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• A multifactorial influence determines the level and kinetics of torque teno (TT) viral load. • Numerous new influencing factors were identified. • Significant differences were only visible after day 50 after allogeneic hematopoietic stem cell transplantation. • Clinically relevant events showed no significant impact on TT viral load. • An early prognostic statement regarding the further clinical outcome is limited. Torque teno virus (TTV) is a nonenveloped, single-stranded, circular DNA virus of the family of Anelloviridae. The first contact with TTV usually occurs in early childhood, followed by persistent infection in bone marrow and lymphocytes. Increased levels of TTV-DNA are found in the serum in various states of immune deficiency. The objective of this study was to assess if monitoring of TTV viremia after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a predictive marker for immune-related clinical complications. In a retrospective study, 2054 whole-blood samples from 123 patients were tested for viral loads of TTV-DNA by real-time PCR within 345 days after allo-HSCT. We enrolled all patients who underwent allo-HSCT between September 2015 and April 2018. Clinical and laboratory data were collected and statistically analyzed. Patients with an underlying lymphatic malignancy had significantly higher torque teno (TT) viral loads compared with patients with an underlying malignant myeloid disease (P <.05). Complete remission before allo-HSCT correlated significantly with higher TT viral loads after allo-HSCT (P <.05). Myeloablative conditioning regimens led to significantly higher TT viral loads than reduced-intensity conditioning regimens (P <.05). A higher anti-thymocyte globulin (ATG) dose was associated with a significantly higher TT viral load. We did not observe any significant differences of TT viral load correlating with accompanying clinically relevant events such as virus reactivations (cytomegalovirus, Epstein-Barr virus, Adenovirus), acute graft-versus-host disease (aGVHD), relapse, or death. TT viral load after allo-HSCT did weakly correlate with T cell, T suppressor cell, T helper cell, and natural killer and B cell count. Although statistically significant differences between study groups were observed, virus reactivations, aGVHD, and clinical outcomes could not be predicted by monitoring TTV viremia. Therefore, TTV seems not to be suitable as a marker for the degree of immunosuppression or as a prognostic marker for clinically critical events in patients after allo-HSCT. [ABSTRACT FROM AUTHOR]

Introduction: This study explored qualitatively, in a sample of German hematologists working in clinical allogeneic hematopoietic stem cell transplantation (alloHSCT), perceptions of barriers and facilitators to participate in continuous medical education (CME), to provide detailed information on how to improve participation in CME activities related to alloHSCT, which may also be applicable to other areas of medicine. Methods: Based on a recruitment campaign of the German Association for Hematopoietic Stem Cell Transplantation (DAG-HSZT), 21 semi-structured telephone interviews were conducted, transcribed, and analyzed using framework analysis. Results: Three clusters of barriers were identified that explain why alloHSCT physicians may or may not participate in CME: individual constraints (e.g., better networking, young physicians being overwhelmed by the complexity of alloHSCT), structural constraints (e.g., time and financial issues, tailoring CME courses according to the targeted audience), and content-related constraints (e.g., requirement of CME sessions, provision of an overview of CME courses, more flexible offers). We discuss the ten most frequently raised issues, including the use of incentives and the need for support at the start of residency, staff shortages, and requirements for learning sessions. Conclusion: There is a need for a paradigm shift in CME related to alloHSCT toward a more individualized and needs-based approach. Close monitoring of residents' needs and learning progress, as well as feedback systems, could help identify appropriate CME courses that should be integrated into a tiered learning system. CME should be more targeted to specific audiences (i.e., residents, fellows, and attendees) to provide training that is tailored to individual CME needs. On-demand courses can help balance work and family obligations. Finally, peer-reviewed, up-to-date information platforms should be expanded. [ABSTRACT FROM AUTHOR]

It was previously shown that chronic myeloid leukemia (CML) patients transplanted with peripheral blood progenitor cells (PBPC) from HLA-C allele-matched donors had better clinical outcome when lacking the HLA-C-encoded KIR epitope C2. We investigated whether this holds true in other diseases and in HLA-C allele-mismatched patients. Twenty-four myelodysplastic syndrome (MDS), 39 acute myeloid leukemia (AML)/CML, and 34 acute lymphoblastic leukemia/non-Hodgkin lymphoma patients received unrelated unmanipulated PBPC. HLA matching was analyzed retrospectively (including DNA-based direct sequencing of HLA-C). Only in AML/CML, the C2 ligand was associated with impaired overall survival (OS, p < 0.05). We next calculated the impact of donor/recipient HLA-C allele matching within the C1 and C2 groups. Surprisingly, AML/CML and MDS patients with C2 ligands profited from HLA-C allele mismatching (OS, p < 0.01), whereas in the C1 group, allele matching was beneficial ( p < 0.05). HLA-C allele mismatching in the C2 KIR ligand group was associated with lower TRM (OR 0.48, p < 0.009) and lower relapse rate (OR 2.7 p < 0.1) when compared to allele-matched C2 patients. Thus, patients could be assigned to a low- and a high-risk group according to their C1/C2 ligand status and the HLA-C allele matching degree. These data suggest that four-digit allele matching of HLA-C has differential effects dependent on the presence of C1 and C2 KIR epitopes in the patient. [ABSTRACT FROM AUTHOR]

Bendamustine is a unique bifunctional cytotoxic agent that includes a nitrogen mustard group with alkylating properties and a benzimidazole ring with potential antimetabolite properties. It shows only partial cross-resistance with other alkylators in vitro and remains highly active in heavily pretreated patients. The history of bendamustine began in the former East German Democratic Republic, where it was developed in the early 1960s. Re-discovered in the 1990s, it demonstrated excellent response rates in several clinical trials with a favorable side-effect profile leading to its approval in 2008 by the U.S. Food and Drug Administration for the treatment of patients with chronic lymphocytic leukemia and for the treatment of patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma. Further studies showed efficacy in the first-line treatment of B-cell NHL and in the treatment of patients with multiple myeloma. We review the data on bendamustine published so far and discuss the future role of this promising agent in the treatment of patients with lymphoproliferative malignancies. [ABSTRACT FROM AUTHOR]

: ObjectiveAllogeneic blood stem cell transplantation (BSCT) can cure patients with hematologic malignancies by high-dose chemotherapy and allogeneic graft-vs-tumor (GvT) reactions. To avoid high-dose conditioning and evaluate engraftment, toxicity, and GvT reactions, we treated a group of high-risk patients with a minimal intensive conditioning regimen followed by allogeneic BSCT.: Materials and MethodsThirty-four patients with lymphoma (11), myeloma (10), chronic myeloid leukemia (4), myelodysplastic syndrome (5), and acute myeloid leukemia (4) were treated with fludarabine (3 × 30 mg/m2) and 200 cGy total-body irradiation followed by the infusion of peripheral blood stem cells from related (28) or unrelated (6) donors. Cyclosporine or tacrolimus and mycophenolate mofetile were given posttransplant. Most patients had advanced disease, were intensively pretreated, and had contraindications against conventional myeloablative transplantation.: ResultsThirty-two patients (94%) had engraftment of donor cells. Patients with lymphatic malignancies developed complete donor chimerism significantly faster than patients with myeloid malignancies (p < 0.05). Clinical responses were observed in 16 of 27 patients (59%) who had active disease at transplantation. Of 7 patients who were treated in remission, 5 remain free of disease. After a median follow-up of 325 days (range 100–844) 22 patients are alive (65%, 14 CR, 4 PR, 4 PD). Two patients (6%) died of treatment-related complications and 10 patients (29%) died of progressive disease. Acute graft-vs-host-disease (GvHD) of grade II or more developed in 17 patients (50%). Chronic GvHD is present in 10 of 22 patients (45%) who are alive beyond day 100.: ConclusionsToxicity and survival in this group of high-risk patients are superior to those expected with conventional allogeneic transplantation. GvT reactions frequently occur in conjunction with GvHD and can induce durable remissions in patients with advanced hematologic malignancies. [Copyright &y& Elsevier]

Simple Summary: Simple Summary: Myeloid and lymphoid malignant cells can become the dominant population in the bone marrow and thus inhibit healthy hematopoiesis. Patients suffer enormously as a result. In addition to the directly mediated inhibition of healthy hematopoietic stem and progenitor cells, indirect mechanisms via so-called mesenchymal stromal cells can also play a role. We are focusing our research on the latter and would like to identify functional and molecular overlapping mechanisms within the various myeloid and lymphoid neoplasms. In the future, it may be possible to block these mechanisms and thus prevent disease progression or improve healthy hematopoiesis. Myeloid and lymphoid neoplasms share the characteristics of potential bone marrow infiltration as a primary or secondary effect, which readily leads to hematopoietic insufficiency. The mechanisms by which clonal malignant cells inhibit normal hematopoietic stem and progenitor cells (HSPCs) in the bone marrow (BM) have not been unraveled so far. Given the pivotal role of mesenchymal stromal cells (MSCs) in the regulation of hematopoiesis in the BM niche it is assumed that MSCs also play a relevant role in the pathogenesis of hematological neoplasms. We aimed to identify overlapping mechanisms in MSCs derived from myeloid and lymphoid neoplasms contributing to disease progression and suppression of HSPCs to develop interventions that target these mechanisms. MSCs derived from healthy donors (n = 44) and patients diagnosed with myeloproliferative neoplasia (n = 11), myelodysplastic syndromes (n = 16), or acute myeloid leukemia (n = 25) and B-Non-Hodgkin lymphoma (n = 9) with BM infiltration and acute lymphoblastic leukemia (n = 9) were analyzed for their functionality and by RNA sequencing. A reduced growth and differentiation capacity of MSCs was found in all entities. RNA sequencing distinguished both groups but clearly showed overlapping differentially expressed genes, including major players in the BMP/TGF and WNT-signaling pathway which are crucial for growth, osteogenesis, and hematopoiesis. Functional alterations in healthy MSCs were inducible by exposure to supernatants from malignant cells, implicating the involvement of these factors in disease progression. Overall, we were able to identify overlapping factors that pose potential future therapeutic targets. [ABSTRACT FROM AUTHOR]

Introduction: Chimeric antigen receptor positive T cell (CAR-T cell) treatment became standard therapy for relapsed or refractory hematologic malignancies, such as non-Hodgkin's lymphoma and multiple myeloma. Owing to the rapidly progressing field of CAR-T cell therapy and the lack of generally accepted treatment guidelines, we hypothesized significant differences between centers in the prevention, diagnosis, and management of short- and long-term complications. Methods: To capture the current CAR-T cell management among German centers to determine the medical need and specific areas for future clinical research, the DAG-HSZT (Deutsche Arbeitsgemeinschaft für Hämatopoetische Stammzelltransplantation und Zelluläre Therapie; German Working Group for Hematopoietic Stem Cell Transplantation and Cellular Therapy) performed a survey among 26 German CAR-T cell centers. Results: We received answers from 17 centers (65%). The survey documents the relevance of evidence in the CAR-T cell field with a homogeneity of practice in areas with existing clinical evidence. In contrast, in areas with no – or low quality – clinical evidence, we identified significant variety in management in between the centers: management of cytokine release syndrome, immune effector cell-related neurotoxicity syndrome, IgG substitution, autologous stem cell backups, anti-infective prophylaxis, and vaccinations. Conclusion: The results indicate the urgent need for better harmonization of supportive care in CAR-T cell therapies including clinical research to improve clinical outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: In patients with hematologic malignancies, especially those undergoing intensive treatments like chemotherapy, infections pose a significant and life-threatening risk. This is particularly true for individuals with myelodysplastic syndromes (MDS), a condition commonly affecting the elderly and characterized by low blood-cell counts, including anemia and neutropenia. A retrospective study involving 1593 patients from the Düsseldorf MDS Registry aimed to address two key objectives: describe the incidence of infections in MDS patients and identify risk factors contributing to increased susceptibility to infections. The study highlights the critical need for tailored approaches to prevent and manage infections in immunocompromised individuals, underlining the importance of understanding and addressing factors influencing the risk of developing infections in this vulnerable patient population. Despite notable advancements in infection prevention and treatment, individuals with hematologic malignancies still face the persistent threat of frequent and life-threatening complications. Those undergoing chemotherapy or other disease-modifying therapies are particularly vulnerable to developing infectious complications, increasing the risk of mortality. Myelodysplastic syndromes (MDS) predominantly affect the elderly, with the incidence rising with age and peaking at around 70 years. Patients with MDS commonly present with unexplained low blood-cell counts, primarily anemia, and often experience varying degrees of neutropenia as the disease progresses. In our subsequent retrospective study involving 1593 patients from the Düsseldorf MDS Registry, we aimed at outlining the incidence of infections in MDS patients and identifying factors contributing to heightened susceptibility to infectious complications in this population. [ABSTRACT FROM AUTHOR]

Simple Summary: Allogeneic stem cell transplantation (aHSCT) is the only potentially curative treatment option for patients with high-risk myeloid malignancies. Depending on the underlying genetic risk profile, up to 50% of patients die of relapse even after aHSCT in first remission. Therefore, further improvement of conditioning regimens is an urgent medical need. Current sequential conditioning regimens combine intensive AML-like induction therapy with total body irradiation or alkylators like treosulfan or melphalan. The first and currently widely accepted prototype of this treatment strategy is the fludarabine/amsacrine/ara-C (FLAMSA) protocol, which has been modified multiple times by changing parts or adding additional cytotoxic drugs to improve clinical results. Knowing that venetoclax, an inhibitor of B-cell lymphoma-2 protein (BCL2), has synergistic effects to chemotherapy without increasing the level of non-hematologic toxicity, several German transplant centers have added venetoclax to the FLAMSA protocol as an individualized treatment approach to improve long term outcome in patients with high-risk myeloid malignancies. Up to 50% of patients with high-risk myeloid malignancies die of relapse after allogeneic stem cell transplantation. Current sequential conditioning regimens like the FLAMSA protocol combine intensive induction therapy with TBI or alkylators. Venetoclax has synergistic effects to chemotherapy. In a retrospective survey among German transplant centers, we identified 61 patients with myeloid malignancies that had received FLAMSA-based sequential conditioning with venetoclax between 2018 and 2022 as an individualized treatment approach. Sixty patients (98%) had active disease at transplant and 74% had genetic high-risk features. Patients received allografts from matched unrelated, matched related, or mismatched donors. Tumor lysis syndrome occurred in two patients but no significant non-hematologic toxicity related to venetoclax was observed. On day +30, 55 patients (90%) were in complete remission. Acute GvHD II°–IV° occurred in 17 (28%) and moderate/severe chronic GvHD in 7 patients (12%). Event-free survival and overall survival were 64% and 80% at 1 year as well as 57% and 75% at 2 years, respectively. The off-label combination of sequential FLAMSA-RIC with venetoclax appears to be safe and highly effective. To further validate these insights and enhance the idea of smart conditioning, a controlled prospective clinical trial was initiated in July 2023. [ABSTRACT FROM AUTHOR]

The 2023 International CMV Symposium took place in Barcelona in May 2023. During the 2‐day meeting, delegates and faculty discussed the ongoing challenge of managing the risk of cytomegalovirus infection (the Troll of Transplantation) after solid organ or hematopoietic cell transplantation. Opportunities to improve outcomes of transplant recipients by applying advances in antiviral prophylaxis or pre‐emptive therapy, immunotherapy, and monitoring of cell‐mediated immunity to routine clinical practice were debated and relevant educational clinical cases presented. This review summarizes the presentations, cases, and discussions from the meeting and describes how further advances are needed before the Troll of Transplantation is slain. [ABSTRACT FROM AUTHOR]

Simple Summary: High-dose therapy with melphalan followed by autologous stem cell transplantation and lenalidomide maintenance has long been the standard of care for newly diagnosed patients with multiple myeloma. However, it is unclear how lenalidomide dosage or experienced side effects govern patients' quality of life during long-term treatment. The LenaMain trial (NCT00891384) investigated lenalidomide maintenance at a high (25 mg) and a low dose (5 mg) and demonstrated that dosage had no impact on patients' quality of life. Instead, high baseline scores for global health were maintained throughout the trial without difference between treatment arms which supports the feasibility of continuous lenalidomide treatment with a dose tailored to patients' quality of life. Introduction: The LenaMain trial (NCT00891384) reported increased progression-free survival with 25 mg of lenalidomide maintenance compared to 5 mg. Here, we report the patient-reported outcomes. Materials and Methods: Scores obtained from the EORTC Quality of Life Questionnaire C30 were analyzed for longitudinal changes from baseline within the groups as well as cross-sectional scores. Results: Compliance rates were high, with 95.7% at baseline and 70% during maintenance. At study entry, scores were high for functioning and low for symptoms. During maintenance, the median global health status/quality of life (GHS/QoL) was constant, without significant differences over time (median GHS/QoL: 68 at baseline and 58 for Len high and 68 for Len low at 2 years) and between treatment arms (mean change < 2). Similarly, most functional scale domains were constant. Notably, diarrhea increased consistently for both treatment arms (baseline: −1.905 (range: −5.78–1.97); end of year 2: 16.071 (range: 5.72–26.42); p < 0.05). The subgroup analysis showed that neither disease activity, duration of treatment, nor adverse events affected the health-related quality of life (HR-QoL) or utility. Conclusion: High baseline scores were maintained throughout the trial without significant differences between the Len dosages, which supports continuous treatment with a dose tailored to patients' HR-QoL. [ABSTRACT FROM AUTHOR]

Only a sudden and prominent increase in the peripheral B-cell count months later paved the way for measurable antibody production in this patient, emphasizing the importance of B-cell reconstitution for successful vaccination. As patients who have received B-cell depleting antibodies before autoHSCT may, at the same time, have delayed B-cell recovery, anti-virus-titers may be low or even absent following a first vaccination round. B-cell lymphomas have been identified as an important risk factor for insufficient serologic response to vaccination, especially in patients with recent B-cell-directed therapy, e.g., BTK inhibitors and CD20-directed antibodies [[2]]. [Extracted from the article]

Patients with acute myeloid leukemia (AML) and nucleophosmin 1 gene mutations (NPM1mut) show a favorable prognosis with chemotherapy (CT) in the absence of negative prognostic genetic abnormalities. Between 2008 and 2021 64 patients with NPM1mutAML received alloHSCT because of additional adverse prognostic factors (1st line), inadequate response to or relapse during or after CT (2nd line). To expand the evidence in alloTX in NPM1mut AML, clinical and molecular data were retrospectively analyzed with respect to pre-transplant strategies and outcome. Patients with minimal residual disease negative (MRD−) CR at transplant had better 2-y-PFS and 2-y-OS (77% and 88%) than patients with minimal residual disease positive (MRD+) CR (41% and 71%) or patients with active disease (AD) at transplant (20% and 52%). The 2nd line patients with relapse after completing CT responded well to high dose cytarabine based salvage chemotherapy (salvage CT) in contrast to patients relapsing while still on CT (90% vs 20%, P = 0.0170). 2-y-PFS and 2-y-OS was 86% in patients who achieved a 2nd MRD− CR pre alloHSCT. Outcome in NPM1mutAML depends on disease burden at alloHSCT. Time and type of relapse in relation to CT are predictive for response to salvage CT. [ABSTRACT FROM AUTHOR]

Simple Summary: Relapse as the most common reason for treatment failure after allogeneic hematopoietic stem-cell transplantation (allo-SCT) in myeloid neoplasms usually occurs during the first year post-transplant, but several patients experience late relapse. This retrospective study aimed to characterize early and late relapses regarding clinical and cytogenetic parameters. Analyzing 91 consecutive patients, we demonstrated an improved overall survival for late compared with early relapsed patients and carved out cytogenetics and disease risk stratification at diagnosis as well as pretransplant strategy as major determinants for the timepoint of relapse. The impact of cytogenetics was highlighted by comparative karyotype analyses demonstrating a higher frequency of clonal evolution in early relapses. Improving knowledge about factors predicting early relapse may enable a selection of patients who may benefit from strategies to prevent or delay relapse, and identifying patients being at risk for late relapse may trigger prolonged surveillance strategies, including bone marrow biopsies and measurable residual disease (MRD) assessment. An improved understanding of relapse kinetics is required to optimize detection and treatment strategies for the post-transplant relapse of myeloid neoplasms. Therefore, we retrospectively analyzed data from 91 patients allografted for MDS (n = 54), AML-MRC (n = 29) and chronic myelomonocytic leukemia (CMML, n = 8), who relapsed after transplant. Patients with early (<12 months, n = 56) and late relapse (>12 months, n = 35) were compared regarding patient-, disease- and transplant-related factors, including karyotype analyses at diagnosis and relapse. After a median follow-up of 17.4 months after relapse, late relapses showed improved outcomes compared with early relapses (2-yr OS 67% vs. 32%, p = 0.0048). Comparing frequency of distinct patient-, disease- and transplant-related factors among early and late relapses, complex karyotype (p = 0.0004) and unfavorable disease risk at diagnosis (p = 0.0008) as well as clonal evolution at relapse (p = 0.03) were more common in early than in late relapses. Furthermore, patients receiving transplant without prior cytoreduction or in complete remission were more frequently present in the group of late relapses. These data suggest that cytogenetics rather than disease burden at diagnosis and transplant-related factors determine the timepoint of post-transplant relapse and that upfront transplantation may be favored in order to delay relapse. [ABSTRACT FROM AUTHOR]

Overall, 33 patients (52%) continued treatment beyond investigator assessed PD and a total of 16 patients received additional concomitant radiotherapy and/or chemotherapy. The majority of patients experiencing PD during or after anti-PD1 treatment received additional therapies (21/37, 57%). Outcomes of anti-programmed death 1 treatment for relapsed/refractory Hodgkin lymphoma: A German Hodgkin Study Group multicentre real-world analysis. [Extracted from the article]

Background: The main goal of this post hoc analysis of the Collaboration to Collect Autologous Transplant Outcomes in Lymphoma and Myeloma (CALM) study was to evaluate the rate of short- and long-term infectious and non-infectious complications occurring after ASCT in patients with multiple myeloma (MM). Methods: The analysis included all patients with MM from the CALM study who underwent ≥1 ASCT. The primary endpoint of the analysis was to determine the rate of infectious and non-infectious complications after ASCT and to compare them in three time periods: 0–100 days, 101 days–1 year, and >1 year after the first transplant. Results: The analysis included a total of 3552 patients followed up for a median of 56.7 months (range 0.4–108.1). Complication rates decreased with the time from ASCT with 24.85 cases per 100 patient-years from day 0 to 100 days after the transplant, and <2.31 cases per 100 patient-years from the 101st day. At 100 days after ASC T, 45.7% of patients had complications, with infectious events being twice as frequent as non-infectious complications. Bacterial infections (6.5 cases per 100 patient-years, 95% CI: 6.1–7.0) and gastrointestinal complications (4.7 cases per 100 patient-years, 95% CI: 4.3–5.1) were the most common early events. The pattern of complications changed with time from ASCT. The presence of complications after ASCT was not associated with overall survival. Conclusions: Our data provide a solid basis for comparing ASCT-related complications to those caused by emerging treatments in multiple myeloma, such as CAR T-cell therapy and other immunotherapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Over the past decade, randomized controlled trials as an established instrument of evidence-based medicine have contributed fundamentally to the development and approval of new substances. However, it has been frequently shown that less than 5% of adult cancer patients enroll in clinical trials. Barriers to trial participation have been extensively studied, but the rate of trial participation has not changed substantially. In this retrospective analysis, we found that 53% of newly diagnosed multiple myeloma patients met the eligibility criteria, while only 38% of relapsed refractory patients were eligible. Moreover, our data show for the first time that eligible patients tend to become more reluctant to participate over the course of the disease, with 42% of newly diagnosed patients consenting, and only 7% of relapsed/refractory patients consenting. Thus, our results may assist with trial design improvements and address patient expectations and priorities in order to increase enrollment. Randomized controlled trials (RCT) are the driver of therapeutic innovations. However, it has been frequently shown that less than 5% of adult cancer patients enroll in clinical trials, although 70% of patients are considered as being willing to participate. Barriers to trial participation have been extensively studied. Although there is evidence that trial participation correlates with improved survival and reduced mortality, the rate of participation has not changed substantially. We provide retrospective data from a single-center analysis of 411 patients with multiple myeloma (MM) who were treated at the University Hospital Duesseldorf in Germany between January 2014 and December 2016. Each patient was analyzed for the real-world possibility of participating in a clinical study, based on the inclusion and exclusion (I/E) criteria and the recruiting period of open studies. The overall rate of study participation was 19%. A total of 53% of NDMM patients were eligible for first-line studies (GMMG-HD6, LenaMain). Of these, 80% consented to enrolment (42% of all). In contrast, only 38% of the RRMM population was eligible (GMMG-Relapse, Castor, Tourmaline, Admyre). Of these, only 22% (7% of all) consented. This was confirmed by virtual analysis, showing that only 29% of all RRMM patients would have been eligible for six internationally recruiting trials leading to later drug approval. The majority of cases were rendered ineligible by only one I/E criterion. The most common criteria were study-specific (prior therapies or refractory disease to a specific drug), kidney disease, and previous malignancy, followed by internal, neurologic, and infectious disease. In summary, this single-center analysis showed that I/E criteria permit study participation for most NNDM patients, with a dramatic decrease in the RRMM population. This is aggravated by the fact that the willingness for study participation also significantly declines in RRMM. Thus, addressing patient expectations and priorities seems to be the most promising approach to increasing patient enrollment in clinical trials. [ABSTRACT FROM AUTHOR]

PURPOSE: Intensive treatment protocols for aggressive hematologic malignancies harbor a high risk of serious clinical complications, such as infections. Current techniques of monitoring vital signs to detect such complications are cumbersome and often fail to diagnose them early. Continuous monitoring of vital signs and physical activity by means of an upper arm medical wearable allowing 24/7 streaming of such parameters may be a promising alternative. METHODS: This single-arm, single-center observational trial evaluated symptom-related patient-reported outcomes and feasibility of a wearable-based remote patient monitoring. All wearable data were reviewed retrospectively and were not available to the patient or clinical staff. A total of 79 patients (54 inpatients and 25 outpatients) participated and received standard-of-care treatment for a hematologic malignancy. In addition, the wearable was continuously worn and self-managed by the patient to record multiple parameters such as heart rate, oxygen saturation, and physical activity. RESULTS: Fifty-one patients (94.4%) in the inpatient cohort and 16 (64.0%) in the outpatient cohort reported gastrointestinal symptoms (diarrhea, nausea, and emesis), pain, dyspnea, or shivering in at least one visit. With the wearable, vital signs and physical activity were recorded for a total of 1,304.8 days. Recordings accounted for 78.0% (63.0-88.5; median [interquartile range]) of the potential recording time for the inpatient cohort and 84.6% (76.3-90.2) for the outpatient cohort. Adherence to the wearable was comparable in both cohorts, but decreased moderately over time during the trial. CONCLUSION: A high adherence to the wearable was observed in patients on intensive treatment protocols for a hematologic malignancy who experience high symptom burden. Remote patient monitoring of vital signs and physical activity was demonstrated to be feasible and of primarily sufficient quality. Wearables enable remote therapy monitoring of patients with hematologic malignancies with high adherence. [ABSTRACT FROM AUTHOR]

PURPOSE: Intensive treatment protocols for aggressive hematologic malignancies harbor a high risk of serious clinical complications, such as infections. Current techniques of monitoring vital signs to detect such complications are cumbersome and often fail to diagnose them early. Continuous monitoring of vital signs and physical activity by means of an upper arm medical wearable allowing 24/7 streaming of such parameters may be a promising alternative. METHODS: This single-arm, single-center observational trial evaluated symptom-related patient-reported outcomes and feasibility of a wearable-based remote patient monitoring. All wearable data were reviewed retrospectively and were not available to the patient or clinical staff. A total of 79 patients (54 inpatients and 25 outpatients) participated and received standard-of-care treatment for a hematologic malignancy. In addition, the wearable was continuously worn and self-managed by the patient to record multiple parameters such as heart rate, oxygen saturation, and physical activity. RESULTS: Fifty-one patients (94.4%) in the inpatient cohort and 16 (64.0%) in the outpatient cohort reported gastrointestinal symptoms (diarrhea, nausea, and emesis), pain, dyspnea, or shivering in at least one visit. With the wearable, vital signs and physical activity were recorded for a total of 1,304.8 days. Recordings accounted for 78.0% (63.0-88.5; median [interquartile range]) of the potential recording time for the inpatient cohort and 84.6% (76.3-90.2) for the outpatient cohort. Adherence to the wearable was comparable in both cohorts, but decreased moderately over time during the trial. CONCLUSION: A high adherence to the wearable was observed in patients on intensive treatment protocols for a hematologic malignancy who experience high symptom burden. Remote patient monitoring of vital signs and physical activity was demonstrated to be feasible and of primarily sufficient quality. Wearables enable remote therapy monitoring of patients with hematologic malignancies with high adherence. [ABSTRACT FROM AUTHOR]

Objective: As peripheral blood (PB) Wilm'sTumor 1 (WT1)‐mRNA expression is established as MRD‐marker during conventional AML chemotherapy, impact of pretransplant WT1 expression remains unclear. Therefore, we aimed to assess prognostic impact of pretransplant WT1 expression on post‐transplant outcome in patients with AML/MDS. Methods: In 64 AML/MDS patients, pretransplant WT1 expression was retrospectively analyzed using a standardized assay offering high sensitivity, specificity, and a validated cut‐off. Patients were divided into three groups determined by pretransplant remission and WT1 expression. Post‐transplant outcome of these groups was compared regarding cumulative incidence of relapse (CIR), relapse‐free (RFS), and overall survival (OS). Results: Pretransplant forty‐six patients (72%) showed hematologic remission, including 21 (46%) MRD‐negative and 25 (54%) MRD‐positive patients indicated by WT1 expression, while 18 refractory patients (28%) showed active disease. Two‐year estimates of post‐transplant CIR, RFS, and OS were similar in MRD‐positive (61%, 37%, 54%) and refractory patients (70%, 26%, 56%), but significantly inferior compared with MRD‐negative patients (10%, 89%, 90%). After multivariable adjustment, pretransplant MRD negativity measured by WT1 expression retained its prognostic impact on CIR (P =.008), RFS (P =.005), and OS (P =.049). Conclusions: PB WT1 expression represents a useful method to estimate pretransplant MRD, which is highly predictable for post‐transplant outcome and may help improving peri‐transplant management in AML/MDS patients. [ABSTRACT FROM AUTHOR]

Most myelodysplastic syndromes (MDS)-patients receive multiple red blood cell transfusions (RBCT). Transfusions may cause iron-related toxicity and mortality, influencing outcome after allogeneic HSCT. This prospective non-interventional study evaluated 222 MDS and CMML patients undergoing HSCT. Overall survival (OS), relapse-free survival (RFS), non-relapse mortality (NRM), and relapse incidence (RI) at 36 months were 52%, 44%, 25%, and 31%, respectively. Age, percentage of marrow blasts and severe comorbidities impacted OS. RFS was significantly associated with RBCT burden prior to HSCT (HR: 1.7; p =.02). High ferritin levels had a significant negative impact on OS and RI, but no impact on NRM. Administration of iron chelation therapy prior to HSCT did not influence the outcome, but early iron reduction after HSCT (started before 6 months) improved RFS significantly after transplantation (56% in the control group vs. 90% in the treated group, respectively; p =.04). This study illustrates the impact of RBCT and related parameters on HSCT-outcome. Patients with an expected prolonged survival after transplantation may benefit from early iron reduction therapy after transplantation. [ABSTRACT FROM AUTHOR]

• Upfront transplantation in high-risk MDS and sAML is at least not inferior compared with pretransplant cytoreductive approaches. • Pretransplant treatment may impact response and survival after salvage therapy in patients who relapse after allo-HSCT. • An upfront transplant strategy may be augmented by HMA + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment for patients with advanced myelodysplastic syndrome (MDS) and secondary acute myelogenous leukemia (sAML), but in the absence of prospective trials the impact of pretransplant cytoreduction is controversially discussed. We retrospectively analyzed the outcome of 165 patients with MDS and excess blasts (n = 126, 76%) and sAML (n = 39, 24%) according to a pretransplant strategy. Sixty-seven patients (41%) were directly transplanted (upfront group), whereas 98 patients (59%) had received pretransplant cytoreductive treatment (induction chemotherapy [CTX], n = 64; hypomethylating agents [HMAs], n = 34) resulting in a significantly higher complete remission rate in the CTX group (59% versus HMA 18%, P <.0001). Estimated rates of 5-year overall survival (OS) and relapse-free survival (RFS) for the entire group were 54% and 39%, respectively. The 5-year OS rates of the upfront, CTX, and HMA groups were 61%, 50%, and 45%, respectively (P =.116), whereas RFS rates were 38%, 41%, and 38% (P =.926). Cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) did not differ between treatment groups. In the upfront group no difference regarding OS and RFS was seen with respect to pretransplant blast count (>10% versus <10%). In multivariate analyses type of pretransplant strategy did not have an effect on OS, RFS, CIR, and NRM, whereas cytogenetics (OS, RFS, CIR), reduced-intensity conditioning (OS, RFS, CIR), and an unrelated donor (RFS, CIR) were identified as negative predictors. When compared with the upfront group, 5-year OS was significantly lower in patients with CTX-refractory disease (34% versus 64%, P =.0346) and by clear trend in HMA nonresponders (42% versus 61%, P =.073), whereas RFS did not differ significantly. In further support of the concept, that pretransplant therapy may favor the selection of resistant clones, patients in the upfront group had a higher likelihood to respond to HMAs as salvage therapy for relapse in comparison with pretreated patients (complete remission, 58% versus 10%; P =.0005) and a higher 2-year OS rate after relapse (59% versus 19%, P =.0001). These data suggest that an upfront transplant strategy is at least not inferior to pretransplant cytoreduction and may be augmented by HMAs + donor lymphocyte infusion salvage therapy in case of relapse after allo-HSCT. [ABSTRACT FROM AUTHOR]

• First-line treatment is applied relatively homogeniously among German, Austrian, and Swiss transplant centers except initial treatment of progressive onset. • Second-line treatment varies considerably with new agents entering clinic through the last 10 years. • Even in the presence of evidence clinical practice in treatment of lung manifestations varies considerably. Chronic graft-versus-host disease (cGVHD) remains the leading cause of late morbidity and mortality. Despite the growing number of treatment options in cGVHD, evidence remains sparse. The German-Austrian-Swiss GVHD Consortium performed a survey on clinical practice in treatment of cGVHD among transplant centers in Germany, Austria, and Switzerland in 2009 and 2018 and compared the results. The survey performed in 2009 contained 20 questions on first-line treatment and related issues and 4 questions on second-line scenarios followed by a survey on all systemic and topic treatment options known and applied, with 31 of 36 transplant centers (86%) responding. The survey in 2018 repeated 7 questions on first-line treatment and 3 questions on second-line scenarios followed by an updated survey on all current systemic treatment options known and applied, with 29 of 66 centers (43%) responding. In summary, the results show a large overlap of first-line treatment practice between centers and the 2 surveys because of a lack of new data that changes practice, except significant heterogeneity of treatment of cGVHD progressive onset type, which can be explained by the lack of trials focusing on this high-risk entity. In contrast, treatment options applied to second-line therapy vary considerably, with new agents like ibrutinib and ruxolitinib entering clinical practice. Moreover, treatment of bronchiolitis obliterans syndrome demonstrates heterogeneity in applied therapeutic options and sequence because of a lack of controlled data and different conclusions from already existing evidence. In summary, the survey results demonstrate an increasing number of treatment options applied to cGVHD accompanied by a significant heterogeneity in second-line treatment and underline the urgent need for clinical trials and registry analyses on rare entities with high mortality like progressive onset type and lung involvement of cGVHD. [ABSTRACT FROM AUTHOR]

Summary: Myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPN) and chronic myelomonocytic leukaemia (CMML) can progress to secondary acute myeloid leukaemia (sAML). We compared the outcome of 4214 sAML patients who received allogeneic haematopoietic stem cell transplantation (allo‐HSCT) from an unrelated (62%) or human leucocyte antigen (HLA)‐identical sibling donor (38%) according the underlying disease: MDS (n = 3541), CMML (n = 251) or MPN (n = 422). After a median follow up of 46·5 months, the estimated 3‐year progression‐free (PFS) and overall survival (OS) for the entire group was 36% (34–37%) and 41% (40–43%), respectively. The cumulative incidence of relapse and non‐relapse mortality (NRM) was 37% (35–39%) and 27% (26–29%), respectively. In a multivariable analysis for OS, besides age (P < 0·001), unrelated donor (P = 0·011), cytomegalovirus ± constellation (P = 0·007), Karnofsky index ≤ 80 (P < 0·001), remission status (P < 0·001), peripheral blood as stem cell source (P = 0·009), sAML from MPN (P = 0·003) remained a significant factor in comparison to sAML from MDS, while worse outcome of sAML from CMML did not reach statistical significance (P = 0·06). This large registry study demonstrates a major impact of the underlying disease on outcome of sAML after allo‐HSCT. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (aHSCT) cures a considerable number of patients with myeloid malignancies, but relapse is the most frequent cause of death. We retrospectively studied relapse rate, kinetics, treatment, and outcome after first aHSCT in 446 patients during a 13-year period. Relapse occurred in 167 patients after a median of 4.6 months (116 hematologic (HR), 38 molecular (MR), and 13 extramedullary relapses (XR)). Median survival after relapse was 8.4 months and 2-year overall survival was 25%. Regarding survival after relapse, type (MR/HR/XR) and timepoint of relapse ( 12 months), age ( 50), diagnosis (MDS/AML and sAML), and remission status at transplant (CR and untreated MDS vs. refractory disease) were relevant in univariate analyses, in multivariate analyses timepoint, and type of relapse, age, and diagnosis. One hundred fifty-six patients were treated, most frequently with hypomethylating agents (HMA, n = 109) or intensive chemotherapy (n = 12). Donor lymphocyte infusion (DLI) was administered to 99 patients. Second aHSCT was performed in three patients as first and in 21 as higher salvage treatment. A complete remission (CR) was achieved in 46 patients (30%). Among CR patients, 65% had received HMA and DLI. Median survival of patients achieving CR was 105 months and 2-year overall survival was 80%. We conclude that with HMA and DLI or second aHSCT, a substantial number of patients, who relapse after aHSCT, can re-achieve remission and long-term survival. Techniques to further improve the detection of minimal residual disease are urgently needed because early treatment of MR results in significantly better survival. [ABSTRACT FROM AUTHOR]

Highlights • Major mechanisms of relapse include HLA loss, HLA down-regulation, and expression of coinhibitory ligands. • Combination of donor lymphocyte infusion with immunomodulating agents and tyrosine kinase inhibitors may enhance the graft-versus-leukemia (GVL) effect. • Immune checkpoint inhibitors can induce a significant GVL effect, but toxicity is high. ABSTRACT The curative potential of allogeneic hematopoietic cell transplantation (allo-HCT) in the treatment of acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) relies mainly on the graft-versus-leukemia effect. Relapse after allo-HCT occurs in a considerable proportion of patients and has a dismal prognosis, with still very limited curative potential. This review provides an overview of the established and evolving approaches to preventing or treating relapse of AML and MDS after allo-HCT, in the context of novel insight into the biology of relapse. Established prophylactic measures to prevent relapse include optimized conditioning and graft-versus-host disease (GVHD) prophylaxis, as well as donor lymphocyte infusion (DLI) for high-risk patients; novel immunomodulatory interventions and maintenance approaches are still experimental. Improved diagnostics can detect persistent or recurring disease at a molecular level, enabling early preemptive interventions. Established options include hypomethylating agents and DLI. Standard treatments for hematologic relapse include chemotherapy, cessation of immunosuppressive treatment, and DLI. Experimental approaches include molecular targeted therapies, novel immunomodulatory treatments, and second allo-HCT. For all interventions, the potential risks, including occurrence of GVHD, must be weighed against the benefits individually in each patient. Concurrently, prevention and treatment of relapse after allo-HCT remain challenging and unmet medical needs. [ABSTRACT FROM AUTHOR]

The article offers information on the chronic lymphocytic leukaemia (CLL) X4 trial which was conducted to harness the anti-CD20 antibody, ofatumumab, for disease-control peri-transplantation and prevention of chronic graft-versus-host disease (GVHD.) Topic discussed diagnosis of patients by flow cytometry of peripheral blood; treatment which comprised of induction therapy and observed that allogeneic Hematopoietic Cell Transplantation (alloHCT) had no significant impact on overall survival.

Objective: We evaluated the development of ICU survival of patients with hematopoietic malignancies and discussed changes in admittance policies. Method: We compared 166 patients treated between 2009 and 2012 with 138 patients treated between 2013 and 2016. Patient characteristics and outcome were analyzed. Results: ICU survival was 45.2% in the first group and 66.7% in the second (P < 0.0005). Infection (P = 0.033), invasive ventilation (IMV) (P = 0.014) and SOFA score at day 3 (SOFA‐48h) (P = 0.007) independently indicated worse ICU survival in the first group, IMV (P = 0.013) and SOFA‐48h (P = 0.019) in the second group. The second group showed lower frequencies of infection (P = 0.003), IMV (P < 0.0005), need for vasopressors (P < 0.0005) and RRT (P = 0.021) at ICU admittance than the first. Further, the accumulation of hyperkaliemia, acidosis, low bicarbonate, high lactate and hypotension showed worse ICU survival in both groups and was lower in second group. Conclusion: ICU survival increased distinctly between 2009 and 2016. At ICU admittance, parameters showing severity of illness were less frequent in the second group. Our findings indicate general treatment improvements especially of infections and changes of admittance policies toward early ICU admittance during time. [ABSTRACT FROM AUTHOR]

Highlights • The impact of donor age and sex but not CMV matching is comparable with that of single HLA disparity on survival after HSCT. • Similar survival after matched unrelated and related donor HSCT for AML or MDS reflects lower NRM but higher relapse risks in the latter. Abstract Increasing donor–recipient HLA disparity is associated with negative outcomes of allogeneic hematopoietic stem cell transplantation (HSCT), but its comparative relevance amid non-HLA donor characteristics is not well established. We addressed this question in 3215 HSCTs performed between 2005 and 2013 in Germany for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Donors were HLA-matched related (MRD; n = 872) or unrelated (10/10 MUD, n = 1553) or HLA-mismatched unrelated (<10/10 MMUD, n = 790). Overall survival (OS) was similar after MRD compared with 10/10 MUD HSCT, reflecting opposing hazards of relapse (hazard ratio [HR], 1.32; P <.002) and nonrelapse mortality (HR,.63; P <.001). After UD HSCT, increasing HLA disparity was associated with inferior OS (HR, 1.21 [ P <.02] and HR, 1.57 [ P <.001] for 9/10 and ≤8/10 MMUD, respectively, compared with 10/10 MUD). Among non-HLA donor characteristics, age, sex mismatching (male recipient–female donor), and cytomegalovirus (CMV) mismatching (positive recipient–negative donor) impacted OS. Multivariate subgroup analysis showed that OS was similar after HSCT from the youngest 9/10 MMUD (<30 years) compared with the oldest 10/10 MUD (>40 years) (HR, 1.18; P =.25) and also in male patients transplanted from female 10/10 MUD compared with male 9/10 MMUD (HR,.89; P =.46). In contrast, OS of CMV-positive patients tended to be better with CMV-negative 10/10 MUDs compared with CMV-positive 9/10 MMUDs (HR, 1.31; P =.04). Because of low patient numbers in subgroups, definite conclusions and establishment of a hierarchy among HLA matching and non-HLA donor characteristics could not be made. Our data suggest that the impact of donor age and sex mismatch but not CMV mismatch on outcome of allogeneic HSCT may be comparable with that of single HLA disparity. [ABSTRACT FROM AUTHOR]

Intensive chemotherapy (IC) used to be a common treatment approach for patients with higher-risk myelodysplastic syndromes (MDS) or acute myeloid leukemia after MDS (sAML). We conducted a retrospective analysis of 299 patients, including a matched pair analysis comparing 96 patients receiving IC with 96 patients not undergoing IC, in order to evaluate the impact of IC on overall survival (OS) and to identify factors that influence remission rates and OS. Complete remission (CR) after first induction chemotherapy was reached in 50% of patients. Parameters influencing the probability of achieving CR were blast count in the bone marrow (< 30%), age < 65 years, presence of Auer rods, duration of antecedent MDS shorter than 6 months, and timing of IC in relation to first diagnosis. The difference in survival time was not significantly better for patients receiving IC (median OS 12.7 months vs. 7 months). Parameters favorably influencing survival were the presence of Auer rods, age below 60 years, blast count below 30%, IC given shortly after first diagnosis, and achievement of CR. On multivariate analysis, achieving CR, presence of Auer rods, and percentage of blasts below or above 30% significantly influenced median survival. Relapse occurred in 63% of patients after a median of 9.9 months with a median survival of 7.6 months. Considering the high relapse rate and short survival, we conclude that intensive chemotherapy is not promising for high-risk MDS or sAML. [ABSTRACT FROM AUTHOR]

Highlights • WT1 mRNA expression level is applicable as MRD marker in most patients with AML and MDS. • WT1 mRNA expression level is measurable by a standardized assay providing a validated cutoff level. • WT1 mRNA expression level is measurable in peripheral blood and therefore coherent with high patient comfort. • WT1 mRNA expression level predicts relapse after allo-HSCT with a sensitivity of 85% and specificity of 97%. • In 62% of cases, overexpression of WT1 led to earlier BM biopsy and diagnosis of relapse. Abstract Overexpression of the Wilms' tumor 1 (WT1) gene is informative in many patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) and is measurable in peripheral blood (PB). Despite these advantages, WT1 has not broadly been established as a marker for minimal residual disease (MRD) monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to limited patient numbers, differing sample sources, and nonstandardized in-house methods. To estimate the value of WT1 as an MRD marker, we serially quantified PB WT1 expression using a standardized European LeukemiaNet-certified assay in 59 patients with AML and MDS after allo-HSCT. We compared its performance with routine methods such as chimerism, XY-fluorescence in situ hybridization (FISH), disease-specific cytogenetic, and molecular analyses, which were accessible in 100%, 34%, 68%, and 37%, respectively. Twenty-four patients (41%) relapsed within a median of 126 days after allo-HSCT, and 20 of them showed at least 1 elevated WT1 value above the validated cutoff. The other 35 patients (59%) remained in complete remission, and only 1 patient had a transient increase in WT1 expression. This reflects a sensitivity of 83% and a specificity of 97% for WT1 and appears to be favorable compared with the sensitivities and specificities observed for chimerism (33% and 91%), XY-FISH (67% and 73%), cytogenetic (33% and 77%), and molecular (78% and 85%) analyses. Further supporting its predictive impact, elevated WT1 expression prompted an earlier BM biopsy and consecutively the diagnosis of relapse in 62% of patients. The results of this real-life experience imply that PB WT1 expression is measurable by a standardized assay and predicts imminent relapse after allo-HSCT with high sensitivity and specificity in most patients with AML and MDS. [ABSTRACT FROM AUTHOR]

The advent of novel agents for multiple myeloma (MM) is cause for a re-examination of the incidence of second primary malignancies (SPMs). We examined the SPM rate in MM patients who were enrolled in the prospective observational CALM (Collaboration to Collect Autologous Transplant outcome in Lymphoma and Myeloma) study. Between 2008 and 2012, 3204 patients with MM underwent a first autologous hematopoietic stem cell transplantation. Plerixafor was used as a mobilizing agent for patients with poor (or potentially poor) stem cell mobilization as defined by the respective centers. A total of 135 patients developed SPMs, with a cumulative incidence of 5.3% (95% confidence interval, 4.4 to 6.3) at 72 months. Ninety-four patients developed solid tumors, 30 developed hematologic malignancies, and 11 developed an SPM of an unknown type. The cumulative incidence of known hematologic and solid malignancies were 1.4% and 3.6%, respectively, at 72 months. In a univariate analysis, use of radiotherapy, type of induction regimen, hematopoietic stem cell dose, poor mobilizer status, plerixafor use, and sex did not influence the cumulative incidence of SPMs. Only age over 65 years was statistically associated with an increased incidence. Overall, the incidence of SPMs was comparable to earlier estimations of SPMs in MM. [ABSTRACT FROM AUTHOR]

In contrast to the evidence regarding azacitidine (Aza), there is limited knowledge about the combination of decitabine (DAC) and donor lymphocyte infusions as salvage therapy for relapse after allogeneic stem cell transplantation (allo-SCT) so far. We retrospectively analyzed data of 36 patients with hematological (n = 35) or molecular relapse (n = 1) of acute myeloid leukemia (AML, n = 29) or myelodysplastic syndrome (MDS, n = 7) collected from 6 German transplant centers. Patients were treated with a median of 2 cycles DAC (range, 1 to 11). DAC was the first salvage therapy in 16 patients (44%), whereas 20 patients (56%) had previously received 1 to 5 lines of salvage therapy including 16 of them had been treated with Aza. In 22 patients (61%), a median of 2 DLI per patient (range, 1 to 5) was administered in addition to DAC. As a result, overall response rate was 25% including 6 complete remissions (CR, 17%) and 3 partial remissions (PR, 8%). Three patients within the first-line group achieved CR, while also 3 patients receiving DAC as second-line treatment reached CR including 2 patients with previous Aza failure. Median duration of CR was 10 months (range, 2 to 33) and no patient relapsed so far. The 2-year OS rate was 11% (± 6%) without any difference between first-line and pretreated patients. Incidence of acute and chronic graft-versus-host disease was 19 and 5%. Taken together, DAC exerts clinical efficacy in patients with AML or MDS relapsing after allo-SCT and is able to induce durable remissions in individual patients suggesting that DAC may be an alternative to Aza or even a second choice after Aza failure. [ABSTRACT FROM AUTHOR]

Background: The karyotype of bone marrow cells at the time of diagnosis is a strong prognostic parameter for overall survival as well as acute myeloid leukemia (AML) progression in patients with myelodysplastic syndromes (MDS). However, to the authors' knowledge, few data exist regarding the prognostic impact of cytogenetic clonal evolution during the course of MDS.Methods: The authors evaluated follow-up karyotype analyses in 549 patients from the Dusseldorf MDS Registry.Results: Clonal evolution was detectable in 24% of the entire cohort and in 18% of 294 patients receiving best supportive care. The authors noted a clear adverse effect of clonal evolution on the risk of leukemic transformation (hazard ratio, 2.233; P = .036) and overall survival (hazard ratio, 3.677; P<.001). The authors also analyzed the prognostic influence of subclones detectable at the time of diagnosis. Again, such a finding was associated with a significantly shorter overall survival and a higher 5-year-probability of acute myeloid leukemia progression (30% vs 22%).Conclusions: The results of the current study support the belief that follow-up karyotype analyses should be performed, especially in patients with lower-risk and intermediate-risk MDS, to identify those patients who are at higher risk of disease progression and therefore might benefit from earlier or more intensive treatment. Cancer 2017;123:4608-4616. © 2017 American Cancer Society. [ABSTRACT FROM AUTHOR]

We integrated molecular data with available prognostic factors in patients undergoing allogeneic hematopoietic cell transplantation (alloHCT) for myelodysplastic syndrome (MDS) or secondary acute myeloid leukemia (sAML) from MDS to evaluate their impact on prognosis. Three hundred four patients were sequenced for mutations in 54 genes. We used a Cox multivariate model and competing risk analysis with internal and cross validation to identify factors prognostic of overall survival (OS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). In multivariate analysis, mutated NRAS, U2AF1, IDH2, and TP53 and/or a complex karyotype were significant prognostic markers for OS besides age above 60 years, remission status, IPSS-R cytogenetic risk, HCT-CI > 2 and female donor sex. Mutated NRAS, IDH1, EZH2, and TP53 and/or a complex karyotype were genetic aberrations with prognostic impact on CIR. No molecular markers were associated with the risk of NRM. The inclusion of molecular information results in better risk prediction models for OS and CIR when assessed by the Akaike information criterion. Internal cross validation confirmed the robustness of our comprehensive risk model. In summary, we propose to combine molecular, cytogenetic, and patient- and transplantation-associated risk factors into a comprehensive risk model to provide personalized predictions of outcome after alloHCT. [ABSTRACT FROM AUTHOR]

Azacitidine has become an available therapy for high-risk myelodysplastic syndromes. Infectious complications (IC) may impede the success of therapy. Since most patients are managed in an outpatient setting, often with low level of clinical and microbiological documentation, the impact of IC remains unclear. We retrospectively evaluated the clinical course of 77 patients with MDS treated with azacitidine between 2004 and 2015 (median age 69 years). Clinical workup included severity and type of IC, days in the hospital and with antimicrobial therapy, response to azacitidine, and overall survival (OS). In total, 614 azacitidine cycles were administered, 81 cycles with at least one IC. The median number of administered cycles was 6 (range 1-43). Median OS after the start of azacitidine was 17 months (range 1-103). Infection rates were higher in the first 3 cycles with bacterial infections leading. The better patients' hematological response to azacitidine with less IC occurred, and fewer days with antimicrobial treatment were needed. Compared to progressive disease, stable disease made no significant improvement in occurrence of IC and days in the hospital. Older age was associated with more IC and longer time in the hospital. Comorbidities or IPSS-R had no influence on IC. The incidence of IC correlated with hematological response and age. Stable disease led to longer OS, but incidence of IC was comparable to progressive disease and survival seemed to be bought by a considerable number of IC. IC rates were highest in the first 3 cycles. We recommend response evaluation after 4-6 cycles. [ABSTRACT FROM AUTHOR]

Objective Patients with acute myeloid leukemia ( AML) carrying FLT3- ITD mutations ( FLT3- ITD+) who relapse after allogeneic transplantation (allo- SCT) have a very dismal prognosis with the currently available treatment options. Methods We treated eight patients with FLT3- ITD+ AML who had relapsed in median 91 d (range, 28-249) following allo- SCT with a combination of the multikinase inhibitor sorafenib and the DNA methyltransferase inhibitor azacitidine (Aza). Results Patients received a median of five cycles of Aza (range, 2-9) and sorafenib with a median daily dosage of 750 mg (range 400-800) for 129 d (range, 61-221). Six of eight patients received donor lymphocyte infusions ( DLI) with a median number of two DLI per patient (range, 1-4). Following this treatment, four patients (50%) achieved a complete remission and three of them a complete molecular remission. Median duration of CR was 182 d (range, 158-406), and two patients remain in ongoing remission for 406 and 168 d. Median overall survival was 322 d (range, 108-574 d) with three patients being currently alive. Conclusion Taken together, the combination of sorafenib, Aza, and DLI shows promising efficacy and deserves further evaluation in larger patient groups. [ABSTRACT FROM AUTHOR]

An international expert panel, active within the European Society for Blood and Marrow Transplantation, European LeukemiaNet, Blood and Marrow Transplant Clinical Trial Group, and the International Myelodysplastic Syndromes Foundation developed recommendations for allogeneic hematopoietic stem cell transplantation (HSCT) in myelodysplastic syndromes (MDS) and chronic myelomonocytic leukemia (CMML). Disease risks scored according to the revised International Prognostic Scoring System (IPSS-R) and presence of comorbidity graded according to the HCT Comorbidity Index (HCT-CI) were recognized as relevant clinical variables for HSCT eligibility. Fit patients with higher-risk IPSS-R and those with lower-risk IPSS-R with poor-risk genetic features, profound cytopenias, and high transfusion burden are candidates for HSCT. Patients with a very high MDS transplantation risk score, based on combination of advanced age, high HCT-CI, very poor-risk cytogenetic and molecular features, and high IPSS-R score have a low chance of cure with standard HSCT and consideration should be given to treating these patients in investigational studies. Cytoreductive therapy prior to HSCT is advised for patients with £10% bone marrow myeloblasts. Evidence from prospective randomized clinical trials does not provide support for specific recommendations on the optimal high intensity conditioning regimen. For patients with contraindications to high-intensity preparative regimens, reduced intensity conditioning should be considered. Optimal timing of HSCT requires careful evaluation of the available effective nontransplant strategies. Prophylactic donor lymphocyte infusion (DLI) strategies are recommended in patients at high risk of relapse after HSCT. Immune modulation by DU strategies or second HSCT is advised if relapse occurs beyond 6 months after HSCT. [ABSTRACT FROM AUTHOR]

Spontaneous remission (SR) of acute myeloid leukemia (AML) represents a rare phenomenon and is usually of short duration although long‐term remissions are reported. Indeed, mechanisms underlying SR remain unclear, but it is suggested that immunactivation, e.g. caused by infections, plays an important role. Here we report on a patient who suffered from pneumonia and simultaneously experienced very late hematologic AML relapse seventeen years after allogeneic blood stem cell transplantation (allo‐BSCT). Surprisingly in parallel to recovery from pneumonia peripheral blood count which previously showed pancytopenia, had normalized and bone marrow (BM) aspiration revealed spontaneous remission of AML. To the best of our knowledge we here report on the latest AML relapse after allo‐BSCT experiencing SR. [ABSTRACT FROM AUTHOR]

The results of allogeneic stem cell transplantation (allo- SCT) in chronic myelomonocytic leukaemia ( CMML) are usually reported together with other categories of myelodysplastic syndrome. We analysed transplantation outcome in 513 patients with CMML, with a median age of 53 years reported to the European Group for Blood and Marrow Transplantation. Conditioning was standard ( n = 249) or reduced-intensity ( n = 226). Donors were human leucocyte antigen-related ( n = 285) or unrelated ( n = 228). Disease status at transplantation was complete remission ( CR) in 122 patients, no CR in 344, and unknown in 47. Engraftment was successful in 95%. Grades 2-4 acute graft- versus-host disease (Gv HD) occurred in 33% of the patients and chronic Gv HD was reported in 24%. The 4-year cumulative incidence of non-relapse mortality was 41% and 32% for relapse, resulting in a 4-year estimated relapse-free and overall survival (OS) of 27% and 33%, respectively. Patients transplanted in CR had lower probability for non-relapse death ( P = 0·002) and longer relapse-free and OS ( P = 0·001 and P = 0·005, respectively). In multivariate analysis the only significant prognostic factor for survival was the presence of CR at transplantation ( P = 0·005). Allo- SCT remains a curative treatment option for patients with CMML and should preferably be performed early after diagnosis or after establishing the best possible remission status. [ABSTRACT FROM AUTHOR]

Bcl-2/IgH rearrangements can be quantified in follicular lymphoma (FL) from peripheral blood (PB) by polymerase chain reaction (PCR). The prognostic value of Bcl-2/IgH levels in FL remains controversial. We therefore prospectively studied PB Bcl-2/IgH levels from 173 first-lineFLpatientswhowere consecutively enrolled, randomized, and treated within the multicenter phase 3 clinical trial NHL1-2003 comparing bendamustine-rituximab(B-R) with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone. FromApril 2005 to August 2008, 783 pre- and posttreatment PB samples were quantified by quantitative PCR. At inclusion, 114 patients (66%) tested positive and 59 (34%) were negative for Bcl-2/ IgH. High pretreatment Bcl-2/IgH levels had an adverse effect on progression-free survival (PFS) compared with intermediate or low levels (high vs intermediate: hazard [HR], 4.28; 95% confidence interval [CI], 1.70-10.77; P = .002; high vs low: HR, 3.02; 95% CI, 1.55-5.86; P=.001). No PFS difference between treatment arms was observed in Bcl-2/IgH-positive patients. A positive posttreatment Bcl-2/IgH status was associated with shorter PFS (8.7 months vs not reached; HR, 3.15; 95% CI, 1.51-6.58; P = .002). By multivariate analysis, the pretreatment Bcl-2/IgH level was the strongest predictor for PFS. Our data suggest that pre- and posttreatment Bcl-2/IgH levels from PB have significant prognostic value for PFS in FL patients receiving first-line immunochemotherapy. This trial was registered at www.clinicaltrials.gov as #NCT00991211 and at the German Federal Institute for Drugs and Medical Devices as #BfArM-4021335. [ABSTRACT FROM AUTHOR]

During the last years, more and more treatment modalities are available for MDS patients. Therefore, we were interested if this is reflected in an improvement of the outcome of the patients. We analyzed the survival and rate of leukemic progression of 4147 patients from the Duesseldorf MDS registry diagnosed during the last 30 years and found an improvement of survival in those patients diagnosed after 2002 (30 vs. 23 months, p < 0.0001). In detail, the improvement of the prognosis was restricted to high-risk MDS patients diagnosed between 2002 and 2014 in comparison to the patient group diagnosed between 1982 and 2001 (19 vs. 13 months, p < 0.001), whereas the prognosis of low-risk MDS patients did not change significantly. The improvement of survival was still measurable after exclusion of RAEB-t patients and of those, that received an allogeneic stem cell transplantation. In line with this finding, we found a lower AML progression rate in the later diagnosed group. Unfortunately, we could not identify a clear reason for this finding but rather a multifactorial cause should be assumed. As death due to bleeding complications and infections was significantly lower, an improvement of BSC may be one of the underlying causes. [ABSTRACT FROM AUTHOR]

The objective was to evaluate the prognostic and predictive impact of allelic ratio and insertion site (IS) of internal tandem duplications (ITDs), as well as concurrent gene mutations, with regard to postremission therapy in 323 patients with FLT3-ITD-positive acute myeloid leukemia (AML). Increasing FLT3-ITD allelic ratio (P = .004) and IS in the tyrosine kinase domain 1 (TKD1, P = .06) were associated with low complete remission (CR) rates. After postremission therapy including intensive chemotherapy (n = 121) or autologous hematopoietic stem cell transplantation (HSCT, n = 17), an allelic ratio ;> 0.51 was associated with an unfavorable relapse-free (RFS, P = .0008) and overall survival (OS, P = .004); after allogeneic HSCT (n = 93), outcome was significantly improved in patients with a high allelic ratio (RFS, P = .02; OS, P = .03), whereas no benefit was seen in patients with a low allelic ratio (RFS, P = .38; OS, P = .64). Multivariable analyses revealed a high allelic ratio as a predictive factor for the beneficial effect of allogeneic HSCT; ITD IS in TKD1 remained an unfavorable factor, whereas no prognostic impact of concurrent gene mutations was observed. The clinical trials described herein were previously published or are registered as follows: AMLHD93 and AMLHD98A, previously published; AML SG 07-04, ClinicalTrials.gov identifier #NCT00151242. [ABSTRACT FROM AUTHOR]

Relapse is the major cause of treatment failure after allogeneic stem-cell transplantation ( AHSCT) for patients with myelodysplastic syndrome/myeloproliferative syndrome neoplasms ( MDS/ MPN). We evaluated the impact of molecular mutations on outcome and the value of molecular monitoring post-transplantation. We screened 45 patients with chronic myelomonocytic leukemia ( n = 39 patients, including seven with transformed-acute myeloid leukemia), MDS/ MPN unclassifiable ( n = 5), and atypical BCR- ABL1-negative CML ( n = 1) for mutations in ASXL1, CBL, NRAS, and TET2 genes by molecular genetics including a sensitive next-generation sequencing ( NGS) technique. In 36 patients, sufficient DNA was available for molecular analyses. In particular, TET2 and CBL mutations were screened applying amplicon deep sequencing. In 89% of cases, at least one mutation could be detected: ASXL1: n = 18 (50%); CBL: n = 7 (19%); TET2: n = 15 (42%); and NRAS: n = 11 (32%). Survival after AHSCT at 5 yr was 46% (95% CI 28-64%) and was not influenced by any mutation. After a median of 6 months after AHSCT in 33% of the patients, one of the molecular markers was still detectable, resulting in a higher incidence of relapse than in patients with undetectable mutations (50% vs. 15%, P = 0.04). In conclusion, pretransplant molecular mutation analysis can help to detect biomarkers in patients with MPN/ MDS, which may be subsequently used as minimal residual disease markers after AHSCT. [ABSTRACT FROM AUTHOR]

Abstract: The revised IPSS (IPSS-R) was developed aiming at a better prognostication, taking into account patients treated with best supportive care. We herein validated this model on the basis of data from 1314 patients who received BSC only as well as patients who underwent induction chemotherapy (n =214) or allogeneic transplantation (n =167). We could demonstrate a clear distinction of the IPSS-R risk categories with regard to survival and risk of AML evolution in all patient cohorts. When comparing IPSS-R, IPSS, WHO prognostic scoring system (WPSS) and Duesseldorf score, the best results regarding the ability to predict survival were obtained by the IPSS-R. [Copyright &y& Elsevier]

Abstract: The prognostic relevance of minimal residual disease (MRD) in patients with multiple myeloma is still an open question. In bone marrow, the level of residual myeloma cells is associated with treatment outcome, but the role of clonotypic cells in the peripheral blood (PB) for the prognosis of patients is not identified yet. In this study, we retrospectively analyzed MRD by quantitative real-time IgH-PCR (IgH-qPCR) in the PB of 42 patients undergoing high-dose therapy followed by autologous PB stem cell transplantation as first-line therapy for multiple myeloma. The MRD level of PB samples was in median 40-fold lower than in bone marrow samples, collected on the same day, with a wide intra- and interindividual variation (range, .4- to 4628-fold). The presence or absence of detectable MRD levels in PB did not correlate with the serological remission status. Still, patients with negative PCR results in PB 3 months after high-dose therapy and PB stem cell transplantation had lower International Staging System stage (P = .01), lower levels of β2-microglobulin (P = .02), higher hemoglobin levels (P = .01), and a prolonged event-free (median, 15 versus 4 months; P = .004) and overall (median, 52 versus 17 months; P = .03) survival. Importantly, by sequential monitoring of clonotypic cells in PB, in 19 of 29 patients (66%) with progressive disease, an increase of the 2IgH/β-actin ratio of at least 1 log step could be detected in median 4 months (range, .8 to 13 months) before the relapse was diagnosed on the basis of the European Group for Blood and Marrow Transplantation criteria. These patients with a molecular relapse in PB before a serological relapse had a significantly shorter overall survival than other patients (median, 17 months versus median not reached, P = .02). In conclusion, IgH-qPCR is a sensitive technique for the detection of clonotypic cells in PB, which precede clinical relapse. Future studies are needed to evaluate whether these circulating tumor cells play a role in promoting disease recurrence. [Copyright &y& Elsevier]

Thirty myelofibrosis patients (21 males, nine females) with relapse ( n = 27) or graft-rejection ( n = 3) after dose-reduced allografting underwent a salvage strategy including donor lymphocyte infusions ( DLIs) and/or second allogeneic haematopoietic stem cell transplantation ( HSCT). Twenty-six patients received a median number of three (range, 1-5) DLIs in a dose-escalated mode starting with a median dose of 1·2 × 106 (range, 0·003-8 × 106) up to median dose of 40 × 106 T-cells/kg (range, 10-130 × 106). 10/26 patients (39%) achieved complete response ( CR) to DLIs. Acute (grade II- IV) and chronic graft- versus-host ( GvHD) disease occurred in 12% and 36% cases. Thirteen non-responders to DLI and four patients who did not receive DLI due to graft-rejection or acute transformation of the blast phase underwent a second allogeneic HSCT from alternative ( n = 15) or the same ( n = 2) donor. One patient (6%) experienced primary graft-failure and died. Acute ( II- IV) and chronic Gv HD were observed in 47% and 46% of patients. Overall responses after second HSCT were seen in 12/15 patients (80%: CR: n = 9, partial response: n = 3). The 1-year cumulative incidence of non-relapse mortality for recipients of a second allograft was 6%, and the cumulative incidence of relapse was 24%. After a median follow-up of 27 months, the 2-year overall survival and progression-free survival for all 30 patients was 70% and 67%, respectively. In conclusion, our two-step strategy, including DLI and second HSCT for non-responding or ineligible patients, is an effective and well-tolerated salvage approach for patients relapsing after reduced-intensity allograft after myelofibrosis. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is a clonal plasma cell disorder frequently accompanied by hematopoietic impairment. We show that hematopoietic stem and progenitor cells (HSPCs), in particular megakaryocyte-erythrocyte progenitors, are diminished in the BM of MM patients. Genomic profil-ing of HSPC subsets revealed deregula-tions of signaling cascades, most notably TGFβ signaling, and pathways involved in cytoskeletal organization, migration, adhesion, and cell-cycle regulation in the patients. Functionally, proliferation, colony formation, and long-term self-renewal were impaired as a consequence of activated TGFβ signaling. In accor-dance, TGFβ levels in the BM extracellu-lar fluid were elevated and mesenchymal stromal cells (MSCs) had a reduced capac-ity to support long-term hematopoiesis of HSPCs that completely recovered on blockade of TGFβ signaling. Further-more, we found defective actin assembly and down-regulation of the adhesion re-ceptor CD44 in MM HSPCs functionally reflected by impaired migration and adhesion. Still, transplantation into myeloma-free NOG mice revealed even enhanced engraftment and normal differentiation capacities of MM HSPCs, which under-lines that functional impairment of HSPCs depends on MM-related microenviron-mental cues and is reversible. Taken to-gether, these data implicate that hemato-poietic suppression in MM emerges from the HSPCs as a result of MM-related mi-croenvironmental alterations. (Blood. 2012; 120(13):2620-2630). [ABSTRACT FROM AUTHOR]

Despite improvements in first-line therapies, published results on the treatment of relapsed adult acute lymphoblastic leukemia (ALL) show that prognosis is still poor. The aim of the present retrospective analysis of the German Multicenter Study Group for Adult ALL was to identify prognostic factors and options for improvement. A total of 547 patients with a median age of 33 years (range, 15-55) experiencing their first relapse (406 vs 141 shorter or longer than 18 months from diagnosis) were evaluated. The aim of salvage therapy was to achieve a complete remission (CR) with subsequent a stem cell transplantation (SCT). The CR rate (assessed in Philadelphia chromosome-and BCfMBL-negative ALL without CNS involvement) after the first salvage in relapse after chemotherapy (n = 224) was 42%. After failure of first salvage (n = 82), the CR rate after second salvage was 33%. In relapse after SCT (n = 48) the CR rate after first salvage was 23%. The median overall survival after relapse was 8.4 months and survival was 24% at 3 years. Prognostic factors for survival were relapse localization, response to salvage, performance of SCT, and age. Overall survival appeared superior compared with previously published studies, likely because of the high rate of SCT in the present study (75%). Further improvement may be achieved with earlier relapse detection and experimental approaches in early relapse. The study is registered at www.clinicaltrials.gov as NCT00199056 and NCT00198991. [ABSTRACT FROM AUTHOR]