR-T cells represent a new anti-tumor immunotherapy which has shown its clinical efficacy in B-cell malignancies. The results of clinical trials carried out in this context have shown that certain immunological characteristics of patients before (at the time of apheresis) and after the administration of the treatment, or of the CAR-T cells themselves, are correlated with the response to the treatment or to its toxicity. However, to date, there are no recommendations on the immunological monitoring of patients treated in real life. The objectives of this workshop were to determine, based on data from the literature and the experience of the centers, the immunological analyses to be carried out in patients treated with CAR-T cells. The recommendations relate to the characterization of the patient's immune cells at the time of apheresis, the characterization of the injected CAR-T cells, as well as the monitoring of the CAR-T cells and other parameters of immune reconstitution in the patient after administration of the treatment. Harmonization of practices will allow clinical-biological correlation studies to be carried out in patients treated in real life with the aim of identifying factors predictive of response and toxicity. Such data could have a major medico-economic impact by making it possible to identify the patients who will optimally benefit from these expensive treatments.

We aimed to investigate the 1-month humoral response to two or three doses of a messenger RNA coronavirus disease 2019 (COVID-19) vaccine as a primary vaccination regimen in specific populations compared with that in healthy adults.Agence Nationale Recherche contre le Sida (ANRS)0001S-COV-POPART (NCT04824651) is a French nation-wide, multi-centre, prospective, observational cohort study assessing the immune response to COVID-19 vaccines routinely administered to 11 sub-groups of patients with chronic conditions and two control groups. Patients and controls who received at least two vaccine doses and whose results 1 month after the second dose were available were included. The humoral response was assessed 1 month after the first, second and third doses (if applicable) based on the percentage of responders (positive for anti-Spike severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] IgG antibodies), geometric means of anti-Spike SARS-CoV-2 IgG antibodies (enzyme-linked immunosorbent assay) and proportion of participants with anti-SARS-CoV-2-specific neutralizing antibodies (in vitro neutralization assay for the original SARS-CoV-2 strain). All analyses were centralized.We included 4091 participants in this analysis: 2979 participants from specific sub-populations and 1112 controls. Only 522 (17.5%) participants from the specific populations received three doses as a primary vaccination regimen. Patients living with human immunodeficiency virus, cancer and diabetes had high percentages of responders after two doses, whereas patients with solid organ transplants, allogeneic hematopoietic stem cell transplants and hypogammaglobulinaemia had the lowest percentage of responders (35.9% [95% CI, 29.2-43.0], 57.4% [95% CI, 48.1-66.3] and 77.1% [95% CI, 65.6-86.3], respectively). In those who received the third dose, the percentage of responders reached 54.2% (95% CI, 42.9-65.2) (vs. 32.3% [95% CI, 16.7-51.4] after 2 doses) among those with solid organ transplants and 73.9% (95% CI, 58.9-85.7) (vs. 56.1% [95% CI, 46.2-65.7] after 2 doses) among those with hematopoietic stem cell transplants. Similar results were found with anti-SARS-CoV-2-specific neutralizing antibodies.A lower humoral response to COVID-19 vaccines was observed in the specific populations compared with that in the controls. The third dose of this vaccine in the primary regimen had a positive effect on the percentages of patients who developed anti-Spike IgG antibodies and specific neutralizing antibodies.

Prognosis of patients with graft failure is dismal, and retransplantation is the sole option for long-term survival. To address the interest of haploidentical transplantation as a salvage option in this context, we analyzed data from 24 patients with graft failure or loss retransplanted with a haploidentical donor who received post-transplant cyclophosphamide (PTCy) as graft-versus-host disease prophylaxis (GVHD). Fludarabine-based reduced-intensity conditioning was used in 23 patients and the Baltimore regimen in 14 patients. The median delay between previous and salvage transplantation for graft failure was 63 days (range, 39 to 98). In addition to PTCy, all patients received cyclosporine, and 22 patients also received mycophenolate mofetil for GVHD prophylaxis. With a median follow-up of 353 days (range, 16 to 2010), 1-year overall survival (OS) was 56% (95% confidence interval, 38% to 81%). Transplant complications accounted for 80% of deaths. The cumulative incidence of neutrophil engraftment at day +30 was 79%. Cumulative incidence of grades II to IV acute GVHD at day 100 was 14%, and 1-year cumulative incidence of chronic GVHD was 31%. One-year cumulative incidence of relapse was 13%. Stem cell source did not impact on engraftment, GVHD, relapse, or OS. Salvage haploidentical transplant with PTCy for rescuing graft failure patients leads to an acceptable 1-year OS and might be a valid option in this poor situation.

International audience; We report the results of the French Temporary Authorization of Use (ATU) compassionate program of letermovir for primary prophylaxis conducted in 21 transplant centers. Patients were CMV seropositive allogeneic hematopoietic cell transplantation recipients and at high risk for CMV infection. Primary prophylaxis was defined as initiation of letermovir between day 0 and day +28 post-transplant. Between November 2017 and January 2019, 96 patients with a median age of 56 years received letermovir and follow-up data were available for 78 patients. The median time from transplant to letermovir initiation was 4 days, and the median duration of exposure to letermovir was 78 days, with 57 patients still on treatment at the cutoff date. Letermovir was temporarily discontinued in 4 patients (5.1%) and stopped in 39 patients (50.0%), in most cases due to planned end of treatment (n = 16, 20.5%). Fifteen patients (19.2%) each presented one positive CMV PCR, in median 13 days after letermovir initiation. Clinically significant CMV infection was reported in 5 patients (6.4%). No CMV disease was reported. At least one adverse drug reaction was reported for 12 patients (15.4%). In this early access program, letermovir was effective with comparable results of the phase 3 study with a low rate of clinically significant CMV infection, including in patients who were at high-risk for CMV infection.

Given the poor prognosis of relapsed/refractory myeloid malignancies, the concept of sequential conditioning before allogeneic hematopoietic stem cell transplantation (allo-HSCT) has proven to be an effective approach. We sought to evaluate a sequential scheme combining fludarabine, amsacrine, and cytarabine (FLAMSA) for cytoreduction, followed by reduced-intensity conditioning with busulfan and melphalan (FLAMSA-BuMel), which was designed to be suitable for both HLA-matched and haploidentical HSCT. This single-center retrospective study included 36 adult patients with high-risk myeloid malignancies who underwent allo-HSCT from HLA-matched (n = 19) or haploidentical (n = 17) donors. Along with the standard prophylaxis for graft-versus-host disease (GVHD), patients with a haploidentical donor received post-transplantation high-dose cyclophosphamide. A post-transplantation consolidation treatment with low-dose 5-azacytidine and prophylactic donor lymphocyte infusions was provided whenever possible. Thirty patients (83%) achieved complete remission on day +30. With a median follow-up of 30.0 months, the 2-year overall survival was 89% in the HLA-matched group versus 34% in the haploidentical group (P = .0018). The 2-year disease-free survival in these 2 groups was 68% and 34%, respectively (P = .013). At 2 years, the probability of relapse was 32% and 20%, respectively, and nonrelapse mortality was 0% and 58%, respectively (P = .0003). The leading cause of death was relapse in the HLA-matched group (3 of 19) and hemorrhagic events (5 of 17) in the haploidentical group, favored by significantly delayed platelet reconstitution and a severe GVHD context. These data confirm the feasibility of FLAMSA-BuMel as a sequential conditioning in allo-HSCT for high-risk myeloid malignancies. The use of bone marrow as the preferred graft source might reduce the incidence of acute GVHD and nonrelapse mortality in the haploidentical transplantation setting.

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly in the case of after autologous stem cell transplantation if remission can be achieved. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This section specifically reports on our conclusions regarding diffuse large B cell lymphoma.

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation (allo-HCT) is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allo-HCT for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript reports on general considerations regarding allo-HCT for lymphoma and elaborates on the use of alternative donors in this setting.

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic haematopoietic cell transplantation is a potentially curative option, in particular in the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic haematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This manuscript specifically reports on our conclusions regarding Hodgkin's lymphoma as well as rarer entities, such as T cell lymphomas.

Despite great improvements in the outcome of patients with lymphoma, some may still relapse or present with primary refractory disease. In these situations, allogeneic hematopoietic cell transplantation is a potentially curative option, this is true particularly the case of relapse after autologous stem cell transplantation. Recently, novel agents such as anti-PD1 and BTK inhibitors have started to challenge the use of allogeneic hematopoietic cell transplantation for relapsed or refractory lymphoma. During the 2016 annual workshop of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC), we performed a comprehensive review of the literature published in the last 10 years and established guidelines to clarify the indications and transplant modalities in this setting. This paper specifically reports on our conclusions regarding indolent lymphomas, mainly follicular lymphoma and chronic lymphocytic leukemia.

Resume L’allogreffe de cellules souches hematopoietiques constitue en soi un parfait exemple d’immunotherapie. Ses effets positifs sont lies a la reaction du greffon contre la tumeur, malheureusement souvent associee a la toxicite de la reaction du greffon contre l’hote. Si les mecanismes de ces deux reactions restent imparfaitement connus, certaines modalites de traitements associes ou certains choix therapeutiques peuvent modifier cette reaction immunologique. Il est ainsi devenu possible de la moduler. Dans ce contexte, le choix des donneurs, du type de conditionnement, du type de greffon ou encore l’utilisation de reinjection de cellules du donneur apres la transplantation sont autant d’outils ou de variables qui peuvent optimiser au mieux la procedure. Cet article a pour objectif de presenter l’ensemble de ces parametres en fonction des donnees actuelles.

Haploidentical hematopoietic stem cell transplantation (HSCT) is being increasingly used due to improvement of the transplantation procedures allowing a reduction of graft-versus-host-disease (GVHD) and of transplant-related mortality (TRM). Such improvements have been particularly observed after administration of T-replete HSCT graft associated to an in vivo T cell depletion by the administration of high-doses of cyclophosphamide (HD-Cy) after transplantation. Here, we have analyzed the results of haplo-identical T replete HSC transplants, in particular, when performed with post-transplant HD-Cy in order to provide recommendations for the clinical practice. Criteria of choice for a haploidentical donor by priority order are absence of donor-specific antibodies (DSA) and to prioritize: CMV seronegative recipient/donor couples, ABO matching in case of deserythrocytation, male donor for a male recipient, the youngest donor. There is no clear argument in favor of the use of bone marrow versus peripheral blood stem cells (PBSC) after non myeloablative conditioning regimen, while after ablative conditioning PBSC seem to be associated with higher risks of GVHD without obvious impact on survival. Results of haploidentical HSCT, confirmed by several groups, are interesting in lymphomas (in particular Hodgkin disease) and for acute leukemia. Outcomes of patients rely on age, disease status at transplant and conditioning intensity. At equivalent disease risk, results of haploidentical HSCT seem comparable to those of HLA matched HSCT, raising the question of the classification of such transplants as alternatives. In all cases, we recommend to include patients in prospective clinical trials.

Background Post-transplant non-Hodgkin lymphoma (NHL) is a well-recognized complication of solid-organ transplantation, and pharmacologic suppression of adaptive immunity plays a major role in its development. However, the role of natural killer (NK) cells in post-lung transplant de novo NHL is unknown. Methods Extensive phenotypic analyses of NK cells from patients diagnosed with NHL after liver or lung transplantation were conducted with multicolor flow cytometry. Polyfunctionality assays simultaneously assessed NK cell degranulation (CD107a) and intracellular cytokine production (interferon-γ and tumor necrosis factor-α) in the presence of NHL target cells. Results The development of de novo NHL is linked to NK-cell maturation defects, including overexpression of NKG2A and CD62L and down-modulation of inhibitory killer immunoglobulin-like receptors and CD57 receptors. More importantly, in patients who developed NHL after lung transplantation, we observed a specific down-modulation of the activating receptors (NKp30, NKp46, and NKG2D) and a sharp decrease in perforin expression and degranulation against NHL target cells. Conclusions Our results suggest that accumulation of abnormal NK cells could play a role in the outgrowth of NHL after lung transplantation, independently of the immunosuppressive regimen.

A prospective phase II multicenter trial was performed with the aim to obtain less than 25% nonrelapse mortality (NRM) after unrelated cord blood transplantation (UCBT) for adults with acute myeloid leukemia (AML) using a reduced-intensity conditioning regimen (RIC) consisting of total body irradiation (2 Gy), cyclophosphamide (50 mg/kg), and fludarabine (200 mg/m2). From 2007 to 2009, 79 UCBT recipients were enrolled. Patients who underwent transplantation in first complete remission (CR1) (n = 48) had a higher frequency of unfavorable cytogenetics and secondary AML and required more induction courses of chemotherapy to achieve CR1 compared with the others. The median infused total nucleated cells (TNC) was 3.4 × 107/kg, 60% received double UCBT, 77% were HLA mismatched (4/6), and 40% had major ABO incompatibility. Cumulative incidence of neutrophil recovery at day 60 was 87% and the cumulative incidence of 100-day acute graft-versus-host disease (II to IV) was 50%. At 2 years, the cumulative incidence of NRM and relapse was 20% and 46%, respectively. In multivariate analysis, major ABO incompatibility (P = .001) and TNC (

Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part two of the recommendations regarding allogeneic stem cell transplantation from an HLA-haploidentical related donor.

Haploidentical allogeneic stem cell transplantation (CST) has globally taken off in the past decade. It appears to be a valid alternative to other sources of stem cells; however, further research is necessary to validate the use of this approach in standard patient care. In the attempt to harmonize clinical practices between different French transplantation centers, the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) set up its fourth annual series of workshops which brought together practitioners from all of its member centers. These workshops took place in September 2013 in Lille. This is part one of the recommendations regarding allogeneic stem cell transplantation from an HLA-haploidentical related donor.

Introduction La maladie aigue du greffon contre l’hote post-transplantation hepatique (GVH-TH) est rare et grave. Nous en rapportons un cas simulant une toxidermie de type necrolyse epidermique toxique (NET). Observation Un homme de 66 ans, transplante a 2 reprises en 15 ans pour une cholangite sclerosante primitive, etait en deuxieme recidive avec evolution vers une insuffisance renale terminale chez un diabetique. Admis en reanimation pour une troisieme transplantation hepatique et une premiere transplantation renale (donneur unique) son traitement comprenait : mycophenolate mofetil (MMF), tacrolimus (cible 10 ng/mL) et prednisone (20 mg/j). Le patient developpait rapidement une peritonite biliaire necessitant plusieurs lignes d’antibiotherapie et une reprise chirurgicale avec jejunostomie d’elimination. A j28 post-TH, le patient revelait une pancytopenie avec moelle deserte au myelogramme. Une reduction des traitements immunosuppresseurs a j31 etait realisee en raison de l’infection non controlee ( Fig. 1 et 2 ). A j38, le patient developpait une eruption maculopapuleuse avec intervalles de peau saine, touchant le tronc et les membres sur 45 % de la surface cutanee, avec bulles et erosions (decollement de 5 %). Un signe de Nikolsky et une cheilite erosive sans atteinte des autres muqueuses etaient presents. Le patient ne presentait pas d’augmentation du volume des selles, ni modification notable du bilan hepatique. L’histologie cutanee montrait un decollement supra-basal avec des corps apoptotiques confluents des couches basales prenant l’aspect d’une NET ; l’immunofluorescence directe etait negative. L’hypothese d’une GVH-TH etait evoquee sur l’aspect cutanee et l’atteint hematologique, puis confirmee par la recherche d’un macrochimerisme sanguin qui etait positif a 7 % des cellules circulantes. L’enquete de pharmacovigilance montrait plusieurs medicaments faiblement imputables (scores Alden bas), renforcant cette hypothese. A j42, le patient recevait une corticotherapie a 2 mg/kg/j de prednisone. Avec un decollement progressant a 10 %, il decedait a j49 post-TH. Discussion La GVH-TH est rare (156 cas rapportes) et grave (mortalite de 73 %). Ses principales manifestations, observees entre la 3e et la 5e semaine post-TH, sont : une eruption cutanee (92 %), une pancytopenie (78 %) et une diarrhee (65 %). Le diagnostic doit etre confirme par un macrochimerisme superieur a 1 %. Une NET, principal diagnostic differentiel de cette presentation de GVH-TH, est ici peu probable du fait de l’absence de lesion muqueuse en dehors de la cheilite et des faibles scores Alden. Conclusion Ce cas illustre une GVH grave sur organe solide, pour laquelle l’atteinte cutanee est au premier plan a distinguer d’une NET par enquete de pharmacovigilance et recherche de macrochimerisme, afin d’adapter tres rapidement le traitement.

Waldenström macroglobulinemia is a rare chronic lymphoproliferative disorder. Treatments are currently reserved for symptomatic patients and usually consist of nucleoside analogues (NAs), alkylating agents, bortezomib, and monoclonal antibodies, alone or in combination. Fludarabine and 2-chlorodeoxyadenosine (2-CdA) have been studied in first-line treatment of Waldenström macroglobulinemia (WM) since the end of the 1990s. In monotherapy, response rates vary between 36% and 94%. In a phase III trial, fludarabine in monotherapy was more efficient than chlorambucil for progression-free survival (PFS) (37.8 vs. 27.1 months), duration of response (DOR) (38.5 vs. 21.3 months) and overall survival (OS) (median not reached vs. 69.8 months), but the overall response rate (ORR) was similar (45.6% and 35.9%). NAs have been studied in combination with rituximab and/or alkylating agents for increasing the quality and duration of the response. Hematologic toxicities are a major concern, limiting the indication for NAs in first-line treatment to patients who are not candidates for autologous stem cell transplantation, those in need of rapid control of the disease, or those with poor prognostic factors.

Invariant natural killer T (iNKT) cells have a pivotal role in immune regulation, tumor surveillance, and the induction of allograft tolerance. In this report, we analyze the recovery of iNKT cells after unrelated cord blood transplantation (UCBT) of adult patients with high-risk acute myeloid leukemia. We found that iNKT cells were reconstituted within 1 month after UCBT, at the same time as NK cells and before conventional T cells. These iNKT cells displayed a unique primed/central memory CD4(+)CD45RO(+)CCR7(+)CD62L(+) phenotype soon after the transplant. Interestingly, the functional competence of these cells was poor, except for their high GM-CSF production capacity. However, this post-graft functionally immature state was transient and all of the patients tested had fully functional iNKT cells 3 to 6 months post-UCBT and high cytolytic capacity for destroying primary CD1d(+) myeloid blast cells. Our results raise the possibility that iNKT cells might play a key role in graft-versus-leukemia activity after UCBT.

Le polynucleaire neutrophile (PN) est un acteur majeur de la defense anti-aspergillaire. Dans le cadre d’une etude sur les interactions entre PN et Aspergillus fumigatus , nous avons mis en evidence le fait que les PN des patients allogreffes de moelle osseuse (AGMO) en sortie d’aplasie presentent un deficit fonctionnel dans leur reponse vis-a-vis du champignon. En effet, la capacite d’inhibition par les PN de la croissance des hyphes aspergillaires est diminuee chez les patients AGMO par rapport aux donneurs sains. Ce deficit est en partie relie a l’utilisation des inhibiteurs de calcineurine, utilises chez ces patients pour la prevention du rejet et de la survenue de la reaction du greffon contre l’hote. Les neutrophiles possedent differents moyen d’action : phagocytose, production de formes reactives de l’oxygene, liberation de molecules anti-microbiennes ainsi que la formation de neutrophils extracellular traps (NET). Cette derniere, de description plus recente est une forme de mort cellulaire atypique conduisant a la liberation extracellulaire d’un reseau d’ADN contenant differents effecteurs anti-microbiens. Il a ete montre precedemment que la formation des NET par les neutrophiles entrainait une inhibition de la croissance d’ Aspergillus sans toutefois tuer le champignon. De plus, d’autres travaux recents indiquent que la calcineurine est un regulateur de la production des NET. En ce sens, nous avons observe que les PN obtenus chez les patients AGMO produisaient moins de NET que les PN issus de donneurs sains. Ceci pourrait donc resulter de l’utilisation des inhibiteurs de calcineurine chez les patients AGMO et etre la cause de la moindre capacite des PN des patients AGMO a inhiber la croissance fongique. Le deficit qualitatif d’elimination d’ A. fumigatus par les PN observe dans cette etude pourrait etre un facteur supplementaire de risque de survenue d’aspergillose invasive chez les patients AGMO ainsi que chez les transplantes d’organe solide.

Le polynucleaire neutrophile (PN) est un acteur majeur de la defense anti-aspergillaire. Actuellement, la neutropenie prolongee n’est plus le principal facteur de risque de survenue d’aspergillose invasive (AI) chez le patient allogreffe de moelle osseuse (AGMO). L’objectif de notre travail etait d’etudier les principales fonctions des PN vis-a-vis d’ Aspergillus fumigatus au cours de l’allogreffe de moelle. Pour cela, nous avons suivi des patients AGMO de facon longitudinale (en sortie d’aplasie ; a 2 mois ; a 6 mois et a 9–12 mois post-greffe). Nous avons teste les principales fonctions (activation, degranulation, production de formes reactives de l’oxygene) des PN ainsi que leur capacite a inhiber in vitro la croissance d’ A. fumigatus . Nous avons aussi etudie la presence a leur surface de recepteurs impliques dans la reponse antifongique. Nos resultats indiquent notamment que la capacite des PN a inhiber la croissance d’ A. fumigatus est alteree chez les patients AGMO par rapport aux donneurs sains. Cette capacite d’inhibition est la plus abaissee chez les patients en sortie d’aplasie, puis revient progressivement a la normale a 12 mois post-greffe. Les differents traitements immunosuppresseurs recus par les patients jouent un role important dans la diminution de la capacite des PN a inhiber la croissance d’ Aspergillus . En effet, nos resultats indiquent que les PN des patients n’ayant plus de traitement immunosuppresseur ou etant sous doses, ne presentent pas de baisse d’activite alors que ceux des patients ayant une concentration serique residuelle normale ont les capacites les plus alterees. Les raisons permettant d’expliquer ces observations demeurent pour la plupart encore inconnues. En effet, les fonctions de reconnaissance, d’activation et de production de formes reactives de l’oxygene, pourtant un des mecanismes principaux de lutte contre le champignon, semblent (en dehors de la prise de corticoides) n’etre que peu modifiees au cours de la greffe de moelle osseuse. Le deficit qualitatif d’elimination d’ A. fumigatus par les PN, observe dans cette etude peut etre une des explications aux risques d’AI encourus par les patients allogreffes de moelle osseuse mais de nombreuses voies restent a explorer afin de comprendre les raisons de cette perte d’activite anti-aspergillaire.

sotatercept (ACE-011), a novel first-in-class activin type IIA receptor fusion protein, in anemic patients with IPSS Low/Intermediate-1risk MDS or non-proliferative CMML. ClinicalTrials.gov identifier: NCT01736683. Methods: The primary endpoint of this study is erythroid hematological improvement (HI-E; defined by modified IWG 2006 criteria). Secondary endpoints include rate of RBC-transfusion independence (RBC-TI) ≥8 weeks and safety. Eligible patients have lower-risk MDS or non-proliferative CMML and anemia, with no response, loss of response, or low chance of response to ESAs. Patients receive subcutaneous sotatercept at 0.1, 0.3, 0.5, or 1.0 mg/kg every 3 weeks. Results: As of May 22, 2014, 54 MDS patients were enrolled: 7, 6, 21, and 20 in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg groups, respectively. Median age 71 years, median time from diagnosis 4 years, and 70% of patients were male. Patients received a median 6 RBC units (range 0–16) in the 8 weeks before starting treatment; 46 received ≥4 RBC units (high transfusion burden; HTB) and 8 received. Of 53 patients evaluable for efficacy, 24 achieved HI-E: 0, 4, 8, and 12 patients in the sotatercept 0.1, 0.3, 0.5, and 1.0 mg/kg groups, respectively. Five of 46 (11%) HTB patients achieved RBCTI ≥8 weeks; duration of response ranged from 59–345+ days. Five of 8 (63%) LTB patients achieved RBC-TI ≥8 weeks with a mean hemoglobin increase of ≥1.5 g/dL sustained for ≥8 weeks; duration ranged from 76–233+ days. Sotatercept was generally well tolerated. Twenty (37%) patients reported ≥1 suspected treatment-related adverse event. The most common were: fatigue/asthenia (13%), headache (9%), decreased appetite (7%), and nausea (7%). Three patients discontinued due to suspected treatment-related adverse events: 1 each with grade 2 hemolytic anemia, grade 3 hypertension, and grade 2 muscular weakness in the sotatercept 0.3, 0.5, and 1.0 mg/kg groups, respectively. Conclusions: Sotatercept was well tolerated, with promising evidence of clinical activity in this cohort of anemic, lower-risk MDS patients. Further exploration of sotatercept treatment is ongoing. PF and AFL contributed equally to this abstract as senior coauthors.