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).

Complex karyotype but not other cytogenetic abnormalities is associated with worse posttransplant survival of patients with nucleophosmin 1-mutated acute myeloid leukemia: A study from the European Society for Blood and Marrow Transplantation Acute Leukemia Working Party.

In the 2022 European LeukemiaNet classification, patients with nucleophosmin 1 (NPM1)-mutated acute myeloid leukemia (AML) were classified in the adverse-risk category in the presence of high-risk cytogenetics (CG). Nonetheless, the impact of various CG aberrations on posttransplant outcomes remains to be unraveled. This registry study analyzed adult patients with NPM1-mutated de novo AML who underwent their first allogeneic hematopoietic cell transplantation in the first complete remission from 2005 to 2021. A total of 3275 patients were identified, 2782 had normal karyotype, 493 had chromosomal aberrations including 160 with adverse-risk CG, 72 patients had complex karyotype (CK), and 66 monosomal karyotype (MK). Overall, 2377 (73%) patients had FLT3-ITD. On univariate analysis, only FLT3-ITD, minimal/measurable residual disease (MRD) positivity and CK, but not abnormal CG, affected posttransplant outcomes. On multivariable analysis, CK was associated with lower overall survival (OS) (hazard ratio [HR] 1.72, p = .009). In the subgroup of 493 patients with aberrant CG, the 2-year leukemia-free survival (LFS) and OS were around 61% and 68%, respectively. On multivariable analysis for this subgroup, CK and MRD positivity were associated with increased risk of relapse (HR 1.7, p = .025; and 1.99, p = .003 respectively) and worse LFS (HR 1.62, p = .018; and 1.64, p = .011 respectively) while FLT3-ITD, MK, or other CG abnormalities had no significant effect. Importantly, CK negatively affected OS (HR 1.91, p = .002). In the first complete remission transplant setting, CK was found as the only cytogenetic risk factor for worse outcomes in NPM1-mutated AML. Nevertheless, even for this subgroup, a significant proportion of patients can achieve long-term posttransplant survival.

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.

Allogeneic hematopoietic stem cell transplantation for adults with therapy-related acute myeloid leukaemia: a retrospective multicentre study on behalf of the SFGM-TC.

We report the results from a multicentre retrospective study of 220 adult patients who underwent allogeneic hematopoietic stem cell transplantation (alloHSCT) for therapy-related acute myeloid leukaemia (t-AML). Median age at t-AML diagnosis was 56 years, with a prior history of haematological (45%) or breast (34%). Median time from cytotoxic exposure to t-AML diagnosis was 54.7 months. At transplant, around 20% of patients had measurable residual disease and 3% of patients were not in complete remission. The median follow-up was 21.4 months (Q1-Q3, 5.9-52.8). At 12 months, overall survival (OS), event-free survival (EFS), and graft-versus-host-disease (GVHD)-free-relapse-free survival (GRFS) were 60.7% (95% CI 54.6-67.5), 52.8% (95% CI 46.5-68.4), and 44.1% (95% CI 37.6-51.8), respectively. At 5 years, OS, EFS, and GRFS were 44.1% (95% CI 37.4-52.1), 40.4% (95% CI 33.9-48.1), and 35.3% (95% CI 28.8-43.3), respectively. At last follow-up, 44% of patients were in complete remission (n = 96) and transplant-related mortality accounted for 21% of all deaths (n = 119). Multivariable analysis revealed that uncontrolled t-AML at transplant was associated with lower EFS (HR 1.94, 95% CI 1.0-3.7, p = 0.041). In conclusion, alloHSCT for t-AML shows encouraging results and offers additional opportunity with the emergence of novel pre-graft therapies.

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.

Impact of allele-level HLA matching on outcomes after double cord blood transplantation in adults with malignancies.

In single unrelated cord blood transplantation (UCBT), an increasing number of HLA allele mismatches (MM) has been associated with inferior overall survival (OS) and attributed to higher transplant-related mortality (TRM). Previous studies on the role of allele-level HLA matching after double UCBT (dUCBT) showed conflicting results. In this study, we report the impact of allele-level HLA matching on the outcomes of a large dUCBT cohort. We included 963 adults with hematologic malignancies, with available allele-level HLA matching at HLA-A, -B, -C, and -DRB1, receiving dUCBT between 2006 to 2019. Assignment of donor-recipient HLA match was performed considering the unit with the highest disparity with the recipient. Three hundred ninety-two patients received dUCBT with 0 to 3 MM and 571 with ≥4 allele MM. For recipients of dUCBT with 0 to 3 MM, day-100 and 4-year TRM were 10% and 23%, respectively, compared with 16% and 36% for those with ≥4 MM. A higher degree of allele MM was also associated with the worse neutrophil recovery and lower incidence of relapse; no significant effect on graft-versus-host disease was observed. Patients receiving units with 0 to 3 MM had a 4-year OS of 54% compared with 43% for those receiving units with ≥4 MM. The inferior OS associated with higher HLA disparity was only partially mitigated by increased total nucleated cell doses. Our results confirm that allele-level HLA typing is a significant factor for OS after dUCBT, and units with ≥4 MM (≤4/8 HLA-matched) should be avoided if possible.

Nilotinib efficacy and safety as salvage treatment following imatinib intolerance and/or inefficacy in steroid refractory chronic graft-versus-host-disease (SR-cGVHD): a prospective, multicenter, phase II study on behalf of the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC).

Imatinib is used for patients with SR-cGVHD. However, in 50% of cases imatinib is discontinued due to intolerance or inefficacy. In order to investigate nilotinib's role as salvage therapy in those patients, we conducted a prospective, multicenter, phase II study. (NCT02891395). Patients with SR-cGVHD were included to receive imatinib. Patients who stopped imatinib due to intolerance or inefficacy switched to Nilotinib. The primary endpoint was defined as the week-12 response rate to Nilotinib. The response was considered successful if superior to the 30% endpoint. Sixty-two patients started the IM-phase. Fourteen patients (22%) discontinued imatinib before week 12 due to: cGVHD progression (10%) or TKI-class-specific intolerance (12%). At week 12, we observed complete remission in 13 patients (21%) and partial response in 8 patients (13%). Twenty-nine patients switched to Nilotinib. Nilotinib response at week-12 was observed in 6 patients (21%) while 23 patients (79%) discontinued Nilotinib due to intolerance/cGVHD progression. The primary endpoint was not reached. This prospective study confirmed the efficacy of imatinib in patients with steroid refractory cGVHD. It failed to demonstrate the efficacy of nilotinib as a salvage therapy in patients who were intolerant/unresponsive to imatinib.

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.

Refractory invasive pulmonary aspergillosis due to Aspergillus flavus detected with the combination of two in-house Aspergillus qPCR.

We present a case of probable invasive pulmonary aspergillosis due to Aspergillus flavus, in a female patient treated for an acute myeloid leukemia. Two weeks after an allogenic stem cell transplantation a probable invasive pulmonary aspergillosis was diagnosed based on thoracic imaging combined with positive galactomannan antigen and positive in-house mitochondrial Aspergillus qPCR in serum. Although an antifungal treatment was initiated, Aspergillus qPCR and galactomannan antigen remained positive in serum and worsening of the thoracic lesions was observed. The discordance between the negativity of the in-house ribosomal Aspergillus qPCR (specific to A. fumigatus) and the positivity of the in-house mitochondrial Aspergillus qPCR (targeting A. fumigatus and some other Aspergillus) allowed the suspicion of a thermophilic Aspergillus species that was not A. fumigatus. No strain was obtained in culture but the involvement of A. flavus was confirmed using a specific A. flavus qPCR. This case illustrated the usefulness of our original strategy combining two different in-house Aspergillus qPCRs, in addition to galactomannan assay, to diagnose invasive aspergillosis in hematology patients.

Chimeric antigen receptor T-cells targeting IL-1RAP: a promising new cellular immunotherapy to treat acute myeloid leukemia.

BACKGROUND: Acute myeloid leukemia (AML) remains a very difficult disease to cure due to the persistence of leukemic stem cells (LSCs), which are resistant to different lines of chemotherapy and are the basis of refractory/relapsed (R/R) disease in 80% of patients with AML not receiving allogeneic transplantation. METHODS: In this study, we showed that the interleukin-1 receptor accessory protein (IL-1RAP) protein is overexpressed on the cell surface of LSCs in all subtypes of AML and confirmed it as an interesting and promising target in AML compared with the most common potential AML targets, since it is not expressed by the normal hematopoietic stem cell. After establishing the proof of concept for the efficacy of chimeric antigen receptor (CAR) T-cells targeting IL-1RAP in chronic myeloid leukemia, we hypothesized that third-generation IL-1RAP CAR T-cells could eliminate AML LSCs, where the medical need is not covered. RESULTS: We first demonstrated that IL-1RAP CAR T-cells can be produced from AML T-cells at the time of diagnosis and at relapse. In vitro and in vivo, we showed the effectiveness of IL-1RAP CAR T-cells against AML cell lines expressing different levels of IL-1RAP and the cytotoxicity of autologous IL-1RAP CAR T-cells against primary cells from patients with AML at diagnosis or at relapse. In patient-derived relapsed AML xenograft models, we confirmed that IL-1RAP CAR T-cells are able to circulate in peripheral blood and to migrate in the bone marrow and spleen, are cytotoxic against primary AML cells and increased overall survival. CONCLUSION: In conclusion, our preclinical results suggest that IL-1RAP CAR T-based adoptive therapy could be a promising strategy in AML treatment and it warrants the clinical investigation of this CAR T-cell therapy.

Impact of the Addition of Antithymocyte Globulin to Post-Transplantation Cyclophosphamide in Haploidentical Transplantation with Peripheral Blood Compared to Post-Transplantation Cyclophosphamide Alone in Acute Myelogenous Leukemia: A Retrospective Study on Behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

The use of haploidentical hematopoietic cell transplantation (haplo-HCT) with peripheral blood stem cells (PBSCs) to treat acute myelogenous leukemia (AML) is increasing. We explored whether the addition of antithymocyte globulin (ATG) to post-transplantation cyclophosphamide (PTCy) allows better outcomes compared with PTCy alone in haplo-HCT with PBSCs (haplo-PBSCT). We included 441 adult patients undergoing a first haplo-PBSCT for AML in first or second complete remission; graft-versus-host disease (GVHD) prophylaxis contained either PTCy alone (n = 374) or ATG plus PTCy (n = 67), in addition to cyclosporine A (CsA) and mycophenolate mofetil (MMF) as other immunosuppressive agents. All transplantations were performed between 2011 and 2019. No major imbalances were observed between the 2 groups. For both groups, the median patient age was 56 years, and the median year of haplo-PBSCT was 2017. Most patients received a reduced-intensity conditioning regimen (57% in the PTCy group and 61% in the ATG+PTCy group; P = .54). The median follow-up was 19 months in the PTCy group versus 15 months in the ATG+PTCy group (P = .59), and the rate of neutrophil engraftment in the 2 groups was 97% and 98%, respectively. In univariate analysis, there were no statistical differences in transplantation outcomes between the 2 groups. In multivariate analysis, ATG+PTCy was associated with a lower risk of chronic GVHD compared with PTCy alone (hazard ratio, .46; 95% confidence interval, .23 to .93; P = .03). No between-group differences in the other transplantation outcomes were seen. In haplo-PBSCT, the addition of ATG to PTCy (with CsA and MMF) is feasible and better at preventing chronic GVHD and is associated with survival and transplantation outcomes comparable to those with PTCy alone, without increasing transplantation toxicity, mortality, or relapse incidence.

CD123 and More: How to Target the Cell Surface of Blastic Plasmacytoid Dendritic Cell Neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive leukemia derived from plasmacytoid dendritic cells (pDCs). It is associated with a remarkably poor prognosis and unmet need for better therapies. Recently, the first-in-class CD123-targeting therapy, tagraxofusp, was approved for treatment of BPDCN. Other CD123-targeting strategies are in development, including bispecific antibodies and combination approaches with tagraxofusp and other novel agents. In other blood cancers, adoptive T-cell therapy using chimeric antigen receptor (CAR)-modified T cells represents a promising new avenue in immunotherapy, showing durable remissions in some relapsed hematologic malignancies. Here, we report on novel and innovative therapies in development to target surface molecules in BPDCN currently in clinical trials or in preclinical stages. We also discuss new cell surface targets that may have implications for future BPDCN treatment.

Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.

OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Measurable residual disease, FLT3-ITD mutation, and disease status have independent prognostic influence on outcome of allogeneic stem cell transplantation in NPM1-mutated acute myeloid leukemia.

Nucleophosmin-1 (NPM1) mutations in acute myeloid leukemia (AML) confer a survival advantage in the absence of FLT3-internal tandem duplication (FLT3-ITD). Here, we investigated the main predictors of outcome after allogeneic hematopoietic stem cell transplantation (allo-HCT). We identified 1572 adult (age ≥ 18 year) patients with NPM1-mutated AML in first complete remission (CR1:78%) or second complete remission (CR2:22%) who were transplanted from matched sibling donors (30.8%) or unrelated donors (57.4%) between 2007 and 2019 at EBMT participating centers. Median follow-up for survivors was 23.7 months. FLT3-ITD was present in 69.3% of patients and 39.2% had detectable minimal/measurable residual disease (MRD) at transplant. In multivariate analysis, relapse incidence (RI) and leukemia-free survival (LFS) were negatively affected by concomitant FLT3-ITD mutation (HR 1.66 p = 0.0001, and HR 1.53, p < 0.0001, respectively), MRD positivity at transplant (HR 2.18, p < 10-5 and HR 1.71, p < 10-5 , respectively), and transplant in CR2 (HR 1.36, p = 0.026, and HR 1.26, p = 0.033, respectively), but positively affected by Karnofsky score ≥90 (HR 0.74, p = 0.012, and HR 0.7, p = 0.0002, respectively). Overall survival (OS) was also negatively influenced by concomitant FLT3-ITD (HR 1.6, p = 0.0001), MRD positivity at transplant (HR 1.61, p < 10-5 ), and older age (HR 1.22 per 10 years, p < 0.0001), but positively affected by matched sibling donor (unrelated donor: HR 1.35, p = 0.012; haploidentical donor: HR 1.45, p = 0.037) and Karnofsky score ≥90 (HR 0.73, p = 0.004). These results highlight the independent and significant role of FLT3-ITD, MRD status, and disease status on posttransplant outcomes in patients with NPM1-mutated AML allowing physicians to identify patients at risk of relapse who may benefit from posttransplant prophylactic interventions.

High-density lipoprotein infusion protects from acute graft-versus-host disease in experimental allogeneic hematopoietic cell transplantation.

Acute graft-versus-host disease (aGVHD) is a major limitation of the therapeutic potential of allogeneic hematopoietic cell transplantation. Lipopolysaccharides (LPS) derived from intestinal gram-negative bacteria are well-known aGVHD triggers and amplifiers. Here, we explored the LPS metabolism in aGVHD mouse models using an innovative quantification method. We demonstrated that systemic LPS accumulation after transplantation was due, at least partly, to a defect in its clearance through lipoprotein-mediated transport to the liver (i.e., the so-called reverse LPS transport). After transplantation, reduced circulating HDL concentration impaired LPS neutralization and elimination through biliary flux. Accordingly, HDL-deficient (Apoa1tm1Unc ) recipient mice developed exacerbated aGVHD. Repeated administration of HDL isolated from human plasma significantly decreased the mortality and the severity of aGVHD. While the potential role of HDL in scavenging circulating LPS was examined in this study, it appears that HDL plays a more direct immunomodulatory role by limiting or controlling aGVHD. Notably, HDL infusion mitigated liver aGVHD by diminishing immune infiltration (e.g., interferon-γ-secreting CD8+ T cells and non-resident macrophages), systemic and local inflammation (notably cholangitis). Hence, our results revealed the interest of HDL-based therapies in the prevention of aGVHD.

Allogeneic hematopoietic cell transplantation in patients with myeloid/lymphoid neoplasm with FGFR1-rearrangement: a study of the Chronic Malignancies Working Party of EBMT.

Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for patients with myeloid/lymphoid neoplasm (MLN) with FGFR1 rearrangement, but data on overall results are limited. We report on the largest series of patients (n = 22) with FGFR1-rearranged MLN undergoing allo-HCT. Distribution according to cytogenetic subtype was: t(8;13) in 11 cases, t(8;22) in 7 cases, t(6;8) in 2 cases, and other (n = 2). Over a third of patients displayed a chronic myeloproliferative (MPN) phenotype, another third showed MPN features with concomitant lymphoma or acute leukemia, and the remaining ones presented as acute leukemia. After a median follow-up of 4.1 years from transplant, the estimated 5-year survival rate, progression-free survival, non-relapse mortality and relapse incidence was 74%, 63%, 14% and 23%, respectively. Causes of death were relapse/progression (n = 4), graft-versus-host disease (n = 2) and organ toxicity (n = 1). Six patients experienced disease relapse at a median of 6.1 months (range: 2.3-119.6). Two of them achieved complete remission with ponatinib or pemigatinib and were alive at 34.5 and 37 months from relapse, respectively. These data highlight the significant curative potential of allo-HCT in this aggressive disease. Maintenance with tyrosine kinase inhibitors may be a promising approach, at least in cases with detectable residual disease after transplant.

Eltrombopag Added to Immunosuppression in Severe Aplastic Anemia.

BACKGROUND: A single-group, phase 1-2 study indicated that eltrombopag improved the efficacy of standard immunosuppressive therapy that entailed horse antithymocyte globulin (ATG) plus cyclosporine in patients with severe aplastic anemia. METHODS: In this prospective, investigator-led, open-label, multicenter, randomized, phase 3 trial, we compared the efficacy and safety of horse ATG plus cyclosporine with or without eltrombopag as front-line therapy in previously untreated patients with severe aplastic anemia. The primary end point was a hematologic complete response at 3 months. RESULTS: Patients were assigned to receive immunosuppressive therapy (Group A, 101 patients) or immunosuppressive therapy plus eltrombopag (Group B, 96 patients). The percentage of patients who had a complete response at 3 months was 10% in Group A and 22% in Group B (odds ratio, 3.2; 95% confidence interval [CI], 1.3 to 7.8; P = 0.01). At 6 months, the overall response rate (the percentage of patients who had a complete or partial response) was 41% in Group A and 68% in Group B. The median times to the first response were 8.8 months (Group A) and 3.0 months (Group B). The incidence of severe adverse events was similar in the two groups. With a median follow-up of 24 months, a karyotypic abnormality that was classified as myelodysplastic syndrome developed in 1 patient (Group A) and 2 patients (Group B); event-free survival was 34% and 46%, respectively. Somatic mutations were detected in 29% (Group A) and 31% (Group Β) of the patients at baseline; these percentages increased to 66% and 55%, respectively, at 6 months, without affecting the hematologic response and 2-year outcome. CONCLUSIONS: The addition of eltrombopag to standard immunosuppressive therapy improved the rate, rapidity, and strength of hematologic response among previously untreated patients with severe aplastic anemia, without additional toxic effects. (Funded by Novartis and others; RACE ClinicalTrials.gov number, NCT02099747; EudraCT number, 2014-000363-40.).