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A randomized inter-group trial comparing more intensive treatment strategies to a common standard arm 3 + 7 (CSA) was conducted in patients with non-M3 AML. Untreated patients ≥ 60 years were allocated to the CSA (n = 132) or to the study group arms (n = 1154) of the AMLCG (TAD/HAM versus HAM/HAM ± G-CSF followed by TAD and maintenance) and the OSHO (intermediate-dose ara-C/mitoxantrone followed by ara-C/mitoxantrone). Median age of the 1147 eligible patients was 69 (range 60-87) years. CR/CRi status at 90 days was not significantly different between the CSA (54% (95%CI: 45-64)) and the study group arms (53% (95%CI: 47-60) and 59% (95%CI: 58-63)). The five-year event-free survival (EFS) probability (primary endpoint) was 6.2% (95%CI: 2.7-14.0) in the CSA, 7.6% (95%CI: 4.5-12.8) in study group A and 11.1% (95%CI: 9.0-13.7) in B. The 5-year OS was 17.2% (95%CI: 11.0-26.9), 17.0% (95%CI: 2.0-23.9), and 19.5% (95%CI: 16.7-22.8) in CSA, study group A and B, respectively. Neither study group differed significantly from the CSA regarding EFS, OS, or relapse-free survival. In multivariate analyses, allocation to the treatment strategy was not significantly associated with the time-to-event endpoints. The evaluation of more intensive treatment strategies did not show clinically relevant outcome differences when compared to CSA., (© 2023. The Author(s).)

Although the presence of FLT3 -ITD, as well as levels of the FLT3 -ITD allelic ratio, have been described as prognostic factors in acute myeloid leukemia (AML), little is known about how the FLT3 -ITD allelic ratio impacts patients' outcomes when receiving an allogeneic hematopoietic stem cell transplantation (HSCT). We analyzed 118 patients (median age at diagnosis 58.3, range 14.3-82.3 years) harboring FLT3 -ITD, of whom 94 patients were consolidated with an allogeneic HSCT and included in outcome analyses. A high FLT3 -ITD allelic ratio was associated with a higher white blood cell count, higher blood and bone marrow blasts, and worse ELN2017 risk at diagnosis. Patients with a high FLT3 -ITD allelic ratio more often had NPM1 mutations, while patients with a low allelic ratio more often had FLT3 -TKD mutations. Patients with a high FLT3 -ITD allelic ratio were less likely to achieve a measurable residual disease (MRD)-negative remission prior to allogeneic HSCT and had a trend for a shorter time to relapse. However, there was no distinct cumulative incidence of relapse, non-relapse mortality, or overall survival according to the FLT3 -ITD allelic ratio in transplanted patients. While co-mutated FLT3 -TKD was associated with better outcomes, the MRD status at HSCT was the most significant factor for outcomes. While our data indicates that an allogeneic HSCT may mitigate the adverse effect of a high FLT3 -ITD allelic ratio, comparative studies are needed to evaluate which FLT3 -ITD mutated patients benefit from which consolidation strategy.

Somatic mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) are common in acute myeloid leukemia (AML). The prognostic impact of the presence of IDH mutations may be influenced by the comutational status, the specific location of the mutation (ie, IDH1 R132, IDH2 R140, and IDH2 R172) at diagnosis, and the dynamics of the mutation burden during disease course. Even though many patients with IDH-mutated AML are consolidated by hematopoietic stem cell transplantation (HSCT), the underlying biology and prognostic consequences remain largely unknown. Here, we present a large analysis of 292 patients with AML who received HSCT in complete remission (CR) or CR with incomplete peripheral recovery (CRi), in which we assessed the IDH mutation status at diagnosis and HSCT as a potential marker for measurable residual disease (MRD). About a quarter of all patients were IDH-mutated at diagnosis. The diagnostic presence of IDH mutations in AML did not have a significant prognostic impact when consolidated with HSCT. However, IDH1 R132 and IDH2 R172 MRD positivity in remission at HSCT associated with an increased risk of relapse, while IDH2 R140 mutations did not. The IDH2 R140 variant allele frequency (VAF) at diagnosis was higher, clustering around 50%, and the mutation clearance at HSCT in morphologic remission was much lower compared with IDH1 R132 and IDH2 R172. In our cohort, IDH2 R140 mutations behaved more like a clonal hematopoiesis-related aberration, while IDH1 R132 and IDH2 R172 harbored AML disease-specific features., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

For most acute myeloid leukemia (AML) patients an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. The introduction of less toxic non-myeloablative conditioning (NMA) regimes enabled older and/or comorbid patients to be consolidated with an allogeneic HSCT. While the hematopoietic cell transplantation comorbidity index (HCT-CI) predicted outcomes in many younger patient cohorts its impact in older AML patients receiving NMA-HSCT remains unknown. Here we analyzed 289 AML patients 60 years or older (median age 66, range 60-77 years) undergoing NMA-HSCT (2 or 3 Gray total body irradiation and 3 days of fludarabine 30 mg/m 2 ). HCT-CI risk was low, intermediate, or high in 36%, 31%, and 33% of patients, respectively. Non-relapse mortality (NRM), cumulative incidence of relapse (CIR), and overall survival (OS) did not differ between HCT-CI groups. The HCT-CI also did not impact outcomes when considering the European LeukemiaNet 2017 risk at diagnosis or the measurable residual disease (MRD) status at HSCT. Notably, MRD-negative older NMA-transplanted AML patients had a beneficial OS of 49% after 5 years. Since a higher HCT-CI did not impair outcomes, age or comorbidities per se should not impede NMA-HSCT, presenting a feasible consolidation option for this group of AML patients., (© 2022. The Author(s).)

For most patients with acute myeloid leukemia (AML), an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of cure. Recently, the European LeukemiaNet (ELN) published updated recommendations on the diagnosis and risk classification in AML based on genetic factors at diagnosis as well as a dynamic adjustment (reclassification) according to the measurable residual disease (MRD) status for the favorable and intermediate risk groups. Validation of the ELN2022 risk classification has not been reported. We retrospectively analyzed 522 AML patients who received an HSCT at a median age of 59 (range 16-76) years. For patients with adequate material available and in remission prior to HSCT (n = 229), the MRD status was evaluated. Median follow-up after HSCT was 3.0 years. ELN2022 risk at diagnosis was in 22% favorable, in 26% intermediate, and in 52% adverse. ELN2022 risk at diagnosis is associated with the cumulative incidence of relapse/progression (CIR), event-free survival (EFS), and overall survival (OS) in the whole patient cohort, as well as the subgroup of patients transplanted in first remission. However, the risk stratification based on the ELN2022 classification did not significantly improve outcome prognostication in comparison to the ELN2017 classification. In our study, the newly added group of patients with myelodysplasia-related gene mutations did not have adverse outcomes. Re-classifying these patients into the intermediate risk group and adjusting the grouping for all AML patients by MRD at HSCT, led to a refined and improved risk stratification, which should be validated in independent studies., (© 2022. The Author(s).)

Clonal hematopoiesis (CH) is characterized by somatic mutations in blood cells of individuals without hematologic disease. While the mutational landscape of CH in peripheral blood (PB) has been well characterized, detailed analyses addressing its spatial and cellular distribution in the bone marrow (BM) compartment are sparse. We studied CH driver mutations in healthy individuals (n = 261) across different anatomical and cellular compartments. Variant allele frequencies were higher in BM than PB and positively correlated with the number of driver variants, yet remained stable during a median of 12 months of follow-up. In CH carriers undergoing simultaneous bilateral hip replacement, we detected ASXL1-mutant clones in one anatomical location but not the contralateral side, indicating intra-patient spatial heterogeneity. Analyses of lineage involvement in ASXL1-mutated CH showed enriched clonality in BM stem and myeloid progenitor cells, while lymphocytes were particularly involved in individuals carrying the c.1934dupG variant, indicating different ASXL1 mutations may have distinct lineage distribution patterns. Patients with overt myeloid malignancies showed higher mutation numbers and allele frequencies and a shifting mutation landscape, notably characterized by increasing prevalence of DNMT3A codon R882 variants. Collectively, our data provide novel insights into the genetics, evolution, and spatial and lineage-specific BM involvement of CH., (© 2022. The Author(s).)

Allogeneic hematopoietic stem cell transplantation (HSCT) offers the best chance for relapse-free survival to most patients with acute myeloid leukemia (AML). It may be performed during complete remission or delayed until after the first relapse because of relevant treatment-related morbidity and mortality. The measurable residual disease (MRD) status at HSCT adds refined prognostic information to the assigned European LeukemiaNet (ELN) 2017 genetic risk at diagnosis. We analyzed 580 patients with AML who underwent allogeneic HSCT during either the first (79%) or second (21%) remission. Although, because of common treatment strategies, some adverse risk characteristics, such as monosomal or complex karyotypes, were less frequent in patients who underwent transplant in the second remission, those patients had worse outcomes compared with patients who had transplant in the first remission. The MRD status at HSCT was an independent prognostic factor, irrespective of the number of remissions at HSCT. Notably, patients who were MRD+ who underwent HSCT in the first remission and those who were MRD- and underwent transplant in the second remission had similar outcomes. In the clinically highly relevant group of individuals who had ELN2017 intermediate risk, the MRD status provided the highest prognostic value with very dismal outcomes for patients who were MRD+ and underwent second-remission transplants. The adverse outcomes of patients who are MRD+ and of those who undergo transplant in the second remission should be considered when planning consolidation treatment, to avert an allogeneic HSCT in MRD+ second remission when possible., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Ewing sarcoma is one of the most frequent soft-tissue tumors in pediatric patients. The current treatment protocols recommend stem cell apheresis (SCA) after completion of the second course of induction therapy with vincristine, ifosfamide, doxorubicine, and etoposide (VIDE). The feasibility of SCA and graft compositions in adult patients with Ewing sarcoma have not been previously analyzed., Methods and Materials: The authors analyzed 29 stem cell collections of 19 adult patients (9 male, 10 female) at a median age of 27 (range 19-53) years mobilized after VIDE (n = 17), cyclophosphamide/topotecan (n = 1) or vincristine, dactinomycin and ifosfamide (n = 1) chemotherapy. All patients were mobilized with filgrastim 5 μg/kg twice daily from day +7 of chemotherapy. The collections were performed if CD34+ cell count in peripheral blood was >10/μL. The target yields were ≥4×10 6 CD34+ cells/kg body weight., Results: Median CD34+ cells/μL in peripheral blood before SCA were 45.8 (range 6.7-614.4)/μL. The median cumulative yields were 10.6 (range 1.5-38.8) CD34+ cells/kg body weight and ≥2×10 6 in all but two patients (89%). CD34, CD3, and CD56 yields in collections after the third VIDE and after later courses did not differ. Four patients underwent high-dose therapy with autologous transplantation, and all were engrafted., Discussion: Stem cell mobilization is feasible in most Ewing sarcoma patients. Additionally, the present study's data suggest that it is safe to postpone stem cell collection to a later VIDE chemotherapy cycle if medically indicated., (© 2022 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: Pegfilgrastim is a covalently bound conjugate of filgrastim and mono-methoxypolyethylene glycol with a longer half-life., Study Design and Methods: We report on phase II prospective monocentric trial examining the feasibility of stem cell mobilization with 12 mg single dose pegfilgrastim in related donors. The objectives were to determine the optimal collection day, defined as CD34+ concentration in peripheral blood (PB) >50 cells/μl, the number of donors collected with single leukapheresis, and the peak level of pegfilgrastim in donor-serum. Furthermore, the cell composition of grafts was assessed and compared to published data., Results: The results included about 28 matched related donors. The median pegfilgrastim serum level remained >200 ng/mL for 48 hours before declining, with the maximal measured concentration of 259.49 ng/ml 24 h after application. The median white blood cell count and CD34 count in PB peaked on day four with 52.6 (range 22.8-85.0) Gpt/l and 66.25 (range 22.9-136.6) cells/μl, respectively. A CD34+ count >50 cells/μl on day four was detected in 75% of donors. 79% of the donors underwent a single collection. Conventional filgrastim was administered additionally in two donors, due to insufficient CD 34+ concentration in PB. 89% of donors showed CD34+ yields ≥4 (median 6.5, range 4.6-14.5) × 10/kg body weight of the recipient. All grafts were administered without rejections., Discussion: The results of this trial showed that stem cell mobilization with pegfilgrastim is a feasible, and attractive option. This is the first trial presenting the kinetics of pegfilgrastim serum levels in healthy donors., (© 2021 The Authors. Transfusion published by Wiley Periodicals LLC on behalf of AABB.)

Background: For most patients with acute myeloid leukemia (AML) harboring a trisomy 8 an allogeneic hematopoietic stem cell transplantation (HSCT) is a suitable and recommended consolidation therapy. However, comparative outcome analyses between patients with and without trisomy 8 undergoing allogeneic HSCT have not been performed so far., Methods: We retrospectively analyzed clinical features, outcomes, and measurable residual disease (MRD) of 659 AML (12%, n = 81, with a trisomy 8) patients subjected to allogeneic HSCT as a consolidation therapy., Results: The presence of a trisomy 8 associated with a trend for higher age at diagnosis, AML of secondary origin, lower white blood cell counts at diagnosis, worse ELN2017 genetic risk, wild-type NPM1 , and mutated IDH1/2 and JAK2 . Outcomes after allogeneic HSCT in the entire cohort did not differ between patients with a sole trisomy 8, trisomy 8 with additional cytogenetic aberrations or without a trisomy 8. A trisomy 8 did not affect outcomes within the three ELN2017 risk groups. In accordance with findings in unselected patient cohorts, persistent MRD at allogeneic HSCT in patients with a trisomy 8 identified individuals with a higher risk of relapse following allogeneic HSCT., Conclusions: Outcomes of trisomy 8 patients after allogeneic HSCT did not compare unfavorably to that of other AML patients following allogeneic HSCT. Rather than the presence or absence of a trisomy 8, additional genetic aberrations and MRD at HSCT define outcome differences and aid in informed treatment decisions.

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders with heterogeneous presentation, ranging from indolent disease courses to aggressive diseases similar to acute myeloid leukemia (AML). Approximately 90% of MDS patients harbor recurrent mutations , which - with the exception of mutated SF3B1 -have not (yet) been included into the diagnostic criteria or risk stratification for MDS. Accumulating evidence suggests their utility for diagnostic workup, treatment indication and prognosis. Subsequently, in patients with unexplained cytopenia or dysplasia identification of these mutations may lead to earlier diagnosis. The acquisition and expansion of additional driver mutations usually antecedes further disease progression to higher risk MDS or secondary AML and thus, can be clinically helpful to detect individuals that may benefit from aggressive treatment approaches. Here, we review our current understanding of somatic gene mutations, gene expression patterns and flow cytometry regarding their relevance for disease evolution from pre-neoplastic states to MDS and potentially AML., (Copyright © 2021. Published by Elsevier Inc.)

The SRSF2 mutations are frequently found in acute myeloid leukemia (AML) and mostly affect the P95 residue. Mutations in this splicing factor mediate abnormal splicing associated with exon skipping events, including EZH2 as a crucial target. While SRSF2 mutations are enriched in secondary AML and associated with worse outcomes following chemotherapy consolidation, very little is known about the associated biological and clinical implications in AML patients consolidated with allogeneic hematopoietic stemcell transplantation (HSCT). Here we retrospectively analyzed 263 adult AML patients who received an allogeneic HSCT regarding the biological and clinical implications of the SRSF2 mutation status at diagnosis and in morphologic remission at HSCT. We found 12.5% of the patients to be SRSF2 mutated at diagnosis. Mutated patients had increased EZH2 missplicing events with P95H likely driving this pathobiology most effectively. However, the amount of EZH2 missplicing events, as a functional surrogate marker did not associate with relevant biological or clinical characteristics. We observed a persistence of mutations in remission before HSCT in the majority (93%) of SRSF2 mutated AML patients. Importantly, the variant allele frequency (VAF) levels of SRSF2 mutations in remission at HSCT did not correlate with outcomes following HSCT consolidation, limiting the applicability of SRSF2 mutations as a marker for residual AML disease. Following allogeneic HSCT SRSF2 mutated AML patients experienced a 2-year overall survival of 77%, indicating that SRSF2 mutated AML patients may benefit from HSCT consolidation., (© 2021 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Introduction: Light chain involvement is observed in almost every patient (pt) with newly diagnosed multiple myeloma (MM). Owing to a relatively short half-life, rapid reduction in the involved free light chain (iFLC) is of potential prognostic value., Methods: This retrospective analysis included 92 pts with newly diagnosed MM treated with bendamustine, prednisone, and bortezomib (BPV)., Results: After a median number of two (range 1-5) BPV cycles, the majority of pts (n = 86; 93%) responded with either sCR (n = 21), CR (n = 1), nCR (n = 25), VGPR (n = 20), or PR (n = 19). PFS and OS at 48 months were 39% and 67%, respectively. At baseline, 79 out of 92 pts (86%) had iFLC levels above the upper standard level and an abnormal ratio of involved to uninvolved free light chain ≥ 8. In a subgroup analysis of these pts, we evaluated the prognostic importance of an early reduction of the iFLC during the first two BPV cycles. A reduction ≥ 50% of the iFLC on day 8 of the first cycle was observed in 31 of 69 pts. These pts had a significantly better median PFS of 49 months as compared to 20 months in 38 pts with a lower iFLC reduction (p = 0.002). In contrast, OS did not differ significantly with a 48 months survival of 77% vs 69% (p > 0.05)., Conclusion: These results indicate that a rapid decrease in the iFLC on day 8 is an early prognostic marker for newly diagnosed MM pts undergoing BPV treatment.

Secondary or therapy-related acute myeloid leukemia (s/tAML) differs biologically from de novo disease. In general s/tAML patients have inferior outcomes after chemotherapy, compared to de novo cases and often receive allogeneic stem cell transplantation (HSCT) for consolidation. The European LeukemiaNet (ELN) risk stratification system is commonly applied in AML but the clinical significance is unknown in s/tAML. We analyzed 644 s/tAML or de novo AML patients receiving HSCT. s/tAML associated with older age and adverse risk, including higher ELN risk. Overall, s/tAML patients had similar cumulative incidence of relapse (CIR), but higher non-relapse mortality (NRM) and shorter overall survival (OS). In multivariate analyses, after adjustment for ELN risk and pre-HSCT measurable residual disease status, disease origin did not impact outcomes. Within the ELN favorable risk group, CIR was higher in s/tAML compared to de novo AML patients likely due to a different distribution of genetic aberrations, which did not translate into shorter OS. Within the ELN intermediate and adverse group outcomes were similar in de novo and s/tAML patients. Thus, not all s/tAML have a dismal prognosis and outcomes of s/tAML after allogeneic HSCT in remission are comparable to de novo patients when considering ELN risk.

The nutritional status at diagnosis, as well as weight loss during chemotherapy, are important factors for morbidity and mortality in cancer patients. They might also influence outcomes in patients with acute myeloid leukemia (AML) receiving allogeneic hematopoietic stem cell transplantation (HSCT). We evaluated the body mass index (BMI) at diagnosis, prior to HSCT, and the BMI difference (ΔBMI = BMI HSCT -BMI diagnosis ) in 662 AML patients undergoing allogeneic HSCT. Patients being obese at AML diagnosis had significantly higher nonrelapse mortality (NRM) and shorter overall survival (OS) after HSCT, but no distinct cumulative incidence of relapse than nonobese patients. Weight loss during chemotherapy (ΔBMI > -2) was a strong predictor for higher NRM and shorter OS in univariate and multivariate analyses. These results were observed across all European LeukemiaNet (ELN) 2017 risk groups but especially in patients with favorable or intermediate ELN2017 risk and patients transplanted in morphologic complete remission. Only in patients being obese at AML diagnosis, weight loss did not result in adverse outcomes. ΔBMI > -2 represents a strong, independent, and modifiable risk factor for AML patients treated with HSCT. Nutritional monitoring and supplementation during disease course might improve patients' outcomes., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

The mutant IDH1 (mIDH1) inhibitor BAY1436032 demonstrated robust activity in preclinical AML models, supporting clinical evaluation. In the current dose-escalation study, BAY1436032 was orally administered to 27 mIDH1 AML subjects across 4 doses ranging from 300 to 1500 mg twice-daily. BAY1436032 exhibited a relatively short half-life and apparent non-linear pharmacokinetics after continuous dosing. Most subjects experienced only partial target inhibition as indicated by plasma R-2HG levels. BAY1436032 was safe and a maximum tolerated dose was not identified. The median treatment duration for all subjects was 3.0 months (0.49-8.5). The overall response rate was 15% (4/27; 1 CRp, 1 PR, 2 MLFS), with responding subjects experiencing a median treatment duration of 6.0 months (3.9-8.5) and robust R-2HG decreases. Thirty percent (8/27) achieved SD, with a median treatment duration of 5.5 months (3.1-7.0). Degree of R-2HG inhibition and clinical benefit did not correlate with dose. Although BAY1436032 was safe and modestly effective as monotherapy, the low overall response rate and incomplete target inhibition achieved at even the highest dose tested do not support further clinical development of this investigational agent in AML.

Background: Crohn's disease (CD) and ulcerative colitis (UC) commonly affect women in their childbearing years. Vedolizumab (VDZ) is approved for treatment of moderate-to-severe CD and UC, but there is a knowledge gap regarding its use during pregnancy. This targeted literature review describes available evidence on safety of VDZ in pregnant patients in order to offer physicians a detailed and balanced view on persistent data during their decision-making process for an individualized treatment concept., Methods: The search included literature from the MEDLINE database and abstracts of five gastroenterological conferences published until November 2019. Publications were included if pregnancy outcomes in women receiving VDZ or neonatal outcomes in newborns of women previously exposed to VDZ were reported., Results: Out of 196 initially identified records, 18 publications reporting results of five different studies were identified. In total, for 213 of 284 VDZ-exposed documented pregnancies the following pregnancy outcomes were reported: 167 live births (172 infants due to twin births), 1 stillbirth, 35 miscarriages, 10 elective terminations (1 due to detected Down syndrome). Furthermore, during pregnancy, the following complications were observed: seven cases of (pre) eclampsia, three cases of premature rupture of membranes and one case each of placenta previa, chorioamnionitis, pneumonia, first-trimester bleeding, cholestasis, sepsis, or neonatal intraventricular hemorrhage. Based on 172 infants, 30 preterm deliveries (17.4%), 9 cases of low birth weight (5.2%), 5 infections (2.9%), and 6 cases (3.8%) with congenital anomalies were reported., Conclusion: There was no evidence for safety concerns regarding pregnancy outcomes associated with VDZ therapy. Due to the limited scope of included records, further research is needed to understand the safety profile regarding the use of VDZ during pregnancy., Competing Interests: Conflict of interest statement: Renate Schmelz reports personal fees from AbbVie, Falk Foundation, Janssen, MSD, Pharmacosmos, Pfizer, and Takeda. Birgit Terjung reports personal fees from AbbVie, Falk Foundation, Janssen, MSD, Microbiotica, Pfizer, and Takeda. Robert Ehehalt reports personal fees from Falk, Janssen, Amgen, AbbVie, MSD, Ferring, Norgine, Takeda, Shield, Mundipharma, Pfizer, Vifor, Ardeypharm, Novartis, Microbiotika, Biogen, Ferring, Norgine, Celgene, Recordati, Fresenius, Tillotts, Diasorin, and Ethicon. Jochen Klaus reports personal fees and grants from AbbVie, Amgen, Biogen, CED Service GmbH, Falk-Foundation, Janssen, MSD, Pharmacosmos, Pfizer, Takeda, Thieme, Tillotts Pharma and Vifor Pharma. Thomas Wilke reports personal fees from several pharmaceutical/consultancy companies, for example, AbbVie, Astra Zeneca, Bayer, BMS, Boehringer Ingelheim, GSK, LEO Pharma, Merck, Novo Nordisk, Pfizer, and Takeda. Andreas Stallmach reports personal fees and grants from AbbVie, Amgen, AllergoSan, Astellas, Biogen, Falk Foundation, Janssen, MSD, Pfizer, and Takeda. Jana Knop and Sabine Schwind are employees of Takeda Pharma Vertrieb GmbH & Co. KG., (© The Author(s), 2020.)

For most acute myeloid leukemia (AML) patients, an allogeneic hematopoietic stem cell transplantation (HSCT) offers the highest chance of sustained remissions and long-term survival. At diagnosis, high expression of the AML-associated genes BAALC (brain and acute leukemia, cytoplasmic) and MN1 (meningioma-1) were repeatedly linked to inferior outcomes in patients consolidated with chemotherapy while data for patients receiving HSCT remain limited. Using clinically applicable digital droplet PCR assays, we analyzed the diagnostic BAALC/ABL1 and MN1/ABL1 copy numbers in 302 AML patients. High BAALC/ABL1 and MN1/ABL1 copy numbers associated with common adverse prognostic factors at diagnosis. However, while high diagnostic copy numbers of both genes associated with shorter event free survival (EFS) and overall survival (OS) in patients receiving chemotherapy, there was no prognostic impact in patients undergoing HSCT. Our data suggests that the adverse prognostic impact of high BAALC and MN1 expression are mitigated by allogeneic HSCT. But preHSCT BAALC/ABL1 and MN1/ABL1 assessed in remission prior to HSCT remained prognosticators for EFS and OS independent of the diagnostic expression status. Whether allogeneic HSCT may improve survival for AML patients with high diagnostic BAALC or MN1 expression should be investigated prospectively and may improve informed decisions towards individualized consolidation options in AML.

In 2017, an updated European LeukemiaNet (ELN) risk classification was published allocating patients with acute myeloid leukemia (AML) to 3 risk groups on the basis of certain cytogenetic and molecular aberrations. To date, studies of the prognostic significance of the ELN2017 risk classification in the context of an allogeneic hematopoietic stem cell transplantation (HSCT) are lacking. We performed risk stratification according to the ELN2017 classification in 234 patients with AML who underwent allogeneic HSCT as a consolidation therapy. In our cohort, the risk of 39.7% of the patients was classified as favorable, that of 12.8% as intermediate, and that of 47.4% as adverse. In the context of allogeneic HSCT, the assignment to the 3 ELN2017 risk groups retained its prognostic significance, with patients with favorable risk having the best prognosis and those with adverse risk having the worst one. Subgroup analyses showed that patients with a monosomal karyotype or TP53 mutation had considerably increased relapse rates, even in the adverse-risk group. When we analyzed the impact of digital droplet PCR-based measurable residual disease (MRD) before allogeneic HSCT, MRD+ patients had impaired prognoses, with cumulative incidence of relapse and overall survival comparable to those of patients classified as having an ELN2017 adverse genetic risk. This study is the first to demonstrate that the ELN2017 classification distinguishes the 3 risk groups with significantly distinct prognoses, even after allogeneic HSCT, and emphasizes the dismal prognosis of patients with AML with TP53 mutations, monosomal karyotype, or MRD positivity after allogeneic HSCT., (© 2020 by The American Society of Hematology.)

Infections with Neisseriameningitidis are life-threatening conditions, generally presenting as meningitis. This case of a young woman who had a history of paroxysmal nocturnal hemoglobinuria under treatment with the complement inhibitor eculizumab had been presented with septic shock. While blood cultures were positive for Neisseria meningitidis, she showed no evidence for bacterial meningitis in the cerebrospinal fluid. This case shows that meningococcal sepsis without signs for bacterial meningitis despite repetitive vaccinations is possible in adults under eculizumab.

Opinion Statement: The expanding availability of minimal or more precisely measurable residual disease (MRD) assessment in acute myeloid leukemia (AML) with its possible implications for therapeutic decisions is of high interest to clinicians treating AML patients. A variety of mostly retrospective studies have shown that AML patients with a positive MRD test, assessed by different techniques at defined cutoffs and time-points, are at significantly higher risk of relapse and experience shorter overall survival compared to MRD-negative patients. How this valuable information may be adapted in the daily routine of patients' treatment to distinguish individuals who need more aggressive therapy from the ones who can be spared additional therapy to avoid treatment-related toxicities is still being investigated. With the exception of MRD analyses in acute promyelocitic leukemia (APL), the clinical implications of MRD tests for the individual AML patient are still mostly unknown. We currently lack hard evidence that MRD-based therapy modulation during treatment or pre-emptive intervention in MRD-positive patients after therapy would improve outcomes in non-APL AML patients. These questions will be evaluated in prospective randomized clinical trials. Today, however, some conclusions with regard to MRD assessment in AML can be drawn from the published data and are reviewed in this article.

Allogeneic stem cell transplantation (HSCT) remains the only curative treatment for myelodysplastic syndromes (MDS) or myelodysplastic/myeloproliferative neoplasms (MDS/MPN) patients. The introduction of reduced intensity (RIC) and non-myeloablative (NMA) conditioning enabled HSCT in older or comorbid individuals representing the majority of patients. Studies comparing RIC and NMA conditioning are limited. We retrospectively analyzed 151 MDS or MDS/MPN patients older than 50 years who received NMA- or RIC-HSCT. Patients younger or older than 65 years at HSCT were analyzed separately. Patients receiving RIC-HSCT or NMA-HSCT were balanced in factors reflecting disease aggressiveness and the HCT-CI comorbidity score. The NMA conditioned patients had a higher incidence of graft rejection and chronic graft-vs-host disease. Cumulative incidence of relapse (CIR), non-relapse mortality (NRM) and overall survival (OS), did not differ significantly with regard to the conditioning regime in the whole cohort. In patients <65 years at HSCT, NMA conditioning associated with higher NRM and shorter OS by trend, while CIR was similar in both groups. In multivariable analyzes, the conditioning regimen remained a prognostic factor for NRM and OS in patients <65 years at HSCT. In MDS patients NMA and RIC conditioning result in similar disease control, but especially patients <65 years may benefit from RIC-HSCT., (© 2019 Wiley Periodicals, Inc.)

The ability to detect residual levels of leukemic blasts (measurable residual disease, MRD) has already been integrated in the daily routine for treatment of patients with chronic myeloid and acute lymphoblastic leukemia. In acute myeloid leukemia (AML), a variety of mostly retrospective studies have shown that individuals in AML remission who tested positive for MRD at specific time-points or had increasing MRD levels are at significantly higher risk of relapse and death compared to MRD-negative patients. However, these studies differ with respect to the "MRD-target", time-point of MRD determination, material analyzed, and method applied. How this probably very valuable MRD information in individual patients may be adapted in the daily clinical routine, e.g., to separate patients who need more aggressive therapies from those who may be spared additional-potentially toxic-therapies is still a work-in-progress. With the exception of MRD assessment in acute promyelocytic leukemia (APL), the lack of randomized, prospective trials renders MRD-based decisions and clinical implications in AML a difficult task. As of today, we still do not have proof that early intervention in MRD-positive AML patients would improve outcomes, although this is very likely. In this article, we review the current knowledge on non-APL AML MRD assessment and possible clinical consequences.

Age-related somatic mutations linked to clonal hematopoiesis have been found in apparently healthy individuals and increase the risk of developing hematologic malignancies. In acute myeloid leukemia (AML) the clinical relevance of clonal hematopoiesis remains controversial and data on patients with detectable clonal hematopoiesis, consolidated with hematopoietic stem cell transplantation are limited. We analyzed samples from 113 AML patients in complete remission prior to hematopoietic stem cell transplantation for the presence of clonal hematopoiesis-associated mutations. The results were correlated with clinical and biological data. In complete remission we found 75 mutations previously linked to clonal hematopoiesis in 47 patients (41.6%). Twenty patients had ≥2 mutations linked to clonal hematopoiesis. DNMT3A, TET2, and ASXL1 were most frequently mutated. When compared to pre-treatment samples we found variable patterns of mutation persistence depending on the gene mutated. In AML patients after allogeneic hematopoietic stem cell transplantation the presence of clonal hematopoiesis-associated mutations in complete remission did not associate with inferior clinical outcome. This study demonstrates that clonal hematopoiesis is a frequent phenomenon in AML patients. Presence of clonal hematopoiesis has no negative prognostic impact in the context of an allogeneic hematopoietic stem cell transplantation and might be beneficial if certain genes are affected.

Myelodysplastic syndrome (MDS) is a highly heterogeneous clonal hematopoietic disorder. Allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative treatment and is of particular interest in patients at high risk for progression to acute myeloid leukemia (AML). In MDS, CD34 + /CD38 - cells possess MDS stem cell potential, and secondary AML (sAML) clones originate from the MDS disease stage. However, the prognostic impact of the pretreatment stem cell population burden in MDS remains unknown. We retrospectively analyzed the prognostic impact of the pretreatment CD34 + /CD38 - cell burden in 124 MDS patients who received allogeneic HSCT at our institution. A high pretreatment bone marrow CD34 + /CD38 - cell burden (≥1%) was associated with worse genetic risk and a higher incidence of blast excess. Patients with a high CD34 + /CD38 - cell burden had a significantly higher cumulative incidence of MDS relapse, a higher cumulative incidence of secondary AML, and a trend for shorter overall survival after allogeneic HSCT. In multivariable analyses this prognostic impact was shown to be independent of other clinical and cytogenetic risk factors in MDS. Patients suffering MDS relapse or progression to AML also had a higher pre-treatment CD34 + /CD38 - cell burden as a continuous variable. The observed prognostic impact is likely mediated by MDS stem cells within the CD34 + /CD38 - cell population initiating MDS relapse or progression to AML. New therapeutic strategies targeting MDS stem cells might improve outcomes., (Copyright © 2019 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

High expression of the leukemia-associated gene meningioma-1 ( MN1 ) is frequently found at diagnosis of acute myeloid leukemia (AML) and associates with adverse outcomes. The presence of measurable residual disease (MRD) in complete remission (CR) indicates high risk of relapse and worse outcome in AML patients. However, the prognostic impact of MN1 expression levels as MRD marker has not been evaluated. Digital droplet polymerase chain reaction (ddPCR) is a novel technique allowing sensitive and specific absolute gene expression quantification. We retrospectively analyzed 124 AML patients who received allogeneic hematopoietic stem cell transplantation (HSCT) in CR or CR with incomplete peripheral recovery. Absolute MN1 copy numbers in peripheral blood were assessed prior to HSCT (median 7; range 0-29 days) using ddPCR. High pre-HSCT MN1 /Abelson murine leukemia viral oncogene homolog 1 gene ( ABL1 ) copy numbers associated with a higher cumulative incidence of relapse after HSCT and-in relapsing patients-shorter time to relapse. In multivariable analysis, high pre-HSCT MN1 / ABL1 copy numbers remained an independent prognosticator for relapse after HSCT. Patients with the highest pre-HSCT MN1 / ABL1 copy numbers also had the highest risk of relapse. MN1 copy number assessment also added prognostic information to nucleophosmin 1 gene ( NPM1 ) mutation- and brain and acute leukemia, cytoplasmic ( BAALC ) and Wilm's tumor gene 1 ( WT1 ) expression-based MRD evaluation. Our study demonstrates the feasibility of the novel ddPCR technique for MN1 / ABL1 copy number assessment as a marker for MRD. Evaluation of MN1 / ABL1 copy numbers allows the identification of patients at high risk of relapse, independently of other diagnostic risk factors and MRD markers., (Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the European Hematology Association.)

Allogeneic hematopoietic stem cell transplantation is an established consolidation therapy for patients with acute myeloid leukemia. However, relapse after transplantation remains a major clinical problem resulting in poor prognosis. Thus, detection of measurable ("minimal") residual disease to identify patients at high risk of relapse is essential. A feasible method to determine measurable residual disease may be digital droplet PCR (ddPCR) that allows absolute quantification with high sensitivity and specificity without the necessity of standard curves. Using ddPCR, we analyzed pre-transplant peripheral blood and bone marrow of 51 NPM1-mutated acute myeloid leukemia patients transplanted in complete remission or complete remission with incomplete recovery. Mutated NPM1 measurable residual disease-positive patients had higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.014). Restricting the analyses to patients receiving non-myeloablative conditioning, mutated NPM1 measurable residual disease positivity is associated with higher cumulative incidence of relapse (P < 0.001) and shorter overall survival (P = 0.006). Positive mutated NPM1 measurable residual disease status determined by ddPCR before allogeneic stem cell transplantation is associated with worse prognosis independent of other known prognostic markers-also for those receiving non-myeloablative conditioning. In the future, mutated NPM1 measurable residual disease status determined by ddPCR might guide treatment and improve patients' outcomes.

Hematopoiesis, the formation of blood cells from hematopoietic stem cells (HSC), is a highly regulated process. Since the discovery of microRNAs (miRNAs), several studies have shown their significant role in the regulation of the hematopoietic system. Impaired expression of miRNAs leads to disrupted cellular pathways and in particular causes loss of hematopoietic ability. Here, we report a previously unrecognized function of miR-143 in granulopoiesis. Hematopoietic cells undergoing granulocytic differentiation exhibited increased miR-143 expression. Overexpression or ablation of miR-143 expression resulted in accelerated granulocytic differentiation or block of differentiation, respectively. The absence of miR-143 in mice resulted in a reduced number of mature granulocytes in blood and bone marrow. Additionally, we observed an association of high miR-143 expression levels with a higher probability of survival in two different cohorts of patients with acute myeloid leukemia (AML). Overexpression of miR-143 in AML cells impaired cell growth, partially induced differentiation, and caused apoptosis. Argonaute2-RNA-Immunoprecipitation assay revealed ERK5, a member of the MAPK-family, as a target of miR-143 in myeloid cells. Further, we observed an inverse correlation of miR-143 and ERK5 in primary AML patient samples, and in CD34 + HSPCs undergoing granulocytic differentiation and we confirmed functional relevance of ERK5 in myeloid cells. In conclusion, our data describe miR-143 as a relevant factor in granulocyte differentiation, whose expression may be useful as a prognostic and therapeutic factor in AML therapy.

Introduction: While lenalidomide monotherapy is established for relapsed and/or refractory multiple myeloma (MM) treatment, combination therapies including lenalidomide are still under investigation in a number of phase 2/3 studies. In the current study, a treatment regime of lenalidomide (Revlimid ® ), bendamustine and prednisolone (RBP) was tested in patients with relapsed/refractory MM., Methods: In the previously completed phase 1 study RBP with a dose of 75 mg/m 2 bendamustine days 1-2, prednisolone 100 mg days 1-4 and 25 mg lenalidomide days 1-21 was well tolerated., Results: Between July 2011 and September 2013, 25 patients were included in this analysis. The median number of previous treatments was 1 (range 1-2). Twenty-two patients (88%) responded after at least two cycles of RBP (one sCR, five nCR, eight VGPR and eight PR). The median time to first haematological response was 28 days, and median time to best response was 56 days. Due to increased haematological toxicity a dose reduction in most patients required in subsequent cycles of therapy. The median progression-free and overall survival was 22 and 38 months, respectively. In conclusion RBP is a highly effective therapy for patients with relapsed/refractory MM. In contrast to our phase 1 study, dose reduction was necessary in many patients because of haematological toxicity.

Active BCR related ( ABR ) gene deactivates ras-related C3 botulinum toxin substrate 1 (RAC1), which plays an essential role in regulating normal hematopoiesis and in leukemia. BCR gene, closely related to ABR, acts as a tumor suppressor in chronic myeloid leukemia and has overlapping functions with ABR . Evidence for a putative tumor suppressor role of ABR has been shown in several solid tumors, in which deletion of ABR is present. Our results show downregulation of ABR in AML. A block of ABR prevents myeloid differentiation and leads to repression of the myeloid transcription factor C/EBPα, a major regulator of myeloid differentiation and functionally impaired in leukemia. Conversely, stable overexpression of ABR enhances myeloid differentiation. Inactivation of the known ABR target RAC1 by treatment with the RAC1 inhibitor NSC23766 resulted in an increased expression of C/EBPα in primary AML samples and in AML cell lines U937 and MV4;11. Finally, AML patients with high ABR expression at diagnosis showed a significant longer overall survival and patients who respond to azacitidine therapy showed a significant higher ABR expression. This is the first report showing that ABR expression plays a critical role in both myelopoiesis and AML. Our data indicate the tumor suppressor potential of ABR and underline its potential role in leukemia therapeutic strategies., Competing Interests: CONFLICTS OF INTEREST None.

Introduction: Patients with light chain myeloma frequently have a light chain tubular cast nephropathy, which can lead to severe renal impairment. In the present retrospective study, bortezomib was combined with other active substances like bendamustine and prednisone (BPV), in order to assess the efficacy and toxicity of the combination therapy in patients with light chain multiple myeloma., Methods: Between September 2008 and May 2015, 25 patients with newly diagnosed light chain multiple myeloma were treated with bendamustine 60 mg/m 2 on days 1 and 2, bortezomib 1.3 mg/m 2 on days 1, 4, 8 and 11, and prednisone 100 mg on days 1, 2, 4, 8 and 11 once every 21 days (BPV). Prior to treatment, 4 patients (16%) had moderate renal dysfunction and 14 patients (56%) severe renal dysfunction or renal failure/dialysis., Results: The median number of the BPV cycles was 2 (1-5). 24 patients (96%) responded with 4 stringent complete responses, 6 near-complete responses, 5 very good partial responses and 9 partial responses. The myeloma light chains decreased rapidly, reaching the best response after the first cycle in 9 and after the second cycle in additional 12 patients. 17 patients discontinued therapy after median 2 cycles of BPV treatment to receive autologous or allogeneic SCT. All together 12 of 18 patients with at least moderate renal failure improved their renal function. 3 of the 6 dialysis-dependent patients became dialysis-independent. With a median follow-up of 27 months, median progression-free survival and overall survival for patients at 30 months were 68 and 96%, respectively. The most common severe side effect was grade 3/4 leukocytopenia in 20% of the patients. Grade 3/4 thrombocytopenia was observed in 12% of the patients. Moderate to severe infection were seen in six patients. We conclude that BPV is effective and well tolerated in patients with newly diagnosed/untreated light chain multiple myeloma.

High BAALC expression levels at acute myeloid leukemia diagnosis have been linked to adverse outcomes. Recent data indicate that high BAALC expression levels may also be used as marker for residual disease following acute myeloid leukemia treatment. Allogeneic hematopoietic stem cell transplantation (HSCT) offers a curative treatment for acute myeloid leukemia patients. However, disease recurrence remains a major clinical challenge and identification of high-risk patients prior to HSCT is crucial to improve outcomes. We performed absolute quantification of BAALC copy numbers in peripheral blood prior (median 7 days) to HSCT in complete remission (CR) or CR with incomplete peripheral recovery in 82 acute myeloid leukemia patients using digital droplet PCR (ddPCR) technology. An optimal cut-off of 0.14 BAALC / ABL1 copy numbers was determined and applied to define patients with high or low BAALC / ABL1 copy numbers. High pre-HSCT BAALC / ABL1 copy numbers significantly associated with higher cumulative incidence of relapse and shorter overall survival in univariable and multivariable models. Patients with high pre-HSCT BAALC / ABL1 copy numbers were more likely to experience relapse within 100 days after HSCT. Evaluation of pre-HSCT BAALC / ABL1 copy numbers in peripheral blood by ddPCR represents a feasible and rapid way to identify acute myeloid leukemia patients at high risk of early relapse after HSCT. The prognostic impact was also observed independently of other known clinical, genetic, and molecular prognosticators. In the future, prospective studies should evaluate whether acute myeloid leukemia patients with high pre-HSCT BAALC / ABL1 copy numbers benefit from additional treatment before or early intervention after HSCT., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

Allogeneic hematopoietic cell transplantation (HCT) is an important treatment for many severe hematologic disorders; however, HCT can be associated with significant complications, including organ toxicity, graft-versus-host disease, and relapse. Another serious, but rare, complication is the transmission of hematologic and nonhematologic diseases from the donor to the recipient. With older donors, the risk of an abnormality may be increased. Here we describe the transmission of an inversion 3 constitutional cytogenetic abnormality from an unrelated donor to a recipient, and review the clinical implications of the discovery of donor-derived constitutional cytogenetic abnormalities., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Transcription factor C/EBPα is a master regulator of myelopoiesis and its inactivation is associated with acute myeloid leukemia. Deregulation of C/EBPα by microRNAs during granulopoiesis or acute myeloid leukemia development has not been studied. Here we show that oncogenic miR-182 is a strong regulator of C/EBPα. Moreover, we identify a regulatory loop between C/EBPα and miR-182. While C/EBPα blocks miR-182 expression by direct promoter binding during myeloid differentiation, enforced expression of miR-182 reduces C/EBPα protein level and impairs granulopoiesis in vitro and in vivo. In addition, miR-182 expression is highly elevated particularly in acute myeloid leukemia patients with C-terminal CEBPA mutations, thereby depicting a mechanism by which C/EBPα blocks miR-182 expression. Furthermore, we present miR-182 expression as a prognostic marker in cytogenetically high-risk acute myeloid leukemia patients. Our data demonstrate the importance of a controlled balance between C/EBPα and miR-182 for the maintenance of healthy granulopoiesis.C/EBPα is a critical transcription factor involved in myelopoiesis and its inactivation is associated with acute myeloid leukemia (AML). Here the authors show a negative feedback loop between C/EBPα and miR-182 and identify this miRNA as a marker of high-risk AML.

In acute myeloid leukemia (AML), leukemia-initiating cells exist within the CD34+/CD38- cell compartment. They are assumed to be more resistant to chemotherapy, enriched in minimal residual disease cell populations, and responsible for relapse. Here we evaluated clinical and biological associations and the prognostic impact of a high diagnostic CD34+/CD38- cell burden in 169 AML patients receiving an allogeneic stem cell transplantation in complete remission. Here, the therapeutic approach is mainly based on immunological graft-versus-leukemia effects. Percentage of bone marrow CD34+/CD38- cell burden at diagnosis was measured using flow cytometry and was highly variable (median 0.5%, range 0%-89% of all mononuclear cells). A high CD34+/CD38- cell burden at diagnosis associated with worse genetic risk and secondary AML. Patients with a high CD34+/CD38- cell burden had shorter relapse-free and overall survival which may be mediated by residual leukemia-initiating cells in the CD34+/CD38- cell population, escaping the graft-versus-leukemia effect after allogeneic transplantation. Evaluating the CD34+/CD38- cell burden at diagnosis may help to identify patients at high risk of relapse after allogeneic transplantation. Further studies to understand leukemia-initiating cell biology and develop targeting therapies to improve outcomes of AML patients are needed., (© 2017 Wiley Periodicals, Inc.)