Allogeneic transplantation in advanced cutaneous T-cell lymphomas (CUTALLO): a propensity score matched controlled prospective study.

BACKGROUND: Advanced-stage cutaneous T-cell lymphomas (CTCLs) are rare, usually refractory, and fatal diseases. Case series have suggested that allogeneic haematopoietic stem cell transplantation (HSCT) might improve the prognosis of advanced-stage CTCLs. The objective of this study was to investigate the effect of allogeneic HSCT compared with non-HSCT therapy on the outcome of individuals with advanced-stage CTCLs. METHODS: In this prospective, multicentre, matched controlled trial, conducted at 30 hospitals, participants with advanced CTCLs were allocated treatment: if they had an available compatible related donor they were assigned to allogeneic HSCT, or if not they were allocated to non-allogeneic HSCT therapy. Key inclusion criteria were participants aged 18-70 years, with advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criteria. Participants were excluded if they were not in complete or partial remission of the disease. Propensity score 1:1 matching with replacement (ie, that each participant treated with HSCT was matched to the participant with the closest propensity score treated with non-HSCT therapy, even if they had already been matched) was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was progression-free survival in the matched intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02520908), and is currently active but not recruiting. FINDINGS: From June 1, 2016, to March 3, 2022, total of 99 participants were enrolled at 17 centres in France. Participants with a sibling or matched unrelated donor were assigned to allogeneic HSCT (HSCT group, n=55 [56%]) and participants without a donor were assigned to non-allogeneic HSCT treatment (non-HSCT group, n=44 [44%]). The median follow-up among survivors was 12·6 months (IQR 11·0-35·2). In the HSCT group, 51 participants (93%) were 1:1 matched to participants from the non-HSCT group. In the intention-to-treat analysis, median progression-free survival was significantly longer in the HSCT group (9·0 months [95% CI 6·6-30·5]) than in the non-HSCT group (3·0 months [2·0-6·3]), with a hazard ratio of 0·38 (95% CI 0·21-0·69; p<0·0001). In the per-protocol population, 40 participants (78%) in the HSCT group had 101 serious events and 29 participants (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 participants (59%) in the HSCT group and in 19 participants (44%) in the non-HSCT group. INTERPRETATION: Allogeneic HSCT was associated with significantly longer progression-free survival in participants with advanced-stage CTCLs. These results indicate that allogeneic HSCT treatment should be made available to individuals with high-risk, advanced-stage mycosis fungoides or Sézary syndrome who achieve pre-transplant disease remission. FUNDING: French Ministry of Health, National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.

PD-1 blockade and allogeneic hematopoietic stem cell transplantation in Hodgkin lymphoma, a matter of time: a national study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

Not available.

Peripheral blood stem cell versus bone marrow graft for patients ≥60 years undergoing reduced intensity conditioning haploidentical transplantation for acute myeloid leukemia in complete remission: An analysis of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

In the context of T-cell replete haploidentical stem cell transplantation (Haplo-SCT) using post-transplantation cyclophosphamide (PT-Cy), it is still unknown whether peripheral blood (PB) or bone marrow (BM) is the best graft source. While PB is associated with a higher incidence of graft-versus-host disease (GVHD), it may induce a stronger graft-versus-leukemia effect compared to BM, notably in acute myeloid leukemia (AML). From the EBMT registry database, we compared T-cell replete PB (n = 595) versus BM (n = 209) grafts in a large cohort of 804 patients over the age of 60 years who underwent Haplo-SCT with PT-Cy for an AML in first or second complete remission. The risk of acute GVHD was significantly higher in the PB group (Grade II-IV: HR = 1.67, 95% CI [1.10-2.54], p = 0.01; Grade III-IV: HR = 2.29, 95% CI [1.16-4.54], p = 0.02). No significant difference was observed in chronic GVHD or non-relapse mortality. In the PB group, the risk of relapse was significantly lower in the PB group (HR = 0.65, 95% CI [0.45-0.94], p = 0.02) and leukemia-free survival was significantly better (HR = 0.76, 95% CI [0.59-0.99], p = 0.04), with a trend toward better overall survival (HR = 0.78, 95% CI [0.60-1.01], p = 0.06). We conclude that in the specific context of Haplo-SCT with PT-Cy, PB grafts represent a valid option to decrease the risk of relapse and improve outcome of older AML patients who usually do not benefit from conditioning intensification.

On Behalf of the SFGM-TC: Prophylactic Donor Lymphocyte Infusion in Patients Treated with Allogeneic Stem-Cell Transplantation for High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia.

INTRODUCTION: Allogeneic hematopoietic stem-cell transplantation (allo-HSCT) remains the best curative option for high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Unfortunately, it is still associated with a significant risk of relapse due to mechanisms of escape from the control of alloreactive T cells. Repetitive adjuvant donor lymphocyte infusion (DLI), termed prophylactic DLI (proDLI), as an effective strategy in preventing relapse is still debated. METHODS: We performed a retrospective multicenter study to evaluate the efficacy of proDLI in allografted AML and MDS. We identified 56 patients treated with proDLI (DLI planned in full chimeras without any sign of disease relapse) and matched them to 167 patients in control group, (DLI performed for mixed chimerism or positive minimal residual disease) based on similar age, initial disease, cytogenetic prognosis, and conditioning intensity. RESULTS: In univariate analysis, the incidence of severe aGVHD at 100 days and incidence of all grades of chronic GVHD 1 year after allo-HSCT were similar in the two groups. We also observed a trend of higher 3-year RI (52.61% [95% confidence interval 25.99-79.23]) in the proDLI group versus the control group (29.31% [20.28-38.34], p = 0.067). However, 3-year overall survival (p = 0.892), progression-free survival (p = 0.239), and nonrelapse mortality (p = 0.343) were similar between the two groups. In multivariate analysis, the only factor influencing overall and progression-free survival was anti-thymocyte globulin administration during the conditioning regimen. CONCLUSION: The proDLI strategy had an acceptable toxicity profile but did not improve patient outcomes compared to the pre-emptive strategy.

Evaluation of Serum Mucorales Polymerase Chain Reaction (PCR) for the Diagnosis of Mucormycoses: The MODIMUCOR Prospective Trial.

BACKGROUND: Early diagnosis and prompt initiation of specific antifungal treatment are essential for improving the prognosis of mucormycosis. We aimed to assess the performance of serum Mucorales quantitative polymerase chain reaction (qPCR) for the early diagnosis and follow-up of mucormycosis. METHODS: We prospectively enrolled 232 patients with suspicion of invasive mold disease, evaluated using standard imaging and mycological procedures. Thirteen additional patients with proven or probable mucormycosis were included to analyze DNA load kinetics. Serum samples were collected twice-a-week for Mucorales qPCR tests targeting the Mucorales genera Lichtheimia, Rhizomucor, and Mucor/Rhizopus. RESULTS: The sensitivity was 85.2%, specificity 89.8%, and positive and negative likelihood ratios 8.3 and 0.17, respectively in this prospective study. The first Mucorales qPCR-positive serum was observed a median of 4 days (interquartile range [IQR], 0-9) before sampling of the first mycological or histological positive specimen and a median of one day (IQR, -2 to 6) before the first imaging was performed. Negativity of Mucorales qPCR within seven days after liposomal-amphotericin B initiation was associated with an 85% lower 30-day mortality rate (adjusted hazard ratio = 0·15, 95% confidence interval [.03-.73], P = .02). CONCLUSIONS: Our study argues for the inclusion of qPCR for the detection of circulating Mucorales DNA for mucormycosis diagnosis and follow-up after treatment initiation. Positive results should be added to the criteria for the consensual definitions from the European Organization for the Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC), as already done for Aspergillus PCR.

Splenectomy before allogeneic hematopoietic cell transplantation for myelofibrosis: A French nationwide study.

The value of pretransplant splenectomy in patients with myelofibrosis (MF) is subject to debate, since the procedure may preclude subsequent allogeneic hematopoietic cell transplantation (allo-HCT). To determine the impact of pretransplant splenectomy on the incidence of allo-HCT, we conducted a comprehensive retrospective study of all patients with MF for whom an unrelated donor search had been initiated via the French bone marrow transplantation registry (RFGM) between 1 January 2008 and 1 January 2017. Additional data were collected from the patients' medical files and a database held by the French-Language Society for Bone Marrow Transplantation and Cell Therapy (SFGM-TC). We used a multistate model with four states ("RFGM registration"; "splenectomy"; "death before allo-HCT", and "allo-HCT") to evaluate the association between splenectomy and the incidence of allo-HCT. The study included 530 patients from 57 centers. With a median follow-up time of 6 years, we observed 81 splenectomies, 99 deaths before allo-HCT (90 without splenectomy and nine after), and 333 allo-HCTs (268 without splenectomy and 65 after). In a bivariable analysis, the hazard ratio [95% confidence interval (CI)] for the association of splenectomy with allo-HCT was 7.2 [5.1-10.3] in the first 4 months and 1.18 [0.69-2.03] thereafter. The hazard ratio [95% CI] for death associated with splenectomy was 1.58 [0.79-3.14]. These reassuring results suggest that splenectomy does not preclude allo-HCT in patients with MF.

Sequential allogeneic hematopoietic stem cell transplantation for active refractory/relapsed myeloid malignancies: results of a reduced-intensity conditioning preceded by clofarabine and cytosine arabinoside, a retrospective study on behalf of the SFGM-TC.

Allogeneic stem cell transplantation (allo-SCT) represents the most beneficial treatment for patients with active relapsed/refractory (R/R) hematologic malignancies. Recently, sequential regimens combining debulking chemotherapy followed by reduced-intensity conditioning (RIC) have shown encouraging results for these patients. In this retrospective study, we report the extended results of a sequential regimen of clofarabine, cytosine arabinoside, and RIC in 131 adults with active R/R myeloid disease at transplant. Conditioning consisted of clofarabine (30 mg/m2/day) and cytosine arabinoside (1 g/m2/day) for 5 days, followed, after a rest of 3 days, by an RIC combining cyclophosphamide (60 mg/kg) for 1 day, iv busulfan (3.2 mg/kg/day) for 2 days, and anti-thymocyte globulin (2.5 mg/kg/day) for 2 days. Between 2007 and 2016, 131 patients (males n = 75, median age: 52.6 years) were identified from the SFGM-TC registry. There were 111 acute myeloid leukemia (AML) patients and 20 cases with myelodysplastic or myeloproliferative syndrome. Status at transplant was known for all but 4 patients and was primary refractory (n = 81) and 1st or 2nd relapse (n = 46). All patients received allo-SCT from a matched donor (sibling n = 64, unrelated n = 67). Engraftment was observed in 105/122 (86%) evaluable cases and 63% of the patients achieved complete remission (CR) after transplant. The 1-year overall survival, disease-free survival, relapse incidence, non-relapse mortality, and graft-versus-host disease-free/relapse-free survival were 39.2%, 28.1%, 41.0%, 30.8%, and 22.2%, respectively. This study confirms that this sequential clofarabine-based regimen provides a high CR rate in this critical population, although relapse remains a matter of concern.

Iatrogenic cutaneous graft versus host disease.

A 65-year-old man with acute myeloid leukemia 6 was treated by bone marrow allograft, developed a systemic classic chronic graft versus host disease with hepatic, rheumatologic, ophthalmic, and muco-cutaneous involvement. He received systemic corticosteroid, ruxolitinib and extracorporeal photopheresis which resulted in complete remission. During follow-up the patient presented with viral cutaneous warts on his neck and submandibular area. After various subsequent topical treatments, he developed localized cutaneous GVHD without any general GVHD reactivation symptoms. To the best of our knowledge, there has been no description in the literature of a graft versus host disease developing after local immunomodulatory or cytotoxic treatments. Topical therapies are commonly used by dermatologists for superficial skin cancers and some viral skin lesions, in high risk populations such as organ transplant patients with regular follow-up.Practitioners should be made aware of a possible localized cutaneous GVHD reactivation induced by Koebner phenomenon after local therapy.

Outcomes of Salvage Haploidentical Transplant with Post-Transplant Cyclophosphamide for Rescuing Graft Failure Patients: a Report on Behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy.

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.

The lenalidomide/bortezomib/dexamethasone regimen for the treatment of blastic plasmacytoid dendritic cell neoplasm.

We describe the use and value of a lenalidomide/bortezomib/dexamethasone regimen for the treatment of three patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN, a disease that lacks a consensus treatment). After five cycles of chemotherapy, we observed two complete responses and one clinical remission. Together with the encouraging literature data on the effects of lenalidomide and bortezomib on BPDCN cells, our results might prompt further investigations of this regimen's value in BPDCN.

Similar outcome of allogeneic stem cell transplantation after myeloablative and sequential conditioning regimen in patients with refractory or relapsed acute myeloid leukemia: A study from the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire.

Patients with acute myeloid leukemia (AML) in relapse or refractory to induction therapy have a dismal prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative option. In these patients, we aimed to compare the results of a myeloablative transplant versus a sequential approach consisting in a cytoreductive chemotherapy followed by a reduced intensity conditioning regimen and prophylactic donor lymphocytes infusions. We retrospectively analyzed 99 patients aged 18-50 years, transplanted for a refractory (52%) or a relapsed AML not in remission (48%). Fifty-eight patients received a sequential approach and 41 patients a myeloablative conditioning regimen. Only 6 patients received prophylactic donor lymphocytes infusions. With a median follow-up of 48 months, 2-year overall survival was 39%, 95% confidence interval (CI) (24-53) in the myeloablative group versus 33%, 95% CI (21-45) in the sequential groups (P = .39), and 2-year cumulative incidence of relapse (CIR) was 57% versus 50% respectively (P = .99). Nonrelapse mortality was not higher in the myeloablative group (17% versus 15%, P = .44). In multivariate analysis, overall survival, CIR and nonrelapse mortality remained similar between the two groups. However, in multivariate analysis, sequential conditioning led to fewer acute grade II-IV graft versus host disease (GVHD) (HR for sequential approach = 0.37; 95% CI: 0.21-0.65; P < .001) without a significant impact on chronic GVHD (all grades and extensive). In young patients with refractory or relapsed AML, myeloablative transplant and sequential approach offer similar outcomes except for a lower incidence of acute GvHD after a sequential transplant.

[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.

Platelet transfusions in haploidentical haematopoietic stem cell allograft candidates: Protecting HLA-A and HLA-B antigens through eplet analysis.

In patients awaiting an allogeneic haematopoietic stem cell transplantation, platelet transfusion is a risk factor for anti-HLA class I immunization because the resulting donor-specific antibodies complicate the allograft process. The objective of the present study was to determine the feasibility of a novel eplet-based strategy for identifying HLA class I mismatches between potential donors and the recipient when pre-allograft platelet transfusions were required. We included 114 recipient/haploidentical relative pairs. For each pair, we entered HLA-class I typing data into the HLA Eplet Mismatch calculator, defined the list of mismatched eplets (for the recipient versus donor direction) and thus identified the shared HLAs to be avoided. Using this list of HLAs, we defined the theoretical availability of platelet components (PCs) by calculating the virtual panel-reactive antibody (vPRA). We also determined the number of PCs actually available in France by querying the regional transfusion centre's database. The mean ± standard deviation number of highly/moderately exposed eplets to be avoided in platelet transfusions was 5.8 ± 3.3, which led to the prohibition of 38.5 ± 2 HLAs-A and -B. Taking into account the mismatched antigens and the eplet load, the mean ± standard deviation theoretical availability of PCs (according to the vPRA) was respectively 34.49% ± 1.95% for HLA-A and 80% ± 2.3% for HLA-B. A vPRA value below 94.9% for highly or moderately exposed eplets would predict that 10 PCs were actually available nationally. Although epitope protection of HLA molecules is feasible, it significantly restricts the choice of PCs.

Bone marrow graft versus peripheral blood graft in haploidentical hematopoietic stem cells transplantation: a retrospective analysis in1344 patients of SFGM-TC registry.

The use of peripheral blood (PB) or bone marrow (BM) stem cells graft in haploidentical hematopoietic stem cell transplantation with post-transplant cyclophosphamide (PTCy) for graft-versus-host disease (GVHD) prophylaxis remains controversial. Moreover, the value of adding anti-thymoglobulin (ATG) to PTCy is unknown. A total of 1344 adult patients received an unmanipulated haploidentical transplant at 37 centers from 2012 to 2019 for hematologic malignancy. We compared the outcomes of patients according to the type of graft, using a propensity score analysis. In total population, grade II-IV and III-IV acute GVHD (aGVHD) were lower with BM than with PB. Grade III-IV aGVHD was lower with BM than with PB + ATG. All outcomes were similar in PB and PB + ATG groups. Then, in total population, adding ATG does not benefit the procedure. In acute leukemia, myelodysplastic syndrome and myeloproliferative syndrome (AL-MDS-MPS) subgroup receiving non-myeloablative conditioning, risk of relapse was twice greater with BM than with PB (51 vs. 22%, respectively). Conversely, risk of aGVHD was greater with PB (38% for aGVHD II-IV; 16% for aGVHD III-IV) than with BM (28% for aGVHD II-IV; 8% for aGVHD III-IV). In this subgroup with intensified conditioning regimen, risk of relapse became similar with PB and BM but risk of aGVHD III-IV remained higher with PB than with BM graft (HR = 2.0; range [1.17-3.43], p = 0.012).

5-Azacytidine treatment for relapsed or refractory acute myeloid leukemia after intensive chemotherapy.

Despite progress in the understanding of leukemia pathophysiology, the treatment of acute myeloid leukemia (AML) remains challenging. In patients with refractory or relapsed (R/R) AML, the prognosis is still poor and this group is targeted for new drug development. We reviewed the outcome of 47 patients, with R/R AML after at least one course of intensive chemotherapy, treated with 5-azacytidine in three different French institutions. The overall response rate was 38% including complete remission in 21%, partial remission in 11%, and hematological improvement in 6% of cases. Median time to relapse was 6 (range, 1-39) months. Median overall survival was 9 months (not reached by responders vs. 4.5 months for nonresponders patients, P = 0.0001). Univariate analysis identified the absence of peripheral blood blasts and <20% bone marrow blasts as prognostic factors for both overall response and survival, but not age, ECOG/PS, type of AML, cytogenetic, status of the disease, number of previous lines of therapy, previous hematological stem cell transplantation, or white blood cells count. Bone marrow blasts percentage <20% was the only independent prognostic factor identified by multivariate analysis for overall response (P = 0.0013) and survival (P = 0.0324). Six patients in remission could proceed to an allogenic hematological stem cell transplantation. The drug-related grade 3/4 adverse events were hematopoietic toxicities (38%) and infection (32%). In conclusion, this study suggests that a salvage therapy with 5-azacytidine is an interesting option for patients with R/R AML after intensive chemotherapy. Prospective randomized studies are needed to demonstrate a superiority of this approach over others strategies.

Ruxolitinib-induced reactivation of cytomegalovirus and Epstein-Barr virus in graft-versus-host disease.

OBJECTIVES: Steroid-refractory graft-versus-host disease (SR-GVHD) is a challenging complication of allogeneic hematopoietic stem cell transplantation, and leads to high morbidity and mortality rates. The orally administered, selective Janus-associated kinase 1/2 inhibitor ruxolitinib gives overall response rates (ORR) of more than 70 % in acute and chronic SR-GVHD. However, several studies have highlighted an elevated risk of cytomegalovirus (CMV) reactivation in patients with ruxolitinib-treated SR-GVHD. METHODS: We therefore analyzed risk of CMV and Epstein-Barr virus (EBV) primary infection or reactivation in 57 patients with ruxolitinib-treated GVHD, while taking account of the competing risk (CR) of death prior to the first reactivation. RESULTS: Initiation of ruxolitinib treatment was a significant adverse prognostic factor for the CR of first CMV reactivation (hazard ratio (HR)= 1.747, 95 % confidence interval (CI): 1.33-2.92, p < 0.0001) and first EBV reactivation (HR=2.657, 95 % CI: 1.82-3.87, p < 0.0001) during GVHD. In our cohort of ruxolitinib-treated patients, the ORR (48 % and 58 % for acute and chronic GVHD, respectively) and the toxicity profile (haematological adverse events in 29.8 % of the patients) were similar to the literature values. CONCLUSION: Given ruxolitinib's efficacy in SR-GVHD, use of this drug should not be limited by the fear of viral reactivation; however, our present results emphasize the importance of monitoring the viral load.

Outcome after allogeneic stem cell transplantation with haploidentical versus HLA-matched donors in patients with higher-risk MDS.

Allogeneic hematopoietic stem cell transplantation remains the best curative option for higher-risk myelodysplastic syndrome. The presence of monosomal karyotype and/or complex karyotype abnormalities predicts inferior survival after allo-SCT in MDS patients. Haploidentical allo-SCT has been increasingly used in acute leukemia (AL) and has similar results as using HLA-matched donors, but data on higher-risk MDS is sparse. We compared outcomes in 266 patients with higher-risk MDS after HLA-matched sibling donor (MSD, n = 79), HLA-matched unrelated donor (MUD, n = 139) and HLA haploidentical donor (HID, n = 48) from 2010 to 2019. Median donor age differed between the three groups (p < 0.001). The overall survival was significantly different between the three groups with a better OS observed in the MUD group (p = 0.014). This observation could be explained by a higher progression-free survival with MUD (p = 0.014). The cumulative incidence of grade 2-4 acute GvHD was significantly higher in the HID group (p = 0.051). However, in multivariable analysis, patients transplanted using an HID had comparable mortality to patients transplanted using a MUD (subdistribution hazard ratio [sHR]: 0.58 [0.32-1.07]; p = 0.080) and a MSD ([sHR]: 0.56 [0.28-1.11]; p = 0.094). MUD do not remain a significant positive predictor of survival, suggesting that beyond the donor-recipient HLA matching, the donor age might impact recipient outcome.

Pooled allogeneic faecal microbiota MaaT013 for steroid-resistant gastrointestinal acute graft-versus-host disease: a single-arm, multicentre phase 2 trial.

Background: Failure of gastrointestinal acute graft-versus-host disease (GI-aGvHD) to respond to steroid therapy is associated with limited further therapeutic options. We aimed to assess the safety and efficacy of the first-in-human use of the pooled allogeneic faecal microbiota, MaaT013, for the treatment of steroid-refractory GI-aGvHD. Methods: This prospective, international, single-arm, phase 2a study reports clinical outcomes from a 24-patient cohort with grade III-IV, steroid refractory GI-aGvHD treated with the pooled allogeneic faecal microbiota MaaT013. MaaT013 involved pooling faecal matter from 3 to 8 screened donors then transplanting the pooled batches into patients to treat GI-aGVHD. The 24 patients were treated in the HERACLES study (Aug 2018 to Nov 2020) at 26 sites in Europe and an additional 52 patients were treated in a compassionate use/expanded access program (EAP) in France (July 2018 to April 2021). The primary endpoint was GI response at day 28, defined as the proportion of patients with GI-aGvHD who had a complete response (CR) or very good partial response (VGPR). GvHD grading and staging were assessed according to the revised Glucksberg criteria. Adverse events and severe adverse events were monitored for 6 months and 12 months, respectively. The HERACLES study was registered with ClinicalTrials.gov (NCT03359980). Findings: Compared with single donors, MaaT013 is characterised by higher microbial richness and reduced variability across batches. At day 28 (D28), the GI-overall response rate (ORR) was 38% in the prospective population, including 5 complete responses (CR), 2 very good partial responses (VGPR) and 2 partial responses (PR). In the EAP, the GI-ORR was 58% (17 CR, 9 VGPR and 4 PR). The 12-month overall survival (OS) was 25% in the prospective study and 38% in the EAP. Regarding safety, five infectious complications, including 3 sepsis, could not be excluded from being related to the study procedure in HERACLES. Shotgun sequencing analyses of the identified strains suggest that none were found in MaaT013. In the EAP, 18 pharmacovigilance cases were reported among 52 treated patients, including 11 bacteraemia/sepsis. In HERACLES, we observed in stools from responding patients at D28 a higher microbiota richness and increased levels of beneficial bacteria, in particular butyrate producers, along with increased levels of short-chain fatty acid and bile acids. In contrast, stools from non-responding (NR) patients displayed increased levels of pathogenic pro-inflammatory bacteria along with increased systemic inflammatory parameters. Interpretation: Overall, MaaT013 was safe in this population of highly immunocompromised patients and was associated with responses in some patients with GI-aGvHD and deserves further investigation. Funding: MaaT Pharma.

Beneficial outcomes and epidemiologics of atypical electrophoretic profiles arising after allogeneic hematopoietic stem cell transplantation for myeloid malignancies.

PURPOSE OF THE STUDY: Atypical serum protein electrophoresis (SPE) profiles may arise in patients who received allogeneic hematopoietic stem cell transplantation (allo-HSCT), but little is known about their clinical significance. Atypical SPE combine either monoclonal and oligoclonal components, suspected on SPE and confirmed by immunofixation. The aim of the study is to analyze the incidence, the etiology and the clinical significance of atypical SPE profiles in patients who received allo-HSCT. PATIENTS AND METHODS: This retrospective study enrolled 117 patients with myeloid malignancies who received an allo-HSCT between 2012 and 2018. We excluded patients with lymphoid malignancies or multiple myeloma, patients presenting atypical electrophoresis prior to transplantation and patients who died within 100 days post-transplant. RESULTS: Atypical SPE occurred in 42.7% of patients. The cumulative incidence of atypical profiles was significantly higher in patients with acute Graft Versus Host Disease (GVHD, p = 0.019) and in patients with Cytomegalovirus (CMV) reactivation (p = 0.0017). We observed for the first time that atypical SPE profiles mostly occurred in patients transplanted from a CMV+ donor (p = 0.031). CMV reactivation preceded the occurrence of atypical SPE in the majority of patients. We show that atypical SPE delay the relapse of the underlying malignant disease (486 vs 189 days, p = 0.006), and significantly improve overall survival (OS; 33.1 months vs 28.3 months, p = 0.049). In both univariate and multivariate analyzes, the presence of an atypical SPE is the only factor that significantly improves OS. CONCLUSIONS: The occurrence of atypical SPE profiles after allo-HSCT may reflect an adapted post-transplant immune response leading to favourable outcomes.