Clinical and Genomic-Based Decision Support System to Define the Optimal Timing of Allogeneic Hematopoietic Stem-Cell Transplantation in Patients With Myelodysplastic Syndromes.

PURPOSE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only potentially curative treatment for patients with myelodysplastic syndromes (MDS). Several issues must be considered when evaluating the benefits and risks of HSCT for patients with MDS, with the timing of transplantation being a crucial question. Here, we aimed to develop and validate a decision support system to define the optimal timing of HSCT for patients with MDS on the basis of clinical and genomic information as provided by the Molecular International Prognostic Scoring System (IPSS-M). PATIENTS AND METHODS: We studied a retrospective population of 7,118 patients, stratified into training and validation cohorts. A decision strategy was built to estimate the average survival over an 8-year time horizon (restricted mean survival time [RMST]) for each combination of clinical and genomic covariates and to determine the optimal transplantation policy by comparing different strategies. RESULTS: Under an IPSS-M based policy, patients with either low and moderate-low risk benefited from a delayed transplantation policy, whereas in those belonging to moderately high-, high- and very high-risk categories, immediate transplantation was associated with a prolonged life expectancy (RMST). Modeling decision analysis on IPSS-M versus conventional Revised IPSS (IPSS-R) changed the transplantation policy in a significant proportion of patients (15% of patient candidate to be immediately transplanted under an IPSS-R-based policy would benefit from a delayed strategy by IPSS-M, whereas 19% of candidates to delayed transplantation by IPSS-R would benefit from immediate HSCT by IPSS-M), resulting in a significant gain-in-life expectancy under an IPSS-M-based policy (P = .001). CONCLUSION: These results provide evidence for the clinical relevance of including genomic features into the transplantation decision making process, allowing personalizing the hazards and effectiveness of HSCT in patients with MDS.

Anti-T-lymphocyte globulin improves GvHD-free and relapse-free survival in myelofibrosis after matched related or unrelated donor transplantation.

Acute and chronic graft-versus-host disease (GvHD) are major complications of allogeneic hematopoietic cell transplantation (alloHCT). In vivo T-cell depletion with anti-T-lymphocyte globulin (ATLG) as part of the conditioning regimen prior to alloHCT is frequently used as GvHD prophylaxis, but data on its role in myelofibrosis is scarce. We took advantage of an international collaborative network to investigate the impact of ATLG in myelofibrosis undergoing first alloHCT. We included 707 patients (n = 469 ATLG and n = 238 non-ATLG prophylaxis). The cumulative incidence of acute GvHD grade II-IV was 30% for the ATLG group vs. 56% for the non-ATLG group (P < 0.001). Acute GvHD grade III-IV occurred in 20% vs. 25%, respectively (P = 0.01). Incidence of mild-to-severe chronic GvHD was 49% vs. 50% (P = 0.52), while ATLG showed significantly lower rates of severe chronic GvHD (7% vs. 18%; P = 0.04). GvHD-free and relapse-free survival (GRFS) at 6 years was 45% for the ATLG group vs. 37% for the non-ATLG group (P = 0.02), driven by significantly improved GRFS of ATLG in matched related and matched unrelated donors. No significant differences in risk for relapse, non-relapse mortality, and overall survival were observed. Multivariable modeling for GRFS showed a 48% reduced risk of GvHD, relapse, or death when using ATLG.

Does IPSS-R down staging before transplantation improve the prognosis of patients with Myelodysplastic neoplasms?

In MDS patients higher IPSS-R at transplant is associated with worse transplant outcome. Thus, it may seem beneficial to improve IPSS-R by therapeutic intervention prior to transplantation in order to "down-stage" the disease risk. However, there is no evidence to date to support this approach. A retrospective analysis of the EBMT transplant registry was performed to investigate the role of therapeutic interventions prior to transplantation with regard to changes in IPSS-R and transplant outcomes. A total of 1482 MDS patients with sufficient data to calculate IPSS-R at diagnosis and at time of transplantation were selected and analysed for transplant outcome in a multivariable Cox model including IPSS-R at diagnosis, treatment intervention, change in IPSS-R before transplant and several patient and transplant variables. Transplant outcome was unaffected by IPSS-R change in untreated patients and moderately superior in chemotherapy-treated patients with improved IPSS-R at transplant. Improved IPSS-R after hypomethylating agents (HMA) or other therapies showed no beneficial effect. However, when IPSS-R progressed after chemotherapy, (HMA) or other therapies, transplant outcome was worse than without any prior treatment. Similar results were found when reduction or increase in bone marrow (BM) blasts between diagnosis and transplantation was considered. The results show a limited benefit of IPSS-R down staging or reduction of BM blasts after chemotherapy and no benefit for HMA or other treatments and thus question the role of prior therapy in MDS patients scheduled for transplantation. The model-based survival estimates should help inform decision making for both doctors and patients.

Donor/recipient Rh-mismatched allogeneic hematopoietic stem cell transplantation: transfusion strategy and allo-immunization to red blood cell antigens.

In the case of donor/recipient rhesus (Rh)-incompatibility after allogeneic hematopoietic stem cell transplantation (alloHSCT), the transfusion policy in France is to transfuse red blood cells (RBC) in the donor's Rh phenotype from the day of transplantation, leading to a risk of allo-immunization, either of donor or recipient origin. In this single-center retrospective study, the incidence of donor/recipient Rh incompatibility was 7.1% over an 8-year period including 1012 alloHSCT. Six of 58 evaluable patients (10.3%) developed alloantibodies to RBC antigens within one year of alloHSCT. None of these allo-immunizations were directed against the donor-mismatched Rh antigens and none could have been prevented by the transfusion of recipient and donor Rh-compatible RBC units. None of these allo-immunizations led to immune-mediated hemolytic anemia. We observed a statistically significant higher incidence of chronic GVHD among patients with anti-RBC allo-immunization. In the context of donor/recipient Rh incompatibility, the transfusion of packed RBC units in the donor's Rh phenotype from the day of alloHSCT is feasible and not associated with a high risk of allo-immunization. The generalization of this strategy could be discussed even when donor and recipient Rh phenotypes could be respected, to allow the preservation of units of infrequent phenotypes for other indications.

Mismatched related donor allogeneic haematopoietic cell transplantation compared to other donor types for Ph+ chronic myeloid leukaemia: A retrospective analysis from the Chronic Malignancies Working Party of the EBMT.

Allogeneic haematopoietic cell transplantation (allo-HCT) remains an option for tyrosine kinase inhibitor-resistant chronic myeloid leukaemia (CML) in first chronic phase (CP1) and high-risk patients with advanced disease phases. In this European Society for Blood and Marrow Transplantation (EBMT) registry-based study of 1686 CML patients undergoing first allo-HCT between 2012 and 2019, outcomes were evaluated according to donor type, particularly focusing on mismatched related donors (MMRDs). Median age at allo-HCT was 46 years (IQR 36-55). Disease status was CP1 in 43%, second CP (CP2) or later in 27%, accelerated phase in 12% and blast crisis in 18%. Donor type was matched related (MRD) in 39.2%, MMRD in 8.1%, matched unrelated (MUD) in 40.2%, and mismatched unrelated (MMUD) in 12.6%. In 4 years, overall survival (OS) for MRD, MMRD, MUD and MMUD was 61%, 56%, 63% and 59% (p = 0.21); relapse-free survival (RFS) was 48%, 42%, 52% and 46% (p = 0.03); cumulative incidence of relapse (CIR) was 33%, 37%, 27% and 30% (p = 0.07); non-relapse mortality (NRM) was 19%, 21%, 21% and 24% (p = 0.21); and graft-versus-host disease (GvHD)-free/relapse-free survival (GRFS) was 16%, 18%, 22% and 15% (p = 0.05) respectively. On multivariate analysis, MMRD use associated with longer engraftment times and higher risk of graft failure compared to MRD or MUD. There was no statistical evidence that MMRD use associated with different OS, RFS and incidence of GvHD compared to other donor types.

Reduced intensity versus myeloablative conditioning for MDS: long-term results of an EBMT phase III study (RICMAC).

Short-term outcome of myeloablative (MAC) and reduced intensity (RIC) conditioning in the prospective randomized international EBMT RICMAC study in patients with myelodyplastic syndrome (MDS) was comparable but longer follow up is lacking. Patients with MDS aged 18-65 years were randomized to receive MAC (N = 64) with busulfan/cyclophosphamide or RIC (n = 65) with busulfan/fludarabine followed by stem cell transplantation -(HCT) from HLA matched or mismatched donor. After a median follow-up of 6.2 (0.4-12.5) years, 10-year OS and RFS were 54.0% and 43.9% for RIC and 44.4% and 44.2% for MAC (p = 0.15 and p = 0.78), respectively. Since the first report, 6 patients died on NRM, 4 after RIC, and 2 after MAC. Similarly, 8 patients relapsed (4 in each arm), increasing the number of relapsed patients to 28. The second HCT was performed in 18 pts, 8 in the MAC, and 10 in the RIC arm. In a multivariate analysis, ECOG status and chemotherapy prior to HCT were independent risk factors for OS and RFS, ECOG and low cytogenetic risk for NRM and chemotherapy prior to HCT for RI. Patients with low cytogenetic risk had better OS [p = 0.002], RFS [p = 0.02], and NRM (p = 0.015) after RIC as compared to MAC.

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

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

Management of adult patients with CMML undergoing allo-HCT: recommendations from the EBMT PH&G Committee.

ABSTRACT: Chronic myelomonocytic leukemia (CMML) is a heterogeneous disease presenting with either myeloproliferative or myelodysplastic features. Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only potentially curative option, but the inherent toxicity of this procedure makes the decision to proceed to allo-HCT challenging, particularly because patients with CMML are mostly older and comorbid. Therefore, the decision between a nonintensive treatment approach and allo-HCT represents a delicate balance, especially because prospective randomized studies are lacking and retrospective data in the literature are conflicting. International consensus on the selection of patients and the ideal timing of allo-HCT, specifically in CMML, could not be reached in international recommendations published 6 years ago. Since then, new, CMML-specific data have been published. The European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonization and Guidelines (PH&G) Committee assembled a panel of experts in the field to provide the first best practice recommendations on the role of allo-HCT specifically in CMML. Recommendations were based on the results of an international survey, a comprehensive review of the literature, and expert opinions on the subject, after structured discussion and circulation of recommendations. Algorithms for patient selection, timing of allo-HCT during the course of the disease, pretransplant strategies, allo-HCT modality, as well as posttransplant management for patients with CMML were outlined. The keynote message is, that once a patient has been identified as a transplant candidate, upfront transplantation without prior disease-modifying treatment is preferred to maximize chances of reaching allo-HCT whenever possible, irrespective of bone marrow blast counts.

Treosulfan compared to busulfan in allogeneic haematopoietic stem cell transplantation for myelofibrosis: a registry-based study from the Chronic Malignancies Working Party of the EBMT.

We aimed to compare outcomes following treosulfan (TREO) or busulfan (BU) conditioning in a large cohort of myelofibrosis (MF) patients from the EBMT registry. A total of 530 patients were included; 73 received TREO and 457 BU (BU ≤ 6.4 mg/kg in 134, considered RIC, BU > 6.4 mg/kg in 323 considered higher dose (HD)). Groups were compared using adjusted Cox models. Cumulative incidences of engraftment and acute GVHD were similar across the 3 groups. The TREO group had significantly better OS than BU-HD (HR:0.61, 95% CI: 0.39-0.93) and a trend towards better OS over BU-RIC (HR: 0.66, 95% CI: 0.41-1.05). Moreover, the TREO cohort had a significantly better Progression-Free-Survival (PFS) than both the BU-HD (HR: 0.57, 95% CI: 0.38-0.84) and BU-RIC (HR: 0.60, 95% CI: 0.39-0.91) cohorts, which had similar PFS estimates. Non-relapse mortality (NRM) was reduced in the TREO and BU-RIC cohorts (HR: 0.44, 95% CI: 0.24-0.80 TREO vs BU-HD; HR: 0.54, 95% CI: 0.28-1.04 TREO vs BU-RIC). Of note, relapse risk did not significantly differ across the three groups. In summary, within the limits of a registry-based study, TREO conditioning may improve PFS in MF HSCT and have lower NRM than BU-HD with a similar relapse risk to BU-RIC. Prospective studies are needed to confirm these findings.

Splenic irradiation for myelofibrosis prior to hematopoietic cell transplantation: A global collaborative analysis.

Splenomegaly is the clinical hallmark of myelofibrosis. Splenomegaly at the time of allogeneic hematopoietic cell transplantation (HCT) is associated with graft failure and poor graft function. Strategies to reduce spleen size before HCT especially after failure to Janus kinase (JAK) inhibition represent unmet clinical needs in the field. Here, we leveraged a global collaboration to investigate the safety and efficacy of splenic irradiation as part of the HCT platform for patients with myelofibrosis. We included 59 patients, receiving irradiation within a median of 2 weeks (range, 0.9-12 weeks) before HCT. Overall, the median spleen size prior to irradiation was 23 cm (range, 14-35). Splenic irradiation resulted in a significant and rapid spleen size reduction in 97% of patients (57/59), with a median decrease of 5.0 cm (95% confidence interval, 4.1-6.3 cm). The most frequent adverse event was thrombocytopenia, with no correlation between irradiation dose and hematological toxicities. The 3-year overall survival was 62% (95% CI, 48%-76%) and 1-year non-relapse mortality was 26% (95% CI, 14%-38%). Independent predictors for survival were severe thrombocytopenia and anemia before irradiation, transplant-specific risk score, higher-intensity conditioning, and present portal vein thrombosis. When using a propensity score matching adjusted for common confounders, splenic irradiation was associated with significantly reduced relapse (p = .01), showing a 3-year incidence of 12% for splenic irradiation versus 29% for patients with immediate HCT and 38% for patients receiving splenectomy. In conclusion, splenic irradiation immediately before HCT is a reasonable approach in patients experiencing JAK inhibition failure and is associated with a low incidence of relapse.

Impact of comorbidities and body mass index on the outcomes of allogeneic hematopoietic cell transplantation in myelofibrosis: A study on behalf of the Chronic Malignancies Working Party of EBMT.

Investigating the evaluation of eligibility for transplant in myelofibrosis (MF): The role of HCT-CI and BMI. HCT-CI emerges as a key prognostic factor, while BMI shows limited impact. This study expands insights for better clinical decision-making in MF allo-HCT.

Monitoring the phenology of plant pathogenic fungi: why and how?

Phenology is a key adaptive trait of organisms, shaping biotic interactions in response to the environment. It has emerged as a critical topic with implications for societal and economic concerns due to the effects of climate change on species' phenological patterns. Fungi play essential roles in ecosystems, and plant pathogenic fungi have significant impacts on global food security. However, the phenology of plant pathogenic fungi, which form a huge and diverse clade of organisms, has received limited attention in the literature. This diversity may have limited the use of a common language for comparisons and the integration of phenological data for these taxonomic groups. Here, we delve into the concept of 'phenology' as applied to plant pathogenic fungi and explore the potential drivers of their phenology, including environmental factors and the host plant. We present the PhenoFun scale, a phenological scoring system suitable for use with all fungi and fungus-like plant pathogens. It offers a standardised and common tool for scientists studying the presence, absence, or predominance of a particular phase, the speed of phenological phase succession, and the synchronism shift between pathogenic fungi and their host plants, across a wide range of environments and ecosystems. The application of the concept of 'phenology' to plant pathogenic fungi and the use of a phenological scoring system involves focusing on the interacting processes between the pathogenic fungi, their hosts, and their biological, physical, and chemical environment, occurring during the life cycle of the pathogen. The goal is to deconstruct the processes involved according to a pattern orchestrated by the fungus's phenology. Such an approach will improve our understanding of the ecology and evolution of such organisms, help to understand and anticipate plant disease epidemics and their future evolution, and make it possible to optimise management models, and to encourage the adoption of cropping practices designed from this phenological perspective.

Impact of post-transplant cyclophosphamide (PTCy)-based prophylaxis in matched sibling donor allogeneic haematopoietic cell transplantation for patients with myelodysplastic syndrome: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

We retrospectively compared outcomes of 404 MDS patients undergoing 1st matched sibling donor allo-HCT receiving either PTCy-based (n = 66) or other "conventional prophylaxis" (n = 338; mostly calcineurin inhibitor + methotrexate or MMF). Baseline characteristics were balanced, except for higher use of myeloablative regimens in the PTCy group (52.3% vs. 38.2%, p = 0.047). Incidences of neutrophil (Day +28: 89% vs. 97%, p = 0.011) and platelet (Day +100: 89% vs. 97%, p < 0.001) engraftment were lower for PTCy-based. Day +100 cumulative incidences of grade II-IV and III-IV aGVHD, and 5-year CI of extensive cGVHD were 32%, 18% and 18% for PTCy-based and 25% (p = 0.3), 13% (p = 0.4) and 31% (p = 0.09) for the conventional cohort. Five-year OS (51% vs. 52%, p = 0.6) and GRFS (33% vs. 25%, p = 0.6) were similar between groups. Patients receiving PTCy had a trend to a lower cumulative incidence of relapse (20% vs. 33%, p = 0.06), not confirmed on multivariable analysis (p = 0.3). Although higher NRM rates were observed in patients receiving PTCy (32% vs. 21%, p = 0.02) on univariate analysis, this was not confirmed on multivariate analysis (HR 1.46, p = 0.18), and there was no resultant effect on OS (HR 1.20, p = 0.5). Based on these data, PTCy prophylaxis appears to be an attractive option for patients with MDS undergoing MSD allo-HCT.

Allogeneic haematopoietic cell transplantation for therapy-related myeloid neoplasms arising following treatment for lymphoma: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Therapy-related myeloid neoplasms (t-MN), either myelodysplastic neoplasms (t-MDS) or acute myeloid leukemias (t-AML), have a poor prognosis and allogeneic haematopoietic cell transplantation (allo-HCT) represents the only curative option. In this multicenter, registry-based study, we analyzed outcomes of 378 patients undergoing first allo-HCT between 2006-2017 for t-MN arising secondary to lymphoma treatment. Median age was 58 years at allo-HCT; 222 (59%) had a diagnosis of t-MDS and 156 (41%) of t-AML, respectively. At the time of allo-HCT, 46% of t-MN cases were reported as in complete remission (CR) and 15% of lymphomas were recorded as not in remission. A reduced intensity conditioning regimen was used in 70% of cases. For the entire cohort, 5-year OS, and t-MN PFS, relapse incidence and NRM were 32%, 28%, 35% and 37%, respectively. In multivariable analysis, undergoing allo-HCT with t-MN not in CR and older age were associated with significantly worse OS, PFS and NRM. At 5 years post allo-HCT, the relapse incidence of lymphoma was low at 3%, while the rate of secondary malignancies was 8%. This analysis shows the curative potential of allo-HCT for patients with t-MN arising secondary to lymphoma treatment in approximately a third of patients.