Continuously improving outcome over time after second allogeneic stem cell transplantation in relapsed acute myeloid leukemia: an EBMT registry analysis of 1540 patients.

Second allogeneic stem cell transplantation (alloSCT2) is among the most effective treatments for acute myeloid leukemia (AML) relapse after first alloSCT (alloSCT1). Long-term EBMT registry data were used to provide large scale, up-to-date outcome results and to identify factors for improved outcome. Among 1540 recipients of alloSCT2, increasing age, better disease control and performance status before alloSCT2, more use of alternative donors and higher conditioning intensity represented important trends over time. Between the first (2000-2004) and last (2015-2019) period, two-year overall and leukemia-free survival (OS/LFS) increased considerably (OS: 22.5-35%, LFS: 14.5-24.5%). Cumulative relapse incidence (RI) decreased from 64% to 50.7%, whereas graft-versus-host disease and non-relapse mortality (NRM) remained unchanged. In multivariable analysis, later period of alloSCT2 was associated with improved OS/LFS (HR = 0.47/0.53) and reduced RI (HR = 0.44). Beyond, remission duration, disease stage and patient performance score were factors for OS, LFS, RI, and NRM. Myeloablative conditioning for alloSCT2 decreased RI without increasing NRM, leading to improved OS/LFS. Haploidentical or unrelated donors and older age were associated with higher NRM and inferior OS. In summary, outcome after alloSCT2 has continuously improved over the last two decades despite increasing patient age. The identified factors provide clues for the optimized implementation of alloSCT2.

Remission induction versus immediate allogeneic haematopoietic stem cell transplantation for patients with relapsed or poor responsive acute myeloid leukaemia (ASAP): a randomised, open-label, phase 3, non-inferiority trial.

BACKGROUND: Whether high-dose cytarabine-based salvage chemotherapy, administered to induce complete remission in patients with poor responsive or relapsed acute myeloid leukaemia scheduled for allogeneic haematopoietic stem-cell transplantation (HSCT) after intensive conditioning confers a survival advantage, is unclear. METHODS: To test salvage chemotherapy before allogeneic HSCT, patients aged between 18 and 75 years with non-favourable-risk acute myeloid leukaemia not in complete remission after first induction or untreated first relapse were randomly assigned 1:1 to remission induction with high-dose cytarabine (3 g/m2 intravenously, 1 g/m2 intravenously for patients >60 years or with a substantial comorbidity) twice daily on days 1-3 plus mitoxantrone (10 mg/m2 intravenously) on days 3-5 or immediate allogeneic HSCT for the disease control group. Block randomisation with variable block lengths was used and patients were stratified by age, acute myeloid leukaemia risk, and disease status. The study was open label. The primary endpoint was treatment success, defined as complete remission on day 56 after allogeneic HSCT, with the aim to show non-inferiority for disease control compared with remission induction with a non-inferiority-margin of 5% and one-sided type 1 error of 2·5%. The primary endpoint was analysed in both the intention-to-treat (ITT) population and in the per-protocol population. The trial is completed and was registered at ClinicalTrials.gov, NCT02461537. FINDINGS: 281 patients were enrolled between Sept 17, 2015, and Jan 12, 2022. Of 140 patients randomly assigned to disease control, 135 (96%) proceeded to allogeneic HSCT, 97 (69%) after watchful waiting only. Of 141 patients randomly assigned to remission induction, 134 (95%) received salvage chemotherapy and 128 (91%) patients subsequently proceeded to allogeneic HSCT. In the ITT population, treatment success was observed in 116 (83%) of 140 patients in the disease control group versus 112 (79%) of 141 patients with remission induction (test for non-inferiority, p=0·036). Among per-protocol treated patients, treatment success was observed in 116 (84%) of 138 patients with disease control versus 109 (81%) of 134 patients in the remission induction group (test for non-inferiority, p=0·047). The difference in treatment success between disease control and remission induction was estimated as 3·4% (95% CI -5·8 to 12·6) for the ITT population and 2·7% (-6·3 to 11·8) for the per-protocol population. Fewer patients with disease control compared with remission induction had non-haematological adverse events grade 3 or worse (30 [21%] of 140 patients vs 86 [61%] of 141 patients, χ2 test p<0·0001). Between randomisation and the start of conditioning, with disease control two patients died from progressive acute myeloid leukaemia and zero from treatment-related complications, and with remission induction two patients died from progressive acute myeloid leukaemia and two from treatment-related complications. Between randomisation and allogeneic HSCT, patients with disease control spent a median of 27 days less in hospital than those with remission induction, ie, the median time in hospital was 15 days (range 7-64) versus 42 days (27-121, U test p<0·0001), respectively. INTERPRETATION: Non-inferiority of disease control could not be shown at the 2·5% significance level. The rate of treatment success was also not statistically better for patients with remission induction. Watchful waiting and immediate transplantation could be an alternative for fit patients with poor response or relapsed acute myeloid leukaemia who have a stem cell donor available. More randomised controlled intention-to-transplant trials are needed to define the optimal treatment before transplantation for patients with active acute myeloid leukaemia. FUNDING: DKMS and the Gert and Susanna Mayer Stiftung Foundation.

Allogeneic hematopoietic stem-cell transplantation for patients with Richter transformation: a retrospective study on behalf of the Chronic Malignancies Working Party of the EBMT.

Management of Richter transformation (RT) is particularly challenging, with survival estimates <1 year. We report on outcomes of 66 RT patients undergoing allogeneic-HCT (allo-HCT) between 2008 and 2018 registered with the EBMT. Median age at allo-HCT was 56.2 years (interquartile range (IQR), 51.3-63.1). Median time from RT to allo-HCT was 6.9 months (IQR, 4.9-11) and 28 (42.4%) were in complete remission (CR). The majority underwent reduced intensity conditioning (66.2%) using peripheral blood derived stem cells. Eighteen (27.3%) patients had a matched sibling donor, 24 (36.4%) a matched unrelated donor and the remaining were mismatched. Median follow-up was 6.6 years; 1- and 3- year overall and progression free survival (PFS) (95% CI) was 65% (54-77) and 39% (27-51) and 53% (41-65) and 29% (18-40), respectively. Patients in CR at time of allo-HCT had significantly better 3-year PFS (39% vs. 21%, p = 0.032). Cumulative incidences of grade II-IV acute graft versus host disease (GVHD) at day +100 was 41% (95% CI 29-53) and chronic GVHD at 3 years was 53% (95% CI 41-65). High rates of non-relapse mortality (NRM) were observed; 38% (95% CI, 26-50) at 3 years. Although potentially curative, approaches to reduce considerable NRM and chronic GVHD rates are required.

Epigenetic aging of human blood cells is influenced by the age of the host body.

Allogenic hematopoietic stem cell transplantation is a therapeutic procedure performed over a wide range of donor and recipient age combinations, representing natural experiments of how the age of the recipient affects aging in transplanted donor cells in vivo. We measured DNA methylation and epigenetic aging in donors and recipients and found that biological epigenetic clocks are accelerated in cells transplanted into an older body and decelerated in a younger body. This is the first evidence that the age of the circulating environment influences human epigenetic aging in vivo.

Fludarabine-treosulfan versus fludarabine-melphalan or busulfan-cyclophosphamide conditioning in older AML or MDS patients - A clinical trial to registry data comparison.

A randomized study (acronym: MC-FludT.14/L Trial II) demonstrated that fludarabine plus treosulfan (30 g/m²) was an effective and well tolerated conditioning regimen for allogeneic hematopoietic cell transplantation (allo-HCT) in older patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). To further evaluate this regimen, all 252 study patients aged 50 to 70 years were compared with similar patients, who underwent allo-HCT after fludarabine/melphalan (140 mg/m²) (FluMel) or busulfan (12.8 mg/kg)/cyclophosphamide (120 mg/kg) (BuCy) regimens and whose data was provided by the European Society for Blood and Marrow Transplantation registry. In 1:1 propensity-score matched-paired analysis (PSA) of AML patients, there was no difference in 2-year-relapse-incidence after FluTreo compared with either FluMel (n = 110, p = 0.28) or BuCy (n = 78, p = 0.98). However, 2-year-non-relapse-mortality (NRM) was lower compared with FluMel (p = 0.019) and BuCy (p < 0.001). Consequently, 2-year-overall-survival (OS) after FluTreo was higher compared with FluMel (p = 0.04) and BuCy (p < 0.001). For MDS patients, no endpoint differences between FluTreo and FluMel (n = 30) were evident, whereas 2-year-OS after FluTreo was higher compared with BuCy (n = 25, p = 0.01) due to lower 2-year-NRM. Multivariate sensitivity analysis confirmed all significant results of PSA. Consequently, FluTreo (30 g/m²) seems to retain efficacy compared with FluMel and BuCy, but is better tolerated by older patients.

Development and Validation of a Prediction Model of Outcome After B-Cell Maturation Antigen-Directed Chimeric Antigen Receptor T-Cell Therapy in Relapsed/Refractory Multiple Myeloma.

PURPOSE: Although chimeric antigen receptor T therapy (CAR-T) cells are an established therapy for relapsed/refractory multiple myeloma (RRMM), there are no established models predicting outcome to identify patients who may benefit the most from CAR-T. PATIENTS AND METHODS: This is an international retrospective observational study including patients with RRMM infused with currently available commercial or academically produced anti-B-cell maturation antigen (BCMA) CAR-T. We describe characteristics and outcomes in Europe (n = 136) and the United States (n = 133). Independent predictors of relapse/progression built a simple prediction model (Myeloma CAR-T Relapse [MyCARe] model) in the training cohort (Europe), which was externally validated (US cohort) and tested within patient- and treatment-specific subgroups. RESULTS: The overall response rate was 87% and comparable between both cohorts, and complete responses were seen in 48% (Europe) and 49% (the United States). The median time to relapse was 5 months, and early relapse <5 months from infusion showed poor survival across cohorts, with the 12-month overall survival of 30% (Europe) and 14% (the United States). The presence of extramedullary disease or plasma cell leukemia, lenalidomide-refractoriness, high-risk cytogenetics, and increased ferritin at the time of lymphodepletion were independent predictors of early relapse or progression. Each factor received one point, forming the three-tiered MyCARe model: scores 0-1 (low risk), scores 2-3 (intermediate risk), and a score of 4 (high risk). The MyCARe model was significantly associated with distinct 5-month incidence of relapse/progression (P < .001): 7% for low-risk, 27% for intermediate-risk, and 53% for high-risk groups. The model was validated in the US cohort and maintained prognostic utility for response, survival, and outcomes across subgroups. CONCLUSION: Outcomes of patients with RRMM after CAR-T are comparable between Europe and the United States. The MyCARe model may facilitate optimal timing of CAR-T cells in patient-specific subgroups.

Graft-versus-host-disease prophylaxis with ATG or PTCY in patients with lymphoproliferative disorders undergoing reduced intensity conditioning regimen HCT from one antigen mismatched unrelated donor.

Post-transplant cyclophosphamide (PTCY) has been introduced as graft-versus-host disease (GvHD) prophylaxis in mismatched and matched unrelated hematopoietic cell transplant (HCT). However, data comparing outcomes of PTCY or ATG in patients undergoing a 1 antigen mismatched HCT for lymphoproliferative disease are limited. We compared PTCY versus ATG in adult patients with lymphoproliferative disease undergoing a first 9/10 MMUD HCT with a reduced intensity conditioning regimen from 2010 to 2021. Patients receiving PTCY were matched to patients receiving ATG according to: age, disease status at transplant, female to male matching, stem cell source and CMV serology. Grade II-IV acute GvHD at 100 day was 26% and 41% for the ATG and PTCY group, respectively (p = 0.08). Grade III-IV acute GvHD was not significantly different between the two groups. No differences were observed in relapse incidence, non-relapse mortality, progression-free survival, overall survival and GvHD-relapse-free survival at 1 year. The cumulative incidence of 1-year extensive chronic GvHD was 18% in the ATG and 5% in the PTCY group, respectively (p = 0.06). In patients with lymphoproliferative diseases undergoing 9/10 MMUD HCT, PTCY might be a safe option providing similar results to ATG prophylaxis. Due to the limited number of patients, prospective randomized trials are needed.

Ex vivo drug response profiling for response and outcome prediction in hematologic malignancies: the prospective non-interventional SMARTrial.

Ex vivo drug response profiling is a powerful tool to study genotype-drug response associations and is being explored as a tool set for precision medicine in cancer. Here we conducted a prospective non-interventional trial to investigate feasibility of ex vivo drug response profiling for treatment guidance in hematologic malignancies (SMARTrial, NCT03488641 ). The primary endpoint to provide drug response profiling reports within 7 d was met in 91% of all study participants (N = 80). Secondary endpoint analysis revealed that ex vivo resistance to chemotherapeutic drugs predicted chemotherapy treatment failure in vivo. We confirmed the predictive value of ex vivo response to chemotherapy in a validation cohort of 95 individuals with acute myeloid leukemia treated with daunorubicin and cytarabine. Ex vivo drug response profiles improved ELN-22 risk stratification in individuals with adverse risk. We conclude that ex vivo drug response profiling is clinically feasible and has the potential to predict chemotherapy response in individuals with hematologic malignancies beyond clinically established genetic markers.

Allogeneic hematopoietic cell transplantation for patients with AML aged 70 years or older in first remission. A study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Accessibility to allogeneic hematopoietic cell transplantation (HCT) programs for older patients is growing constantly. We report on the clinical outcomes of a group of 701 adults aged ≥70 years, with acute myeloid leukemia (AML) in first complete remission (CR1), who received a first HCT, from HLA-matched sibling donors (MSD), 10/10 HLA-matched unrelated donors (UD), 9/10 HLA-mismatched unrelated donors (mUD) or haploidentical (Haplo) donors. The 2-year overall survival (OS) was 48.1%, leukemia-free survival (LFS) 45.3%, relapse incidence (RI) 25.2%, non-relapse mortality (NRM) 29.5% and GVHD-free, relapse-free survival (GRFS), 33.4%. Compared to MSD, patients transplanted from Haplo and UD presented lower RI (HR 0.46, 95% CI 0.25-0.8, p = 0.02 and HR 0.44, 95% CI: 0.28-0.69, p = 0.001, respectively); this translated into prolonged LFS for Haplo (HR 0.62, 95% CI: 0.39-0.99, p = 0.04). Patients transplanted from mUD exhibited the highest NRM incidence (HR 2.33, 95% CI: 1.26-4.31, p = 0.007). HCT in selected adult CR1 AML patients >70 years is feasible and could be associated with good clinical outcomes. Prospective clinical trials are warranted.

Unsupervised meta-clustering identifies risk clusters in acute myeloid leukemia based on clinical and genetic profiles.

BACKGROUND: Increasingly large and complex biomedical data sets challenge conventional hypothesis-driven analytical approaches, however, data-driven unsupervised learning can detect inherent patterns in such data sets. METHODS: While unsupervised analysis in the medical literature commonly only utilizes a single clustering algorithm for a given data set, we developed a large-scale model with 605 different combinations of target dimensionalities as well as transformation and clustering algorithms and subsequent meta-clustering of individual results. With this model, we investigated a large cohort of 1383 patients from 59 centers in Germany with newly diagnosed acute myeloid leukemia for whom 212 clinical, laboratory, cytogenetic and molecular genetic parameters were available. RESULTS: Unsupervised learning identifies four distinct patient clusters, and statistical analysis shows significant differences in rate of complete remissions, event-free, relapse-free and overall survival between the four clusters. In comparison to the standard-of-care hypothesis-driven European Leukemia Net (ELN2017) risk stratification model, we find all three ELN2017 risk categories being represented in all four clusters in varying proportions indicating unappreciated complexity of AML biology in current established risk stratification models. Further, by using assigned clusters as labels we subsequently train a supervised model to validate cluster assignments on a large external multicenter cohort of 664 intensively treated AML patients. CONCLUSIONS: Dynamic data-driven models are likely more suitable for risk stratification in the context of increasingly complex medical data than rigid hypothesis-driven models to allow for a more personalized treatment allocation and gain novel insights into disease biology.

There are various ways in which clinicians can predict the risk of disease progression in patients with leukemia, helping them to treat the patients accordingly. However, these approaches are usually designed by human experts and might not fully capture the complexity of a patient's disease. Here, with a large cohort of patients with acute myeloid leukemia, we design an unsupervised machine learning model ­ a type of computer model that learns from patterns in data without human input­to separate these patients into subgroups according to risk. We identify four distinct groups which differ with regards to patient genetics, laboratory values, and clinical characteristics. These groups have differences in response to treatment and patient survival, and we validate our findings in another dataset. Our approach might help clinicians to better predict outcomes in patients with leukemia and make decisions on treatment.

Long-term outcome of second allogeneic hematopoietic stem cell transplantation (HSCT2) for primary graft failure in patients with acute leukemia in remission: A study on behalf of the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation.

Second transplantation (HSCT2) is a potential treatment for primary graft failure (pGF). We assessed the outcome of HSCT2, performed between 2000 and 2021, for pGF in 243 patients with acute leukemia. Median age was 44.8 years. Conditioning at first HSCT (HSCT1) was myeloablative (MAC) in 58.4%. Median time from HSCT1 to HSCT2 was 48 days. Donors for HSCT2 were the same as for HSCT1 in 49%. Engraftment post HSCT2 was achieved by 73.7% of patients. The incidence of acute (a) graft versus host disease (GVHD) grades II-IV and III-IV was 23.2 and 8.1%. 5-year total and extensive chronic (c) GVHD was 22.3 and 10.1%. 5-year nonrelapse mortality (NRM), relapse incidence (RI), leukemia-free survival (LFS), overall survival (OS) and GVHD free, relapse-free survival (GRFS) was 51.6, 18.8, 29.6, 30.7 and 22.4%, respectively. Infections were the main cause of death. In multivariable analysis, being transplanted at second vs. first remission, lower Karnofsky performance status (KPS; <90) and receiving MAC at HSCT1 were adverse prognostic factors for NRM, LFS, OS, and GRFS, as was increased age for NRM, LFS, OS. We conclude that HSCT2 can rescue about a third of the patients who experienced pGF, but NRM is as high as 50%.

Discriminant Principal Component Analysis of ToF-SIMS Spectra for Deciphering Compositional Differences of MSC-Secreted Extracellular Matrices.

Identifying characteristic extracellular matrix (ECM) variants is a key challenge in mechanistic biology, bioengineering, and medical diagnostics. The reported study demonstrates the potential of time-of-flight secondary ion mass spectrometry (ToF-SIMS) to detect subtle differences between human mesenchymal stromal cell (MSC)-secreted ECM types as induced by exogenous stimulation or emerging pathology. ToF-SIMS spectra of decellularized ECM samples are evaluated by discriminant principal component analysis (DPCA), an advanced multivariate analysis technique, to decipher characteristic compositional features. To establish the approach, signatures of major ECM proteins are determined from samples of pre-defined mixtures. Based on that, sets of ECM variants produced by MSCs in vitro are analyzed. Differences in the content of collagen, fibronectin, and laminin in the ECM resulting from the combined supplementation of MSC cultures with polymers that induce macromolecular crowding and with ascorbic acid are detected from the DPCA of ToF-SIMS spectra. The results are verified by immunostaining. Finally, the comparative ToF-SIMS analysis of ECM produced by MSCs of healthy donors and patients suffering from myelodysplastic syndrome display the potential of the novel methodology to reveal disease-associated alterations of the ECM composition.

GVHD occurrence does not reduce AML relapse following PTCy-based haploidentical transplantation: a study from the ALWP of the EBMT.

The association between graft-versus-host disease (GVHD) occurrence and acute myeloid leukemia (AML) relapse in patients treated with HLA-haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) with post-transplant cyclophosphamide (PTCy)-based GVHD prophylaxis has remained debated. Here, we addressed this issue in patients with active AML at transplantation. 2-year cumulative incidences of relapse and leukemia-free survival (LFS) were 49% and 32.3%, respectively. There were no associations between acute nor chronic GVHD of any grade and lower relapse incidence. However, grade I acute GVHD was associated with better LFS (HR = 0.71, 95% CI 0.51-0.99, P = 0.04). In contrast, grade III-IV acute (HR = 3.09, 95% CI 1.87-5.12, P < 0.0001) as well as extensive chronic (HR = 3.3, 95% CI 1.81-6.04, P = 0.0001) GVHD correlated with higher nonrelapse mortality leading to lower LFS (HR = 1.36, 95% CI 0.99-1.86, P = 0.056 and HR = 1.97, 95% CI 1.35-2.89, P = 0.0004, respectively). In conclusion, these data suggest a dissociation of graft-versus-leukemia effects from GVHD in patients with active AML treated with PTCy-based Haplo-HCT.

Allogeneic Hematopoietic Cell Transplantation vs Standard Consolidation Chemotherapy in Patients With Intermediate-Risk Acute Myeloid Leukemia: A Randomized Clinical Trial.

Importance: The ideal postremission strategy in intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR) has been a matter of debate. Objective: To explore the optimal therapy for patients with intermediate-risk AML after first complete remission. Design, Settings, and Participants: This investigator-initiated, open-label, 2-armed, phase 3 randomized clinical trial assessed patients at 16 hospitals in Germany from February 2, 2011, until July 1, 2018. Key eligibility criteria included cytogenetically defined intermediate-risk AML according to Medical Research Council classification, first CR or CR with incomplete blood cell count recovery after conventional induction therapy, age of 18 to 60 years, and availability of a human leukocyte antigen (HLA)-matched sibling or unrelated donor. A detailed statistical analysis plan was written and finalized on July 7, 2020. Data were exported for analysis on April 13, 2021. Interventions: Patients were randomized 1:1 to receive allogeneic hematopoietic cell transplantation (HCT) or high-dose cytarabine for consolidation and salvage HCT only in case of relapse. Strata for randomization included age (18-40 vs 41-60 years), NPM1 and CEBPA variation status, and donor type (unrelated vs related). Main Outcomes and Measures: End points included overall-survival as the primary outcome and disease-free survival, cumulative incidence of relapse, treatment-related mortality, and quality of life measured according to the Medical Outcomes Study 36-Item Short-Form Health Survey as secondary outcomes. Results: A total of 143 patients (mean [SD] age, 48.2 [9.8] years; 81 [57%] male) with AML who fulfilled the eligibility criteria were randomized. In the intention-to-treat analysis, the probability of survival at 2 years was 74% (95% CI, 62%-83%) after primary allogeneic HCT and 84% (95% CI, 73%-92%) after consolidation chemotherapy (P = .22). Disease-free survival after HCT at 2 years was 69% (95% CI, 57%-80%) compared with 40% (95% CI, 28%-53%) after consolidation chemotherapy (P = .001). Allogeneic HCT during the first CR was associated with a cumulative incidence of relapse at 2 years of 20% (95% CI, 13%-31%) compared with 58% (95% CI, 47%-71%; P < .001). Nonrelapse mortality at 2 years after primary allogeneic HCT was 9% (95% CI, 5%-19%) and 2% (95% CI, 0%-11%) after consolidation chemotherapy (P = .005). Similar outcomes were observed when analyses were confined to the 96 patients at intermediate risk according to the European Leukemia Network classification. Most importantly, all 41 patients relapsing after consolidation chemotherapy (36 hematologic, 4 molecular, and 1 extramedullary) proceeded to allogeneic HCT. No significant differences in health-related quality of life measures were observed between groups. Conclusions and Relevance: Primary allogeneic HCT during first CR was not associated with superior overall survival compared with consolidation chemotherapy in patients 60 years or younger with intermediate-risk AML during the first CR and an available donor. Trial Registration: ClinicalTrials.gov Identifier: NCT01246752.

Impact of trisomy 19 on outcome according to genetic makeup in patients with acute myeloid leukemia.

We retrospectively studied 97 acute myeloid leukemia patients with trisomy 19 (median age at diagnosis 57 years; range, 17- 83 years) treated between 2001 and 2019 within two multicenter study groups. Trisomy 19 occurred alone in ten (10.5%) patients, with additional abnormalities being present in non-complex karyotypes in eight (8%) patients and in complex karyotypes in 79 (82%) patients. Altogether, karyotypes characterized by trisomies only were present in 27 (28%) patients. Data on response and outcome of intensively treated patients were available for 92 cases. The median follow-up was 6.4 years (95% confidence interval [95% CI]: 2.9-9.0 years). The complete remission (CR) rate after induction therapy was 52% (48 patients); the early death rate was 10% (n=9). Notably, patients with trisomy 19 as the sole abnormality had a CR rate of 89%. Allogeneic hematopoietic stem cell transplantation (allo-HCT) was performed in 34 (35%) patients (CR, n=19; active disease, n=15). Five-year relapse-free and overall survival rates were 26% (95% CI: 16-43%) and 20% (95% CI: 13-31%), respectively. Overall survival rates were significantly higher in patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only (P=0.05). An Andersen-Gill model including allo-HCT as a time-dependent covariable on overall survival revealed that trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only was a favorable factor (hazard ratio [HR]=0.47; P=0.021); higher age at diagnosis had an adverse impact (10 years difference; HR=1.29; P=0.002), whereas allo-HCT did not have a beneficial impact (odds ratio=1.45; P=0.21). In our cohort, patients with trisomy 19 as the sole abnormality or within karyotypes characterized by trisomies only had a high CR rate and better clinical outcome.

Large case-control study indicates no association of KIR genotype and risk of developing acute myeloid leukemia.

Immunogenetic association studies may give rise to new hypotheses on the immune surveillance of cancer. We hypothesized that certain combinations of killer immunoglobulin-like receptor (KIR) and HLA genotypes may enhance natural killer (NK) cell immunity against nascent acute myeloid leukemia (AML) and, thereby, lead to a skewed genotype distribution among patients. For this purpose, we analyzed KIR and HLA genotypes of 1767 German patients with AML and compared the results with that of the data of 51 890 German volunteers who had registered with German bone marrow donor file (DKMS). Patient samples were retrieved from the Collaborative Biobank and the biorepository of the Study Alliance Leukemia. All samples were genotyped with high-resolution amplicon-based next-generation sequencing. Because of the large number of controls, this study was very sensitive to detect the impact of KIR genotype. Knowledge on KIRs and their cognate HLA ligands allowed for testing of several hypotheses of NK cell-mediated endogenous leukemia surveillance. We did not find significant differences between the 2 cohorts in regard to the presence or absence of single KIR genes. When grouped based on telomeric or centromeric gene content, the major haplotypes A/A, A/B, and B/B were equally distributed among patients and control subjects. Using information on KIRs and their HLA ligands, we further tested receptor-ligand models and summation models without revealing markedly significant differences between patients and controls, albeit we observed a trend pointing at a minor protective effect of a low number of inhibitory KIR/KIR-ligand pairs. The results suggest that the KIR/KIR-ligand genotype has no effect on the susceptibility for the development of de novo AML.

A phase II, prospective, randomized, open-label study of defibrotide added to standard-of-care prophylaxis for the prevention of acute graft-versus-host disease after allogeneic hematopoietic cell transplantation.

Acute graft-versus-host disease (aGvHD) is a life-threatening complication typically occurring within 100 days after allogeneic hematopoietic cell transplantation (allo-HCT). This hypothesis-generating, phase II, prospective, open-label, randomized study (clinicaltrials gov. Identifier: NCT03339297) compared defibrotide added to standard-of-care (SOC) GvHD prophylaxis (defibrotide prophylaxis arm) versus SOC alone (SOC arm) to prevent aGvHD post-transplant. This study estimated incidences of aGvHD and was not statistically powered to assess differences among treatment arms. Patients were randomized 1:1 to defibrotide prophylaxis arm (n=79; median age 57 years; range, 2-69 years) or SOC arm (n=73; median age 56 years; range, 2-72 years). Patient demographics in the two arms were similar except for conditioning regimen type (myeloablative: defibrotide, 76% vs. SOC, 61%) and stem cell source for allo-HCT (bone marrow: defibrotide, 34% vs. SOC, 26%). In the intent-to-treat primary endpoint analysis, the cumulative incidence of grade B-D aGvHD at day 100 post-transplant was 38.4% in the defibrotide prophylaxis arm versus 47.1% in the SOC arm (difference: -8.8%, 90% confidence interval [CI]: -22.5 to 4.9). The difference noted at day 100 became more pronounced in a subgroup analysis of patients who received antithymocyte globulin (defibrotide: 30.4%, SOC: 47.6%; difference: -17.2%; 90% CI: -41.8 to 7.5). Overall survival rates at day 180 post-transplant were similar between arms, as were the rates of serious treatment-emergent adverse events (defibrotide: 42%, SOC: 44%). While the observed differences in endpoints between the two arms were not substantial, these results suggest defibrotide prophylaxis may add a benefit to currently available SOC to prevent aGvHD following allo-HCT without adding significant toxicities.